Stereoselective synthesis of functionalized dihydropyrans via a formal [4+2]-annulation of chiral crotylsilanes [1]

Full text of DOI:10.1021/ja002087u

9836
J. Am. Chem. Soc. 2000, 122, 9836-9837
Communications to the Editor
enantiomers of silanes 1a and 1b are available,9 four possible
cis-2,6- and trans-2,6-dihydropyrans can be prepared.
This study was initiated with the notion that chiral silanes of
1 would show similar characteristics for the intramolecular
crotylation reactions as we have previously documented in an
intermolecular process.10 In initial experiments, silanes 1a and
1b and aldehydes were found to cyclize to 2,5,6-trisubstituted
Stereoselective Synthesis of Functonalized
Dihydropyrans via a Formal [4+2]-Annulation of
Chiral Crotylsilanes
Hongbing Huang and James S. Panek*
Department of Chemistry and Center for Streamlined Synthesis
Metcalf Center for Science and Engineering
590 Commonwealth AVenue, Boston UniVersity
Boston, Massachusetts 02215
ReceiVed June 12, 2000
As a consequence of their frequent occurrence in natural
products with useful biological activities,1 numerous methods have
been devised for the synthesis of functionalized pyran ring
systems.2 Methods available for the asymmetric synthesis of
hydropyrans include hetero Diels-Alder cycloaddition,3 SN2
cyclization,4 dioxanone Claisen rearrangement,5 and ring closing
metathesis.6 Another useful approach to these oxygen heterocycles
utilizes vinylsilane-terminated cyclization of oxocarbenium ions.7
In a related development in this area, the preparation of tetrahy-
dropyrans by C-C bond construction using Prins cyclization has
emerged as a useful approach.8 Although these methods are
capable of achieving useful levels of diastereoselectivity for the
synthesis of cis-2,6-substituted pyrans, there are few reported
methods concerning the synthesis of the complementary trans-
2,6-substituted isomers.6b,8
Methodologies that provide ready access to enantiomerically
enriched cis-2,6- and trans-2,6-dihydropyrans would make a
useful contribution to this area. In this communication we describe
a new use of the illustrated silanes in a highly diastero- and
enantioselective process for the preparation of functionalized
dihydropyrans. These experiments underscore the important role
of the silicon-bearing center as a dominant stereocontrol element
in these heterocyclizations (eq 1 and 2). Also, since both
dihydropyrans in the presence of a catalytic amount of TMSOTf
(0.1 equiv) in CH2Cl2 (0.3 M, 0 °C).11 However, significant
amounts of protodesilylation products were also observed.
Performing the reaction at lower temperature and at a decreased
concentration provided the best results (CH2Cl2, 0.05 M, -20 oC).
Importantly, the annulation proceeded with high levels of enan-
tioselectivity, providing optically active dihydropyrans in up to
98% ee by a direct coupling-cyclization of the silanes with a
wide range of aldehydes.12 Accordingly, the relative stereochem-
ical relation of the individual silane diastereomers was evaluated
for the effect of silane configuration on diastereoselection. Of
the cases examined, the level of diastereoselectivity is independent
of which silane isomer is used. However, there appears to be a
correlation between aldehyde structure and reaction diastereo-
selectivity. Conjugated aldehydes generally gave higher selectivity
(Table 1, entries 4 and 7-9), while selectivity from alkyl
aldehydes was somewhat lower (Table 1, entries 1-3).
Considering that TMSOTf is a highly reactive and reliable
O-silylating agent, we anticipated that the in situ formation of a
R-silyl group on silane 1c could also lead to the desired
dihydropyran via trapping of the same oxocarbenium ion.
Experiments using silane 1c effectively cyclized to dihydropyrans
in the presence of 1 equiv of TMSOTf (Table 1, entries 10-12).
Similar levels of diastereoselectivity were achieved.
