The Nakada Synthesis of (+)-Ophiobolin A

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.

The Overman Synthesis of (-)-Actinophyllic Acid

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 ◽  
Stereogenic Center

(-)-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 Fukuyama Synthesis of Gelsemoxonine

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Geometric Isomer ◽  
Cope Rearrangement ◽  
Magnesium Bromide ◽  
Unsaturated Ketone ◽  
Enantiomerically Pure ◽  
Selective Protection ◽  
Silyl Enol Ether ◽  
Ethyl Magnesium Bromide ◽  
The University ◽  
Stereogenic Center

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

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 ◽  
Stereogenic Center

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 Briarellin F

2013 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Lewis Acid ◽  
Membered Ring ◽  
University Of California ◽  
Central Feature ◽  
Soft Corals ◽  
Enantiomerically Pure ◽  
Single Diastereomer ◽  
Convergent Approach ◽  
The University ◽  
Polycyclic Ethers

Briarellin F 4 is an elegant representative of the complex polycyclic ethers produced by soft corals such as Briareum abestinum. Larry E. Overman of the University of California, Irvine, developed (J. Org. Chem. 2009, 74, 5458) a triply convergent approach to 4, the central feature of which was the Prins-pinacol combination of 1 with 2 to give 3. The aldehyde 2 was assembled by Wittig homologation of the aldehyde 5 with the phosphorane 6, followed by metalation and formylation. The aldehyde 10 was prepared by opening the enantiomerically pure epoxide 8 with the acetylide 9. Hydroboration of carvone 11 could not be effected with sufficient diastereocontrol. As an alternative, the mixture of diols was oxidized to the lactone 12 . Kinetic quench of the derived silyl ketene acetal followed by reduction led to the diastereomerically pure crystalline diol 13. This key intermediate will have many other applications in target-directed synthesis. The ketone 14 was converted to the alkenyl iodide 15 by stannylation of the enol triflate, followed by exposure of the stannane to N-iodosuccinimide. Addition of the alkenyl iodide 15 to the aldehyde 10 gave the diol 1 as an inconsequential 3:1 mixture of diastereomers. This mixture was combined with the aldehyde 2 to give, via Lewis acid–mediated rearrangement of the initially prepared acetal, the aldehyde 3 . The aldehyde 3 was readily decarbonylated by irradiation in dioxane. Face-selective Al-mediated epoxidation of the derived homoallylic alcohol proceeded with 10:1 selectivity, and subsequent MCPBA epoxidation of the cyclohexene was also secured with 10:1 facial control. This set the stage for the triflic anhydride–mediated closure of the six-membered ring ether. The Nozaki-Hiyama-Kishi cyclization of 18 proceeded with remarkable selectivity, delivering briarellin E 19 as a single diastereomer. Dess-Martin oxidation converted 19 into briarellin F 4.

Enantioselective Assembly of Oxygenated Stereogenic Centers

2011 ◽  
Author(s):  
Douglass Taber
Keyword(s):  
Catalyst Loading ◽  
Enantioselective Hydrolysis ◽  
State University ◽  
Stable Free Radical ◽  
Enantiomerically Pure ◽  
Institute Of Technology ◽  
North Dakota State University ◽  
The University ◽  
Low Catalyst Loading ◽  
Stereogenic Center

