The Fukuyama Synthesis of Gelsemoxonine

The compact and highly functionalized Gelsemium alkaloids, exemplified by gelsemine (OHL20060403) and gelsemoxonine 3, offer a substantial challenge. The cytotoxicity of closely related alkaloids adds to the interest in this class. Tohru Fukuyama of the University of Tokyo envisioned (J. Am. Chem. Soc. 2011, 133, 17634) that cyclopropane-accelerated Cope rearrangement of 1 could deliver 2, ready for further functionalization to 3. The starting material for the synthesis was the enantiomerically pure acetate 4, for which a practical synthetic route was developed. Conjugate addition of 5 then proceeded away from the acetoxy group to give, after intramolecular alkylation, the cyclopropane 6. Selective protection of the derived triol 7 led to a monopivalate that was oxidized to the keto aldehyde 8. Condensation with the oxindole 9 followed by silylation then completed the assembly of 1. The trisubstituted alkene of 1 was established as a single geometric isomer. It followed that in the product 2, the oxindole and the bridging ether had the appropriate relative stereochemical arrangement. The product silyl enol ether was deprotected with fluoride to liberate the ketone 2. With 2 in hand, the next challenge was the kinetic installation of the less stable secondary aminated stereogenic center. To this end, the aldehyde 10 was exposed to TMS-CN and DBU. Under the reaction conditions, the alkene of the intermediate β,γ-unsaturated silylated cyanohydrin was brought into conjugation. Kinetic quench with allyl alcohol gave 11 with a 4:1 preference for the desired endo diastereomer 11. Inversion of the carboxyl then led to the protected amine 12. The ketone 12 was formylated under modified Vilsmeier-Haack conditions, first with Bredereck’s reagent 13 and then with oxalyl chloride, leading to the chloro aldehyde 14. The chlorine was removed by selective Pd-catalyzed reduction, and the product aldehyde was exposed to ethyl magnesium bromide followed by IBX to give the ethyl ketone 15. Epoxidation of the α,β-unsaturated ketone proceeded across the expected exo face leading to 16. The deprotected amine then opened the epoxide to establish the aminated quaternary center and complete the synthesis of gelsemoxonine 3.

The Smith Synthesis of (−)-Nodulisporic Acid D

Organic Synthesis ◽

10.1093/oso/9780190646165.003.0103 ◽

2017 ◽

Author(s):

Douglass F. Taber

Keyword(s):

Functional Group ◽

University Of Pennsylvania ◽

Magnesium Bromide ◽

Ring Closing Metathesis ◽

Enantiomerically Pure ◽

Model Study ◽

Silyl Enol Ether ◽

Robinson Annulation ◽

The University ◽

The nodulisporic acids, isolated from the endophytic fungus Nodulisporium sp., show promising insecticidal activity. Amos B. Smith III of the University of Pennsylvania envisioned (J. Am. Chem. Soc. 2015, 137, 7095) the construction of the central indole of nodulisporic acid D 4 by the convergent coupling of the chloroaniline 1 with the enol triflate 2. The preparation of 2 began (Org. Process Res. Dev. 2007, 11, 19) with the monoketal 5 of the Wieland–Miescher ketone, available in enantiomerically-pure form by organocatalyzed Robinson annulation. Condensation with thiophenol and formaldehyde gave 6, which, under dissolving metal conditions, was reduced to an enolate that was trapped as the silyl enol ether 7. Condensation again with formaldehyde gave 8, that was converted by reduction and protecting group exchange to the ketone 9. Pd-catalyzed formylation of the derived enol triflate led to 10. The Cu-meditated conjugate addition of vinyl magnesium bromide to the unsaturated aldehyde 10 was carefully optimized to maximize equatorial addition, away from the angular methyl group. Subsequent C-methylation of the aldehyde was achieved by generating the Li enolate and carrying out the alkylation in diglyme. With 11 in hand, the third carbocyclic ring was assembled by 1,2-addition of vinylmagnesium bromide to the aldehyde followed by ring-closing metathesis and oxidation to give 12. Hydrogenation followed by functional group interconversion then completed the assembly of the enol triflate 2. The stereogenic center of 1 was established by Enders alkylation of 13 with the iodide 14. The ketone 15 was best liberated by ozonolysis under non-epimerizing conditions. The critical Barluenga indole construction that formed 3 also required careful optimization in a model study, the key observation being the value of the Buchwald ligand RuPhos. The conditions developed were found, remarkably, to be compatible with the aldehyde functional group, so subsequent Horner–Wadsworth–Emmons condensation with 16 could be carried out directly, to complete the synthesis of (−)-nodulisporic acid D 4.