(1) (a) Westly, J. W., Ed. Polyether Antibiotics; Marcel Dekker: New York,
1983; Vols. I and II. (b) Dobler, M. Ionophors and Their Structures; Wiley-
Interscience: New York, 1981. (c) Faulkner, D. J. Nat. Prod. Rep. 2000, 17,
7-55 and earlier reviews in this series.
(2) Recent examples, see: (a) Angle, S. R.; El-Said, N. A. J. Am. Chem.
Soc. 1999, 121, 10211-10212 (b) Trost, B. M.; Li, C. J. J. Am. Chem. Soc.
1994, 116, 10819-10820. (c) Danishefsky, S. J.; DeNinno, S.; Lartey, P. J.
Am. Chem. Soc. 1987, 109, 2082-2089.
(3) (a) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 2398-2400. (b) Danishefsky, S. J.; Selnick, H. G.;
Zelle, R. E.; DeNinno, M. P. J. Am. Chem. Soc. 1988, 110, 4368-4378. (c)
Danishefsky, S. J.; DeNinno, M. P. Angew. Chem., Int. Ed. Engl. 1987, 26,
15-23.
(4) (a) Mandai, T.; Ueda, M.; Kashiwagi, K.; Kawada, M.; Tsuji, J.
Tetrahedron Lett. 1993, 34, 111-114. (b) Martin, V. S.; Nunez, M. T.;
Ramirez, M. A.; Soler, M. A. Tetrahedron Lett. 1990, 31, 763-766.
(5) (a) Burke S. D.; Armistead, D. M.; Schoenen, F. J. J. Org. Chem. 1984,
49, 4320-4322. (b) Burke, S. D.; Armistead, D. M.; Schoenen, F. J.
Tetrahedron 1986, 42, 2787-2801.
(6) (a) Mulzer, J.; Hanbauer, M. Tetrahedron Lett. 2000, 41, 33-36 and
references therein. (b) Burke, S. D.; Ng, R. A.; Morrison, J. A.; Alberti, M.
J. J. Org. Chem. 1998, 63, 3160-3161.
(7) For recent examples, see: (a) Semeyn, C.; Blaauw, R. H.; Hiemstra,
H.; Speckamp, W. N. J. Org. Chem. 1997, 62, 3426-3427. (b) Marko, I. E.;
Dobbs, A. P.; Scheirmann, V.; Chelle, F.; Bayston, D. J. Tetrahedron Lett.
1997, 38, 2899-2902.
Although vinylsilanes have been employed to promote cy-
clizations in the synthesis of oxygen- and nitrogen-containing six-
membered rings, the possibility of accessing a Cope rearrangement
pathway can compromise the reaction diastereoselectivity.8,13 In
the present case, both diastereomers 1a and 1b afford good to
(9) Beresis, R. T.; Solomon, J. S.; Yang, M. G.; Jain, N. F.; Panek, J. S.
Org. Synth. 1997, 75, 78-86.
(10) (a) Panek, J. S.; Yang, M.; Xu, F. J. Org. Chem. 1992, 57, 5790-
5792. Related silyl modified Sakurai reaction, see: (b) Mekhalfia, A.; Marko,
I. E. Tetrahedron Lett. 1991, 32, 4779-4782. (c) Marko, I. E.; Mekhalfia,
A.; Bayston, D. J.; Adams, H. J. Org. Chem. 1992, 57, 2211-2213.
(11) For the preparation of R-substituted (E)-crotylsilanes, see: (a) Sparks,
M. A.; Panek, J. S. J. Org. Chem. 1991, 56, 3431-3438. (b) Panek, J. S.;
Yang, M.; Solomon, J. S. J. Org. Chem. 1993, 58, 1003-1010.
(12) Enantiomeric excess (ee) analysis was conducted by chiral HPLC
analysis. The detailed experimental procedure including ee analysis can be
found in the Supporting Information.
(8) For recent examples, see: (a) Cloninger, M. J.; Overman, L. E. J. Am.
Chem. Soc. 1999, 121, 1092-1093. (b) Viswanathan, G. S.; Yang, J.; Li, C.
