TES group removed under acidic conditions to give cycliza-
tion precursor 10 (93% yield from 9).
Table 2. Dihydroxylation of Dihydropyran 11
With hydroxy mesylate 10 in hand, we turned our attention
to the cyclization of 10 to dihydropyran 11. This transforma-
tion was complicated by a competing elimination pathway
(Table 1). Initial attempts to effect the cyclization of 11 using
entry
conditions
yield (%)
dr
Table 1. Cyclization of Mesylate 10 to Dihydropyran 11
1
2
OsO4, NMO, acetone-H2O
K2OsO2(OH)4, DHQD-IND, K3FeCN6,
K2CO3, t-BuOH-H2O
80
97
1.6:1
3:1
3
OsO4, TMEDA, CH2Cl2, -78 °C
75
9:1
DHQD-IND ligand,16 provided a slight increase in selectivity
(dr 3:1). We found, however, that the diastereoselectivity
could be further improved through the use of stoichiometric
OsO4 and TMEDA in CH2Cl2 -78 °C,17 which provided
tetrahydropyran 3 in 75% yield and with 9:1 diastereo-
selectivity (entry 3, Table 2).
Synthesis of the C(43)-C(67) polyene fragment was
initiated by protection of 3 as the bis-PMB ether followed
by deprotection of the TBDPS group, which delivered
primary alcohol 13 in 94% yield (Scheme 2). Oxidation of
yield of
entry
conditions
10/11/12a 11 (%)
1
2
3
4
5
KHMDS, THF, -78 °C
26:0:74
74:0:26
30:54:16
23:50:27
0:85:15
(Bu3Sn)2O, benzene; DMF 80 °C
(Bu3Sn)2O, benzene; NMP 150 °C
KOtBu, t-BuOH; 40 °C (0.05 M)
KOtBu, t-AmOH, 0 °C (0.03 M)
36
41
80
1
a Ratio determined by H NMR analysis.
Scheme 2. Synthesis of Aldehyde 15
a strong base such as KHMDS resulted in exclusive
formation of diene 12 (entry 1, Table 1). We anticipated7
that use of the less basic tributylstannyl ether13 generated
from alcohol 10 would minimize elimination and favor the
cyclization to dihydropyran 11. However, the requisite
tributylstannyl ether, prepared by treatment of 10 with (Bu3-
Sn)2O in benzene, was not sufficiently nucleophilic to
undergo cyclization at 80 °C. Although the cyclization
occurred at higher temperatures (150 °C), significant de-
composition was observed and only poor yields of 11 were
obtained (entry 3, Table 1). After examining a number of
other bases, we discovered that KO-t-Bu in protic solvents,
under high dilution conditions, gave attractive mixtures
(2:1) of 11 relative to the diene 12. Further optimization of
the reaction solvent (tert-amyl alcohol), temperature (0 °C),
and concentration (0.03 M) provided 11 and 12 with 85:15
selectivity (entry 5, Table 1). Dihydropyran was obtained in
80% isolated yield under these conditions.
13 using the Swern protocol18 and treatment of the resulting
aldehyde with vinylmagnesium bromide gave allylic alcohol
14 in 91% yield as a 2:1 mixture of diastereomers. Subjection
of this mixture to a Johnson ortho ester Claisen rearrange-
ment19 followed by DIBAL reduction of the resulting ester
provided aldehyde 15 in 70% yield.
We turned next to the dihydroxylation reaction required
to set the final stereocenters in tetrahydropyran 3. Unfortu-
nately, only a slight preference for dihydroxylation on the
bottom face of 11 was observed (dr 1.6:1) under standard
OsO4/NMO conditions (entry 1, Table 2).14 Attempts to
improve the facial selectivity, through the use of the
Sharpless asymmetric dihydroxylation protocol15 with the
(15) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(16) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568.
(17) (a) Tomioka, K.; Nakajima, M.; Koga, K. J. Am. Chem. Soc. 1987,
109, 6213. (b) Wang, Y.; Babirad, S. A.; Kishi, Y. J. Org. Chem. 1992,
57, 468. (c) Donohoe, T. J.; Moore, P. R.; Waring, M. J.; Newcombe, N.
J. Tetrahedron Lett. 1997, 38, 5027.
(13) (a) Davies, A. G. Organotin Chemistry; Wiley-VCH: Weinheim,
1997. (b) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643.
(14) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
(18) Tidwell, T. T. Org. React. 1990, 39, 297.
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