of a tandem alkynylation-methylation reaction of 1,1-
dibromo-1-alkenes, recently reported by us.18 To this end,
aldehyde 9 was subjected to the Corey-Fuchs reaction6 (98%
yield). The product was first alkynylated with BrZnCt
CSiMe3 in the presence of 5% Cl2Pd(DPEphos), where
DPEPhos is bis(o-diphenylphosphinophenyl) ether, and 10%
DIBAL-H in 75% yield; subsequent methylation with Me2-
Zn in the presence of Pd(tBu3P)2 in quantitative yield,
followed by desilylation with K2CO3 and MeOH (98% yield),
gave 11 (>98% stereoisomerically pure) in 72% combined
yield over three steps from 9. The combined yield indicated
above is the same as that shown in Scheme 2. We judge
that the two procedures are of comparable merits.
Scheme 2a
a Reagents and conditions: (a) TBSCl, DMAP, imidazole. (b)
AD-mix-R. (c) NalO4; 90% (over three steps); (d) (i) Et3SiCLiMe-
CHdNCy, THF, -20 °C; (ii) CF3CO2H, 0 °C; 80%. (e) CBr4, PPh3,
For a convergent final assembly of the carbon framework
of 6,7-dehydrostipiamide, ethyl (2E,4E)-2-methyl-2,4-hep-
tadien-6-ynoate (12) was prepared, as recently reported by
us.19 Thus, (E)-1-bromo-4-trimethylsilyl-1-buten-3-yne,20
obtained in 81% yield by treating commercially available
(Aldrich) (E)-ICHdCHBr with Me3SiCtCZnBr in the
presence of 2% Pd(PPh3)4, was successively treated with
tBuLi (2.0 equiv) in ether, ZnBr2, THF, and (E)-BrCHd
C(Me)COOEt in the presence of 2% Cl2Pd(PPh3)2 and 4%
DIBAL-H in THF (95% yield). After desilylation with K2-
CO3 and EtOH, 12 was obtained in 76% combined yield
over three steps from (E)-ICHdCHBr, Me3SiCtCZnBr, and
(E)-BrCHdC(Me)CO2Et. The 13C NMR spectrum of 12
indicated it to be >98% E,E. For the critical cross-coupling
between 8 and 12, 12 was first converted to its Zn derivative
(13) via lithiation with LDA (1 equiv) in THF, followed by
treatment with dry ZnBr2 in THF. Its cross-coupling with 8,
in the presence of 5% Cl2Pd(PPh3)2 and 10% DIBAL-H,2
proceeded cleanly to give 14 (>99% isomerically pure) in
94% yield. Thus, the synthesis of 14 was achieved in 29%
yield over 12 steps in the longest linear sequence (Schemes
1-3).
n
Zn. (f) (i) BuLi; (ii) NH4Cl; 90%.
configuration may be tentatively, but safely, assigned to the
major isomer on the basis of the use of (+)-(E)-(CH3CHd
CHCH2)BIpc2,4 and the diastereomeric ratio of g30:1
mandates that the configuration at both C3 and C4 is g97%
R.
Although the S and R configurations at C7 were indistin-
guishable by 1H NMR spectroscopy (vide supra), 13C NMR
spectra of crudely isolated 5 showed two sets of signals
separated by at least 0.1 ppm for eight carbon atoms,
including C7 (δ 31.79 (S) and 31.96 (R), S:R ) 9:1). Column
chromatography (silica gel, 1/25 ethyl acetate/hexanes)
provided 5 (g80:1 dr) in 80% yield from 7. Thus, the
stereoisomeric purity at C7 was improved to g99% S by
simple chromatography, and the overall enantiomeric purity
of 5 may safely be estimated to be >99.9% ee.
Conversion of 5 into another key intermediate 8 was
achieved in seven steps in 56% combined yield. Protection
of 5 with tBuMe2SiCl (TBSCl) proceeded in 96% yield, and
the resultant product was converted to aldehyde 9 by two
successive oxidations; first with AD-mix-R16 (Aldrich), and
then with NaIO4, as reported previously,1 in 94% combined
yield. Conversion of 9 into 10 was achieved by using the
Corey-Peterson olefination in 80% yield (>99% E). The
Corey-Fuchs reaction6 of 10 with CBr4, PPh3, and Zn (98%
As recently reported by us,19 12 can be converted to
(E,E,E)-BrCHdCHCtCCHdCHCHdC(Me)COOEt (15) in
82% yield by the Pd-catalyzed reaction of the zinco deriva-
tive of 12 with (E)-ICHdCHBr. We therefore sought a more
convergent and potentially superior route to 14 through the
use of 15. To this end, 9 was converted to >99% pure 16
via the Corey-Fuchs reaction in 96% yield over two steps
(Scheme 4). To our disappointment, however, hydrozircona-
tion of 16 with HZrCp2Cl (2 equiv),21 followed by successive
addition of ZnCl2 (2 equiv), 15 (1.2 equiv), and a catalyst
consisting of 5 mol % Cl2Pd(PPh3)2, 10 mol % tris(o-furyl)-
phosphine (TFP), and 10 mol % DIBAL-H in THF at 23 °C
for 20 h, led to the formation of the desired compound 14
only in 57% yield. Upon iodinolysis of the hydrozirconation
mixture derived from 16, the corresponding 2-iodo derivative
17 and its 3-iodo isomer were isolated in 74 and 18% yields,
respectively, after chromatographic separation. The formation
of the unwanted regioisomer must be partially responsible
for the low yield of 14. To probe this issue further, the
n
yield), treatment of the product with BuLi followed by
acidification to give 11 (92% yield), and its hydrozircona-
tion-iodinolysis (86% yield) provided 8 as a g99% iso-
merically pure compound (Scheme 2).
In the previously reported synthesis of stipiamide and 6,7-
dehydrostipiamide,1 10 was directly converted to 8 by the
reaction of 10 with CHI3 and CrCl217 in 70% yield. It reduces
the number of steps by two but also reduces the yield by
7%. In our hands, an E/Z ratio of approximately 5 was
observed, and a concern about the scalability of the process
was also expressed.1 We also investigated the applicability
(16) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483. (b) Andrus, M. B.; Lepore, S. D.; Sclafani, J. A.
Tetrahedron Lett. 1997, 38, 4043.
(17) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(18) Shi, J.; Zeng, X.; Negishi, E. Org. Lett. 2003, 5, 1825.
(19) Negishi, E.; Qian, M.; Zeng, F.; Anastasia, L.; Babinski, D. Org.
Lett. 2003, 5, 1597.
(20) Zeng, F.; Negishi, E. Org. Lett. 2001, 3, 719.
(21) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912.
Org. Lett., Vol. 6, No. 19, 2004
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