J. Org. Lett. 1999, 1, 993-995. (c) Rychnovsky, S. D.; Hu, Y.; Ellsworth, B.
Tetrahedron Lett. 1998, 39, 7271-7274. (d) Coppi, L.; Ricci, A.; Taddei, M.
J. Org. Chem. 1988, 53, 911-913. (e) Wei, Z. Y.; Wang, D.; Li, J. S.; Chan,
T. H. J. Org. Chem. 1989, 54, 5768-5774.
(13) (a) Castro, P.; Overman, L. E.; Zhang, X.; Mariano, P. S. Tetrahedron
Lett. 1993, 34, 5243-5246. (b) Daub, G. W.; Heerding, D. A.; Overman, L.
E. Tetrahedron 1988, 44, 3919-3930.
10.1021/ja002087u CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/21/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 40, 2000 9837
Table 1. Asymmertic Synthesis of Substituted Dihydropyrans via
Chiral Silanes
Scheme 2
a Stereochemistry assigned by NOE experiments. b All yields are
based on pure materials isolated by chromatography on SiO2. c The
ratio of products was determined by 1H NMR (400 MHz), operating at
an S/N ratio of >200:1.
I and II, cyclization of I proceeds faster than that of conformer
II leading to the cis-trans dihydropyran 2.
Scheme 1
Since 1b provides the trans-trans dihydropyran, the observed
selectivity may be rationalized through cyclization of conformer
III (Scheme 2), which positions the silyl group and the neighbor-
ing ester group in anti orientation to each other. Because the silyl
group possesses considerable size, this pathway may be favored
from both steric and electronic considerations. Accordingly, the
minor all cis isomer can be rationalized with the boatlike transition
state IV, which reverses oxocarbenium ion π-face selectivity. In
this arrangement a severe, nonbonding destabilizing interaction
is created between the aldehyde substituent and the vinyl methyl
group. The higher level of diastereoselectivity obtained with
conjugated aldehydes can be attributed to the stabilization of
oxycarbenium ions through an electron-delocalizing resonance
effect, which may imply that the process of cyclization is under
thermodynamic control.
excellent diastereoselectivity (Table 1). The cyclization of syn-
1a produced the cis-2,6-trans-5,6-trisubstituted dihydropyrans with
trans-2,6-trans-5,6-trisubstituted dihydropyrans as minor diaster-
eomers; meanwhile the cyclization of anti-1b provided trans-
2,6-trans-5,6-trisubstituted dihydropyrans as the major isomers
with all cis dihydropyrans as minor products.
Using chiralsilane reagents, we have developed an efficient
method to synthesize stereochemically well-defined cis-2,6- and
the complementary trans-2,6-dihydropyrans. In principle, tet-
rahydropyrans containing up to five stereocenters can be as-
sembled after functionalization of the double bond.
Results from these experiments demonstrate that the config-
uration of the silane reagent controls the stereochemical course
of the cyclization, which can be rationalized through an anti-SE′
mode of addition.14 As illustrated in a key mechanistic feature of
our hypothesis (Scheme 1), for effective σ-p overlap in the
cyclization step of 1a, we suggest a pseudoaxial orientation for
the silyl group is favored in a boatlike transition state.14b,15 As a
result, for the two equilibrating conformers of oxocarbenium ion
Acknowledgment. Financial support was obtained from the NIH/
NCI (R01CA56304). The authors are grateful to Dr. Scott Schaus
(Harvard) for useful discussions.
Supporting Information Available: General experimental procedures
including spectroscopic and analytical data (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA002087U
(14) (a) Matassa, V. G.; Jenkins, P. R.; Kumin, A.; Damm, L.; Schreiber,
J.; Felix, D.; Zass, E.; Eschenmoser, A. Isr. J. Chem. 1989, 29, 321-343. (b)
Denmark, S. E.; Weber, E. J.; Wilson, T. M. Tetrahedron 1989, 45, 1053-
1065.
(15) Lambert, J. B. Tetrahedron 1990, 46, 2677-2689 and references
therein.