Total Synthesis of Xerulinic Acid

Abstract

An inhibitor of the biosynthesis of cholesterol, xerulinic acid, has been synthesized for the first time. The convergent approach applied involves the palladium‐catalyzed coupling of an enediynoic ester building block, a conjunctive C6 bisstannane, and a bromine‐containing methylenebutenolide (see scheme; R=Me3SiCH2CH2).

Stereocomplementary Syntheses of 1,ω‐DistannylatedE,Z‐Isomeric Conjugated Trienes, Tetraenes, and Pentaenes

“…As a result, we present a set of hitherto unknown all‐ E ‐ or mono‐ Z ‐configured 1,6‐bis(tributylstannyl)hexa‐1,3,5‐trienes, 1,6‐bis(tributylstannyl)octa‐1,3,5,7‐tetraenes, and 1,10‐bis(tributylstannyl)deca‐1,3,5,7,9‐pentaene. Our access routes are based on pertinent experience in this particular class of compound6–8, 19–21 with the stereocomplementarity of two key CC bond‐forming reactions: 1) the Ramberg–Bäcklund olefination22 to E ‐selectively generate the C 3 C 4 bonds of trienes and tetraenes and the C 5 C 6 bond of pentaenes and 2) the (Sylvestre–)Julia olefination23 to establish the same bonds with a Z configuration.…”

“…The 1,6‐distannylated trienes, 1,8‐distannylated tetraenes, and 1,10‐distannylated pentaenes, which became accessible through using the mentioned key reactions, merit interest as bifunctional reagents for three‐component Stille coupling reactions. Such a usage had already been demonstrated for trienes all‐ E ‐ 2 ,6, 7, 8 mono‐ Z ‐ 2 ,46 and all‐ E ‐ 9 9 and for pentaene all‐ E ‐ 32 10. By taking into account the variability of the methylation pattern with which we actually could endow or with which one should be able to endow this class of reagent, a manifold of applications in the stereoselective synthesis of extended polyenes is conceivable.…”

“…The convergency of Stille coupling strategies increases when three components are involved and one is a 1,2‐distannylated ethene, 1,4‐distannylated buta‐1,3‐diene, or 1,ω‐distannylated linear conjugated polyene. In spite of this conceptional advantage, such tandem Stille couplings have been reported only occasionally, that is, for E ‐1,2‐bis(tributylstannyl)ethene a few times,3, 4 an isomeric mixture of 1,4‐bis(trimethylstannyl)buta‐1,3‐dienes in two studies,5 1,6‐bis(tributylstannyl)hexa‐1,3,5‐triene (all‐ E ‐ 2 ; Scheme ) as an intermediate for syntheses of xerulinic acid6–8 and xerulin,8 1,6‐bis(tributylstannyl)hepta‐1,3,5‐triene (all‐ E ‐ 9 ; see Scheme ) as an intermediate for pyrrhoxanthin,9 and 1,10‐bis(tributylstannyl)‐1,3,5,7,9‐decapentaene (mono‐ Z ‐ 32 ; see Scheme ) as an intermediate for β‐carotene 10. The respective distannanes in the cited examples linked two different electrophiles either intramolecularly3 or intermolecularly4f, 5a, 6–9 or two equivalents of a single electrophile 4a.…”

“… Stereoselective syntheses of 1,6‐bis(tributylstannyl)‐1,3,5‐hexatriene isomers all‐ E ‐ and mono‐ Z ‐ 2 . a) CBr 2 F 2 (4.0 equiv), KOH (30 % on Al 2 O 3 , 20 equiv), THF, 0 °C for 15 min to 25 °C for 30 min (73 %, all‐ E /mono‐ Z =96:4 mixture);6, 8 b) 3 (1.28 equiv), 4 , KHMDS (1.2 equiv), THF, −78 °C→RT, overnight (66 %, mono‐ Z /all‐ E =96:4 mixture) 7. 8, 19 …”

Carbon–Carbon Bond Forming Reactions Mediated by Organozinc Reagents

“…Reagents obtained by Zn(0) insertion from the corresponding halide, or by a halogen-lithium or a tin-lithium exchange/transmetallation sequence, are well suited, as illustrated with the preparation of compounds 202 [170] and 205 (Scheme 4.46) [46]. Further evidence for the applicability of this method is its use in recent total syntheses of natural products, such as xerulinic acid [171], 6,7-dehydrostipiamide [172], epolactaene [173], and the side chains of mycolactones A and B [174]. Alternatively, a very powerful reaction [61a] is the one-pot two-step hydrozirconation of alkynes/transmetallation to alkenylzincs/Negishi coupling exemplified in the preparation of compound 209 [61c] (Scheme 4.47).…”