Scalable, efficient total synthesis of (+)-mupirocin H

Abstract

A scalable, efficient total synthesis of mupirocin H was accomplished in 7 longest linear steps with 39% overall yield. The developed strategy is great progress for the construction of pseudomonic acid analogues and all steps in our strategy could be conducted on a gram scale. The strategy is also suitable for other related molecules.

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As early as 1887, Garre found that the fermentation broth of Pseudomonas fluorescens had antimicrobial activity,¹ but it was not until the late 1960s that Fuller et al. determined that pseudomonic acids were responsible for the bioactivity.² In order to avoid ambiguity, the British Pharmacopoeia and World Health Organization use the generic name “mupirocin” instead of “pseudomonic acids”. Mupirocin is a mixture of pseudomonic acids A, B, C and D (Fig. 1) with the principal constituent pseudomonic acid A accounting for 95%. As a polyketide³ antibiotic, it has been widely used clinically for the treatment of skin infections. Due to the unusual structures and important biological activities, the pseudomonic acids have attracted many organic chemists to their total syntheses.^4,5 When Simpson et al. studied the biosynthesis of pseudomonic acid from Pseudomonas fluorescens, two new pseudomonic acid analogues named mupirocin W⁶ and mupirocin H⁷ were isolated and mupirocin W showed similar bioactivity to the pseudomonic acids.

Fig. 1 Chemical structures of pseudomonic acids, mupirocin W (1) and mupirocin H (2).

In 2011, the Chakraborty group reported the first enantioselective total synthesis of mupirocin H in 19 steps with 4.96% overall yield using D-glucose as the chiral source and Julia–Kocienski reaction for construction of the E-olefinic bond.⁸ In 2012, the Willis group also reported a convergent total synthesis of mupirocin H in 11 steps with 6.9% overall yield using a functionalized lactone transformation strategy.⁹ As mentioned by Chakraborty, although mupirocin has excellent antibiotic properties, it exhibits poor bioavailability, which restricts its use as a topical antibiotic. Thus, it is highly desirable to develop a general, scalable and divergent strategy that could be applied to synthesis of a large number of the pseudomonic acid analogues offering convenience for further bioactivity studies. Herein we disclose a scalable and efficient total synthesis of mupirocin H using Suzuki–Miyaura and Mukaiyama aldol reactions as key steps. To the best of our knowledge, this is a great advance in the construction of pseudomonic acid analogues and all steps in our developed strategy could be conducted on a gram scale. The strategy is also suitable to other related molecules (Scheme 1).

Scheme 1 Past synthetic approaches and our synthetic strategy.

Our retrosynthetic approach to mupirocin H (2) is presented in Scheme 2. We rationalized that the γ-lactone moiety could be established by deprotection and lactonization from ester 3. Unlike most of the syntheses performed on pseudomonic acid analogues, our strategy to obtain the E-olefin leaves the formation of the carbon–carbon bond between C7 and C8 through a Suzuki–Miyaura coupling reaction of vinyl iodide 4 and the trialkyl boron reagent 5 to a late stage. The requisite coupling precursor 5 could be generated from aldehyde 7 and 8via a Mukaiyama aldol reaction. For aldehyde 7, it could be obtained from known compound 10. On the other hand, the vinyl iodide 4 could be easily prepared via a Takai reaction from aldehyde 6, which was derived from the known chiral alcohol 9.

Scheme 2 Retrosynthetic analysis of mupirocin H (2).

Our synthesis started with the preparation of segment 4. Protection of the known chiral alcohol 9¹⁰ followed by LiAlH₄ reduction gave the primary alcohol 12 in 83% yield for two steps. Subsequent Swern oxidation of alcohol 12 produced the desired aldehyde 6,¹¹ which was subjected to a Takai reaction to afford the vinyl iodide 4 in 78% overall yield for two steps¹² (Scheme 3).

Scheme 3 Synthesis of vinyl iodide 4.

Having succeeded in construction of building block 4, we then turned our attention to synthesizing segment 5. Our synthesis began with the known 2,3-O-isopropylidene-D-erythrose 10,¹³ oxidation of the aldehyde 10 using Anelli conditions gave erythronolactone 13 in 71% yield.¹⁴ Reaction of MeLi with 13 afforded the protected 1-deoxyribulose 14 in 96% yield.¹⁵ Subsequent Wittig reaction of 14 with methylene triphenylphosphorane gave the olefinic product 15 in 99% yield.¹⁶ Swern oxidation of alcohol 15 produced the desired aldehyde 7 which was used directly in the next step without further purification. Exposure of the crude aldehyde 7 to ZnI₂ and O-silylated ketene acetal 8 gave a (anti : syn over 10 : 1) separable mixture of diastereomers in 80% combined yield for two steps¹⁷ (Scheme 4).

Scheme 4 Synthesis of segment 16.

The observed diastereoselection may arise from the si face addition via a Felkin–Anh type transition state. The enhancement of the anti-selectivity in the presence of ZnI₂ can be explained by chelation with β-oxygen as in the transition state A, the re face of the aldehyde becomes much more crowded than the si face¹⁸ (Fig. 2).

Fig. 2 Transition states for Mukaiyama aldol reactions.

With the two requisite fragments in hand, our attention was directed to their linkage using the Suzuki–Miyaura coupling reaction.¹⁹ Pleasingly, the linkage between vinyl iodide 4 and hydroboration product generated in situ from 16 proceeded well to produce 3 in 82% yield. The desired stereogenic center of the C6 methyl group²⁰ and configuration of the E-olefinic bond (deduced from coupling constant J = 15.2 Hz in ¹H NMR spectrum of the natural product) were established stereoselectively during this process.

The excellent diastereoselective of the C6 methyl group could be explained by the two possible transition states depicted in Fig. 3. Transition state S₂ is favored over the diastereomeric transition state S₁ since the nonbonding interactions between allylic diacetonide protected the hydroxyl group and boron substituents.^20a,b

Fig. 3 Transition states for hydroboration of alkene 16.

At this point, the key core and all of the six stereogenic centers has been established, and the only task that remained was to remove the diacetonide, MOM and TBS protecting groups and γ-lactonization. To our delight, the process could be achieved by treatment of 3 with 2 N HCl in THF all in one pot to yield the natural product mupirocin H (2) in 86% yield.²¹¹H and ¹³C NMR spectra and other physical data of our synthetic compound were all in good agreement with those of the natural mupirocin H (2) (Scheme 5).

Scheme 5 Suzuki–Miyaura coupling reaction and accomplish the synthesis of (+)-mupirocin H (2).

Conclusions

In summary, a scalable and efficient approach for total synthesis of mupirocin H (2) has been achieved in 7 steps (longest linear sequence) with 39% overall yield. The synthetic sequence features a Suzuki–Miyaura coupling reaction for construction of the required E-double bond and a Mukaiyama aldol reaction for establishing the chiral center of C-3. Due to its high efficiency and overall yield, the developed pathway would enable large scale preparation of mupirocin H (2), offering convenience for further studies. The developed strategy is also suitable to synthesize other pseudomonic acid analogues.

Acknowledgements

We are grateful for the financial support by the NSFC (21125207, 21102062, 21072086, 21102064), the MOST (2010CB833203), PCSIRT (IRT1138), the FRFCU (lzujbky-2013-49, lzujbky-2013-ct02), and Program 111.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3qo00038a

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