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Function-oriented synthesis of subersic acid and makassaric acid analogues Schwab, Katerina 2020

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FUNCTION-ORIENTED SYNTHESIS OF SUBERSIC ACID AND MAKASSARIC ACID ANALOGUES  by  Katerina Schwab  B.Sc. (Hons), The University of British Columbia, 2018  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  July 2020  © Katerina Schwab, 2020   ii  The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis entitled:  Function-oriented synthesis of subersic acid and makassaric acid analogues  submitted by Katerina Schwab in partial fulfillment of the requirements for the degree of Master of Science in Chemistry  Examining Committee: Gregory Dake, Associate Professor, Chemistry, UBC Supervisor  Glenn Sammis, Associate Professor, Chemistry, UBC Supervisory Committee Member  Martin Tanner, Professor, Chemistry, UBC Supervisory Committee Member iii  Abstract Concise syntheses towards derivatives of the meroterpenoids makassaric acid and subersic acid were developed. Three methods towards the development of makassaric acid were explored. The E-selective alkylation of an allyl iodide derived from sclareol was conducted, resulting in the synthesis of six new derivatives of subersic acid in 55-90% yield. Subersic acid itself was synthesized from one of these derivatives. Heck couplings were conducted on sclareol to generate four derivatives resembling makassaric acid with yields ranging from 50-74%. Conditions were screened for an alkylation reaction of a β-ketoster compound, from which 3 new makassaric acid analogues were identified in trace yields.   iv  Lay Summary Makassaric acid is a compound isolated from an Indonesian marine sponge. In an attempt to improve the drug-like properties shown by makassaric acid, it is desirable to make and test modified derivatives of makassaric acid, in hopes to develop a drug that will fill the gap for treatment of brain bleeds in humans. The World Health Organization reports that approximately 800,000 strokes occur each year in the United States alone. Of these, there are two types of strokes, one resulting from a blockage in the brain, and one caused by the rupture of blood vessels. The latter is known as a hemorrhagic stroke, for which there are few treatment options available. Makassaric acid has been shown to reverse brain bleeds in zebrafish. This makes it an exciting molecule to examine as a drug lead that can treat these types of strokes that do not yet have a viable treatment. v  Preface All experiments in Chapter 2 were performed by me. The zebrafish assays referred to in the introductory text were performed by Dr.Xiao-Yan at St.Michael’s hospital in the University of Toronto and constitute unpublished results. None of the results found are published data. The crystal structure of intermediate 2.18 was collected by Brian Patrick. Advice and project direction were given by Dr. Gregory Dake, who also edited and provided extensive feedback on this thesis. vi  Table of Contents Abstract ......................................................................................................................................... iii Lay Summary ............................................................................................................................... iv Preface .............................................................................................................................................v Table of Contents ......................................................................................................................... vi List of Tables .............................................................................................................................. viii List of Figures ............................................................................................................................... ix List of Schemes ...............................................................................................................................x List of Abbreviations and Symbols ............................................................................................ xi Acknowledgements .................................................................................................................... xiii Dedication ................................................................................................................................... xiv Chapter 1: Introduction ................................................................................................................1 1.1 Function-oriented synthesis and step economy .............................................................. 1 1.2 The relationship between strokes, makassaric and subersic acid. .................................. 3 1.3 Total synthesis of makassaric acid .................................................................................. 5 1.4 Total syntheses of subersic acid .................................................................................... 10 Chapter 2: Results and Discussion .............................................................................................13 2.1 Preface: functionally simplified derivatives of makassaric acid ................................... 13 2.2 Synthesis of subersic acid derivatives........................................................................... 14 2.3 Heck cross-couplings on sclareol.................................................................................. 22 2.4 Route to makassaric acid via a β-ketoester intermediate .............................................. 23 Chapter 3: Conclusion and Future Directions ..........................................................................32 Chapter 4: Experimental .............................................................................................................35 vii  4.1 Synthesis of subersic acid derivatives........................................................................... 36 4.2 Heck cross-couplings on sclareol.................................................................................. 43 4.3 Route to makassaric acid via a β-ketoester intermediate .............................................. 45 4.4 Miscellaneous work ...................................................................................................... 53 Bibliography .................................................................................................................................59 Appendix: Selected Spectra ........................................................................................................68 A.1 Synthesis of subersic acid derivatives........................................................................... 68 A.2 Heck cross-couplings on sclareol.................................................................................. 90 A.3 Route to makassaric acid via a β-ketoester intermediate .............................................. 95 A.4 Miscellaneous work .................................................................................................... 105  viii  List of Tables Table 1 General reaction scheme for aryl iodide alkylation ......................................................... 16 Table 2: Observed NOESY correlations of 2.2. ........................................................................... 17 Table 3 HMBC Correlations are consistent with a product of C-alkylation................................. 17 Table 4 Heck reactions performed on sclareol to produce subersic acid derivatives. .................. 22 Table 5 Preparation of alkylation substrates ................................................................................. 26 Table 6 Alkylation reactions performed ....................................................................................... 28 Table 7 Comparing 1H NMR shifts for alkylated products and starting material. ....................... 30  ix  List of Figures Figure 1 Bryostatin 1 (left) and a functionally simpler analogue (right) ........................................ 2 Figure 2 A ischemic stroke (left) caused by the blockage of a blood vessel in the brain, and a hemorrhagic stroke (right) caused by a rupture of a blood vessel in the brain. .............................. 4 Figure 3 Nicardapine and Labetalol ................................................................................................ 4 Figure 4 (+)-Makassaric acid and the closely related (+)-subersic acid ......................................... 5 Figure 5 Functional derivatives of makassaric acid synthesized in the following chapters. ........ 13 Figure 6 Solid-state structure confirming the absolute configuration of the intermediate ........... 25 Figure 7 Presumptive nucleophile formed by deprotonation of 2.18. .......................................... 29  x  List of Schemes Scheme 1 The synthetic strategy towards makassaric acid envisioned by the Basabe group. ....... 6 Scheme 2: Synthesis of methyl ent-isocopolate and its derivatives ............................................... 7 Scheme 3 The mechanism of the cationic cyclization from 1.7 to 1.8 ........................................... 8 Scheme 4: Conversion of isocopalic aldehyde (1.4) to makasarric acid (1.1) ................................ 9 Scheme 5 Synthetic route carried out by the Zeng group in 2015 ................................................ 10 Scheme 6 Formal synthesis of subersic acid by the Zeng group.39 .............................................. 11 Scheme 7 Conversion of sclareol into an iodinated derivative40 .................................................. 15 Scheme 8 Cyanation of with a mixed cyanide source to access C-alkylated benzonitrile. .......... 18 Scheme 9  Synthesis of (+)-subersic acid. .................................................................................... 19 Scheme 10 Synthesis of an allyl bromide derivative .................................................................... 20 Scheme 11 Basabe group’s synthesis of the allyl bromide intermediate. ..................................... 21 Scheme 12 Disconnections used by the Basabe group in their synthesis of makassaric acid, and attempted disconnection strategy that we used. ............................................................................ 23 Scheme 13 Route carried out to an alternative intermediate in the synthesis of makassaric acid. 24 Scheme 14 The literature reaction that the attempted alkylation of 2.18 was based upon. .......... 27 Scheme 15 Decarboxylation of cyclic β-ketoester 2.18................................................................ 31 Scheme 16 General scheme of subersic acid synthesis ................................................................ 32 Scheme 17 General scheme of Heck couplings ............................................................................ 33 Scheme 18 Attempted alkylation scheme via a β-ketoester intermediate..................................... 34 Scheme 19 Future directions for makassaric acid derivatives from 2.6 ....................................... 