The Overman Synthesis of (-)-Actinophyllic Acid

Organic Synthesis ◽

10.1093/oso/9780199965724.003.0103 ◽

2013 ◽

Author(s):

Douglass F. Taber

Keyword(s):

Selective Reduction ◽

Cope Rearrangement ◽

Magnesium Bromide ◽

Amine Hydrochloride ◽

Dimethyl Malonate ◽

Mannich Condensation ◽

Actinophyllic Acid ◽

Preliminary Study ◽

The University ◽

(-)-Actinophyllic acid 3, isolated from Alstonia actinophylla, is a promising inhibitor of TAFIa/hippicuricase (0.84 μm). Larry E. Overman of the University of California, Irvine, envisioned (J. Am. Chem. Soc. 2010, 132, 4894) a bold route to 3 based on the aza-Cope/ intramolecular Mannich reorganization of 1 to 3. The absolute configuration of 1 and thus of 3 was set by Noyori hydrogenation of the enone 4. Ozonolysis followed by acetylation delivered the pyridone 6 as an inconsequential mixture of diastereomers. The ketone 9 was assembled by condensation of dimethyl malonate 8 with the acid chloride 7. Cyclization then followed directly on reduction of the nitro group to the amine, to give the crystalline indole 10. Under Lewis acid catalysis, 10 coupled smoothly with the diacetate 6, to give 11 . Selective reduction of the acetate was followed by oxidation, leading to 12. The ketone 12 has only a single acidic stereogenic center. It was not clear whether it could be cyclized without epimerization. A preliminary study with material resolved by enantioselective chromatography, however, showed that this in fact worked well. The LDA kinetically deprotonated the ketone away from the N, at the same time deprotonating the malonate, to give a dianion that underwent smooth oxidative coupling to 13. With 13 in hand, it remained to differentiate the two esters derived from the malonate. This was succinctly accomplished by the addition of vinyl magnesium bromide. Selective reduction of the spontaneously formed lactone 14 cleanly delivered 1. The topological connection between 1 and 3 is not necessarily obvious. Exposure of 1 to HCl gave the amine hydrochloride. Condensation with formaldehyde then gave 15, poised for aza-Cope rearrangement to 2. The enol 2 , then, proceeded via intramolecular Mannich condensation directly to (-)-actinophyllic acid 3.

The Toste Synthesis of ( + )-Fawcettimine

Organic Synthesis ◽

10.1093/oso/9780199764549.003.0091 ◽

2011 ◽

Author(s):

Douglass Taber

Keyword(s):

