Our initial retrosynthetic strategy, as outlined in Scheme 1, involves a Mitsunobu macrolactonization of seco acid 2. Compound 2 could, in turn, be available from Wadsworth—Emmons reaction of a C₉ aldehyde with the phosphonate 4. A diastereoselective aldol reaction between methyl ketone 6 and aldehyde 5 would be used to form the C_18,19 linkage. Finally, the 1,3-diene fragment present in 5 is particularly challenging as it appears that the C₁₆-alkoxy moiety renders a palladium- or copper-mediated strategy problematic for its formation.^7a,9 For this reason, an alternate method for its construction needed to be developed.

The synthesis of aldehyde 5 began with the commercially available (S)-lactic acid (7) (Scheme 2). After acetalization with pivaldehyde, Seebach alkylation¹⁰ with cinnamyl bromide provided the tertiary alkoxy function in 91% yield and greater than 20:1 dr. Subsequent treatment with MeLi and silylation yielded the protected methyl ketone 9. Combination with the readily available allyl silane 12 using freshly distilled TiCl₄ yielded the C_14,15-coupled material 13 in 65−70% yield as 6:1 ratio of diastereomers at C₁₅. Next, elimination of the homoallylic alcohol 13 using SOCl₂ and pyridine in toluene provided the C₁₃–C₁₅ diene 14 as a single stereoisomer at C₁₄–C₁₅. The desired product was contaminated with the unconjugated diene 15 in a 2.2:1 ratio (14/15). While compounds 14 and 15 could be separated by HPLC, purification of the desilylated compounds 16 and 17 proved logistically easier as they were separable by standard chromatographic methods. Subsequent Mitsunobu-type incorporation of the C₉ cyanide¹¹ and protection yielded 18. Next, Sharpless asymmetric dihydroxylation of 18 using AD mix β*¹² provided the C_18,19 diol as an inconsequential 6:1 mixture of diastereomers. The selectivity for the C_18,19 alkene over the C₁₃–C₁₅ diene was attributed to, in part, a beneficial π-stacking interaction between the neighboring aromatic ring and the corresponding Sharpless ligand.¹³ Dihydroxylation under standard OsO₄, NMO conditions provided a complex mixture of products. AD mix α* also proved to be a poor reagent for this transformation. Interestingly, dihydroxylation of the unconjugated diene 20 with AD mix β* was again regioselective for the C_18,19 alkene; however, no diastereoselectvity was observed in the dihydroxylation. Finally, cleavage of the diol 19 yielded the necessary aldehyde 5. An analogous procedure with the unconjugated diene series provided the aldehyde 22.

The synthesis of the eastern subunit 6 commenced with the previously prepared aldehyde 24^6a (Scheme 3). Boron-mediated aldol reaction of aldehyde 24 with the oxazolidinone 23¹⁴ gave the desired C₂₁–C₂₃ syn,syn adduct 25 in good yield. The minor diastereomer in the aldol appeared to be the anti aldol adduct (J_H21,H22 = 9.0 Hz). Subsequent silylation at C₂₂ followed by conversion to the thioester and cuprate addition yielded the desired methyl ketone 6.

With the methyl ketone subunit 6 and the diene fragment 5 constructed, focus shifted toward their union (Scheme 4). Chelation-controlled aldol condensation of lithium enolate derived from the methyl ketone 6 with the aldehyde 5 provided the coupled material 27 in 69% yield as a single diastereomer. This result is in contrast to work by Pattenden's and Kobayashi's laboratories in which poor selectivity (approximately 3:2 dr) was observed using enolates derived from LDA, NaHMDS, or KHMDS.^7a,h In both cases, non-chelating silyl protecting groups¹⁵ were employed on C₂₁ of the enolate. We attribute part of the improved selectivity at C₁₈ to the use of the α-chelating PMB group on the enolate, as shown in the model 26. It should be noted, however, that when the analogous aldol reaction with the unconjugated diene-containing aldehyde 22 was preformed, diminished selectivity (approximately 2:1 dr) was observed. The C₁₈ stereochemistry of 27 was confirmed by Mosher ester analysis.¹⁶ Finally, silyl protection under specific conditions¹⁷ [TBSOTf (1.2 equiv), Et₃N/CH₂Cl₂ (1:1)] provided silyl ether 27. If more traditional silylation conditions were employed [e.g., TBSOTf (1.2 equiv), 2,6-lutidine (1.5 equiv)], migration of the 1,1-disubstituted alkene at C₁₃ into the C₁₂–C₁₃ trisubstituted position appeared to be observed.