34   xi  List of Abbreviations and Symbols °C degrees Celsius AcCl acetyl chloride AIBN azobisisobutyronitrile Ar aryl CCl4 carbon tetrachloride COSY Correlational Spectroscopy dA  deoxyadenosine DCM dichloromethane DCM dichloromethane dd doublet of doublets ddA didieoxy adenosine ddNT didieoxy nucleotide DMF N,N-dimethylformamide EI Electron Impact  equiv equivalents ESI electrospray ionization EtOAc ethyl acetate g grams h hours HMBC Heteronuclear Multiple Bond Coherence spectroscopy HRMS High Resolution Mass Spectrometry HSQC Heteronuclear Single Quantum Coherence spectroscopy IR infrared J coupling constant (Hz) M molar m. p. melting point MAPKAP Kinase 2 Mitogen-Activated Protein Kinase Activated Protein Kinase 2 MeOH methanol mg milligrams MK2 MAPKAP Kinase 2 mL milliliters mmol millimoles MS mass spectrometry NBS n-bromosuccinimide n-Bu3SnH tri-n-butyl tin chloride NMR nuclear magnetic resonance NOE Nuclear Overhauser Effect NOESY Nuclear Overhauser Effect Spectroscopy O=PPh3 triphenylphosphine oxide PDC pyridinium chlorochromate PhMe toluene PPh3 triphenylphosphine xii  ppm parts per million p-TsOH para-toluene sulfonic acid q quartet rt room temperature s singlet t  triplet TBAI tetrabutylammonium iodide THF tetrahydrofuran THP tetrahydropyran   xiii  Acknowledgements To my supervisor, Dr. Gregory Dake, for his support and advice over the course of my studies. I appreciate the professional advice I was given, and that I was supported regardless of the professional path I chose.  Thank you to my labmates, Chris Voth for his wry humour and experienced advice, Melody Shen for her bright mood and encouragement, Dan Kurek, Lirong Cao, Yiran Wei and Katherine He. Thanks to Dr. Ben Loosely.  Thank you to Paul Xia, Maria Ezhova, Ben Herring, Yun Ling, Brian Patrick for their patience and assistance with NMR, mass spectrometry, and X-ray crystallography. xiv  Dedication To my family, for their constant support and unconditional love.1  Chapter 1: Introduction  1.1 Function-oriented synthesis and step economy Chemistry drives dramatic innovation in the field of medicine. In 2018, 59 drugs received FDA approval, and 42 of these were small molecule therapeutics made by chemical synthesis.1,2 More importantly, chemical innovation is a pathway to synthetic structures not found in Nature. Dideoxynucleotides (ddNTs) that were chemically prepared in the 1970s have played an integral role in our current age of personalized medicine.3 These ddNTs would not have been imagined by Nature because of their lack of utility in sustaining life but have nonetheless triggered a flurry of scientific innovation. The result is the ability to sequence a single person’s genome for 6000 dollars.4 This innovation and imagination to tamper with naturally occurring biomolecules is not limited to nucleotides. The complexity of natural products is intriguing and can be a welcome challenge to replicate. However, it can be difficult to compete with the work done by highly evolved, specific enzymes.5 In the area of drug discovery, function-oriented synthesis (FOS) simplifies natural product scaffolds while preserving function, instead of replicating structures exactly as they are in Nature. Function oriented synthesis was coined by Paul Wender in 2008.6 This idea was not novel at the time, as simplified molecular entities have existed since the 1950s, as exhibited by the synthesis of norethindrone, a progestin currently used in birth control pills, and fentanyl, a derivative of morphine.7,8 Using FOS, it is possible to emulate the biological activity of natural products that are synthetically impractical to access. By understanding structure-activity relationships through the synthesis of derivatives, the purpose of each molecular feature is elucidated, and a structure can be edited to both simplify synthesis and optimize efficacy as a drug.9–12 The ideal result is a drug that is not only effective, but also synthetically accessible. The 2  removal of unnecessary chemical elements is something that chemists are uniquely poised to do, building upon biology instead of attempting to replicate it.13  Bryostatin 1 showcased this approach of function-oriented synthesis. The bryostatins are a family of complex marine natural products synthesized in nature by the brown, mossy sea creature Bugula neritina. Bryostatin 1 shows promise in the treatment of a multitude of diseases, notably cancer, HIV and Alzheimer’s disease.14 Bugula neritna extracts were collected from the Gulf of Mexico in 1968, and Bryostatin 1’s structure was elucidated from this extract in 1982.15 The first total synthesis of Bryostatin 1 was reported in 2010 by the Keck group.16,17 The result of this 28-year discrepancy where the chemical supply lagged clinical demand is that the only source of Bryostatin 1 was from the marine organism itself. During this time, all 18 grams of Bryostatin 1 used for clinical trials was sourced from 14 tons of Bugula neritina.18  Figure 1 Bryostatin 1 (left) and a functionally simpler analogue (right) The analogue has a lower Ki in addition to being synthesized in 29 steps, significantly shorter than the original 46 step synthesis of bryostatin.16,19,20 In 2002, Wender’s group constructed an analogue of bryostatin 1 in 29 steps (Figure 1). This analogue had a lower Ki for bryostatin 1’s target protein kinase C (PKC) than bryostatin 1 itself did. This function-oriented synthesis was completed nine years before Keck’s group first 3  synthesized Bryostatin 1, and 15 years before the Wender group would synthesize Bryostatin 1 itself in 29 steps.14,16 The average drug takes 6-12 years to be approved following discovery. In the production of Bryostatin 1 as a therapeutic, this pressure is compounded by the fact that Bryostatin could not be produced on large scale by extraction from Bugula neritna.21 Any work done to accelerate this process, and provide scalable syntheses of potent analogues more quickly, effectively helps to shorten this discovery process. The efficacy of FOS is not restricted to bryostatin. FOS has yielded results for the simplification of caprazamycins by the Matsuda group, to target antibiotic-resistant bacteria like Methicillin Resistant Staphylococcus Aureus.10 It has also had an impact on the development of ion channels, anti-cancer agents, and therapeutics for botulism.9,22,23 1.2 The relationship between strokes, makassaric and subersic acid. Approximately 800,000 strokes devastate the United States each year.24 There are two types of strokes, ischemic and hemorrhagic strokes. Ischemic strokes are caused by blood vessel blockages preventing adequate blood flow to the brain. Hemorrhagic strokes are caused by the rupture of blood vessels in the brain.25 Hemorrhagic strokes account for 10-20% of all strokes, and are devastating events, having a mortality rate of 50% only one month following the initial stroke.26,27 4   Figure 2 A ischemic stroke (left) caused by the blockage of a blood vessel in the brain, and a hemorrhagic stroke (right) caused by a rupture of a blood vessel in the brain. With advances in cerebral imaging, lesions in the blood vessels of the brain can be identified increasingly often prior to a stroke event, but preventative measures prior to a stroke are relatively lacking.28 Current treatments include nicardipine and labetolol.28 Nicardipine is a calcium channel blocker, and labetalol a is a beta blocker. Both achieve the result of reducing blood pressure, as high blood pressure is a key risk factor in stroke patients.28,29 There lies an underexplored avenue in combatting the weakening of the blood vessel walls at the point of the rupture, and thus decreasing the steep mortality rate associated with the short time after hemorrhagic strokes.   Figure 3 Nicardapine and Labetalol, current drugs which decrease blood pressure to treat strokes.30,31 Labetalol is used as a mixture of diastereomers. Makassaric acid (1.1) has been shown to reverse the damage of induced brain bleeds in preliminary zebrafish assays. It was first isolated from the Indonesian marine sponge Acanthodendrilla sp. by the Andersen group in 2004.32A closely related compound (+)-subersic 5  acid (1.2) was also isolated from this marine sponge. Makassaric and subersic acid belong to a class of compounds known as meroterpenoids, consisting of a terpene and a phenolic component. Comparing makassaric acid to nicardipine and labetalol, makassaric acid possesses few heteroatoms and polar functionalities for its size and has a relatively large number of stereocenters.  Figure 4 (+)-Makassaric acid and the closely related (+)-subersic acid  Both (+)-makassaric acid and (+)-subersic acid are known MAPKAP Kinase 2 (MK2) inhibitors. MK2 is a serine/threonine kinase that catalyzes the addition of a phosphate group to these amino acids. MK2 plays a key role in a cascade that effects the body’s inflammatory response by regulating production of TNF-α (Tumour Necrosis Factor alpha). Both makassaric acid and subersic acid play a role as MK2 inhibitors. This suggests that the parahydroxy benzoic acid fragment that subersic acid and makassaric acid share may be more important to activity than the terpene component of either molecule. Makassaric acid and subersic acid have been previously synthesized in literature, and their synthetic studies are detailed in the following sections. 1.3 Total synthesis of makassaric acid Makassaric acid was first synthesized in 2010 by the Basabe group.33 This synthesis identifies the readily available compound sclareol as a convenient chiral starting material for this synthesis. Sclareol(1.3) is converted via a six-step sequence to create intermediate (1.4) that comprises the entirety of the terpene portion of makassaric acid. The aromatic component can be 6  added to 1.4 via nucleophilic attack, forming a secondary alcohol that is subsequently removed via Barton–McCombie deoxygenation, yielding makassaric acid.  Scheme 1 The synthetic strategy towards makassaric acid envisioned by the Basabe group. This sequence begins with the oxidative cleavage of sclareol to the mixture of compounds 1.5a and 1.5b using potassium permanganate and magnesium sulfate in acetone. The generated mixture is dehydrated in the presence of catalytic iodine. The ketone 1.6 is homologated using a Horner Wadsworth Emmons reaction to yield a mixture of alkenes (1.7) that are subsequently treated with anhydrous formic acid, to induce a cationic cyclization yielding 1.8 in 88% yield. Methyl ester 1.8 is reduced to an alcohol using LiAlH4, and re-oxidized with PCC to yield methyl-eneisocopolate (1.4).34 7   Scheme 2: Synthesis of methyl ent-isocopolate and its derivatives isocopalic alcohol and isocopalic aldehyde.34,35   The stereocenters formed during the transformation from 1.7 to 1.8 are dictated by thermodynamic stability, as the polycationic cyclization is reversible. When the polycationic cyclization is initiated by formic acid, the most thermodynamically stable trans decalin linkage is formed, with the methyl ester in the more stable equatorial position.  8   Scheme 3 The mechanism of the cationic cyclization from 1.7 to 1.8  The aldehyde 1.4 is attacked with an organolithium reagent formed through metal halogen exchange of aryl bromide 1.9 and t-butyllithium, forming makassaric acid derivative 1.10 (Scheme 4). The alcohol formed from this reaction is made into xanthate ester 1.11 and decarboxylated using n-Bu3SnH and AIBN in a Barton McCombie deoxygenation reaction forming 1.12. The THP protected alcohol on 1.12 is deprotected to an alcohol in p-TsOH, oxidized to the aldehyde using PDC, and oxidized again to a carboxylic acid using a Pinnick oxidation, yielding 1.13. The MOM protecting group of 1.13 is removed in 6 M hydrochloric acid, yielding makassaric acid (1.1).  