Current Method ◽

Conjugate Addition ◽

Enantioselective Synthesis ◽

University Of California ◽

Lycopodium Alkaloid ◽

Silyl Enol Ether ◽

Terminal Alkene ◽

Robinson Annulation ◽

The University ◽

The tetracyclic Lycopodium alkaloid fawcettimine 3 and its derivatives are of interest as inhibitors of acetylcholine esterase. F. Dean Toste of the University of California, Berkeley recently reported (Angew. Chem. Int. Ed. 2007, 46, 7671) the first enantioselective synthesis of 3. The key to the synthesis was the rapid assembly of the enantiomerically-enriched hydrindane 2. The preparation of 2 began with the enantioselective Robinson annulation of the β-keto ester 4 with crotonaldehyde 5, mediated by the organocatalyst 6. In this protocol, originally developed by Karl Anker Jørgensen, the single stereogenic center was established by conjugate addition, presumably to the chiral iminium salt generated by the condensation of 5 with 6. Subsequent aldol (or more likely Mannich) cyclization followed by elimination gave 7. Hydrolysis and decarboxylation by heating with p-TsOH converted 7 to 1. This procedure was robust enough to allow preparation of a ten gram batch of 1. This Jørgensen annulation is the current method of choice for the enantioselective preparation of 2,5-dialkyl cyclohexenones. Conjugate addition of the propargyl anion equivalent 8 to 1 proceeded with the expected > 95:5 axial diastereoselectivity, to give the silyl enol ether 9. Exposure of the derived iodide 10 to catalytic [Ph3 PAu]Cl and AgBF4 induced smooth cyclization to the cis hydrindane 2. Before constructing the nine-membered ring amine of fawcettimine 3, it was first necessary to protect the ketone as the ketal. Pd-mediated coupling of the alkenyl iodide with the organoborane derived from 11 then proceeded smoothly, as did the subsequent hydroboration of the terminal alkene. Neither the mesylate nor the tosylate derived from 12 could be induced to cyclize. In contrast, intramolecular displacement of the iodide proceeded well, to give 13. Hydroboration followed by oxidation then gave 15, which on deprotection cyclized to (+)-fawcettimine 3. Several aspects of this synthesis are attractive. While the stereochemical outcome of the hydroboration of 14 could not necessarily be predicted with confidence, in fact it did not matter, as the stereogenic center adjacent to the ketone could be epimerized under the trifluoroacetic acid deprotection conditions, and only the desired diastereomer would be able to add in an intramolecular fashion to the cyclohexanone.

Enantioselective Assembly of Alkylated Stereogenic Centers

Organic Synthesis ◽

10.1093/oso/9780199764549.003.0037 ◽

2011 ◽

Author(s):

Douglass Taber

Keyword(s):

Limited Range ◽

Geometric Isomer ◽

High Yield ◽

Enantioselective Reduction ◽

Carbon Nucleophiles ◽

Princeton University ◽

University Of Wisconsin ◽

Silyl Enol Ether ◽

Stereogenic Centers ◽

Oxygenated secondary stereogenic centers are readily available. There is a limited range of carbon nucleophiles that will displace a secondary leaving group in high yield with clean inversion. Teruaki Mukaiyama of the Kitasato Institute has described (Chem. Lett. 2007, 36, 2) an elegant addition to this list. Phosphinites such as 1 are easily prepared from the corresponding alcohols. Quinone oxidation in the presence of a nucleophile led via efﬁcient displacement to the coupled product 2. The sulfone could be reduced with SmI2 to give 3. Enantioselective reduction of trisubstituted alkenes is also a powerful method for establishing alkylated stereogenic centers. Juan C. Carretero of the Universidad Autonoma de Madrid has found (Angew. Chem. Int. Ed. 2007, 46, 3329) that the enantioselective reduction of unsaturated pyridyl sulfones such as 4 was directed by the sulfone, so the other geometric isomer of 4 gave the opposite enantiomer of 5. The protected hydroxy sulfone 5 is a versatile chiral building block. Samuel H. Gellman of the University of Wisconsin has reported (J. Am. Chem. Soc. 2007, 129, 6050) an improved procedure for the aminomethylation of aldehydes. L-Proline-catalyzed condensation with the matched α-methyl benzylamine derivavative 7 gave the aldehyde, which was immediately reduced to the alcohol 8 to avoid racemization. The amino alcohol 8 was easily separated in diastereomerically-pure form. In the past, aldehydes have been efficiently α-alkylated using two-electron chemistry. David W. C. Macmillan of Princeton University has developed (Science 2007, 316, 582; J. Am. Chem. Soc. 2007, 129, 7004) a one-electron alternative. The organocatalyst 9 formed an imine with the aldehyde. One-electron oxidation led to an α-radical, which was trapped by the allyl silane (or, not pictured, a silyl enol ether) leading to the α-alkylated aldehyde 10. This is mechnistically related to the work reported independently by Mukund P. Sibi (J. Am. Chem. Soc. 2007, 129, 4124; OHL Feb. 11, 2008) on one-electron α-oxygenation of aldehydes. Secondary alkylated centers can also be prepared by SN2’ alkylation of prochiral substrates such as 11. Ben L. Feringa of the University of Groningen has shown (J. Org. Chem. 2007, 72, 2558) that the displacement proceeded with high ee even with conventional Grignard reagents.

