Stereoselective Synthesis of Dihydropyrans via Vinylsilane-Terminated Cyclizations of Ester-Substituted Oxycarbenium Ion Intermediates

Full text of DOI:10.1021/jo970369f

3426
J . Org. Chem. 1997, 62, 3426-3427
Ta ble 1. Syn th esis a n d Cycliza tion of (E)-Vin ylsila n es
Ster eoselective Syn th esis of Dih yd r op yr a n s
via Vin ylsila n e-Ter m in a ted Cycliza tion s of
Ester -Su bstitu ted Oxyca r ben iu m Ion
In ter m ed ia tes
Cindy Semeyn, Richard H. Blaauw,
Henk Hiemstra,* and W. Nico Speckamp*
Amsterdam Institute of Molecular Studies, Laboratory of
Organic Chemistry, University of Amsterdam, Nieuwe
Achtergracht 129, 1018 WS Amsterdam, The Netherlands
alcohol acetal
product
(yield, %;
cis/trans ratio)
(yield,
(yield,
Lewis
acid
entry
R
%)a
%)b
Received February 28, 1997
1
2
3
4
5
H
3 (53)c
4 (37)
c-C6H11 5 (60)
8 (51) BF3‚OEt2 13 (62)
Six-membered ring saturated oxygen heterocycles are
an integral part of many biologically active compounds.1
Notable examples, apart from the regular carbohydrates,
are the 2-carboxytetrahydropyrans KDO2 and DAHP3
and the neuraminic acids.4 The 2,6-disubstituted dihy-
dropyrans 1 and 2 (eq 1) are potential starting materials
toward this compound class, as both the double bond and
the ester group enable multiple structural variations.
Me
9 (47) BF3‚OEt2 14 (73; 30:70)
10 (65) BF3‚OEt2 15 (94; 11:89)
t-Bu
6 (60)
7 (60)
11 (76) SnCl4
12 (57) BF3‚OEt2 17 (66; 72:28) +
16 (87; 17:83)
Bn
18 (13)d
a
b
Overall yield from the aldehyde. Ca. 1:1 mixture of diaster-
eomers, except for 8. c From paraformaldehyde. For compound
d
18 see eq 2.
Ta ble 2. Syn th esis a n d Cycliza tion of (Z)-Vin ylsila n es
Cyclic oxycarbenium ions with a carboxyl substituent
on the cationic carbon atom have been implicated as
important intermediates in biological processes.5 We
have shown that acyclic ester-substituted oxycarbenium
ions are useful, highly electrophilic intermediates in
organic synthesis.6 We now wish to report our results
on cyclizations via such intermediates that are termi-
nated by vinylsilane nucleophiles and lead to the dihy-
dropyran building blocks 1 and 2. We have discovered a
remarkable influence of the double bond geometry of the
vinylsilane A on the stereochemistry of the product, viz.
(E)-A gives trans product 1, whereas (Z)-A leads to cis
product 2 (see eq 1). Although vinylsilane-terminated
cyclizations via oxycarbenium7 and iminium8 ions have
been widely studied, the above stereoselectivity is un-
precedented.
alcohol acetal
product
(yield, %;
cis/trans ratio)
(yield,
(yield,
Lewis
acid
entry
R
%)a
%)b
1
2
3
Et
19 (41) 23 (71) BF3‚OEt2 27 (69; 93:7)
20 (50) 24 (36) BF3‚OEt2 15 (86; 92:8)
21 (36) 25 (79) BF3‚OEt2 17 (76; 95:5) +
18 (21)c
c-C6H11
Bn
4
CH2OBn 22 (90)d 26 (62) SnCl4
28 (64; >98:2)e
a
b
Overall yield from the epoxide. Ca. 1:1 mixture of diastere-
d
omers. c For compound 18 see eq 2. 92% ee determined by HPLC
for the benzyl ether of (S)-glycidol precursor of 22. e 92% ee,
By using the methodology delineated in Tables 1 and
2, a variety of homoallylic alcohols containing the vinyl-
silane moiety were constructed from easily available
determined by HPLC, [R]25 ) -68.4 (c ) 1.0, toluene).
