Concise epoxide-based synthesis of the C14–C25 bafilomycin A₁ polypropionate chain

Abstract

An efficient non-aldol convergent synthesis of the C14–C25 polyketide fragment of bafilomycin A₁ was completed in 16% overall yield and 8 steps in its longest linear sequence. This synthesis highlights the formation of the key fragments using a three-step sequence of epoxide cleavage, alkyne reduction, and epoxidation developed in our laboratory; starting from suitably protected enantiomeric epoxides of trans-2,3-epoxybutanol. This chemistry represents a quick asymmetric and diastereoselective construction of the polyketide chain of bafilomycin A₁, in which every stereogenic center was constructed using solely epoxide chemistry.

The bafilomycins (1) belong to a group of molecules in the family of the plecomacrolides. The hygrolidins, the concanamycins, and formamicin have been included in this group. Bafilomycin A₁ (1a) was isolated in 1983 by Wagner from a broth of Streptomyces griseus (Figure 1).¹ Its relative stereochemistry was determined by Corey and Ponder in 1984 using extensive NMR analysis, and confirmed in 1987 using X-Ray crystallography.^2–4 More recently, several previously unknown bafilomycins (F-J) were isolated from a marine strain of Streptomyces.⁵ Common structural features of the bafilomycins include the 16-membered macrolide with a tetraene core, a long polyketide chain with a cyclic hemiacetal, a C14 methoxy, and a C23 isopropyl group. Bafilomycin A₁ exhibits potent antifungal and antibacterial activity. It is also the first known inhibitor of Vacuolar H⁺-ATPase (V-ATPase), providing treatments for bone resorption diseases such as osteoporosis and osteoarthritis, in addition to showing potential as an anticancer treatment for eight different human cancer cell lines.^6–11 These singular biological activities, along with the challenging structural features presented make bafilomycin A₁ a well studied target for synthetic efforts.

Figure 1.

Structures of the bafilomycin family.

The presence of the C19 carbonyl offers the opportunity to apply convergent methods to synthesize this polypropionate chain.¹² To date, there have been five total syntheses of bafilomycin A₁,^13–20 and several reports on the synthesis of the important C13–C25 polypropionate segment.^21–24 The total syntheses of bafilomycin A₁ have focused mainly on facial differentiation for aldolic coupling of fragments. Those who study different methodologies have found creative ways to bring about the stereoselective synthesis of the C13–C25 portion of the molecule. For instance, Patterson applied a series of stereocontrolled aldol additions to α-methylene-β-alkoxy aldehydes, followed by hydroxyl-directed hydrogenation of the methylene moiety.²² Marshall used enantioenriched allenylzinc reagents, starting from nonracemic propargylic mesylates, which undergo S_E2′ additions to aldehydes to yield anti-homopropargylic alcohols to synthesize the C15–C25 fragment.²³ More recently, Cossy used a dynamic kinetic resolution of nonchiral ketones with an optically active ruthenium complex.²⁴

An alternative approach for the synthesis of polypropionates is the regioselective cleavage of an oxirane ring. Epoxides can be prepared enantioselectively with several well-known methodologies, like the Sharpless asymmetric epoxidation.²⁵ They can be cleaved with a number of organometallic reagents, including boranes, alanes, Grignard reagents and cuprates.²⁶ The ring opening of inactivated epoxides can be considered as S_N2 processes; therefore, epoxides will predictably be cleaved at the least hindered carbon (in the absence of coordinating groups) when treated with a nucleophile. The ease of access and the predictability of their cleavage reaction is what has interested us in developing a methodology for the synthesis of polypropionates based on the regioselective cleavage of disubstituted epoxides.^27–35 Our methodology consists in three reiterative steps: the cleavage of a disubstituted epoxide with an alkynyl alane reagent, reduction of the alkyne, and stereoselective epoxidation of the newly formed alkenol (Scheme 1). This provides a new epoxide to which the three-step process is repeated, allowing the preparation of a number of stereochemical possibilities. One of the advantages of this methodology is that the only enantiomeric step is the first epoxidation, given that the absolute configuration of the first hydroxy is given by this step, while the relative configuration between the hydroxy and the adjacent methyl group is given by the epoxide geometry. Because of this, several polypropionate permutations can be constructed without the need for any aldolic steps. For this approach to be successful, we have studied the stereoselective epoxidation of homoallylic alcohols^27,30,35, and the regioselective cleavage of these epoxides.^31–33 This methodology has led to the successful linear synthesis of the all anti fragment of streptovaricin U and other polypropionate modules.³⁴ Aimed at extending our methodology to more varied polypropionate targets and to expand it from linear to convergent, herein we present an epoxide-based approach for the enantioselective synthesis of the C14–C25 polypropionate fragment of bafilomycin A₁.