Diels-Alder Cycloaddition: (+)-Armillarivin (Banwell), Gelsemiol (Gademann), (+)-Frullanolide (Liao), Myceliothermophin A (Uchiro), Peribysin E (Reddy), Caribenol A (Li/Yang)

Organic Synthesis ◽

10.1093/oso/9780190200794.003.0081 ◽

2015 ◽

Author(s):

Douglass F. Taber

Keyword(s):

Elevated Pressure ◽

Diels Alder ◽

Cope Rearrangement ◽

National Chemical Laboratory ◽

Chemical Laboratory ◽

Enantiomerically Pure ◽

Peking University ◽

National University ◽

Diastereoselective Addition ◽

Martin G. Banwell of the Australian National University prepared (Org. Lett. 2013, 15, 1934) the enantiomerically pure diol 1 by fermentation of the aromatic precursor. Diels-Alder addition of cyclopentenone 2 proceeded well at elevated pressure to give 3, the precursor to (+)-armillarivin 4. Karl Gademann of the University of Basel found (Chem. Eur. J. 2013, 19, 2589) that the Diels-Alder addition of 6 to 5 proceeded best without solvent and with Cu catalysis to give 7. Reduction under free radical conditions led to gelsemiol 8. Chun-Chen Liao of the National TsingHua University carried out (Org. Lett. 2013, 15, 1584) the diastereoselective addition of 10 to 9. A later oxy-Cope rearrangement established the octalin skeleton of (+)-frullanolide 12. D. Srinivasa Reddy of CSIR-National Chemical Laboratory devised (Org. Lett. 2013, 15, 1894) a strategy for the construction of the angularly substituted cis-fused aldehyde 15 based on Diels-Alder cycloaddition of 14 to the diene 13. Further transformation led to racemic peribysin-E 16. An effective enantioselective catalyst for dienophiles such as 14 has not yet been developed. Hiromi Uchiro of the Tokyo University of Science prepared (Tetrahedron Lett. 2012, 53, 5167) the bicyclic core of myceliothermophin A 19 by BF3•Et2O-promoted cyclization of the tetraene 17. The single ternary center of 17 mediated the formation of the three new stereogenic centers of 18, including the angular substitution. En route to caribenol A 22, Chuang-Chuang Li and Zhen Yang of the Peking University Shenzen Graduate School assembled (J. Org. Chem. 2013, 78, 5492) the triene 20 from two enantiomerically pure precursors. Inclusion of the radical inhibitor BHT sufficed to suppress competing polymerization, allowing clean cyclization to 21. Methylene blue has also been used (J. Am. Chem. Soc. 1980, 102, 5088) for this purpose.

The Nakada Synthesis of (+)-Ophiobolin A

Organic Synthesis ◽

10.1093/oso/9780190646165.003.0084 ◽

2017 ◽

Author(s):

Douglass F. Taber

Keyword(s):