D
starting materials. The (E)-vinylsilanes 3-7 were pre-
pared by reaction of lithiated allyltrimethylsilane9 with
the corresponding aldehydes (Table 1). Reaction of
lithiated (trimethylsilyl)acetylene with substituted ox-
iranes10 followed by selective cis reduction with P2-Ni11
afforded the (Z)-vinylsilanes 19-21 in reasonable overall
yields (Table 2). Optically active alcohol 22 (entry 4,
Table 2) was prepared in a similar manner from com-
mercially available (S)-glycidol.
The homoallylic alcohols were transformed into the
cyclization precursors 8-12 and 23-26 by a one-pot two-
step procedure involving addition to methyl glyoxylate
and subsequent in situ acetylation of the unstable hemi-
acetal (see Tables 1 and 2).6
* To whom correspondence should be addressed. Tele: +31 20
5255941. Fax: +31 20 5255670. E-mail: henkh@org.chem.uva.nl.
(1) For some examples see: (a) Class, Y. J .; DeShong, P. Chem. Rev.
1995, 95, 1843. (b) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95,
2041. (c) Marko´, I. E.; Bayston D. J . Synthesis 1996, 297.
(2) (a) Gao, J .; Ha¨rter, R.; Gordon, D. M.; Whitesides, G. M. J . Org.
Chem. 1994, 59, 3714. (b) Kragl, U.; Go¨dde, A.; Wandrey, C.; Lubin,
N.; Auge´, C. J . Chem. Soc., Perkin Trans. 1 1994, 119.
(3) (a) Barnes, N. J .; Probert, M. A.; Wightman, R. H. J . Chem. Soc.,
Perkin Trans. 1 1996, 431. (b) Lubineau, A.; Queneau, Y. J . Carbohydr.
Chem. 1995, 14, 1285. (c) Lubineau, A.; Arcostanzo, H.; Queneau, Y.
Ibid. 1995, 14, 1307.
(4) Kuboki, A.; Okazaki, H.; Sugai, T.; Ohta, H. Tetrahedron 1997,
53, 2387 and references therein.
(5) (a) Horenstein, B. A.; Bruner, M. J . Am. Chem. Soc. 1996, 118,
10371 and references therein. (b) Martichonok, V.; Whitesides, G. M.
J . Org. Chem. 1996, 61, 1702.
In most cases, optimal conditions for the cyclization
reactions required BF3‚OEt2 (2 equiv) as the Lewis acid
(6) (a) Lolkema, L. D. M; Hiemstra, H.; Semeyn, C.; Speckamp, W.
N. Tetrahedron 1994, 50, 7115. (b) Lolkema, L. D. M; Semeyn, C.;
Hiemstra, H.; Speckamp, W. N. Ibid. 1994, 50, 7129.
(7) (a) Berger, D.; Overman, L. E. Synlett 1992, 811. (b) Hoffmann,
R. W.; Giesen, V.; Fuest, M. Liebigs Ann. Chem. 1993, 629. (c) Marko´,
I. E.; Bayston, D. J . Tetrahedron 1994, 50, 7141. (d) Blumenkopf, T.
A.; Overman, L. E. Chem. Rev. 1986, 86, 857.
(8) (a) Daub, G. W.; Heerding, D. A.; Overman, L. E. Tetrahedron
1988, 44, 3919. (b) Castro, P.; Overman, L. E.; Zhang, X.; Mariano, P.
S. Tetrahedron Lett. 1993, 34, 5243.
(9) (a) Brandsma, L. Preparative Polar Organometallic Chemistry;
Springer: New York, 1990; Vol. 2, p 116. (b) Ehlinger, E.; Magnus, P.
J . Am. Chem. Soc. 1980, 102, 5004. (c) Chan, T. H.; Labrecque, D.
Tetrahedron Lett. 1992, 33, 7997.
(10) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(11) (a) Brown, C. A.; Ahuja, V. K. J . Chem. Soc., Chem. Commun.
1973, 553. (b) Brown, C. A.; Ahuja, V. K. J . Org. Chem. 1973, 38, 2226.