9   Scheme 4: Conversion of isocopalic aldehyde (1.4) to makasarric acid (1.1)  The Basabe group initially attempted the reduction of alcohol 1.10 by first oxidizing it to a ketone, then reducing using a Wolff-Kishner reaction. They also attempted to convert the alcohol to a diathiane and reduce this dithiane with Raney Nickel.33 While both attempts were unsuccessful, the Barton McCombie radical deoxygenation proceeded in good yield.   10  1.4 Total syntheses of subersic acid In contrast to makassaric acid, there are several established synthetic routes towards subersic acid.36–39 The two most recent were conducted by the Zeng group, published in 2015 and 2017.   Scheme 5 Synthetic route carried out by the Zeng group in 2015 This scheme begins with the same oxidative cleavage and dehydration reactions that began the synthesis of makassaric acid, followed the addition of a vinyl Grignard reagent to the ketone. These steps achieve the dehydration of the alcohol on the decalin, which resisted dehydration under other conditions. Upon producing this dehydrated product 1.14, the allylic alcohol was displaced with a Mitsunobu reaction, yielding the allylic aryl ether 1.15. Upon heating in xylene, this compound underwent a Claisen rearrangement, yielding subersic acid (1.2).  The allylic alcohol must be oxidatively cleaved to facilitate the dehydration of the tertiary alcohol, as the presence of the allylic alcohol, even unprotected, interferes with the process. This 11  alcohol has repeatedly been challenging to dehydrate, requiring harsh permanganate oxidation or treatment with hydroiodic acid.36,37 The reticence of the non-allylic tertiary alcohol to eliminate likely has to do with the syn relationship between the alcohol and its neighboring tertiary proton.  Scheme 6 Formal synthesis of subersic acid by the Zeng group.39  The Zeng group later attempted a more concise synthesis of subersic acid from sclareol.39 The tertiary alcohols of sclareol (1.3) were acetylated using acetyl chloride and N,N-dimethylaniline making 1.16. Next, acetyl sclareol 1.16 was added to a stirring mixture of iodine and triphenylphosphine, concomitantly dehydrating one alcohol and rearranging the other to an allylic iodide.40 This allyl iodide is not stable to long term storage and was displaced to form the acetate 1.17 in one pot. This acetate was displaced with a cuprate reagent derived from aryl iodide 1.18. This reaction resulted in the production of 1.19 as a 4:1 mixture of E- and Z- isomers. 1.19 was converted to (+)-subersic acid with a 57% yield over two steps as a mixture of alkene isomers. 12  These syntheses demonstrate that it is possible to rapidly access subersic acid and its derivatives. This synthesis is much shorter than that of makassaric acid, and because of this, it is interesting to consider exploring the possibility of using subersic acid as a functional analogue of makassaric acid. Subersic acid can be accessed in five steps, while makassaric acid requires twelve. 13  Chapter 2: Results and Discussion 2.1 Preface: functionally simplified derivatives of makassaric acid As mentioned in the introduction, when viewing makassaric acid, we can structurally divide it into the left hand non-polar, terpene component and the right hand, polar aromatic component.   Figure 5 Functional derivatives of makassaric acid synthesized in the following chapters. The zebrafish assays performed by Dr.Xiao-Yan of the University of Toronto show that both makassaric acid and a compound containing an acyclic terpene attached to the same aromatic component as makassaric acid have activity that reverses brain bleeds in zebrafish. As a result, we were interested in a variety of synthetic strategies that would simplify synthesis of the terpene component while maintaining the aromatic component. Comparing the syntheses of makassaric acid (1.1) and subersic acid (1.2) as outlined in the introduction, the syntheses of subersic acid are 14  much shorter and simpler than the synthesis of makassaric acid itself. Therefore, we were interested in making more easily accessible subersic acid derivatives in addition less easily accessible makassaric acid derivatives (Figure 5, 1.2).  In addition to this, we became interested in synthesizing E-alkenes via Heck reactions from sclareol directly (Figure 5 2.14). These derivatives would hopefully be more hydrophilic than that of subersic and makassaric acid, and it might be interesting to see that effect on their activity. Lastly, we attempted to alkylate a β-ketoester in an attempt to make a variety of makassaric acid derivatives that were slightly more polar and tolerated a wider range of aromatic components than the Basabe group’s synthesis of makassaric acid (Figure 5, 2.28). 2.2 Synthesis of subersic acid derivatives Subersic acid is a closely related compound to makassaric acid. As seen in the introduction, syntheses of subersic acid are significantly shorter than those of makassaric acid, and so we decided to synthesize subersic acid derivatives as a functional alternative to makassaric acid.   It would be beneficial to test subersic acid derivatives as a single alkene geometry, so we did not follow the syntheses by the Zeng group as outlined in the introduction as these provided a mixture of E- and Z- isomers. Instead, we decided to modify the Zeng group’s synthesis and attempt to synthesize the allyl iodide 2.1 and alkylate it directly with phenol derivatives. We hoped that this would more rapidly yield a wide variety of subersic acid derivatives with greater alkene selectivity. 15   Scheme 7 Conversion of sclareol into an iodinated derivative40  As previously described in literature, acetyl chloride and N,N-dimethylaniline were added to a solution of sclareol in DCM.40 The resulting mixture was refluxed for 5 h, yielding acetate 1.16. This transformation was confirmed by the appearance of 2 CH3 signals at 2.00 and 1.94 ppm in the NMR spectrum of 1.16, corresponding to protons on each acetyl group added. Acetate 1.16 was treated with PPh3 and I2 in DCM at room temperature forming allyl iodide 2.1 in an Appel reaction. This transformation was confirmed by the disappearance of the methyl ether CH3 signals at 2.00 and 1.94 ppm which previously corresponded to acetate 1.16. In addition to this disappearance, a triplet integrating for 1 at 5.54 ppm was observed in the 1H NMR spectrum of 2.1, corresponding to the alkenyl proton formed in the Appel reaction. This allyl iodide was used an electrophile for attempted C-alkylations with a variety of phenolate anions.41,42        16  Table 1 General reaction scheme for aryl iodide alkylation, and table of substrates    a) 1 equiv NaH (60% mineral oil), 2 equiv phenol, toluene 0 °C to rt , 12 ha      2.2 2.3 2.4 2.5 2.6 90% 74% 57% 59% 55% C-alkylation C-alkylation O-alkylation O-alkylation O-alkylation aReaction run using NaH (0.62 mmol), phenol derivative (1.29 mmol, 2 equiv), and allyl iodide 2.1 (0.62 mmol) in toluene (10 mL). The mixture was stirred 12 h at room rt then purified with column chromatography. Best results were obtained with toluene degassed by freeze pump thaw method.  There are two desired selectivity compounds for this reaction sequence–firstly that of the alkene geometry, which is set during the Appel reaction, and that of C- and O-alkylation, which is set during the enolate attack of the allyl bromide. NOESY experiments were used to assign the E/Z configuration of the alkene. The allylic methyl group should have a strong NOE effect with its cis-vinyl proton. The alkenyl proton and the benzyl proton have diagnostic chemical shifts at 3.39 and 5.38 ppm respectively. The signal at 3.39 ppm corresponding to the benzyl proton showed a strong NOE to the allylic methyl group, while the alkenyl proton (5.38 ppm) correlated to the allylic proton at 2.10 ppm. This evidence suggests that the reaction is completely E selective, and the subsequent displacement reaction did not affect this E selectivity. 17  Table 2: Observed NOESY correlations of 2.2.  Proton Chemical Shift Integration NOESY Correlation Hb 3.39 2 1.83 (Hd) Hb 3.39 2 7.14 (Ha) Hc 5.38 1 2.10 (He) Hd 1.83 3 3.39 (Hb) He 2.10 2 5.38 (Hc) It was possible to confirm the presence of the C- and O-alkylated products from the number of protons on the aryl ring in the product, the HMBC correlations, and IR spectra of the products. For example, in the C-alkylated product 2.3, there are only 3 aromatic protons present in the 1H NMR spectrum, one less proton than would be expected for the O-alkylated product. In addition, the IR spectrum exhibits a broad peak at 3383 cm-1 indicative of a hydroxyl function. Compound 2.5, an O-alkylated product, exhibited signals corresponding to four aromatic protons (7.04-7.86 ppm), and lacked an IR absorption indicative of an O-H stretch. Table 3 HMBC Correlations are consistent with a product of C-alkylation  Chemical Shift Integration HMBC Correlation 3.31 (Ha) 2 154.3 (3) 3.31 (Ha) 2 138.3 (1) 3.31 (Ha) 2 129.6 (2) 5.31 (Hb) 1 154.3 (3) 18  Disappointingly, m-hydroxy methylbenzoate, p-hydroxy benzaldehyde and 4-hydroxybenzonitrile all yielded O-alkylated products 2.4-2.6. To access the C-alkylated p-benzonitrile derivative it was possible to treat the aryl iodide with a mixed cyanide source by a previously described method.43 The reaction was accompanied by the upfield shift of aromatic protons from 7.42 ppm in 2.3 to 7.11 ppm in 2.7, consistent with the replacement of the iodide with a cyanide group.   Scheme 8 Cyanation of with a mixed cyanide source to access C-alkylated benzonitrile.  It was also possible to carboxylate iodophenol derivative 2.3, constructing a short route to subersic acid. Previous syntheses of subersic acid have not been able to use the generated intermediate 2.1 directly, however with careful reaction with dried and degassed solvents, it is possible to react 2.1 to cleanly form derivatives of subersic acid. Compound 2.3was acetylated, forming intermediate 2.8.44 This transformation was confirmed by the presence of a methyl singlet at 2.29 ppm integrating for 3, which was not previously present in the starting material.  19   Scheme 9  Synthesis of (+)-subersic acid. The iodo substituent of intermediate 2.8 was converted to a carboxylic acid using a palladium catalyzed carbon monoxide (CO) insertion reaction with oxalic acid as the in situ source of CO.45 The acetyl group was removed by saponification under basic conditions yielding subersic acid (1.2). The 1H NMR spectrum of subersic acid that matched that of previous literature reports. This reaction sequence yields subsersic acid in 5 steps without the use of HPLC purification, which has previously been needed to resolve E- and Z- configurations at the alkene position of subsersic 20  acid. This route to subersic acid is potentially amenable to the synthesis of a multitude of derivatives of subersic acid but is limited by the poor stability and difficult handling of 2.1.  Scheme 10 Synthesis of an allyl bromide derivative as a more stable alternative for the allyl iodide 2.1 Compound 2.1 could not be easily stored, and its purification from phosphine oxide byproducts was difficult to perform on a gram scale. The analogous bromide compound 2.10 was constructed by reacting 1.16 with triphenyl phosphine and liquid bromine in DCM, analogous to the reaction to produce 2.1. Bromide 2.10 displayed markedly improved stability and handling characteristics. It could also be easily reacted with phenolate anions. 2.10 has been previously used to synthesize subersic acid, but was synthesized in 4 steps from the same acetylated intermediate by the Basabe group, in their own synthesis of (+)- subersic acid.37 21   Scheme 11 Basabe group’s synthesis of the allyl bromide intermediate.   