Second Generation ◽

Selective Reduction ◽

Membered Ring ◽

Magnesium Bromide ◽

Enantioselective Hydrolysis ◽

Central Feature ◽

The University ◽

Stereogenic Center ◽

Hydrolysis Of ◽

Useful Yield

Ophiobolin A 3 shows nanomolar toxicity toward a range of cancer cell lines. A central feature of this sesterterpene, isolated from the rice fungus Ophiobolus miyabeanus, is the highly-substituted eight-membered ring. A key step in the synthesis of 3 described (Chem. Eur. J. 2013, 19, 5476; Angew. Chem. Int. Ed. 2011, 50, 9452) by Masahisa Nakada of Waseda University was the acid-mediated cyclization of 1 to 2. The preparation of 1 began with the enantioselective hydrolysis of 4 to the monoester 5. Selective reduction followed by protection gave 6, that was carried on via 7 to 8. The ethoxyethyl group was selectively removed, and the alcohol was converted to an iodide (not illustrated) that was condensed with the lactone 9 to give 1. The cyclization of 1 could jeopardize the stereogenic center adjacent to the masked carbonyl, so eight diastereomers were possible. Careful optimization led to a preparatively useful yield of the desired product 2. Hydroboration gave 10, that was carried on to the aldehyde 11. The cyclopentanone 15 was prepared from the enantiomerically-enriched epoxide 12. Opening with vinyl magnesium bromide followed by exposure to the second-generation Grubbs catalyst gave the diol 13, that was selectively protected, leading to 14. The derived bromohydrin was a mixture of regioisomers and diastereomers, from which, after oxidation, 15 dominated. Generation of the boron enolate from 15 in the presence of 11 gave the aldol product, that could be dehydrated with the Burgess reagent. Reduction with Raney nickel set the stereogenic center adjacent to the ketone, that was carried on to 16. Metathesis to close the eight-membered ring was not trivial. Finally, it was found that 17 could be induced to cyclize to 18 at an elevated temperature using the second-generation Hoyveda catalyst. Protecting group exchange gave 19. Routine functional group manipulation then completed the synthesis of (+)-ophiobolin 3. Some years ago, Neil E. Schore of the University of California, Davis showed (Tetrahedron Lett. 1994, 35, 1153) that the opening of Sharpless-derived epoxides such as 12 with vinyl nucleophiles was unexpectedly flexible. One set of conditions gave the expected inversion, but alternative conditions led to opening with clean retention (or double inversion) of absolute configuration.

Diels-Alder Cycloaddition: Fawcettimine (Williams), Apiosporic Acid (Helmchen), Marginatone (Abad- Somovilla), Okilactomycin (Hoye), Vinigrol (Barriault), Plakotenin (Bihlmeier/Klopper)

Organic Synthesis ◽

10.1093/oso/9780190200794.003.0079 ◽

2015 ◽

Author(s):

Douglass F. Taber

Keyword(s):

Natural Product ◽

Diels Alder ◽

State University ◽

University Of Minnesota ◽

Enantiomerically Pure ◽

Colorado State University ◽

Institute Of Technology ◽

La Jolla ◽

The University ◽

Highly substituted dienes and dienophiles are often reluctant participants in intermolecular Diels-Alder cycloaddition. Nevertheless, Robert M. Williams of Colorado State University, in the course of a synthesis of fawcettimine 4, was able (J. Org. Chem. 2012, 77, 4801) to prepare 3 by combining the enone 1 with the diene 2. Günter Helmchen of the Universität Heidelberg set (J. Org. Chem. 2012, 77, 4491) the single stereogenic center of 5 by Ir-catalyzed allylic alkylation. The Lewis acid that promoted the cycloaddition also conveniently removed the trityl protecting group, leading to 6, that was saponified to apiosporic acid 7. Antonio Abad-Somovilla of the Universidad de Valencia prepared (J. Org. Chem. 2012, 77, 5664) the triene 8 in enantiomerically pure form from carvone. Despite the additional substitution on the diene, cycloaddition proceeded smoothly to give 9, which was carried on to marginatone 10. One could envision that okilactomycin 13 could be formed by an intramolecular Diels-Alder cycloaddition. Thomas R. Hoye of the University of Minnesota observed (Org. Lett. 2012, 14, 828) that the tetraene tetronic acid corresponding to 11 was inert, but that the methyl ether 11 cyclized smoothly to 12. Demethylation then gave the natural product The complex polycyclic structure of vinigrol 16 challenged organic synthesis chemists for many years, until a route was established by Phil Baran of Scripps/La Jolla (Highlights September 6, 2010). Louis Barriault cyclized (Angew. Chem. Int. Ed. 2012, 51, 2111) 14 to 15 en route to a late intermediate in the Baran synthesis It had been hypothesized that the natural product plakotenin 19 was formed naturally from a tetraene corresponding to 17. The tetraene 17 was prepared and the cyclization was successful, “confirming” both the structure of the natural product and the biosynthetic hypothesis. Angela Bihlmeier and Wim Klopper of the Karlsruhe Institute of Technology calculated (J. Am. Chem. Soc. 2012, 134, 2154) the relative energies of the four competing transition states for the cyclization, leading to a correction of the structure of 18, and so of the natural product 19.