S0022-3263(97)00369-1 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 11, 1997 3427
Sch em e 1
in dichloromethane as the solvent. The Lewis acid was
added to the reaction mixture at -78 °C, which was then
allowed to slowly warm to room temperature. Interest-
ingly, the tert-butyl-containing precursor 11 did not
cyclize under the influence of BF3‚OEt2. In this case, the
stronger Lewis acid SnCl4 was successful. The latter
Lewis acid was also used for the cyclization of the
optically active precursor 26. The stereochemistry of the
separated cis- and trans-2,6-disubstituted dihydropyrans
was proven by NOE-difference measurements.12
The parent (E)-vinylsilane precursor 8 cyclized in 62%
yield to dihydropyran 13 (entry 1, Table 1). This result
is similar to that reported earlier for a 1:6 E/Z mixture.6
The alkyl-substituted precursors 9-12 cyclized in good
to excellent yields to 2,6-disubstituted dihydropyrans 14-
17 (entries 2-5, Table 1). In most cases, the trans isomer
appeared to be the major product. The cyclization of
precursor 12, however, proceeded differently, giving the
cis isomer of 17 as the major product. Moreover, the
bicyclic byproduct 18 was obtained with high selectivity
for the cis isomer. The latter product results from attack
of the benzyl group on the oxycarbenium ion. To confirm
the feasibility of this type of cyclization, acetals 29 and
30 were prepared from the corresponding commercially
available alcohols (eq 2). The cyclizations of 29 and 30
proceeded in excellent yields to 31 and 32, showing that
the phenyl ring is a good nucleophile for the R-ester
oxycarbenium ion. These reactions led to the cis products
with high stereoselectivity.
proceeded with complete retention of optical activity,
which was proven by chiral HPLC analysis.13
These results show that the geometry of the vinylsilane
double bond is important in determining the cis/trans
ratio of the products. In the sequel to this paper, a
probable mechanism is presented to explain this remark-
able stereoselectivity (see Scheme 1). The oxa-Cope
rearrangement of the cationic intermediate is believed
to play an important role in this mechanism. A second
relevant presumption is the relatively high rate of
cyclization of an allylsilane from a chairlike conformation
with an axially disposed silyl substituent.8 In such an
orientation the â-effect of silicon is most effective.14
The preferred formation of the trans product from the
(E)-vinylsilanes can be understood as follows (Scheme 1).
The incipient carbocation 36 (drawn in its most stable
chairlike conformation) is in equilibrium with 37 via a
cationic oxa-Cope equilibrium. The latter is probably
somewhat more stable in view of the substitution pattern
of the carbocation. However, the cyclization of 37, which
would lead to the cis product, will be slow because the
silyl group is not well oriented to assist in the cyclization.
When 37 undergoes chair-chair interconversion of the
oxycarbenium ion, cation 38 is formed featuring an
allylsilane with an axial silyl function. Cyclization of 38
is a fast process and leads to the trans product.
In the case of the (Z)-vinylsilane, the observed cis
selectivity is the result of cyclization of conformation 34
(see Scheme 1) in which the oxycarbenium ion has the
favorable axially oriented trimethylsilyl group due to the
(Z)-double bond geometry of the precursor.
The cyclization reactions of (Z)-vinylsilane precursors
23-26 were also successful and proceeded in similar
The above mechanistic picture may also serve to
explain the somewhat higher selectivity observed with
(Z)-vinylsilanes than with their (E)-isomers. If we make
the reasonable assumption that the conformational equi-
libria are fast compared to the cyclization reactions, it
means that the relative ease of cyclization of 38 versus
37 is less pronounced than the relative ease of cyclization
of 34 versus 35. This observation seems very sensible
in view of the relative number of axial substituents
destabilizing the transition state of cyclization. The
explanation of the exceptional stereochemical outcome
of the cyclization of 12 (Table 1) requires further study.
yields (Table 2). Interestingly, the cis-2,6-disubstituted
products were obtained with high selectivity (>90:10) in
all cases. Cyclization of the benzyl-substituted (Z)-
vinylsilane 25 resulted in a similar amount of byproduct
18 as was obtained from the(E)-vinylsilane 12. Com-
parison of the cyclizations of 12 and 25 furthermore
shows that in the latter case the selectivity for the cis
product is somewhat higher. The cyclization of 26
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the synthesis (including spectroscopic and analytical
data) of alcohols 5, 20, and 22, precursors 10, 24, and 26, and
all cyclization products (10 pages).
J O970369F
(13) Chiralpak AS column, eluent n-heptane/2-propanol 95:5, flow
0.5 mL/min, 250 × 4.5 mm.
(12) For example, in the case of product 15 irradiation of H2 of the
cis product gave an enhancement of 7% on H6 while similar irradiation
of the trans product showed no effect.
(14) Lambert, J . B. Tetrahedron 1990, 46, 2677 and references cited
therein.