This one step process to form compound 2.10 from 1.16 significantly shortens previous routes to this compound and allows for the direct displacement of the allyl halide to form subersic acid derivatives with complete E-selectively.    22  2.3 Heck cross-couplings on sclareol In addition to these subersic acid derivatives, some analogues of subersic acid were quickly accessed by the Heck coupling of various aryl iodide substrates with sclareol itself as according to literature (Table 4).46,47  Table 4 Heck reactions performed on sclareol to produce subersic acid derivatives.a       2.13 2.14 2.15 2.16 52% 74% 50% 55% aReactions run using sclareol (0.5 g, 1 equiv), Pd(OAc)2 (10 mol %), Cu(OAc)2 (2 equiv), KOAc (3 equiv), and arylboronic acid or aryl iodide (1.5 equiv) in DMF (10 mL). The flask was sealed and heated at 80 °C for 3-6 h, then purified by column chromatography on silica gel. The synthesis of sclareol derivative 2.13 was confirmed by the shift of 1H signals from the alkene protons of sclareol (5.04 ppm, 5.22 ppm and 5.93 ppm, each integrating to 1) to alkene shifts of 6.50 and 6.14, each integrating for 1 in the product. The synthesis of 2.14 was confirmed by the diagnostic alkene signals at 6.57 and 6.25 ppm, derivative 2.15 by alkene signals at 6.70 and 6.46, and 2.16 by alkene signals at 6.68 ppm and 6.45 ppm. In all cases, the alkene signals in the product were doublets with a coupling constant of 16 Hz, consistent with an E alkene geometry. 23  These derivatives are constructed with a method previously detailed in literature.46,47 However, they have not yet been tested using the zebrafish assay. In addition, 2.16 is a substrate that was not previously reported. These compounds were submitted for zebrafish assays, which have yet to be conducted. It would be beneficial to follow up on these reactions to make a derivative where the aromatic component better resembles that of makassaric acid. Towards that end, iodination reactions of the appropriate aryl compounds have been conducted, but these compounds have not yet been used in a Heck reaction with sclareol. 2.4 Route to makassaric acid via a β-ketoester intermediate In addition to these syntheses of subersic acid derivatives as functional equivalents to makassaric acid, we felt it was interesting to explore the synthesis of molecules more closely resembling makassaric acid, but also introducing more polarity into the terpene component. The synthesis of makassaric acid by the Basabe group involved the cleavage pf makassaric acid into an electrophilic terpene fragment and a nucleophilic aromatic fragment (Scheme 12, route a).   Scheme 12 Disconnections used by the Basabe group in their synthesis of makassaric acid, and attempted disconnection strategy that we used. 24   We proposed a different intermediate 2.18 that has been previously synthesized in literature, but has not previously been alkylated at the alpha carbon.48 This intermediate, once alkylated, could foreseeably be converted into makassaric acid via a few manipulations, or directly used as a derivative. We repeated the synthesis of intermediate 2.18 as detailed in literature (Scheme 12 by following the literature synthesis of 1.6 conducted by the Basabe group, but instead of conducting a Horner Wadsworth Emmons reaction, a β-ketoester is made instead prior to polycationic cyclization induced by SnCl4.48  Scheme 13 Route carried out to an alternative intermediate in the synthesis of makassaric acid.   The treatment of sclareol (1.3) with harsh oxidant KMnO4 oxidizes the allylic alcohol to a ketone, cleaving the vinyl group in the process. The initially formed product 1.5a condenses to form 1.5b as a byproduct. Fortunately, this mixture of products does not need to be separated. Upon reflux in toluene with catalytic iodine for 3 h with an attached Dean Stark Trap, the tertiary alcohol can be dehydrated forming 1.6. A singlet integrating for 3 at 2.13 ppm was observed in 1H NMR spectrum of 1.6, corresponding to the alpha proton of the ketone formed. Treating 1.6 with 25  excess base forms the kinetic enolate at the less sterically encumbered position. This enolate attacks dimethyl carbonate, forming β-ketoester 2.17. The 1H NMR spectrum of 2.17 contained a signal at 3.46 ppm integrating for 2 protons, corresponding to the alpha protons of the β-ketoester, as well as a singlet CH3 peak at 3.76, indicative of the methoxy group on the newly introduced methyl ester. A 1 M solution of tin tetrachloride was added dropwise to a solution of 2.17 in DCM at -78 °C, initiating the polycationic cyclization which yielded 2.18. A singlet integrating for 1 at 3.25 ppm was observed in the 1H NMR spectrum of 2.18, corresponding to the alpha proton on the cyclic β-ketoester. The configuration of 2.18 was confirmed in a collected solid state molecular structure (Figure 6).  Figure 6 Solid-state structure confirming the absolute configuration of intermediate 2.18   Following the successful preparation of β-ketoester 2.18, the next reaction to be studied was its alkylation. Substitued benzyl bromides were generated using well-established conditions (Table 5).49    26    Table 5 Preparation of alkylation substrates a,b 49     2.19 2.20  2.21 a) 91% 1 equiv ArCOOH MeOH, conc. H2SO4 (cat) Reflux 3 h a) 41% 1 equiv ArOH, DMF 2 equiv K2CO3, 1.5 equiv MeI r. t. 12 h a) 88% 1 equiv ArOH, DMF 2 equiv K2CO3, 5 equiv MeI r. t. 3 h    2.22 2.23 2.24 b) 92% 1 equiv 2.19, 1.1 equiv NBS 5 mol % AIBN benzene, 80 °C, 6 h b) 87% 1 equiv 2.20, 1.1 equiv NBS 2 mol % AIBN CCl4, reflux, 3 h b) 98% 1 equiv 2.21, 1.1 equiv NBS 5 mol % AIBN benzene, 80 °C, 6 h aYields were determined by weighting out mass of product on a tared balance bAll procedures were taken from established literature precedents.   27  The first conditions attempted (Table 6, Entry 1) for alkylation were based off a literature procedure shown in Scheme 14 as the alkylation of β-ketoester 2.18 is not reported in literature.50  Scheme 14 The literature reaction that the attempted alkylation of 2.18 was based upon.  Initially, alkylation to form was confirmed by the observation of 3 alkene protons at 5.85, 5.26, and 5.13 ppm, as well as 2 allyl protons at 4.22 ppm (Table 6, Entry 1). Switching from acetone to THF as a solvent provided a modest increase in isolated yield of the product, however significant starting material 2.18 remained despite the long reaction time and reflux temperature (Table 6, Entry 2). The conditions were repeated with benzyl bromide, only yielding a trace amount of 2.25, indicated by the shift of the 2 diagnostic benzylic protons at 4.81 and 4.75 ppm., which exhibited geminal coupling to each other with 11.9 Hz (Table 6, Entry 3). However, this reaction also did not fully consume starting material. In an attempt to increase the yield of the reaction, the number of equivalents of benzyl bromide were increased to 10 and a catalytic amount of tetrabutylammonium iodide (TBAI) (Table 6, Entries 4-5). No product was observed in either of these reactions by NMR, but a large amount of starting benzyl bromide was. Product purification 28  continued to be an issue when using 2.22 as an alkylation agent (Table 6 Entries 6-7). An attempt to accelerate the reaction in HMPA was unsuccessful and not repeated (Table 6, Entry 8).   Table 6 Reactions performed to screen conditions for alkylation reactions.a Entry Equiv Substrate Substrate Additives Solvent Temperature (°C) Time (h) Yield (%) 1 2 allyl bromide - acetone 65 12 11 (2.25) 2 2 allyl bromide - THF 65 12 15 (2.25) 3 2 benzyl bromide - THF 65 12 NR 4 10 benzyl bromide cat. TBAI THF Rt 12 NR 5 10 benzyl bromide cat. TBAI THF 65 12 NR 6 2 2.22 - THF 65 8 Trace (2.26) 7 2 2.22 cat. KI THF 65 12 Trace (2.26) 8 2 2.23 - HMPA 100 12 n.r. 9 2 2.24 cat. TBAI THF 65 12 Trace (2.27) 10 1 2.24 cat. TBAI DMF 65 3 Trace (2.28) aReactions run using varying equivalents of benzyl bromide derivatives (substrate), 1.5 equiv CsCO3, and other conditions listed. Yields were determined by isolated mass of product from prep TLC. All reactions were done on the 0.1g scale. It was difficult to purify products from reactions in entries 3-10 by column chromatography. Initial attempts to purify the p-methoxy methyl benzoate product (Table 6, Entry 9) were unsuccessful. It was still not possible to consistently separate alkylating agent from the product completely, and so an attempt to reduce the amount of alkylation agent was done in addition to adding a small amount of TBAI as a nucleophilic catalyst for the reaction (Table 6, Entry 10). The recalcitrance of 2.18 to clean attack of an active electrophile is possibly due to steric hindrance of the nucleophile imparted by the neighboring quarternary stereocentre. 29   Figure 7 Presumptive nucleophile formed by deprotonation of 2.18.  In addition to the difficulties purifying the product, there was difficulty identifying the benzylic protons of the product. These protons were expected to appear as a singlet integrating for 2 in the 1H NMR spectrum around 4.5 ppm, and this was observed in the product 2.27 isolated in Table 6, Entry 9. The β-ketoester seems to have been saponified under the reaction conditions, as there is no longer a methyl singlet at 3.7 ppm, corresponding to the methyl ester of the original β-ketoester. Initially, it was believed that product 2.27 was the desired alkylated β-ketoester product following decarboxylation, however the carbon spectrum still retained the carbonyl signal of the carboxylic acid, leading us to believe that despite the saponification of the β-ketoester, decarboxylation did not occur. In contrast, the purified product 2.28 in Table 6, Entry 10 did not exhibit this benzyl singlet, initially leading us to believe that the reaction was unsuccessful. However, looking closely at the 1H NMR spectrum, it became clear that the benzylic protons in product 2.28 are diastereotopic and split each other with a geminal coupling constant of 12.9 Hz, due to the lack of rotation imparted by the neighboring quaternary stereocentre (Table 7, 2.28). It is interesting that 2.27 does not exhibit this same splitting pattern (Table 7, 2.27).     30  Table 7 Comparing 1H NMR shifts for alkylated products and starting material.a     2.27 2.28 2.18 2.26 δH Int δH Int δH Int δH Int 8.01 2 8.08 1 - - 8.05 2 - - 7.97 1 - - 7.57 1 6.91 1 6.86 1 - - 7.46 1 4.55 (s) 2 4.86 (d) 1 - - 4.86(d) 1   4.78 (d) 1   4.81(d) 1 3.96 3 3.88 3 - - - - 3.89 3 3.87 3 - - - - - - 3.73 3 3.68 3 3.72 3 - - - - 3.23 1 - - 0.90 3 1.24 3 1.17 3 1.23 3 0.88 3 0.85 3 0.90 3 0.86 3 0.85 3 0.84 3 0.87 3 0.85 3 0.83 3 0.81 3 0.81 3 0.84 3 aThe bolded ppm values highlight the variation seen for the chemical shifts and splitting on the benzylic protons observed for different compounds isolated. They also highlight the similarities in the ester chemical shift for the betaketoesters. To improve reaction yields and isolation, it would be interesting to explore alternative bases and potentially higher reaction temperatures to try to fully decarboxylate the product prior to purification. Significant difficulties were encountered identifying the NMR spectra of these products initially, especially with products that could not be fully purified.  Alternative usages of this intermediate were considered. The cyclic β-ketoester 2.18 could also be treated with a mixture of potassium hydroxide, methanol, and water, at reflux overnight, resulting in the formation of 2.29 (Scheme 15). A methyl singlet integrating for 3 at 3.69 ppm was not observed in the product 2.29, confirming the successful decarboxylation of the methyl ester. This decarboxylated product 2.29 was dissolved in diethyl ether. A Grignard reagent derived from 31  benzyl bromide and magnesium was added dropwise to this mixture, yielding 2.30. The 1NMR spectrum of 2.30 contained a singlet at 2.65 ppm integrating for 2 corresponding to the benzylic protons, as well as aromatic signals from 7.30 to 7.14 ppm, integrating for 5, corresponding to the aromatic signals.  