The Paterson Synthesis of (−)-Leiodermatolide

Organic Synthesis ◽

10.1093/oso/9780190646165.003.0096 ◽

2017 ◽

Author(s):

Douglass F. Taber

Keyword(s):

Aldol Condensation ◽

Oxidative Cleavage ◽

Magnesium Bromide ◽

Silyl Ether ◽

Enantiomerically Pure ◽

University Of Cambridge ◽

Mukaiyama Aldol ◽

Hydride Elimination ◽

Reduced Toxicity ◽

(−)-Leiodermatolide 4, isolated from the lithistid sponge Leiodermatium sp., showed 5.0-nM activity against PANC-1 pancreatic carcinoma cells, and reduced toxicity toward normal cells. Ian Paterson of the University of Cambridge established (Angew. Chem. Int. Ed. 2014, 53, 2692) a synthetic route to 4 based on sp2–sp2 coupling, as exemplified by the combination of 1 with 2 to give 3. Addition of the boron enolate of the enantiomerically-pure benzoate 5 to the iodoaldehyde 6 gave 7, that was silylated, reduced, and deprotected to give 1. Addition of the boron enolate of ent-5 to propanal gave 8. The α-acyloxy ketone of 8 served as a masked acylating agent. The addition of allyl magnesium bromide followed by oxidative cleavage led to the ketone 9. The preparation of 2 was completed by diastereoselective Mukaiyama aldol condensation of 9 with the ketene silyl acetal 10. The intramolecular Heck coupling of 1 with 2 presumably proceeded by way of the organo-Pd intermediate 11. β-Hydride elimination could have given one or more of four possible dienes, but in fact the E,E product 3 dominated, as expected. The allylic H’s are activated for elimination, while the H’s β to the silyl ether are deactivated both electronically and sterically. The third component of 4 was the stannane 17. Applying the same strategy, the addition of ent-5 to the aldehyde 12 gave 13, that was protected and condensed with 14 to deliver, after oxidative cleavage, the alkynyl ketone 15. Conjugate addition of iodide proceeded with good geometric control to give 16, that was protected and stannylated to complete the preparation of 17. The diol 3 was oxidatively cleaved, and the resulting aldehyde was carried on to the iodide 18. This was coupled with the stannane 17 to give the diene 19. A sequence of deprotection, oxidation, and further deprotection yielded a tetraol, that was lactonized with high selectivity to give the 16-membered ring of (−)-leiodermatolide 4.

Stereocontrolled Construction of Arrays of Stereogenic Centers

Organic Synthesis ◽

10.1093/oso/9780199764549.003.0041 ◽

2011 ◽

Author(s):

Douglass Taber

Keyword(s):

