dihydropyran when using syn-(Z)-crotylsilane 4.15 These
results may suggest that the silicon adopts a pseudoequatorial
orientation for silane 4 (II avoids potential A1,3 destabilizing
interactions arising from a (Z)-olefin and axial silicon III)16
giving the major diastereomer17 as shown in Scheme 4 (I
Table 1. [4 + 2]-Annulation with (Z)-Crotylsilanes 3 and 4
Scheme 4. Comparison of (E)- and (Z)-Crotylsilanes in [4 +
2]-Annulation
gives 6 and II gives 8).18,19
a Reaction of 3 was run in CH2Cl2 (0.05 M) using 1-2 equiv of aldehyde
in the presence of triflic acid (1.0 equiv) at -78 °C unless otherwise noted.
b Reaction of 4 was run in CH2Cl2 (0.05 M) using 1-2 equiv of aldehyde
in the presence of triflic acid (1.0 equiv) at -90 °C unless otherwise noted.
c Stereochemical assignments were determined through NOE and direct
comparison with known materials from ref 3. d All yields are based on
isolated product after purification by chromatography. e The ratio of products
Having established an efficient means to access both 2,6-
cis-5,6-cis and 2,6-trans-5,6-cis dihydropyran systems, we
then applied the annulation strategy in the synthesis of the
C1-C13 fragment of bistramide A.
Bistramide A (17) was first isolated in 1988 from
Lissoclinum bistramide sluiter.20 It belongs to a class of
natural products21 that has been known to display high neuro-
and cytotoxic properties22 as well as profound effects on cell
cycle regulation.23 Its potent activity along with its chal-
1
is determined by H NMR (400 MHz).
diastereoselectivities.13 Reaction conditions required for the
annulation are compatible with a number of functional groups
such as ethers (Table 1, entry 5 and 10), primary alkyl
bromides (Table 1, entry 7), alkenes (Table 1, entry 6), nitro
groups (Table 1, entries 9 and 10), and ketones (Table 1,
entry 8). In addition, R-branched substrates (Table 1, entries
2 and 3) participate in the described annulation albeit with
some loss of diastereoselectivity. Some aromatic aldehydes
(Table 1, entries 9 and 10) are also effective in the annulation.
Interestingly, the stereochemical outcome of the annula-
tions reported in Table 1 was not entirely anticipated.
Previous results with (E)-crotylsilanes gave a 2,6-cis-
dihydropyran 5 with the syn-(E)-crotylsilane 1 and 2,6-trans-
dihydropyran 6 for the anti-(E)-crotylsilane 2 (Scheme 1).14
In the case of the (Z)-crotylsilanes, a 2,6-cis-dihydropyran
was observed for anti-(Z)-crotylsilane 3 and a 2,6-trans-
(15) Enantiomeric excess (ee) analysis was preformed using chiral HPLC
analysis with a CHIRALCEL OD column. See the Supporting Information.
(16) It has been suggested that silicon prefers an axial orientation for
both electronic and steric reasons but may still eliminate even without
optimal orbital overlap. For a detailed discussion and relevant examples,
see: Lambert, J. B. Tetrahedron 1990, 46, 2677.
(17) Intramolecular silyl-modified Sakurai condensations of vinylsilanes
suggest allylic strain plays a role in stereochemical outcome: Bayston, D.
J.; Chelle, F.; Scheirmann, V.; Dobbs, A. P.; Marko´, I. E. Tetrahedron Lett.
1997, 38, 2899.
(18) It is conceivable that an oxonia-Cope rearrangement could play a
role in the stereochemical outcome of these reactions; however, no
byproducts from this pathway were observed. For an example of oxonia-
Cope rearrangements in allyl systems, see: Roush, W. R.; Dilley, G. J.
Synlett 2001, SI, 955.
(19) For an example of oxonia-Cope rearrangement of ester-substituted
oxycarbenium vinylsilanes to form dihydropyrans, see ref 2b.
(20) Gouiffes, D.; Moreau, S.; Helbecque, N.; Bernier, J. L.; Henichart,
J. P.; Barbin, Y.; Laurent, D.; Verbist, J. F. Tetrahedron 1988, 44, 451.
(21) (a) Biard, J. F.; Roussakis, C.; Kornprobst, J. M.; Gouiffes-Barbin,
D.; Verbist, J. F.; Cotelle, P.; Foster, M. P.; Ireland, C. M.; Debitus; C. J.
Nat. Prod. 1994, 57, 1336. (b) Foster, M. P.; Mayne, C. L.; Dunkel, R.;
Pugmire, R. J.; Grant, D. M.; Kornprobst, J. M.; Verbist, J. F.; Biard, J. F.;
Ireland, C. M. J. Am. Chem. Soc. 1992, 114, 1110. (c) Degnan, B. M.;
Hawkins, C. J.; Lavin, M. F.; McCaffrey, E. J.; Parry, D. L.; Watters, D.
J. J. Med. Chem. 1989, 32, 1354.
(13) Minor amounts of side products of the reaction include homo-aldol
coupling followed by dehydration and Peterson olefination to give the
conjugated esters of 3 and 4.
(14) For an interpretation of the stereochemical course of (E)-crotylsilanes
in the [4 + 2]-annulations, see: Huang, H. Ph.D. Thesis, Boston University,
2005.
Org. Lett., Vol. 7, No. 15, 2005
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