Scheme 15 Decarboxylation of cyclic β-ketoester 2.18  This route suffers from similar drawbacks to the Basabe group’s initial synthesis of makassaric acid, namely that the Grignard conditions are incompatible with ester groups and other functionalities, making the scope of addition reagents very limited. However, 2.29 could still potentially be used to make additional derivatives of makassaric acid.   32  Chapter 3: Conclusion and Future Directions The promising preliminary results of makassaric acid reversing brain bleeds in zebrafish prompted attempts to synthesize makassaric acid derivatives. Three main approaches were used to synthesize derivatives of makassaric acid. An E-selective alkylation of an allyl iodide was used to make 6 new subersic acid derivatives, one of which could be easily converted to subersic acid. A previously explored Heck reaction yielded 4 derivatives, one of which was not previously reported. The yet undescribed alkylation of the β-ketoester was attempted, yielding 3 novel compounds. The E-selective synthesis of subersic acid was developed, improving upon current syntheses which had yielded mixtures of alkenes. Using the route outlined in Scheme 20, 5 novel derivatives of subersic acid were synthesized with yields from 55 to 90%. There was competition between O- and C-alkylation, with electron withdrawing groups like aldehydes, nitriles and esters favoring O-alkylation   Scheme 16 General scheme of subersic acid synthesis 33  The p-iodophenol derivative 2.3 was especially useful as it could be converted into subersic acid as well as a p-cyano derivative of subersic acid. Further studies should be conducted to increase scale and substrate scope. The allyl iodide derivative was also unstable to storage, and the analogous bromine derivative was made to remedy this. However, the bromine derivative has not been made successfully at a larger scale.  To develop easily accessible hydrophilic derivatives of subersic acid, Heck couplings were conducted upon sclareol using methodology previously described in literature.  Scheme 17 General scheme of Heck couplings With this method, 4 compounds were made with yields varying from 50 to 74%. Aryl iodides more closely resembling the makassaric acid aromatic fragment were also synthesized but have not yet been coupled to sclareol.  Attempts were made to alkylate the β-Ketoester 2.18. Reaction yields were poor for the alkylation of 2.18 and separation of starting material and alkylated product was often unsuccessful. The most promising alkylation results came about as a result of using an excess of β-ketoester 2.18 to completely consume alkylation agent and adding catalytic TBAI with DMF as a solvent. Column purification of derivatives was initially unsuccessful, but small quantities of pure compound could be obtained by prep TLC.  34   Scheme 18 Attempted alkylation scheme via a β-ketoester intermediate.  More conditions and electrophiles should be screened in this reaction. To remedy purification issues, one could also consider using benzaldehyde derivatives, where the corresponding secondary alcohol would be significantly different in polarity from the starting materials (Scheme 19). This secondary alcohol could also conceivably be removed by Barton McCombie decarboxylation.33 In addition, conducting Horner-Wadsworth-Emmons olefinations on the decarboxylated product 2.15 could also yield a set of promising derivatives.51  Scheme 19 Future directions for makassaric acid derivatives from 2.6  35  Chapter 4: Experimental Unless otherwise noted, all experiments requiring inert atmosphere or vacuum distillation were conducted with Schlenk line techniques under flowing nitrogen. Tetrahydrofuran was dried using sodium metal using benzophenone as an indicator. Dichloromethane was dried over calcium hydride. Toluene was dried using sodium metal. n-Butyllithium was titrated against diphenyl acetic acid. Thin layer chromatography was carried out on DC-Fertigplatten SIL G-25 UV254 pre-coated TLC plates and visualized by UV light (254 nm), potassium permanganate, iodine or p-anisaldehyde stains. All purification using column chromatography was carried out on Silicycle SiliaFlash F60 (40-63 µm, 230-400 mesh) silica gel. NMR spectra were recorded on a Bruker 300 MHz or 400 MHz spectrometer. Chemical shifts are recorded in parts per million (ppm) relative to the residual solvent peak in each spectrum. Coupling constants (J) are reported in Hertz (Hz) and were analyzed with Mestrenova and Topspin. Mass spectra were recorded on a Waters LC-MS (low resolution) or a Water/Micromass LC (high resolution). Infrared spectra were recorded on a PerkinElmer FT-IR.        36  4.1 Synthesis of subersic acid derivatives 1.16 (3R)-5-((1R,2R,8aS)-2-acetoxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)-3-methylpent-1-en-3-yl acetate Acetyl chloride (4.5 mL, 63.3 mmol), sclareol (3.38g, 11 mmol), and N,N-dimethylaniline (6 mL) in DCM (10 mL) were added to a round bottom flask. The resulting mixture was stirred at 50 °C for 5 h and diluted with ethyl acetate (50 mL). The ethyl acetate solution was washed with 1 M HCl until the organic layer was colorless. The organic layer was washed with water, brine and was dried using MgSO4. Solvent was removed in vacuo, and the white crystals that remained were used without further purification. (4.18 g, 97%). 1H NMR (400 MHz, CDCl3) δ 5.96 (dd, J=17.5, 11.0 Hz, 1H), 5.14 (t, J=13.4 Hz, 2H), 2.62 (dt, J=11.8, 3.0 Hz, 1H), 2.00 (s, 3H), 1.94 (s, 3H), 1.89 (d, J=8.7 Hz, 1H), 1.77–1.55 (m, 5H), 1.53 (s, 3H), 1.45 (s, 3H), 1.40–1.34 (m, 2H), 1.43–1.08 (m, 6H), 0.97 (dd, J=12.4, 1.6 Hz, 1H), 0.86 (s, 3H), 0.82 (s, 3H), 0.77 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 170.4, 170.0, 142.1, 113.2, 88.1, 88.4, 58.9, 55.8, 42.8, 42.0, 39.7, 38.9, 33.5, 33.3, 29.9, 23.7, 23.0, 22.4, 21.6, 20.6, 20.1, 19.6, 18.5, 15.9. ESIHRMS: Mass calcd for C24H40O4: 392.2927; found: 392.2933. IR: 2935, 1730, 1461, 1250 cm-1.40 2.1 (8aS)-8-((E)-5-iodo-3-methylpent-3-en-1-yl)-4,4,7,8a-tetramethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalene Resublimed iodine (0.71 g, 2.8 mmol), PPh3 (0.67 g, 2.5 mmol), and DCM (10 mL) were added to a round bottom flask. The mixture was stirred for 5 minutes. A solution of acetyl sclareol (1.1 g, 2.5 mmol) in DCM (2mL) was added and the solution was stirred for 8 h then diluted with ether (20 mL), washed with saturated Na2S2O3, 5% aqueous NaHCO3, water and brine. The organic layer was dried over MgSO4 and 37  evaporated to yield a crude which was purified after flash chromatography in hexane, yielding the product aryl iodide (1.03 g, 92 %). 1H NMR (300 MHz, CDCl3) δ 5.55 (t, J=8.8 Hz, 1H), 3.94 (d, J=8.7 Hz, 2H), 1.68 (s, 3H), 1.56 (s, 3H), 0.93 (s, 3H), 0.88 (s, 3H), 0.83 (s, 3H).40 2.2 2-((E)-3-methyl-5-((8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)pent-2-en-1-yl)phenol NaH (60 % in mineral oil, 0.0280g, 0.62 mmol) and phenol (0.121g, 1.29 mmol) were dissolved in toluene at 0 °C and the solution was stirred for several minutes. The mixture was charged with the allyl iodide (0.25 g, 0.62 mmol) and warmed to rt. The mixture was stirred 12 h at rt, then poured into water, and extracted with ethyl acetate (2 x 10 mL). The crude, dark oil was column purified on silicawith a gradient elution from hexanes to 9:1 hexane to ethyl acetate, and isolated as a yellow oil (0.205, 90 %). 1H NMR (400 MHz, CDCl3) δ 7.14 (t, J=6.4 Hz, 2H), 6.93–6.86 (m, 1H), 6.86–6.80 (m, 1H), 5.39 (t, J=6.8 Hz, 1H), 3.41 (d, J=7.1 Hz, 2H), 2.20–1.92 (m, 6H), 1.84 (s, 3H) 1.82 (m, 1H), 1.67 (ddd, J=14.5, 13.1, 7.9 Hz, 1H), 1.60 (s, 3H), 1.54–1.40 (m, 3H), 1.32–1.29 (m, 1H), 1.24–1.12 (m, 3H), 0.97 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.5, 140.3, 139.7, 130.1, 127.6, 127.0, 126.1, 121.1, 120.8, 115.9, 52.0, 42.0, 40.6, 39.2, 37.1, 37.1, 33.8, 33.5, 29.8, 27.3, 21.9, 20.3, 19.7, 19.2, 19.2, 16.5. ESIHRMS:  Mass calcd for C26H38O: 366.2923; found: 366.2932.IR: 3430, 2928, 1455, 750 cm-1.      38  2.3 4-iodo-2-((E)-3-methyl-5-((8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)pent-2-en-1-yl)phenol As according to procedure used for 2.2, NaH (60 % in mineral oil, 0.0253g, 0.625 mmol), iodophenol (0.184g, 0.84 mmol), and allyl iodide (0.25 g, 0.62 mmol) were combined. The resultant crude red-brown oil was purified with a gradient elution from pure hexanes to 9:1 hexanes to ethyl acetate, yielding the purified product as a yellow oil (0.227 g, 74 %) 1H NMR (400 MHz, CDCl3) δ 7.42–7.36 (m, J=2.4 Hz, 2H), 6.58 (d, J=8.3 Hz, 1H), 5.31 (t, 1H), 3.31 (d, J=7.2 Hz, 2H), 2.17–1.90 (m, 6H), 1.80 (s, 3H), 1.75–1.61 (m, 3H), 1.58 (s, 3H), 1.53–1.36 (m, 4H), 1.27 (t, J=7.1 Hz, 1H), 1.21–1.08 (m, 3H), 0.95 (s, 3H), 0.89 (s, 3H), 0.84 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.5, 140.5, 140.2, 138.6, 136.4, 129.8, 126.2, 120.2, 118.2, 82.9, 52.0, 41.9, 40.6, 39.2, 37.2, 37.2, 33.8, 33.5, 29.5, 27.2, 21.9, 20.3, 19.7, 19.7, 19.2, 16.5. ESIHRMS: Mass calcd for C27H37IO: 492.1889; found: 492.1895. IR: 3383, 2927, 1703, 1266, 809 cm-1.Ref: KS02-53-01.42 2.4 methyl 3-(((E)-3-methyl-5-((8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)pent-2-en-1-yl)oxy)benzoate As according to the procedure used for 2.2, NaH (60 % in mineral oil, 0.0271 g, 0.63 mmol), 3 hydroxy methyl benzoate (0.124g, 0.815 mmol), and allyl iodide (0.25 g, 0.62 mmol) were combined. The resultant crude dark oil was purified with a gradient elution from pure hexanes to 9:1 hexane to ethyl acetate, yielding the purified product as a yellow oil (0.152 g, 57 %). 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=7.7 Hz, 1H), 7.59–7.57 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.13–7.09 (m, 1H), 5.50 (t, J=5.9 Hz, 1H), 4.58 (d, J=6.6 Hz, 2H), 3.91 (s, 3H), 2.15–1.93 (m, 6H), 1.78 (s, 3H), 1.57 (s, 3H), 1.40 (dd, J=12.6, 5.0 Hz, 5H), 39  1.20–1.08 (m, 4H), 0.94 (s, 3H), 0.88 (s, 3H), 0.83 (s, 3H).13C NMR (101 MHz, CDCl3) δ 167.1, 158.9, 142.6, 140.1, 131.4, 129.4, 126.1, 121.9, 120.3, 118.5, 114.8, 65.2, 52.2, 51.9, 41.8, 40.2, 39.1, 37.0, 33.7, 33.4, 33.3, 26.7, 21.7, 20.1, 19.5, 19.1, 19.1, 16.8. ESIHRMS: Mass calcd for C28H40O3: 424.2977; found: 424.2984. IR: 2934, 1724, 1277, 1220, 756 cm-1. Ref KS02-35-01 2.5 4-(((E)-3-methyl-5-((8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)pent-2-en-1-yl)oxy)benzaldehyde As according to the procedure used for 2.2, NaH (60 % in mineral oil, 0.0253g, 0.625 mmol), iodophenol (0.184g, 0.835 mmol), and allyl iodide (0.25 g, 0.62 mmol) were combined. The resulting crude dark yellow oil was purified with a gradient elution from pure hexanes to 9:1 hexanes to ethyl acetate, to give a yellow oil (0.1461g, 59 %). 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 7.86 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 5.53 (t, J=6.1 Hz, 1H), 4.65 (d, J=6.5 Hz, 2H), 2.20–1.94 (m, 6H), 1.90–1.83 (m, 1H), 1.81 (s, 3H), 1.75–1.64 (m, 2H), 1.61 (s, 3H), 1.59–1.36 (m, 4H), 1.31 (ddd, J=14.2, 9.4, 5.9 Hz, 1H), 1.23–1.13 (m, 3H), 0.98 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 190.9, 164.1, 143.2, 140.1, 132.1, 132.1, 130.0, 126.3, 118.0, 115.1, 115.1, 65.4, 52.0, 41.9, 40.3, 39.2, 37.1, 33.8, 33.4, 26.8, 21.8, 20.2, 19.7, 19.2, 19.2, 16.9. ESIHRMS: Mass calcd for C27H39O2: 394.2872; found: 394.2874.      