Reaction with an enantiomerically-pure epoxide is an efficient way to construct a molecule incorporating an enantiomerically-pure oxygenated stereogenic center. The Jacobsen hydrolytic resolution has made such enantiomerically-pure epoxides readily available from the corresponding racemates. Christopher Jones and Marcus Weck of the Georgia Institute of Technology have now (J. Am. Chem. Soc. 2007, 129, 1105) developed an oligomeric salen complex that effects the enantioselective hydrolysis at remarkably low catalyst loading. Any such approach depends on monitoring the progress of the hydrolysis, usually by chiral GC or HPLC. In a complementary approach, we (J. Org. Chem. 2007, 72, 431) have found that on exposure to NBS and the inexpensive mandelic acid 2, a terminal alkene such as 1 was converted into the two bromomandelates 3 and 4. These were readily separated by column chromatography. Individually, 3 and 4 can each be carried on the same enantiomer of the epoxide 5. As 3 and 4 are directly enantiomerically pure, epoxide 5 of high ee can be prepared reliably without intermediate monitoring by chiral GC or HPLC. Another way to incorporate an enantiomerically-pure oxygenated stereogenic center into a molecule is the enantioface-selective addition of hydride to a ketone such as 6. Alain Burgos and his team at PPG-SIPSY in France have described (Tetrahedron Lett. 2007, 48, 2123) a NaBH4 -based protocol for taking the Itsuno-Corey reduction to industrial scale. In the past, aldehydes have been efficiently α-oxygenated using two-electron chemistry. Mukund P. Sibi of North Dakota State University has recently (J. Am. Chem. Soc. 2007, 129, 4124) described a novel one-electron alternative. The organocatalyst 10 formed an imine with the aldehyde. One-electron oxidation led to an α-radical, which was trapped by the stable free radical TEMPO to give, after hydrolysis, the α-oxygenated aldehyde 11. High ee oxygenated secondary centers can also be prepared by homologation of aldehydes. Optimization of the enantioselective addition of the inexpensive acetylene surrogate 13 was recently reported (Chem. Commun. 2007, 948) by Masakatsu Shibasaki of the University of Tokyo. Note that the free alcohol of 13 does not need to be protected.

The Krische Synthesis of Bryostatin 7

2015 ◽  
Author(s):  
Douglass F. Taber
Keyword(s):  
Hydrogen Transfer ◽  
Reductive Coupling ◽  
Selective Hydrolysis ◽  
University Of Texas ◽  
Asymmetric Dihydroxylation ◽  
Carbon Carbon Bond ◽  
Reductive Couplings ◽  
The University ◽  
Stereogenic Center ◽  
Hydrolysis Of

The bryostatins, as exemplified by bryostatin 75, are an exciting class of natural products. In addition to being effective antineoplastic agents, they show activity against Alzheimer’s disease. The central ring-forming step in the synthesis of 5 reported (J. Am. Chem. Soc. 2011, 133, 13876) by Michael J. Krische of the University of Texas, Austin is the triply convergent coupling of the chirons 1 and 2 with the linchpin reagent 3. The preparation of 1 and of 2 showcases the hydrogen transfer strategy for carbon–carbon bond construction developed by the Krische group. The synthesis of 2 began with the previously described double coupling of the simple starting materials 6 and 7. The product diol 8 had >99% ee. Ozonolysis of 8 was followed by a reductive coupling with the allene, which installed the gem dimethyl substituents of 2, and also the third oxygenated stereogenic center. The preparation of 1 proceeded from the aldehyde 10, prepared by Sharpless asymmetric dihydroxylation of 3-pentenenitrile. The chelate-controlled addition of propargyl zinc 11 led to the alkyne 12. Reductive coupling of the alkyne of 12 with the aldehyde of 13, again following a Krische procedure, delivered 1. The triply convergent Keck-Yu condensation of 1 with 3, and then with 2, gave, after some manipulation, the desired tetrahydropyran 4. Selective hydrolysis of the methyl ester in the presence of the acetates followed by selective silylation of two of the three secondary hydroxyls gave a suitable substrate for Yamaguchi cyclization to give 14. Selective oxidative cleavage of two of the three alkenes then gave an intermediate keto aldehyde that was carried on to bryostatin 7 5 following known procedures. The key to the synthesis of the complex bryostatin 7 5 was the ready supply of the chirons 1 and 2, prepared by the simple but powerful enantioselective reductive couplings developed by the Krische group. These couplings will have many other applications in target-directed synthesis.

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