Scheme 2. Synthesis of Pentacyclic Hydroxy Lactone 24a
Scheme 1. a
a Molecular structure of salvileucalin A (1), proposed biosynthetic
intermediate 2, and salvileucalin B (3) indicating the three key structural
domains A, B, and C. Retrosynthetic analysis of salvileucalin B (3)
leading to stannane 4 and synthetic intermediates 5, 6, and 7. TBS =
tert-butyldimethylsilyl.
cross-coupling reaction to install subdomain C [for exam-
ple, a Stille coupling reaction4 engaging stannane 4 to
install the furanyl moiety of salvileucalin B (3)]. Upon
executing this opening retrosynthetic maneuver, our atten-
tion immediately turned to the most challenging aspect of
the foreseeable synthetic campaign, namely the construc-
tion of subdomain A containing the norcaradiene core of
salvileucalin B (3). Inspired by the biosynthetic proposal,
we were intrigued with the possibility of a carefully de-
signed triene system (e.g., 6) to undergo an intramolecular
DielsꢀAlder reaction,5 thereby furnishing the tetracyclic
core structure represented by advanced intermediate 5.
Indeed, several examples of an intramolecular Dielsꢀ
Alder reaction of 5-vinyl-1,3-cyclohexadiene have been
documented.6 Furthermore, a recent quantum mechanical
calculation study has unveiled the influence of functional
groups present in both the substrate and the possible
enzyme active site that could accelerate the intramolecular
DielsꢀAlder reaction leading to the formation of the
norcaradiene core of salvileucalin B (3).7 Finally, the
spirocyclic motif within hydroxy methyl ester 6 could be
conceived from a Coniaꢀene reaction8 engaging alkynyl
β-diketone 7 (represented in its enol form).
a LDA = lithium diisopropyl amide, DMP = DessꢀMartin period-
inane, Dibal-H = diisobutylaluminium hydride, KHMDS = potassium
hexamethyldisilazide, Tf = trifluoromethanesulfonyl, OTf = trifluor-
omethanesulfonate, py = pyridine, HMDS = hexamethyldisilazane.
The realization of our synthetic strategy began with the
preparation of the proposed intramolecular DielsꢀAlder
precursor 6, and thereby accessing the key synthetic inter-
mediate 5 harboring subdomain A, as shown in Scheme 2.
Thus, a lithium aldol reaction (LDA) between cyclohex-
enone (9) and alkynyl aldehyde 8 afforded β-hydroxy
ketone 10, which was further oxidized to diketone 7
(represented in its enol form) under DMP conditions in
75% overall yield. A Coniaꢀene reaction8 engaging alky-
nyl diketone 7 was examined under a variety of reaction
conditions, and ultimately ZnI2 was revealed as the most
effective promoter for this transformation, giving spiro-
cyclic diketone 11 in 85% yield. Chemo- and stereoselec-
tive reduction of keto enone 11 under the Dibal-H
conditions led to hydroxy enone 12 as a single diastereoi-
somer, which was subsequently protected as its TBS ether
(TBSOTf, 13, 85% yield over the two steps). In prepara-
tion for the proposed intramolecular DielsꢀAlder reac-
tion, enone13wasconverted tomethylester 15through the
intermediacy of triflate 14 (KHMDS, PhNTf2, 76% yield)
and its reaction under the standard carboxymethylation
(4) (a) Negishi, E. Angew. Chem., Int. Ed. 2011, 50, 6738–6764. (b)
Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722–6737.
(5) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis,
G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698.
(6) For examples of DielsꢀAlder reaction involving 5-vinyl-1,3-
€
cyclohexadiene, see: (a) Heimbach, P.; Ploner, K. J.; Thomel, F. Angew.
Chem., Int. Ed. 1971, 10, 276–277. (b) Imagawa, T.; Nakagawa, T.;
Kawanisi, M.; Sisido, K. Bull. Chem. Soc. Jpn. 1979, 52, 1506–1510. (c)
ten Have, R.; van Leusen, A. M. Tetrahedron 1998, 54, 1913–1920. (d)
Moses, J. E.; Baldwin, J. E.; Adlington, R. M.; Cowley, A. R.; Marquez,
R. Tetrahedron Lett. 2003, 44, 6625–6627. (e) Ng, S. M.; Beaudry, C. M.;
Trauner, D. Org. Lett. 2003, 5, 1701–1704. (f) Abad, A.; Agullo, C.;
Cunat, A. C.; de Alfonso, I.; Navarro, I.; Vera, N. Molecules 2004, 9,
287–299. (g) Dubarle-Offner, J.; Marrot, J.; Rager, M.-N.; Bideau, F. L.;
Jaouen, G. Synlett 2007, 800–802.
(7) Tantillo, D. J. Org. Lett. 2010, 12, 1164–1167.
(8) Conia, J. M.; Le Perchec, P. Synthesis 1975, 1, 1–19.
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