40  2.6 4-(((E)-3-methyl-5-((8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)pent-2-en-1-yl)oxy)benzonitrile 1H NMR (400 MHz, CD2Cl2) δ 7.58 (d, J=8.9 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 5.47 (t, J=6.0 Hz, 1H), 4.59 (d, J=6.5 Hz, 2H), 2.18–1.89 (m, 6H), 1.77 (s, 3H), 1.72–1.59 (m, 4H), 1.58 (s, 3H), 1.52–1.37 (m, 4H), 1.23–1.09 (m, 4H), 0.95 (s, 3H), 0.89 (s, 3H), 0.84 (s, 3H). Ref: KS02-59-01   2.7 4-hydroxy-3-((E)-3-methyl-5-((8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)pent-2-en-1-yl)benzonitrile Under air, a reaction tube was charged with 2.3 (0.05 g, 0.10 mmol), ammonium chloride (0.03 g, 0.15 mmol), copper acetate (0.04 g, 0.12 mmol), ethylene diamine (0.01 mL) and dry DMF (1 mL). The mixture was stirred at 150 °C for 22 h. The resulting mixture was diluted with ethyl acetate (10 mL), washed with water (2 x 10 mL), and the organic layers were dried with MgSO4, concentrated and purified by column chromatography in 8:2 hexanes : ethyl acetate (0.021g, 52 %). 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J=7.1 Hz, 1H), 6.90–6.77 (m, 2H), 5.35 (brds, 1H), 3.37 (d, J=6.9 Hz, 2H), 2.14–1.91 (m, 4H), 1.80 (s, 3H), 1.72–1.60 (m, 3H), 1.57 (s, 3H), 1.52–0.99 (m, 9H), 0.94 (s, 3H), 0.88 (s, 3H), 0.83 (s, 3H). Ref: KS02-87-01    41  2.8 4-iodo-2-((E)-3-methyl-5-((8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)pent-2-en-1-yl)phenyl acetate DMAP (0.0012g, 0.01 mmol) was added to a solution of compound 2.3 (0.05g, 0.1 mmol) stirring in DCM (2 mL). Acetyl chloride (0.01 mL, 0.15 mmol) and triethylamine (0.02 mL, 0.15 mmol) were added to this solution and the mixture was stirred for 12 h at rt. Saturated NaHCO3 was added to quench the reaction mixture. The organic layer was separated, washed with water, dried with MgSO4 and concentrated in vacuo. The product was purified by column chromatography using a gradient elution of hexanes : ethyl acetate (hexanes, 10:1, 4:1, 1:1), yielding the product as a clear oil (0.0447 g, 81%). 1H NMR (300 MHz, CDCl3) δ 7.57–7.48 (m, 2H), 6.77 (d, J=8.3 Hz, 1H), 5.19 (t, J=7.1 Hz, 1H), 3.19 (d, J=7.1 Hz, 2H), 2.29 (s, 3H), 2.14–1.94 (m, 6H), 1.82 (d, J=15.8 Hz, 2H), 1.71 (s, 3H), 1.58 (s, 3H), 1.49–1.36 (m, 4H), 1.18–1.08 (m, 3H), 0.95 (s, 3H), 0.88 (s, 3H), 0.83 (s, 3H). Ref KS02-82-crd52 Acetylated (+)-subersic acid A sealed flask was charged with oxalic acid (7.9 mg, 1.5 equiv), palladium (II) acetate (1 mol %), triphenylphosphine (3 mol%), compound 2.8 (31.4 mg), acetic anhydride (9.0 mg, 1.5 equiv), N-Ndiisopropylamine (10 mg) and N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 100 oC for 6 h, then cooled to rt. The reaction mixture was diluted with ethyl acetate (10 mL), acidified with 2 M HCl (5 mL x1) and washed with brine (5ml x2). The organic phase was dried with MgSO4 and concentrated in vacuo. (8.3 mg, 31%) 1H NMR (300 MHz, CDCl3) δ 8.02–7.92 (m, 2H), 7.14 (d, J=8.3 Hz, 1H), 5.24 (t, J=6.8 Hz, 1H), 3.30 (d, J=7.0 Hz, 2H), 2.33 42  (s, 3H), 2.16–2.07 (m, 2H), 2.03–1.77 (m, 4H), 1.74 (s, 3H), 1.58 (s, 3H), 1.54–1.35 (m, 4H), 1.26 (m, 1H), 1.22–1.07 (m, 3H), 0.94 (s, 3H), 0.88 (s, 3H), 0.83 (s, 3H). Ref KS02-84-0145 1.2 (+)-subersic acid Compound 2.9 was added to a flask containing THF (0.5 mL), water (0.5 mL), and NaOH solution (0.5 mL, 1M). The mixture was stirred at room temperature for 3 hours, then acidified with HCl solution (5 mL, 1M). The resulting mixture was diluted with ethyl acetate (15 mL) then washed with water (2 x 5 mL) and brine (2 x 5 mL) to produce a crude brown oil (6.3 mg, 84%). 1H NMR (300 MHz, CDCl3) δ 7.86 (dd, J=10.8, 2.3 Hz, 2H), 6.87 (d, J=8.3 Hz, 1H), 5.35 (t, J=7.0 Hz, 1H), 3.40 (d, J=7.1 Hz, 2H), 2.12 (d, J=8.6 Hz, 3H), 2.05 (s, 2H), 1.98 (dd, J=12.5, 7.6 Hz, 3H), 1.81 (s, 3H), 1.65 (d, J=23.3 Hz, 3H), 1.57 (s, 3H), 1.55–1.34 (m, 4H), 1.15 (ddd, J=17.6, 10.8, 3.0 Hz, 2H), 0.94 (s, 3H), 0.88 (s, 3H), 0.83 (s, 3H). ESIHRMS: Mass calcd for C27H38O3: 410.2824; found: 409.2821. Ref KS02-85-crd 2.10 (8aS)-8-((E)-5-bromo-3-methylpent-3-en-1-yl)-4,4,7,8a-tetramethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalene To a solution of PPh3 (0.69 g, 2.6 mmol) in DCM (8 mL), liquid bromine (130 μL, 2.6 mmol) was added. The mixture was stirred 5 minutes at rt. A solution of 1.16 (1 g, 4 mL DCM), was added and the mixture was stirred for 8 h. The mixture was diluted with ether (15 mL), washed with NaHCO3 (5%, 2 x 20 mL) and brine (2 x 20 mL). The organic layer was dried over MgSO4, and solvent was removed in vacuo, yielding a yellow oil (0.81 g, 90 %). 1H NMR (300 MHz, CDCl3) δ 5.55 (t, J=8.2 Hz, 1H), 4.02 (d, J=8.4 Hz, 2H), 1.76 (s, 3H), 1.57 (s, 3H), 0.94 (s, 2H), 0.89 (s, 4H), 0.84 (s, 3H).37  43  4.2 Heck cross-couplings on sclareol 2.13 (2R,8aS)-1-((R,E)-5-(3,4-dimethoxyphenyl)-3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol 1H NMR (400 MHz, CDCl3) δ 6.92–6.84 (m, 2H), 6.77 (d, J=8.2 Hz, 1H), 6.50 (d, J=16.0 Hz, 1H), 6.14 (d, J=16.0 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 2.87 (d, J=38.3 Hz, 2H), 1.86–1.47 (m, 8H), 1.45–1.36 (m, 3H), 1.34 (s, 3H), 1.13 (s, 3H), 1.12–1.04 (m, 2H), 0.99–0.85 (m, 3H), 0.82 (s, 3H), 0.75 (s, 6H). 2.14 (2R,8aS)-1-((R,E)-5-(3,5-dimethylphenyl)-3-hydroxy-3-methylpent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol Under flowing N2, arylboronic acid or aryl iodide (1.5 equiv), Pd(OAc)2 (10 mol %), Cu(OAc)2 (2 equiv) and KOAc (3 equiv), and sclareol (0.5 g, 1 equiv) are added to a round bottom flask. Dimethylformamide (DMF) was added, and the flask sealed. The resulting stirring solution was heated in an oil bath at 80 °C for 3-6 h. The reaction was cooled to rt, diluted with water and extracted with ethyl acetate (3x 15 mL). The combined organic layer was washed with NaOH solution (10%, aqueous), water, and brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified on silica yielding the product as a white powder (0.4966 g, 74 %).46,47 1H NMR (400 MHz, CDCl3) δ 7.01 (s, 2H), 6.86 (s, 1H), 6.57 (dd, J=16.0, 4.2 Hz, 1H), 6.25 (dd, J=25.2, 16.0 Hz, 1H), 3.60 (brds, 1H), 2.82 (brds, 1H), 2.30 (s, 6H), 1.91–1.74 (m, 2H), 1.72–1.52 (m, 5H), 1.48–1.38 (m, 3H), 1.36 (s, 3H), 1.31–1.22 (m, 2H), 1.18 (s, 3H), 1.17–1.08 (m, 2H), 0.99–0.89 (m, 2H), 0.89 (s, 3H), 0.80 (s, 3H), 0.79 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 138.2, 137.9, 137.4, 129.0, 44  126.4, 124.5, 74.9, 73.5, 61.7, 56.2, 45.4, 44.3, 42.1, 39.8, 39.4, 39.3, 33.5, 33.3, 26.9, 24.2, 21.6, 21.4, 20.6, 19.1, 18.6, 15.5. Ref: KS02-91-02 NaOH wash 2.15 (2R,8aS)-1-((R,E)-3-hydroxy-3-methyl-5-(4-nitrophenyl)pent-4-en-1-yl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol 1H NMR (300 MHz, CDCl3) δ 8.16 (dd, J=9.0, 2.1 Hz, 2H), 7.53–7.46 (m, 2H), 6.70 (d, J=16.0 Hz, 1H), 6.46 (d, J=16.0 Hz, 1H), 2.09 (s, 2H), 1.78 (dd, J=15.2, 7.7 Hz, 4H), 1.70–1.48 (m, 6H), 1.38 (s, 3H), 1.16 (s, 3H), 0.85 (s, 3H), 0.78 (s, 6H). 2.16 methyl 2-((3R,E)-3-hydroxy-5-((2R,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)-3-methylpent-1-en-1-yl)benzoate 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 6.68 (d, J=16.0 Hz, 1H), 6.45 (d, J=16.0 Hz, 1H), 2.02 (s, 1H), 1.91–1.67 (m, 3H), 1.66–1.45 (m, 6H), 1.45–1.37 (m, 3H), 1.35 (s, 3H), 1.24 (d, J=2.3 Hz, 3H), 1.14 (s, 3H), 1.14–1.06 (m, 2H), 0.98–0.85 (m, 2H), 0.83 (s, 3H), 0.75 (s, 6H).        45  4-hydroxy-3-iodobenzoic acid 1H NMR (300 MHz, Acetone) δ 9.63 (brds, 2H), 8.41 (d, J=1.9 Hz, 1H), 7.93 (dd, J=8.5, 2.0 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H). Ref KS04-01-crd  3-iodo-4-methoxybenzonitrile Powdered I2 (1.20 g) and NaIO4 (0.34 g, 1.59 mmol) were added portionwise to 95% H2SO4 (30 mL). The mixture was stirred for 30 minutes at rt to give a dark brown solution with an I+ intermediate. 4-Methoxybenzonitrile (1 g, 7.5 mmol) was added in one portion to the brown solution. The resulting mixture was stirred 1 hour at room temperature. The reaction was slowly poured onto stirred ice water (300 g). The crude solid products were collected by filtration, washed with cold water, and dried in vacuo, giving an off white solid (0.60 g, 31%). 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=2.2 Hz, 1H), 7.82 (dd, J=8.6, 2.2 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 3.92 (s, 3H). Ref KS03-19-crd 4.3 Route to makassaric acid via a β-ketoester intermediate Mixture of 1.5a and 1.5b ((+)-8α-Hydroxy-14,15-bisnorlabda-13-one) This procedure was done as according to literature. To a stirring solution of sclareol (32.64 g, 0.105 mol) in acetone (400 mL) at 0 °C, potassium permanganate (58 g, 0.37 mol) was addedin portions over 2 h. The mixture was stirred overnight at rt. Solids were filtered off with copious washing with acetone. The filtrate was removed in vacuo giving a white powder, which was used without further purification (19.29 g, 65%). m.p.=78 °C. MS (EI) m/z: 262.3 (M+). IR: 2924, 1711, 1682, 1451, 1376 cm-1 Ref: KS01-14-crd.34   46  1.6 ((+)-14,15-Bisnorlabda-8-ene-13-one)  Iodine (0.118 g, mmol) was added to a stirring solution of 1.5a and 1.5b (14.3 g, mmol) in toluene (300 mL). The mixture was refluxed for 3 h, with water being removed via an attached Dean Stark trap. The reaction was cooled to rt and diluted with ethyl acetate (200 mL). The organic layer was washed with Na2S2O3 (3 x 20 mL), water (3 x 20 mL), and then brine (3 x 20 mL). The organic layer was dried with MgSO4, and concentrated in vacuo to yield a yellow liquid. This was purified by column chromatography (18: 1 hexane : ethyl acetate), to yield a yellow oil (8.32 g, 58 %). IR: 2927, 1713, 1663, 1453 cm-1.1H NMR (300 MHz, CDCl3) δ 2.53–2.42 (m, 2H), 2.42–2.15 (m, 1H), 2.13 (s, 3H), 1.96 (d, J=6.5 Hz, 1H), 1.78 (d, J=12.6 Hz, 1H), 1.68–1.56 (m, 3H), 1.53 (s, 3H), 1.45–1.35 (m, 3H), 1.11 (d, J=1.9 Hz, 1H), 1.07 (d, J=1.7 Hz, 1H), 1.00 (m, 1H), 0.94 (s, 3H), 0.88 (s, 3H), 0.82 (s, 3H). Ref: KS01-24-01.34 2.17 methyl 3-oxo-5-((4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)pentanoate Sodium hydride (60 % in mineral oil, 0.242 g, 10.1 mmol) was added to a stirring solution of 1.6 (0.706g, 2.66 mmol) in toluene (5 mL). The resulting mixture was stirred for 5 minutes. Dimethyl carbonate (0.6 mL, 4.77 mmol) was added to the mixture of sodium hydride and 1.6. The resulting mixture was stirred at 100 °C for 4 h. The mixture was allowed to cool to room temperature. 3 mL of water was added to the mixture, which was then extracted with diethyl ether (2 x 5 mL). The organic layers were combined and dried over MgSO4, and solvent was then removed in vacuo to yield a yellow oil, which was purified by column chromatography (12 : 1 hexane : ethyl acetate), to give a yellow oil (0.37 g, 44 %). 1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 3.37 (s, 1H), 2.58–2.48 (m, 1H), 1.47 (s, 3H), 0.88 (s, 3H), 0.80 (s, 3H), 0.76 (s, 3H).13C NMR (101 MHz, CDCl3) δ 202.4, 167.6, 138.9, 126.8, 52.2, 47  51.9, 48.9, 43.8, 41.7, 39.0, 36.9, 33.6, 33.3, 21.7, 21.6, 21.3, 19.9, 19.3, 19.0. IR: 2933, 1718, 1655, 1230 cm-1.Ref: KS01-31-0348 2.18 methyl (1S,4bS,8aS,10aR)-4b,8,8,10a-tetramethyl-2-oxotetradecahydrophenanthrene-1-carboxylate Tin tetrachloride (0.2 mL, 1.1 mmol) was added to a stirring solution of 2.17 (0.35 g, 1.1 mmol) in DCM (5 mL) at -78 °C. The mixture was warmed to rt and was then stirred for 12 h. The reaction mixture was diluted with diethyl ether (20 mL), washed with 2M HCl (2 x 10 mL), water (1 x 10 mL), and brine (1 x 10 mL). The organic layer was dried over MgSO4 and solvent was removed in vacuo, yielding an off-white solid. The solid was purified by column chromatography (2 : 1 DCM : hexane), yielding the product as white needle-like crystals (0.151 g, 43 %). m.p.