3800
J . Org. Chem. 1998, 63, 3800-3801
in a synthesis of the C(7)-C(16) segment of the ionophore
Con cer n in g th e Syn th esis of th e Elu sive
a n ti,a n ti-Dip r op ion a te Ster eotr ia d via th e
Cr otyla tion of â-Hyd r oxy r-Meth yl Ald eh yd es
w ith (Z)-Cr otyltr iflu or osila n e. Ap p lica tion to
th e Syn th esis of th e C(7)-C(16) Segm en t of
Zin cop h or in
antibiotic zincophorin.12,13
Sherry R. Chemler and William R. Roush*,1
Department of Chemistry, Indiana University,
Bloomington, Indiana 47405, and Department of Chemistry,
University of Michigan, Ann Arbor, Michigan 48109
Our strategy is based on the substrate-controlled asym-
metric induction model illustrated by the bicyclic transition
state 6. The â-hydroxyl group of aldehyde 4 is coordinated
to the silicon center of the (Z)-crotyltrifluorosilane 5 in 6,
thus forcing the aldehyde alkyl substituent to adopt an axial
position in the Zimmerman-Traxler transition state. Bond
formation would then occur opposite to the aldehyde R-m-
ethyl group, generating the desired anti,anti-dipropionate
stereotetrad 7. Examples of reactions that proceed by way
of similar bicyclic transition states have been previously
described.11,14-17
We chose to use (Z)-crotyltrifluorosilane (5) in these
reactions on the basis of reports that 5 and other allyltri-
fluorosilane reagents require activation by an external
nucleophile (e.g., CsF, ROH, R2NH) in order to react with
carbonyl compounds.11,15,18-20 The initiating nucleophile is
thought to add to the silicon center, generating a pentaco-
ordinate silicate species, which then reacts with the carbonyl
substrate through a six-membered cyclic transition state
wherein the hexacoordinate silicon center adopts an octa-
hedral geometry (as in 6).
Results of reactions of 5 and R-methyl â-hydroxy alde-
hydes 8-12 are summarized in Table 1. Typically, reactions
were performed by treating 1 equiv of the freshly prepared
â-hydroxy aldehyde with 1 equiv (by weight) of 4 Å molecular
sieves in CH2Cl2 (0.08 M) at 23 °C for 20 min. This solution
was then treated with 3 equiv each of 5 and i-Pr2NEt at 0
°C for 36 h.21 A sequential acidic (1 N HCl, 15 min) and
basic (3:1 THF-1 N NaOH, 1 h) workup was required to
hydrolyze the resulting silylene ketals to the desired diol
products. These crotylation reactions require strictly an-
hydrous conditions, as addition of water to the crotylation
reactions of 8 and 9 results in substantially lower selectivity
for the anti,anti adducts 13 and 15. Additionally, it is
necessary to run these reactions at concentrations less than
0.1 M to minimize production of aldehyde dimer,22 which is
formed competitively under more concentrated conditions.
Finally, it should be noted that hydroxyl-protected deriva-
tives of 8 react extremely sluggishly with 5 and generate
primarily the 4,5-anti 5,6-syn adducts.