Aldol Condensation ◽

Simple Procedure ◽

Unsaturated Ester ◽

Magnesium Bromide ◽

National Chemical Laboratory ◽

Chemical Laboratory ◽

Enantiomerically Pure ◽

Stereogenic Centers ◽

Diastereoselective Addition ◽

Complex natural products and even some complex pharmaceuticals contain arrays of stereogenic centers. Sometimes, the desired array is readily available from a natural product, but usually, such arrays of multiple stereogenic centers must be assembled. Armando Córdova of Stockholm University has reported (Angew. Chem. Int. Ed. 2007, 46, 778) a simple procedure for the organocatalyst-mediated addition of the nitrene equivalent 2 to an α, β-unsaturated aldehyde to give the protected aziridine 4 in high ee. Organocatalysis was also used (Organic Lett. 2007, 9, 1001) by Arumugam Sudalai of the National Chemical Laboratory, Pune, to effect coupling of the aldehyde 5 with dibenzylazodicarboxylate 6 to give, following the List procedure, the intermediate aldehyde 7. Osmylation of the derived unsaturated ester 8 proceeded with high diastereocontrol, to give 9. Products 4 and 9 have adjacent stereogenic centers. Hisashi Yamamoto of the University of Chicago has introduced (J. Am. Chem. Soc. 2007, 129, 2762) the linchpin reagent acetaldehyde “super”silyl enol ether 11. Diastereoselective addition of 11 to the enantiomerically-pure aldehyde 10, with concomitant silyl transfer, followed by the addition of allyl magnesium bromide delivered the protected triol 12 in high de and ee. Arrays that combine alkylated and oxygenated or aminated centers are also important. Akio Kamimura of Yamaguchi University took (J. Org. Chem. 2007, 72, 3569) a Baylis- Hillman like approach, adding thiophenoxide to t -butyl acrylate in the presence of an enantiomerically-pure aldehyde N-sulfinimine such as 13 to give the adduct 14 with high diastereocontrol. Keiji Maruoka of Kyoto University has designed (Angew. Chem. Int. Ed. 2007, 46, 1738) the chiral amine 17, that catalyzed the condensation of an aldehyde with ethyl glyoxylate 16 with high enantiocontrol. In a very thoughtful approach, Liu-Zhu Gong of the University of Science and Technology of China in Hefei extended (Chem. Commun. 2007, 736) the now-classic aldol condensation of cyclohexanone to 4-substituted cyclohexanones such as 19. The product 21 could be carried in many directions, including to the Bayer-Villiger product 22. Arrays of alkylated and polyalkylated centers have been among the most challenging to prepare.

The Carreira Synthesis of (–)-Dendrobine

Organic Synthesis ◽

10.1093/oso/9780190200794.003.0098 ◽

2015 ◽

Author(s):

Douglass F. Taber

Keyword(s):

Claisen Rearrangement ◽

Magnesium Bromide ◽

Gel Chromatography ◽

Ring Fusion ◽

Enantiomerically Pure ◽

Schwartz Reagent ◽

Radical Reduction ◽

Silica Gel Chromatography ◽

The tetracyclic alkaloid (–)-dendrobine 3 has at its core a cyclohexane that is substituted at each of its six positions, including one quaternary center. Erick M. Carreira of ETH Zürich chose (Angew. Chem. Int. Ed. 2012, 51, 3436) to assemble this ring by the Ireland-Claisen rearrangement of the lactone 1. The absolute configuration of the final product stemmed from the commercial enantiomerically pure acetonide 4, which was selectively converted to the Z-ester 5. Following the precedent of Costa, TBAF-mediated conjugate addition of 2-nitropropane to 5 proceeded with high diastereocontrol, to give, after free radical reduction, the ester 6, which was carried on the aldehyde 7. Exposure of the alkyne 9 to an in situ-generated Schwartz reagent followed by iodination gave 10 with 10:1 regioselectivity. It was possible to separate 10 from its regioisomer by careful silica gel chromatography. Metalation followed by the addition to 7 gave an intermediate that was conveniently debenzoylated with excess ethyl magnesium bromide to deliver the diol 11. Selective oxidation led to the lactone 1. Exposure of 1 to LDA and TMS-Cl induced rearrangement to the cyclohexene acid, which was esterified to give 2. Deprotection and oxidation then gave the enone 12. Cyclohexene construction by tethered Claisen rearrangement is a powerful transformation that has been little used in target-directed synthesis. Selective addition of pyrrolidine to the aldehyde of 12 generated an enamine, leading to an intramolecular Michael addition to the enone. This selectively gave the cis ring fusion, as expected, but the product was a mixture of epimers at the other newly formed stereogenic center. This difficulty was overcome by forming the enamine from N-methylbenzylamine. After cyclization, hydrogenation set the additional center with the expected clean stereocontrol, and also effected debenzylation to give 14. To close the last ring, the ketone 14 was brominated with the reagent 15, which was developed (Can. J. Chem. 1969, 47, 706) for the kinetic bromination of ketones. Exposure of the crude α-bromo ketone to 4-dimethylaminopyridine then effected cyclization to 16. Following the literature precedent, reduction of the ketone of 16 with NaBH4 followed by gentle warming led to (–)-dendrobine 3.