=168 °C. 1H NMR (300 MHz, CDCl3) δ 3.69 (s, 3H), 3.25 (s, 1H), 2.49 (ddd, J=14.4, 5.4, 1.8 Hz, 1H), 2.38–2.23 (m, 1H), 1.99 (dd, J=6.4, 4.0 Hz, 1H), 1.86–1.34 (m, 13H), 1.18 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.84 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 205.5, 168.6, 70.0, 57.9, 56.6, 51.4, 42.6, 41.9, 40.8, 40.4, 40.1, 38.0, 33.4, 33.2, 21.9, 21.5, 18.4, 18.4, 16.1, 15.5. ESIHRMS: Mass calculated for C20H32O3: 320.2351; found: 320.2362. IR: 2937, 1741, 1715, 1192 cm-1.Ref: KS03-37-0148 2.19 (methyl 3-methylbenzoate) 3-methylbenzoic aicd (1.00 g) was dissolved in dry MeOH (20 mL). Concentrated H2SO4 (6 drops, 95%) was added to this solution. The solution was stirred at reflux overnight, cooled to rt. Solvent was removed in vacuo, yielding an oily residue. This residue was dissolved in water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over MgSO4, filtered, and solvent was removed in vacuo to yield a colourless liquid that was used without further purification. (1.00 g, 91%). 1H NMR (300 MHz, CDCl3) δ 48  7.85 (dd, J=5.6, 4.9 Hz, 2H), 7.34 (dt, J=15.0, 7.5 Hz, 2H), 3.91 (s, 3H), 2.40 (s, 3H). Ref: KS01-63-crd 2.20 (1-methoxy-2-methylbenzene) A solution of o-cresol (1.00 g, 9.25 mmol), potassium carbonate (2.12 g, 13.8 mmol), and methyl iodide (1.97 g, 13.8 mmol) in DMF (30 mL) was stirred overnight at rt. Solids were filtered off the mixture and washed with diethyl ether. The filtrate was neutralized with 1 M HCl (15 mL) and extracted with 2 x 10 mL diethyl ether. The combined organic layers were washed with brine, dried with MgSO4 and solvent was removed in vacuo, yielding a colourless oil. (0.46 g, 41%). 1H NMR (300 MHz, CDCl3) δ 7.16 (dd, J=13.2, 7.2 Hz, 2H), 6.86 (dd, J=12.6, 7.7 Hz, 2H), 3.84 (s, 3H), 2.23 (s, 3H). KS01-95-0153 2.21 (methyl 4-methoxy-3-methylbenzoate) Potassium carbonate (1.44 g, 10.4 mmol) was added to a stirring solution of 4-hydroxy benzoic acid (0.719 g, 5.2 mmol) in DMF. The resulting mixture was stirred at rt for 20 min. Methyl iodide (3 mL, 52 mmol) was added. After 3 h, the reaction was diluted with ethyl acetate and washed with water several times. The organic layer was dried with MgSO4 and concentrated in vacuo, yielding a crude white powder that was used in the next step without further purification (0.8519 g, 88%). 1H NMR (300 MHz, CD3CN) δ 7.87 (dd, J=8.6, 2.1 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 2.23 (s, 3H). KS02-12-crd53 2.22 (methyl 3-(bromomethyl)benzoate) N-bromosuccinimide (0.701 g, 3.9 mmol) and AIBN (16 mg, 0.1 mmol) were added to a stirring solution of methyl 4-methoxy-3-methylbenzoate (0.58 g, 3.9 mmol) in benzene. The resulting reaction mixture was stirred at 80 °C for 6 h. The reaction was cooled, 49  diluted with DCM and washed with saturated NaHCO3 (2 x 15 mL) and water (1 x 15 mL). The organic fraction was dried over MgSO4, filtered, and solvent was removed in vacuo, yielding a white powder that was used without further purification. (0.82 g, 92%).49 1H NMR (300 MHz, CDCl3) δ 8.07 (brds, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.59 (d, J=7.7 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 4.52 (s, 2H), 3.93 (s, 3H). Ref: KS01-90-0154 2.23 (1-(bromomethyl)-2-methoxybenzene) A solution of 2-methyl anisole (0.464 g, 3.8 mmol ), N-bromosuccinimide (NBS) (0.676 g, 3.8 mmol) and Azobisisobutyronitrile (AIBN) (0.012 g, 2 mol %) in carbon tetrachloride (CCl4) (15 mL) was heated to reflux for 1 hour until a white solid was observed floating on the surface. The mixture was filtered, and the filtrate was concentrated in vacuo to produce a residue, which was recrystallized in hexanes to afford a white solid.(0.665 g, 87%) 1H NMR (300 MHz, CDCl3) δ 7.36–7.28 (m, 1H), 6.97–6.85 (m, 2H), 4.58 (s, 2H), 3.90 (s, 3H).49 Ref: KS02-02-crd  2.24 (methyl 3-(bromomethyl)-4-methoxybenzoate) N-bromosuccinimide (0.812 g ,1.1 equiv) and AIBN (0.04g, 5 mol%) were added to a stirring solution of methyl 4-methoxy-3-methylbenzoate (0.75g, 1 equiv) in benzene (30 mL). The resulting reaction mixture was heated to 80 °C and stirred for 6 h. The reaction was cooled, diluted with DCM and washed with saturated sodium carbonate solution, water. The organic fraction was dried with MgSO4, filtered, and solvent was removed in vacuo, yielding an off-white powder that was used without further purification (1.05 g, 98%). 1H NMR (300 MHz, CDCl3) δ 8.05–7.98 (m, 2H), 6.91 (d, J=8.5 Hz, 1H), 4.55 (s, 2H), 3.96 (s, 3H), 3.89 (s, 3H). Ref KS02-13-crd49 50  2.25 methyl (4aR,4bS,8aS,10aR)-1-allyl-4b,8,8,10a-tetramethyl-2-oxotetradecahydrophenanthrene-1-carboxylate Cesium carbonate (0.154 g, 0.5 mmol) and allyl bromide (0.053 g, 0.6 mmol) were added to a stirring solution of 2.18 (0.108 g, 0.3 mmol) in 1.5 mL of THF. The mixture was stirred at 60 °C for 12 h. The mixture was cooled to room temperature and water (1 x 5 mL) was added. The mixture was extracted with ethyl acetate (3 x 5mL) and the combined organic layers were dried over MgSO4. Solvent was removed in vacuo and the resulting oily residue was purified by column chromatography on silica gel with an eluent composition of 10 hexane : 1 ethyl acetate. (18 mg, 15 %) 1H NMR (300 MHz, CDCl3) δ 5.87 (ddd, J=22.3, 10.4, 5.1 Hz, 1H), 5.28 (dd, J=17.2, 1.7 Hz, 1H), 5.15 (dd, J=10.5, 1.5 Hz, 1H), 4.27–4.21 (m, 2H), 3.71 (s, 3H), 2.33–2.12 (m, 2H), 1.83–1.56 (m, 4H), 1.54 (s, 3H), 1.46–1.33 (m, 4H), 1.21 (s, 3H), 1.20–1.08 (m, 3H), 1.00–0.86 (m, 3H), 0.84 (d, J=2.1 Hz, 3H), 0.81 (s, 3H). ESIMS m/z: 383.3 (M+Na)+. Ref: KS01-48-0150 2.26 3-(((4aR,4bS,8aS,10aR)-1-(methoxycarbonyl)-4b,8,8,10a-tetramethyl-2-oxotetradecahydrophenanthren-1-yl)methyl)benzoic acid Cesium carbonate (0.160 g, 0.6 mmol), 2.22 (0.162 g, 0.8 mmol), and potassium iodide (0.09g, 0.4 mmol) were added to a stirring solution of 2.18 (0.102 g, 0.4 mmol) in 3.5 mL of THF. The mixture was stirred at 60 °C for 12 h. The mixture was cooled to room temperature, and water (1 x5 mL) was added. The mixture was extracted with ethyl acetate (3 x 5 mL) and the combined layers were dried over MgSO4. The mixture was filtered and solvent removed in vacuo. The resulting oily residue was added to a mixture of water (0.5 mL), methanol (3 mL) and KOH (0.07g, 1.7 mmol). The mixture was stirred for 12 h at room temperature. The basic mixture was extracted with ethyl 51  acetate (3 x 5 mL), acidified with HCl (1 M, 10 mL), and the acidified aqueous layer was extracted again with ethyl acetate (3 x 5 mL). The combined organic layers extracted from the acidified aqueous layer were dried over MgSO4, filtered, and solvent was removed in vacuo. The crude oily product was purified by column chromatography on silica gel with an eluent composition of 9:1 hexanes: ethyl acetate (1% AcOH). The compound was purified as a clear oil (3 mg, trace yield). 1H NMR (300 MHz, CDCl3) δ 8.06–7.99 (m, 2H), 7.61–7.53 (m, 1H), 7.50–7.41 (m, 1H), 4.86 (d, J=12.0 Hz, 1H), 4.81 (d, J=12.0 Hz, 1H), 3.72 (s, 3H), 1.26 (s, 3H), 1.23 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.81 (s, 3H). KS01-105-01-01 2.27 (4aR,4bS,8aS,10aR)-1-(2-methoxy-5-(methoxycarbonyl)benzyl)-4b,8,8,10a-tetramethyl-2-oxotetradecahydrophenanthrene-1-carboxylic acid  β-ketoester 2.6 (0.15g, 0.46 mmol) was dissolved in THF (4 mL). Cesium carbonate (0.239 g, 0.7 mmol) was added to this stirring solution, followed by 2.24 (0.247 g, 0.94 mmol). The solution was stirred at reflux overnight. The mixture was cooled, diluted with ethyl acetate (10 mL) and filtered to remove excess cesium carbonate. The filtrate was concentrated in vacuo and purified by column chromatography (8 : 2 benzene : diethyl ether). 1H NMR (300 MHz, CDCl3) δ 8.05–7.98 (m, 2H), 6.91 (d, J=8.5 Hz, 1H), 4.55 (s, 2H), 3.96 (s, 3H), 3.89 (s, 3H), 2.43–2.34 (m, 1H), 2.27 (dd, J=13.7, 7.2 Hz, 1H), 2.03–1.91 (m, 2H), 1.73 (d, J=13.5 Hz, 2H), 1.67–1.59 (m, 3H), 1.56 (s, 3H), 1.48–1.33 (m, 6H), 1.18 (m, 2H), 0.90 (s, 3H), 0.88 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 211.8, 166.4, 161.1, 132.5, 132.2, 126.2, 122.6, 110.5, 59.9, 56.9, 56.7, 55.9, 52.0, 43.2, 42.0, 41.5, 40.1, 33.5, 28.0, 22.0, 21.6, 20.5, 18.6, 18.6, 15.9. ESIMS m/z (M+Na+)+ calcd for C30H42O6Na: 521.29; found 521.3.  It is suspected that this compound reformed the methyl ester in the conditions of the ESI MS (solvent used for MS is methanol) Ref KS02-19-03 52  2.28 methyl (4aR,4bS,8aS,10aR)-1-(2-methoxy-5-(methoxycarbonyl)benzyl)-4b,8,8,10a-tetramethyl-2-oxotetradecahydrophenanthrene-1-carboxylate  β-ketoester 2.6 (0.07g, 0.21 mmol) was dissolved in DMF (1mL). Cesium carbonate (0.107g, 0.33 mmol) was added to this stirring solution, followed by 2.24 (0.057g, 0.218 mmol), as well as a catalytic amount of tetrabutyl ammonium iodide (TBAI) (5 mg). The reaction was run for 3 h at 60 °C, quenched with water and diluted with ethyl acetate. This mixture was washed with water (3 x 10 mL), brine (1 x 10 mL), and solvent was removed yielding a crude residue (0.2 g) To analyze the distribution of products, the reaction mixture was analyzed by prep TLC, with a solvent mixture of 9 hexanes : 1 Ethyl acetate. 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J=2.0 Hz, 1H), 7.99 (dd, J=8.7, 2.1 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 4.86 (d, J=12.9 Hz, 1H), 4.78 (d, J=12.9 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 3.75 (s, 3H), 2.47–2.21 (m, 2H), 1.86–1.60 (m, 6H), 1.54–1.30 (m, 6H), 1.25 (s, 3H), 1.16 (t, J=11.8 Hz, 2H), 0.87 (s, 3H), 0.86 (s, 3H), 0.83 (s, 3H). Ref: KS02-30-01 2.29 (4aS,4bS,8aS,10aS)-4b,8,8,10a-tetramethyldodecahydrophenanthren-2(1H)-one  Compound 2.18 (0.2 g) and KOH (0.1 g) were added to a mixture of MeOH (2.5 mL) and water (0.5 mL). The mixture was stirred overnight at 70 °C. The mixture was cooled to rt and MeOH was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water (1 x 5 mL) followed by brine (1 x 5 mL). The organic layer was dried using MgSO4 and solvent was removed under vacuum to yield the product as a white powder (0.14 g, 87%). 1H NMR (300 MHz, CDCl3) δ 2.44–2.33 (m, 1H), 2.27 (dd, J=12.9, 7.2 Hz, 1H), 2.15 (d, J=13.2 Hz, 1H), 1.97 (dd, J=13.1, 2.4 Hz, 2H), 1.78–1.60 (m, 6H), 1.49–1.30 53  (m, 5H), 1.30–1.10 (m, 2H), 0.90 (s, 3H), 0.89 (s, 3H), 0.86 (s, 3H), 0.83 (s, 3H). ESIMS: Mass calcd for C18H30NaO: 285.22; found: 285.3 Ref: KS01-103-crd 2.30 (4bS,10aS)-2-benzyl-4b,8,8,10a-tetramethyltetradecahydrophenanthren-2-ol Diethyl ether (1mL) was poured over magnesium turnings (20 mg) in a round bottom flask. The flask was flushed with nitrogen and a single iodine crystal was added to activate the turnings. A solution of benzyl bromide (0.034 mL, .28 mmol) in diethyl ether (0.5 mL) was added to dropwise to this solution, and the mixture was refluxed for 1 hour. A solution of ketone (KS01-103-crd) (0.0301 g, 0.19 mmol) in diethyl ether (0.5 mL) was added dropwise, and the mixture was heated to reflux for another 2 h. The mixture was cooled to rt. Next 5 % aqueous HCl (10 mL) was added to the reaction vessel. The quenched reaction was extracted with diethyl ether (3 x10 mL). The combined organic layers were dried over MgSO4, solvent was removed in vacuo and the product was purified with flash chromatography using 8 : 2 hexane : EtOAc as an eluent. The product was obtained as a white solid (0.0159 g, 23 %) 1H NMR (300 MHz, CDCl3) δ 7.34–7.27 (m, 2H), 7.25–7.13 (m, 3H), 2.65 (s, 2H), 1.73–1.09 (m, 15H), 1.07 (s, 3H), 1.03–0.87 (m, 1H), 0.85 (s, 3H), 0.84–0.83 (m, 1H), 0.81 (s, 3H), 0.81 (s, 3H), 0.76 (s, 2H). ESIHRMS m/z: (M+Na+)+ calcd for C25H38ONa: 377.2820; found 377.2817. Ref: KS02-10-0255 4.4 Miscellaneous work (4aS,4bR,12bR)-1,1,4a,6a,12b-pentamethyl-2,3,4,4a,4b,5,6,6a,12,12a,12b,13,14,14a-tetradecahydro-1H-naphtho[2,1-a]xanthene To a solution of rac BINOL(78.1 mg, 0.272 mmol) in distilled DCM (4 mL) was added neat tin tetrachloride (36.5 uL, 0.272 mmol) at -78 °C under argon. The mixture was stirred for several minutes, the phenol-sclareol 54  derivative(50 mg, 0.136 mmol) was added dropwise at -78 °C. After stirring for 2 h at -78 °C, pyridine (0.1 equivalents) was added. The mixture was poured onto a saturated NaHCO3 solution and extracted with ether. The combined organic layers were dried using MgSO4, concentrated by rotary evaporation. The crude product obtained following rotary evaporation was purified by column chromatography, with an elution gradient from hexanes to 8: 2 hexane : ethyl acetate, yielding the purified product as a clear oil (13.8 mg, 28 %). This reaction yielded a mixture of products. ESIHRMS: Mass calcd for C26H38O: 366.2923; found: 366.2933. 