Received March 2, 1998
The anti,anti-dipropionate stereotriad 3, a common sub-
unit found in polyketide-derived natural products, has
generally been acknowledged as difficult to synthesize.2,3 The
selective synthesis of this stereotriad by way of aldol or
crotylmetalation protocols is inherently problematic as it
must arise from a disfavored transition state,4,5 where the
reagent adds to the chiral aldehyde in an anti-Felkin manner
(illustrated below for the reaction of 1 with a type 1
crotylmetal reagent).6
In principle, dipropionate 3 can be prepared directly from
1 by using chiral reagents in mismatched double-asymmetric
reactions. Masamune7 and Hoffmann8 have developed highly
enantioselective enol boronate and crotylboronate reagents,
respectively, and have achieved high selectivity for the
anti,anti-dipropionate in challenging mismatched double-
asymmetric reactions. However, the Masamune and Hoff-
mann reagents require several steps to prepare. Addition-
ally, Marshall9 and Panek10 have demonstrated that chelate-
controlled addition of chiral allenylstannane and crotylsilane
reagents to R-methyl-â-benzyloxy-substituted aldehydes pro-
vide anti,anti-dipropionate 3 selectively. Here also, the
Marshall and Panek reagents require multistep prepara-
tions. Other strategies for the synthesis of the anti,anti-
dipropionate stereotriad have been reviewed.3
We report herein a new approach to this problem involving
the crotylation reaction of R-methyl â-hydroxy aldehydes
with (Z)-crotyltrifluorosilane (5),11 which provides the
anti,anti-dipropionate 7 with excellent selectivity using 2,3-
anti â-hydroxy R-methyl aldehydes 4 as the starting mate-
rial. We report as well an application of this methodology
The crotylation reactions of the 2,3-anti aldehydes 8-10
were generally quite selective for the 3,4-anti-4,5-anti dipro-
pionate products 13, 15 and 17 (Table 1, entries 1-5). The
diastereoselectivity ranged from 96:4 to 94:6 for 8a and 9a ,b
to 85:15 for 8b and 82:18:6 for 10. The reaction diastereo-
selectivity and yield were affected only slightly with changes
(1) Address correspondence to this author at the Department of Chem-
istry, University of Michigan, Ann Arbor, MI 48109-1055.
(2) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987, 26, 489.
(3) Hoffmann, R. W.; Dahmann, G.; Andersen, M. W. Synthesis 1994,
629.
(4) Roush, W. R. J . Org. Chem. 1991, 56, 4151.
(5) Roush, W. R.; Palkowitz, A. D.; Ando, K. J . Am. Chem. Soc. 1990,
112, 6348.
(6) Roush, W. R. In Comprehensive Organic Synthesis; Heathcock, C.,
Ed.; Pergamon Press: Oxford, 1991; Vol. 2; p 1.
(7) Tanimoto, N.; Gerritz, S. W.; Sawabe, A.; Noda, T.; Filla, S. A.;
Masamune, S. Angew. Chem., Int. Ed. Engl. 1994, 33, 673.
(8) Hoffmann, R. W.; Dresely, S. Chem. Ber. 1989, 122, 903.
(9) Marshall, J . A.; Perkins, J . F.; Wolf, M. A. J . Org. Chem. 1995, 60,
5556.
(14) Reetz, M.; J ung, A. J . Am. Chem. Soc. 1983, 105, 4833.
(15) Kira, M.; Sato, K.; Sekimoto, K.; Gewald, R.; Sakurai, H. Chem. Lett.
1995, 282.
(16) Gewald, R.; Kira, M.; Sakkurai, H. Synthesis 1996, 111.
(17) Wang, Z.; Meng, X.-J .; Kabalka, G. W. Tetrahedron Lett. 1991, 32,
1945.
(18) Kira, M.; Hino, T.; Sakurai, H. Tetrahedron Lett. 1989, 30, 1099.
(19) Kira, M.; Kobayashi, M.; Sakurai, H. Tetrahedron Lett. 1987, 28,
4081.
(10) J ain, N. F.; Takenaka, N.; Panek, J . S. J . Am. Chem. Soc. 1996,
118, 12475.
(11) Sato, K.; Kira, M.; Sakurai, H. J . Am. Chem. Soc. 1989, 111, 6429.
(12) Brooks, H. A.; Garoner, D.; Poyser, J . P.; King, T. J . J . Antibiot.
1984, 37, 1501.
(13) Radics, L.; Incze, M.; Ujszaszy, K.; Schade, W.; Roth, M. J . Antibiot.
1984, 37, 836.
(20) Kira, M.; Sato, K.; Sakurai, H. J . Am. Chem. Soc. 1990, 112, 257.
(21) Lower yields of the homoallylic alcohol products were obtained when
1 or 2 equiv of 5 was used. Use of 1-8 equiv of (Z)-crotyltrifluorosilane had
no effect on the reaction diastereoselectivity.
(22) Rychnovsky, S. D.; Skalitzky, D. J . J . Org. Chem. 1992, 57, 4336.
S0022-3263(98)00387-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/27/1998