Scheme 1.

Reiterative epoxide-based methodology for polypropionate synthesis.

Our approach is based on the use of both enantiomers of trans-2,3-epoxybutanol 2.²⁵ The (+) enantiomer was used for the construction of the C21–C22 stereocenters, while the (−) enantiomer was used in the C15–C16 centers. Alkyl iodide 9, corresponding to The C20–C25 segment (Scheme 2), was previously synthesized both by Hanessian in his total synthesis of bafilomycin A₁¹⁸, and by Cossy in her C14–C25 synthesis, both using different methodologies.²⁴ Our approach began by protection of epoxide (+)-2 as the benzyl ether 3, which proceeded in 93%. Cleavage with cis-1-propenylmagnesium bromide catalyzed with 5% CuI, yielded 82% of homoallylic alcohol 4. Epoxidation of 4 using our microwave assisted VO(acac)₂/TBHP conditions yielded 60% of syn,anti,cis epoxy alcohol 5 as the only observed epoxide, in complete agreement with previous results using different protecting groups.³⁰ For the introduction of the terminal isopropyl and the C23 hydroxy, epoxide 5 was cleanly cleaved using Me₃Al, producing 80% of 1,3-diol 6, which was subsequently protected as the bis-TBS ether 7. Hydrogenolysis of 7 required a polar 4:1 methanol: ethyl acetate solvent mixture, to produce 98% of the desired alcohol 8. Finally, this alcohol was converted to the alkyl iodide 9 in 91% using Garegg’s conditions.³⁷ The synthesis of 9 was carried out in 7 steps and 30% overall yield, starting from known enantiomeric epoxide (+)-2. We believe this represents an improvement over previous published procedures for this fragment, as it more than doubles previously published yields while rivaling, or even reducing the number of synthetic steps in other syntheses.^18.24

Scheme 2.

Synthesis of alkyl iodide 9.

Racemic epoxide 13, the precursor for the C14–C18 stereotetrad (Scheme 3), was previously prepared stereoselectively by us starting from ethyl 2,3-epoxybutyrate by an iteration of our methodology.^27,36 The anti epoxide relationship was obtained via an iodolactonization/methanolysis and the OTIPS group arose from an ester reduction/alcohol protection sequence. While this route provided stereoselective access to the required syn,anti,trans epoxy alcohol, its many steps and the lack of chiral alternatives led us to explore the non-diastereoselective, but enantiomeric route presented in Scheme 3. The TIPS-protected epoxide 10 was prepared in 93% yield from the known epoxide (−)-2. This was followed by epoxide cleavage with diethylpropynylalane, obtaining homopropargylic alcohol 11 in 61%. Sodium/ammonia reduction of 11 yielded homoallylic alcohol 12 in 64%. At this point, several stereoselective methods for the epoxidation of 12 generated a mixture of epoxides, mostly favoring the syn,syn diastereomer of 13.^27,30 We therefore used the non-stereoselective MMPP epoxidation, obtaining 76% of a 50:50 mixture of 13 and its syn diastereomer. Although this alternate method gives a lower yield of the desired epoxide, this reaction can be made in multigram quantities, and the mixture of epoxides is easily separated by flash chromatography. Once epoxide 13 was procured, we selected 1,3-dithiane as the coupling agent because of known successes and the reliability and versatility of dithianes.³⁸ Cleavage of 13 using 1,3-dithiane generated 70% of diol 14. Protection of the diol as an acetonide provided the C15-C18 syn,anti,syn stereotetrad 15 in 65%.

Scheme 3.

Synthesis of dithiane 5 and polypropionate fragment 16.

With reliable methods to synthesize fragments 9 and 15 now available, the last step in our synthesis was the coupling of these fragments. After unsuccessful attempts using several published conditions,³⁹ we found that the most effective way to obtain the desired product was to first deprotonated dithiane 15 with t-BuLi, followed by addition of HMPA, and finally adding alkyl iodide 9. This resulted in 53% of coupling product 16.

We have successfully completed the enantioselective synthesis of the C14–C25 bafilomycin A1 polypropionate chain in 16% overall yield and 8 steps in its longest linear sequence, starting from known enantiomeric epoxides (−)-2 and (+)-2. Fragments 9 and 15 were synthesized using our epoxide cleavage methodology, thus proving its effectiveness in the synthesis of polypropionate chains. All stereocenters were generated from the epoxide precursors. Completion of the synthesis, along with further studies using this methodology for the elaboration of other polypropionate targets, is currently underway.