1H NMR (400 MHz, CDCl3) δ 7.06 (dd, J=15.9, 7.7 Hz, 2H), 6.85–6.71 (m, 2H), 2.80 –2.74 (m, 2H), 1.57 (s, 2H), 1.46 (s, 2H), 1.33–1.30 (m, 3H), 0.94 (s, 3H), 0.88–0.85 (m, J=3.6 Hz, 3H), 0.84–0.81 (m, 3H). Ref: KS02-57-0156,57 Mix of alkenes 2-(((4aS,4bS,10aS)-2,4b,8,8,10a-pentamethyl-1,4,4a,4b,5,6,7,8,8a,9,10,10a-dodecahydrophenanthren-1-yl)methyl)phenol A solution of BCl3 (2 M in DCM, 0.09 mL, 0.18 mmol, 6 equiv) was added dropwise to a stirring solution of KS02-57-02 (0.0113 g, 0.03 mmol) in DCM (2 mL) at -78 °C. The resulting solution was stirred for 1 hour at -78 °C, warmed to 0 °C and stirred for 2 h, quenched by the addition of water (5 mL). The crude product was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with acidic brine (10 mL), dried with MgSO4 and filtered. Solvent was removed in vacuo, yielding a clear oil composed of a mixture of alkenes. (6.7 mg, 59%) IR: broad 3310, 2940, 1016, 832, 696, 751 cm-1.Ref: KS02-61-crd58   55  2-methyl-1,3-cyclohexanedione  1,3-cyclohexanedione (8 g, 71 mmol) was dissolved in 5M aqueous NaOH (15 mL, 75 mmol) at 0 °C. Upon stirring, a red/brown solution was formed. Iodomethane (9.34 mL, 150 mmol) was added to this solution in one portion. The mixture was warmed to rt and heated at 65 °C for 24 h. The mixture was cooled to rt and consisted of a red oil with beige/white solid. The solid was filtered and washed with petrol and a small amount of cold water until a pale beige solid was obtained. This was dried under vacuum to yield 2-methyl-1,3-cyclohexanedione. 1H NMR (300 MHz, Acetone) δ 2.37 (t, J=6.3 Hz, 4H), 1.90 (quin, J=6.4 Hz, 2H), 1.65 (s, 3H). Ref: KS04-03-crd 2-methylcyclohex-2-en-1-ol LiAlH4 (0.8g, 2.5 equiv) was added to a 0 °C solution of 2-methyl-1,3-cyclohexadione (1g, 7.9 mmol) in THF (0.5 M). The reaction mixture was warmed to rt and stirred for 16 h. The reaction was cooled to 0 °C and diluted with THF. This mixture was quenched successively with water (10 mL), aqueous NaOH (20 mL, 10%), and 30 mL water., The mixture was warmed to rt and stirred for 30 minutes. Next MgSO4 was added to this mixture, the solids were filtered off and the mixture was purified by distillation providing the product as a clear oil (0.4961g, 56%). 1H NMR (300 MHz, DMSO) δ 5.39 (s, 1H), 4.55 (d, J=6.2 Hz, 1H), 3.79 (d, J=4.4 Hz, 1H), 1.95–1.83 (m, J=9.7, 4.7, 2.7 Hz, 2H), 1.67 (s, 3H), 1.65–1.35 (m, 4H). 13C NMR 56  (101 MHz, CDCl3) δ 170.4, 156.3, 151.0, 132.8, 127.5, 126.5, 118.6, 115.9, 112.2, 52.5, 27.8, 25.5, 21.2, 18.0. Ref: KS03-15-crd59  methyl 2-hydroxy-5-((2-methylcyclohex-2-en-1-yl)oxy)benzoate 2,5-dihydroxybenzoic acid (513 mg, 3.05 mmol), 2-methylcyclohex-2-en-1-ol (342 mg, 3.05 mmol, triphenyl phosphine (841 mg, 3.21 mmol), and THF (1.4 mL) were all added to a round bottom flask. The flask was lowered into a sonication bath and sonicated for several minutes. While sonicating, diisopropylazodicarboxylate (DIAD) (0.631 mL, 3.21 mmol) was added dropwise to the reaction mixture over the course of 2 minutes. Upon addition of DIAD, this previously clear mixture turned an amber color. This mixture was sonicated for another 15 minutes. Following this, the mixture was triturated with 3 mL hexanes to remove excess triphenyl phosphine, and the mixture was purified by flash chromatography (9:1 Hexanes : Ethyl Acetate) to yield the product as white powder (162 mg, 23%) 1H NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 7.38 (d, J=3.1 Hz, 1H), 7.13 (dd, J=3.1 Hz, 1H), 6.91 (d, J=1H), 5.72 (s, 1H), 4.43 (s, 1H), 3.95 (s, 3H), 2.11 (m, 1H), 2.03–1.92 (m, 2H), 1.81 (s, 3H), 1.76–1.65 (m, 2H), 1.62–1.53 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 170.4, 156.3, 151.0, 132.8, 127.5, 126.5, 118.6, 115.9, 112.2, 76.0, 52.5, 27.8, 25.5, 21.2, 18.0. KS03-16-0136,60 2-hydroxy-5-((2-methylcyclohex-2-en-1-yl)oxy)benzoic acid KS03-16-01 (0.162g) was added to a solution of methanol (3 mL), water (1mL) and potassium hydroxide (0.825g). This mixture was stirred for one hour at rt. After stirring, the mixture was treated with 1 M HCl (10 mL), extracted with 3 x 5 mL ethyl acetate, and the combined layers were dried with MgSO4, filtered, and solvent was removed in vacuo yielding a white powder (143 mg, 93%). 1H NMR (400 MHz, 57  CDCl3) δ 9.41 (brds, 2H), 7.41 (d, J=3.0 Hz, 1H), 7.12 (dd, J=9.0, 3.1 Hz, 1H), 6.87 (d, J=9.0 Hz, 1H), 5.66 (brds, 1H), 4.39 (brds, 1H), 2.02 (s, 1H), 1.97–1.85 (m, 2H), 1.75 (s, 3H), 1.69–1.59 (m, 2H), 1.56–1.45 (m, 1H). Ref: KS03-18-crd60,61 Diallyl carbonate  Allyl alcohol (9 g, 0.78 mol), dimethylcarbonate (7 g, 0.39 mol), hexane (12.5 mL), and NaOH (0.161 g, 1 mol %) were added to this flask under flowing N2.The reaction was heated to 100 °C in an oil bath, and stirred for 3 h. The reaction was cooled to rt. The product was purified using vacuum distillation at 130 °C, yielding a clear oil (5.67g, 40%).62 1H NMR (300 MHz, CDCl3) δ 5.90 (dq, J=10.9, 5.7 Hz, 1H), 5.33 (d, J=17.2 Hz, 1H), 5.23 (d, J=10.4 Hz, 1H), 4.60 (dd, J=5.7, 0.6 Hz, 2H). Ref: KS03-71-crd62 1.17 (E)-3-methyl-5-((8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)pent-2-en-1-yl acetate Resublimed iodine (3.32g, 13.1 mmol) was added to a solution PPh3 (3.44 g, 13.1 mmol) in DCM (25 mL). The mixture was stirred at rt for 5 minutes, a solution of acetyl sclareol (5 g in 25 mL of DCM, 12.7 mmol) was added. The mixture was stirred for 8 h. Next, 50 mL of DMF and 14 g of KOAc were added to the mixture, which was stirred overnight. The crude product was washed with Na2S2O3, water and brine. The organic solvent was removed in vacuo yielding a crude that was purified by column chromatography with a gradient elution from hexanes to 7:3 hexanes to ethyl acetate. (3.5 g, 82%) 1H NMR (300 MHz, CDCl3) δ 5.31 (t, J=7.0 Hz, 1H), 4.53 (d, J=7.0 Hz, 2H), 1.99 (s, 3H), 1.96–1.72 (m, 6H), 1.68 (s, 3H), 1.64–1.54 (m, 2H), 1.52 (s, 3H), 1.48–1.18 (m, 4H), 1.18–1.02 (m, 3H), 0.89 (s, 3H), 0.83 (s, 3H), 0.78 (s, 3H).39  58  methyl 3-hydroxybenzoate 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J=7.7 Hz, 1H), 7.51 (s, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.05 (ddd, 1H), 5.42 (s, 1H), 3.91 (s, 3H). methyl 4-hydroxybenzoate 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.64 (brds, 1H), 3.89 (s, 3H).   59  Bibliography (1)  Torre, B. G. De; Albericio, F. The Pharmaceutical Industry in 2018. An Analysis of FDA Drug Approvals from the Perspective of Molecules. Molecules 2019, 24, 809–831. (2)  Mullard, A. 2018 FDA Drug Approvals. Nat. Rev. Drug Discov. 2019, 18, 85–89. (3)  Sanger, F.; Nicklen, S. DNA Sequencing with Chain-Terminating Inhibitors. Proc. Natl. Acad. Sci. 1977, 74 (12), 5463–5467. (4)  Schwarze, K.; Buchanan, J.; Fermont, J. 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Probing Sponge-Derived Terpenoids for Human 15-Lipoxygenase Inhibitors. 2001, No. 6, 5576–5580. 68  Appendix: Selected Spectra A.1 Synthesis of subersic acid derivatives 1.16    69    70  1.16   Atom # H C 1   2 1.36 42.04 3 - 33.47 4 0.97 55.79 5   6   7   8   9 - 88.12 10 2.62 38.92 11 0.82 15.90 12 0.86 33.05 13 0.77 21.11 14 1.45 58.50 15   16 Oxygen - 17 1.89 42.49 18 - 83.36 19 5.96 142.08 20 5.14 113.23 21 Oxygen - 22 1.53 39.29 23 - 170.40 24 Oxygen - 25 1.93 23.04 26 - 169.99 27 1.99 22.36 28 Oxygen -    71  2.1     72  2.2  1H NMR shifts for 2.2 (ppm) 1H NMR shifts for subersic acid (ppm)63 7.11 (d, J=7.4 Hz, 2H) 7.91 (s, 2H) 6.85 (dd, J=18.9, 7.7 Hz, 2H) 6.86 (d, J=10 Hz, 1H) 5.35 (t, J=6.7 Hz, 1H) 5.36 (t, J  5 Hz, 1H) 3.37 (d, J=7.0 Hz, 2H) 3.42 (d, J 10 Hz, 2H) 2.33–1.86 (m, 6H) 2.14 (m, 2H) - 2.12 (m, 2H) - 2.09 (m, 2H) 1.64 (m, 1H) 1.83 (m, 1H) 1.81 (s, 3H) 1.83 (s, 3H) 1.64 (m, 1H), 1.51–1.35 (m, 3H) 1.62 (m, 4H) 1.57 (s, 3H) 1.58 (s, 3H) 1.13 (m, 3H) 1.17 (m, 1H) - 1.14 (m, 2H) 0.94 (s, 3H) 0.95 (s, 3H) 0.88 (s, 3H) 0.89 (s, 3H) 0.83 (s, 3H) 0.84 (s, 3H)           73  2.2  13C NMR shifts for 2.2 (ppm) 13C NMR shifts for subersic acid (ppm)63 - 171.7 154.6 159.8 140.3 141.0 139.7 132.9 130.1 130.8 127.7 127.0 126.9 126.3 126.1 121.9 121.1 120.3 115.9 116.0 52.0 52.1 42.0 42.1 33.8 33.6 33.5 33.6 29.9 29.9 27.3 27.3 21.9 21.9 20.3 20.4 19.7 19.8 19.2 19.3 19.2 19.3 16.5 16.7       74  2.2    75  2.3   606570758085909510062511251625212526253125362576    77    78    79    80   Atom # 1H 13C HMBC Correlation 1 1.49, 1.16 18.6  2 2.13, 2.00 26.9  3 - 33.5  4 1.12 51.8  5 - 39.0  6 1.83, 1.18 36.5  7 1.43, 1.15 41.6  8 2.05, 1.96 33.8  9 - 126.0  10 - 140.0  11 0.95 19.6  12 0.85 21.3  13 0.90 33.4  14 1.58 19.2  15 1.65, 1.44 18.6  16 2.10 40.6  17 - 140.4  18 5.31 120.0 154.3 (4 bonds) 19 3.31 28.8 154.3 (3 bonds) 138.3 (3 bonds) 129.64 (2 bonds) 20 1.80 16.1  21 - 129.6 3.31 (2 bonds) 22 - 154.3 5.31 (4 bonds) 3.31 (3 bonds) 23 6.59 118.0  24 7.40 136.0  25 - 82.8  26 7.42 138.3 3.31 (3 bonds) 27 - -  28 Iodine Iodine   81  2.4    455565758595625112516252125262531253625Chart Title82     83  2.5   5055606570758085909510062511251625212526253125362584    85  86         87   Atom # 1H 13C 1 1.66,1.50 19.0 2 2.16, 2.03 26.7 3 - 42.0 4 1.14 52.2 5 - 39.3 6 1.84, 1.19 37.1 7 1.42, 1.17 41.9 8 2.05, 1.97 33.9 9 - 126.4 10 - 140.1 11 0.95 20.0 12 0.83 21.8 13 0.88 33.6 14 1.58 19.7 15 2.13 40.4 16 1.84,1.19 37.1 17 - 143.2 18 5.53 118.6 19 4.62 65.4 20 1.78 17.1 21 Oxygen - 22 - 164.2 23 7.01 115.3 24 7.83 132.3 25 - 130.0 26 7.83 132.3 27 7.01 115.3 28 - 190.8 29 Oxygen - 30 9.88 - 88  2.6     89  2.10     90  A.2 Heck cross-couplings on sclareol 2.14   91    92     93  2.14  Atom # 1H 13C 1 6.26 138.2 2 - 137.9 3 - 137.4 4 6.86 129.1 5 6.55 126.4 6 7.00 124.5 7 - 74.9 8 - 73.5 9 1.18 61.7 10 0.93 56.2 11 1.69 45.4 12 1.86 44.3 13 1.43 42.1 14 1.63 39.8 15 - 39.4 16 - 39.3 17 0.88 33.5 18 - 33.3 19 1.36 26.9 20 1.18? 24.2 21 0.80 21.6 22 2.30 21.4 23 - 20.6 24 - 19.1 25 - 18.6 26 0.79 15.5 OH 3.60 - OH 2.82 -    94  2.15     95  A.3 Route to makassaric acid via a β-ketoester intermediate 1.6            96  2.17               97  2.18     98  2.19     99  2.29     100  2.30     101  2.26     102  2.27     103  2.28      104  2.25     105  A.4 Miscellaneous work 2.31    8486889092949698100102625112516252125262531253625Chart Title106  107    108    109  2.32     50556065707580859095100625112516252125262531253625Chart Title110     111    112      113   Atom # 1H 13C 1 1.70, 1.96 27.0 2 1.96, 2.09 25.2 3 1.56, 1.70 18.0 4 5.73 127.5 5 - 132.8 6 4.43 75.9 7 Oxygen - 8 - 156.3 9 6.91 118.8 10 - 112.2 11 - 151.0 12 7.38 115.6 13 7.13 126.0 14 - 170.4 15 Oxygen - 16 Oxygen - 17 3.95 52.5 18 10.37 - 19 1.81 21.3    114  Diallyl carbonate   

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