Angewandte
Chemie
[3] K. R. Hornberger, C. L. Hamblett, J. L. Leighton, J. Am. Chem.
Inspired by a spontaneous macroacetalization reported by
Kozmin et al.,[4a] we decided for a similar transformation of
nitrile 18. Therefore, careful addition of DIBAL-H to a
solution of 18 in CH2Cl2 at À788C followed by acidic
hydrolysis of the resulting imine furnished a transient
hydroxyaldehyde which spontaneously cyclized into the
desired macrolactol. Oxidation to the macrolactone 19 using
PCC followed by a TBAF-promoted deprotection of the C5-
TBDPS ether provided macrolide 2 in excellent yield,
establishing, at this stage, a formal total synthesis of
leucascandrolide A (1).
It has been reported that it was difficult to achieve a direct
acylation of the axially orientated C5-hydroxy group of 2.[4c]
We therefore turned our attention to the Mitsunobu reac-
tion[17] to install the side chain at this center. Inversion of the
configuration at C5 was achieved by a two-step oxidation–
reduction sequence in excellent yield and with excellent
selectivity (Scheme 5). Acid 3[6c] and macrolide 20 were then
united smoothly under Mitsunobu conditions to conclude the
total synthesis of leucascandrolide A (1); the physical and
spectroscopic properties of our compound were identical to
those reported for 1.[1,3]
Soc. 2000, 122, 12894.
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13670; b) A. Fettes, E. M. Carreira, Angew. Chem. 2002, 114,
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[7] a) H. Huang, J. S. Panek, J. Am. Chem. Soc. 2000, 122, 9836; for
some other examples of pyran syntheses through Prins-type
cyclization, see: b) S. D. Rychnovsky, S. Marumoto, J. J. Jaber,
Org. Lett. 2001, 3, 3815; c) I. E. Markꢁ, D. J. Bayston, Synthesis
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[8] Q. Su, J. S. Panek, J. Am. Chem. Soc. 2004, 126, 2425.
[9] Other electron-withdrawing groups such as acetate, pivaloate,
trifluoroacetate, benzoate, and methyl carbonate as X gave
predominantly the cis isomers, however with lower diastereose-
lectivities and in lower yields.
[10] For a high-yielding preparation of silane 8a, see Supporting
Information.
[11] Aldehyde 7 was prepared in high yield from the known alcohol;
see Supporting Information.
[12] Using a less bulky sulfonate group (p-toluenesulfonate) as X in 8
produced the corresponding cis pyran with lower diastereose-
lectivity (d.r. = 9:1).
[13] H. C. Brown, P. Geoghegan, Jr., J. Am. Chem. Soc. 1967, 89,
1522.
[14] E. J. Corey, J. W. Suggs, Tetrahedron Lett. 1975, 2647.
[15] A. Maercker, Org. React. 1965, 14, 270.
[16] P. Wipf, W. Xu, Tetrahedron Lett. 1994, 35, 5197.
[17] O. Mitsunobu, Synthesis 1981, 1.
Scheme 5. Reagents and conditions. a) Dess–Martin periodinane, pyri-
dine, CH2Cl2; b) NaBH4, MeOH, 08C; c) 3, PPh3, DIAD, THF/benzene.
DIAD=diisopropyl azodicarboxylate.
In summary, we accomplished a convergent and enantio-
selective total synthesis of (+)-leucascandrolide A (1) in 17
steps from available aldehyde 7 and allylsilane 8a. The
present synthesis features an efficient route to 4 using two
consecutive [4+2] annulation reactions between aldehydes
and our chiral allyl- and crotylsilanes for the rapid and
efficient integration of the bispyran moiety into 1. Thus, chiral
organosilane reagents were shown to be of salient utility for
synthesizing complex pyran-containing natural products.
Moreover, studies toward the completion of structural
analogues of 1 using this silane methodology are currently
in progress in our laboratory.
Received: October 22, 2004
Published online: January 17, 2005
Keywords: allylsilanes · annulation · antitumor agents ·
.
asymmetric synthesis · natural products
[1] M. DꢀAmbrosio, A. Guerriero, C. Debitus, F. Pietra, Helv. Chim.
Acta 1996, 79, 51.
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Angew. Chem. Int. Ed. 2005, 44, 1223 –1225
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1225