Our syntheses of the aldehyde and methyl ketone subunits commenced with the previously reported intermediates 11 and 14 (Scheme 2).^1a,c Conversion of the C₉ nitrile 11 into the corresponding acetate 12 followed by selective functionalization of the C_18,19 alkene using AD mix β* provided the C_18,19 diol as an inconsequential 6:1 mixture of diastereomers.^1c Cleavage of the resultant diol with sodium periodate provided the desired aldehyde 8. For the synthesis of the Eastern subunit 9, Horner–Wadsworth–Emmons olefination of aldehyde 14 followed by dihydroxylation yielded the diol 16. Next, bis-silylation followed by selective C₂₅ TES deprotection yielded the free alcohol at C₂₅. Finally, Mitsunobu inversion of the alcohol followed by saponification and TMS protection revealed the ketone 9.

The key diastereoselective aldol coupling is shown in Scheme 3. Treatment of ketone 9 under our standard LDA, Et₂O/THF conditions that proved effective with the C₂₁ OPMB series^1c resulted in low conversion and poor diastereoselectivity favoring the 18S stereochemistry [approximately 1.5:1 dr (5:6)]. Interestingly, addition of TMEDA led to a dramatic rate acceleration and a reversal of the selectivity [2:1 dr (6:5)]. Additional cooling of the reaction to −100 °C led to improved diastereoselectivity [8:1 dr (6:5)] in reasonable yield (65% overall). While we are still exploring the nature of the diastereoselectivity, one possible explanation could be a transition state which minimizes the dipoles of the C₂₁ C–O σ bond and the enolate.⁷ The alternate 18S diastereomer can be obtained by performing the reaction at higher temperatures (−40 °C, 1.2:1 dr 5:6). Silyl protection of alcohols 5 and 6 separately using TESCl/DMAP yielded the silyl ether compounds 17 and 18, respectively.

With an effective strategy for the coupling of the Eastern and Western subunits in hand, we turned our attention to the key macrocyclization event (Scheme 4). We chose to initially explore this sequence on the 18R compound 18. TMS deprotection of silyl ether 18 at C₂₅ and incorporation of the C₁–C₈ subunit provided the keto phosphonate 20.⁸ Removal of the C₉ acetate followed by Ley’s TPAP oxidation revealed the target aldehyde 4. The corresponding aldehyde 4 proved to be highly reactive as attempted isolation led to considerable loss of material. Interestingly, significant amounts of the aldehyde 4, formed during the TPAP oxidation, appeared to undergo spontaneous intramolecular Wadsworth–Emmons olefination to provide the desired macrocycle 22. The conversion could be driven to completion by the addition of LiCl and Hunig’s base⁹ in 51% yield. A similar sequence was followed for construction of the 18S macrocycle 21. In this case, Ba(OH)₂ proved more effective for driving the macrocyclization to completion. Additionally, we were pleased to observe that macrocycle 21 crystallized upon standing–allowing us to confirm the stereochemistry in 21.¹⁰

With an efficient route into the macrocycles 21 and 22, the final challenges were the incorporation of the C₆–C₉ allylic epoxide moiety and deprotection. As before, we explored the initial chemistry on the 18R macrolactone 22 (Scheme 5). Our previous experiences with deprotection of late stage amphidinolide B intermediates made us mindful of the difficulty of the final deprotection sequence.^1d Regioselective and stereoselective reduction of the C₇ carbonyl functionality could be accomplished with the (S)-CBS reagent.¹¹ We next had intended to epoxidize the alkene under Sharpless conditions;¹² however, the presumed steric congestion of the C₇ alcohol thwarted this approach. Fortunately, use of Ti(Oi-Pr)₄ and TBHP in the absence of DIPT led to formation of both the syn and anti diastereomer–favoring the syn stereochemistry (2:1 dr).¹³ As the syn diastereomer 24 contained the proposed stereochemistry in amphidinolide B₂, we initially proceeded forward with that diastereomer. Selenide incorporation¹⁴ and elimination under our recently developed TPAP/NMO conditions^1d,15 yielded the fully functionalized macrocycle. Unfortunately, all attempts to remove the silyl protecting groups under fluoride or acidic conditions led to decomposition. Suspecting that the allylic epoxide might be the culpable functionality, we next explored global deprotection on the epoxy selenide 26. We were quite pleased to find that treatment with TAS-F^6a cleanly removed all silyl protecting groups to provide the polyol 28. The final selenide oxidation/syn elimination proved problematic under standard (H₂O₂) conditions. This issue was not completely surprising as we have previously encountered this problem in our azaspiracid work¹⁵ as well as a previous generation amphidinolide approach. ^1d We have attributed this deleterious reactivity to the α-hydroxy ketone moiety. Although our TPAP/NMO conditions¹⁵ are not compatible with the polyol functionality of 28, we were gratified to find that bistrimethylsilylperoxide (TMSOOTMS) cleanly facilitated selenide oxidation with in situ syn elimination to reveal product 2. Surprisingly, this compound 2 did not match with the spectra data provided for the natural product amphidinolide B₂.³ We followed a similar sequence to the C_{8, 9} epoxide diastereomer 30 which too did not correspond with the reported data for amphidinolide B₂. In both cases, the ¹H NMR shift for the H₁₄ alkene was shifted significantly downfield as compared to the natural product data. Careful inspection of the isolation paper revealed that the stereochemical analysis of amphidinolide B₂ was based primarily on the differences in the ¹H NMR in the C₁₇–C₁₉ region of the natural product as compared to amphidinolide B₁ (1).^3b It is important to note that Shimizu and Clardy obtained X-ray crystallographic structure of natural product 1.^3b It is clear from our work that the structural differences between amphidinolide B₁ and B₂ are more complicated than initially expected. On the basis of this information, we haVe concluded that the proposed structure of amphidinolide B₂ is incorrect .

Next, we shifted our focus to the total synthesis of amphidinolide B₁ (1) (Scheme 6). We applied an analogous strategy for the synthesis of 1 as was described for the 18R series. It appears that a slight reversal in selectivity in the epoxidation occurs with the 18S stereochemistry–now with a modest preference for the undesired C_8,9 epoxide. Fortunately, these diastereomers are chromatographically separable. Conversion of syn epoxide 32 to the selenide followed by TAS-F deprotection yielded the penultimate intermediate. Finally, we were grateful to find that tandem selenide oxidation/elimination using our bis-TMS peroxide conditions yielded the natural product amphidinolide B₁ (1). The synthesized material 1 matched with the spectra data reported by Kobayashi and co-workers for amphidinolide B1.^3c