Scheme 1
Scheme 3a
a (a) (S,S)-Diisopropyltartrate modified (E)-crotylboronate, 4 Å
molecular sieves, - 78 °C, 3 h, then -20 °C, 10 h, aq NaOH; (b)
TIPSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 6-12 h; (c) 5% Pd/C,
H2, rt, 12 h; (d) PPTS, EtOH, 55 °C, 16 h; (e) (COCl)2, DMSO,
CH2Cl2, -78 °C, 30 min, Et3N, -78 to -20 °C, 30 min.
two steps. Reversing the sequence of the last two reactions
led to epimerization at C12.10 Selective cleavage of the
primary TBS group with catalytic PPTS in EtOH and Swern
oxidation of the primary alcohol gave the aldehyde Fragment
B.
Transformation of this imide to the Weinreb amide was
achieved by treatment with AlMe3 and Me(OMe)NH‚HCl.
Addition of 2.5 equiv of 2-propenylmagnesium bromide at
Fragment B was elaborated to homoallylic alcohol 10 via
BF3‚OEt2-mediated crotylstannane addition in 97% yield with
96:4 diastereomeric ratio. Keck has shown that silyl protec-
tion at the hydroxyl group â to the aldehyde functionality is
necessary for the high syn-syn diastereoselectivity seen in
this type of reaction.11 TBS protection of the homoallylic
alcohol, followed by ozonolysis and treatment with dimethyl
sulfide, gave the aldehyde 11, which was further elaborated
to the acetylene 12 using the method of Corey and Fuchs.12
Silylcupration13 of the acetylene 12 gave a vinylsilane, which
was converted with retention of configuration into the vinyl
iodide fragment C with NIS14 in 90% yield over the two
steps (Scheme 4).
Scheme 2a
a (a) Bu2BOTf, Et3N, CH2Cl2, 0 °C, 45 min; BnOCH2CHO, -78
°C, 3 h, H2O2; (b) Me3Al, Me(MeO)NH‚HCl, THF, 0 °C, 3 h; (c)
2-propenylmagnesium bromide, -78 °C, 1 h, -30 °C, 2 h; (d)
Me4NBH(OAc)3, MeCN/AcOH (1:1, v/v), -20 °C, 48 h; (e) 2,2-
dimethoxypropane, PPTS, rt, 2 h.
Scheme 4a
-30 °C proceeded smoothly to furnish the enone 6 in 90%
yield over two steps. Evans 1,3-anti reduction8 with Me4-
BH(OAc)3 gave the anti diol, which was converted to the
acetonide fragment A using Me2C(OMe)2/PPTS.
The synthesis of Fragment C employs Roush’s matched
double asymmetric reaction between the known aldehyde 7
and the (S,S)-diisopropyl tartrate derived (E)-crotylboronate
to give the homoallylic alcohol 8 in 85% yield with 97:3
diastereoselectivity (Scheme 3).9
a (a) (E)-Crotyl tributylstannane, BF3‚OEt2, -98 °C to rt 8 h;
(b) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt, 16 h; (c) O3, CH2Cl2/
MeOH (1:1, v/v), -78 °C, then Me2S, -78 °C to rt, 3 h; (d) CBr4,
The homoallylic alcohol 8 was protected as its TIPS ether,
and hydrogenation gave the disilyl ether 9 in 98% yield over
n
Ph3P, 0 °C, 30 min, 11, 0 °C, 4 h; (e) BuLi, -78 to 0 °C, 2 h,
MeI, 0 °C to rt, 12 h; (f) PhMe2SiLi, CuCN, 0 °C, 40 min, 12, 0
°C, 1 h; (g) N-iodosuccinimide, MeCN/THF (4:1, v/v) rt, 16 h.
(7) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J.
Am. Chem. Soc. 1990, 112, 7001.
(8) Evans, D. A.; Chapman, K. T.; Carreira, E. J. J. Am. Chem. Soc.
1988, 110, 3560.
(9) Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J. J. Org. Chem.
1987, 52, 316.
Stereoselective hydroboration of the acetonide fragment
A with 9-BBN gave the borane 3. This step installed C4
2044
Org. Lett., Vol. 4, No. 12, 2002