Formation of seven-membered carbocycles by the use of cyclopropyl silyl ethers as homoenols

Article abstract of DOI:10.1002/anie.200601011

(Chemical Equation Presented) Straightforward ring-closure: An expedient entry to seven-membered carbocycles is achieved by the Kulinkovich cyclopropanation of acetal-tethered esters and the subsequent addition of the resulting cyclopropyl silyl ethers to

Full text of DOI:10.1002/anie.200601011

Communications
Carbocycles
DOI: 10.1002/anie.200601011
Formation of Seven-Membered Carbocycles by
the Use of Cyclopropyl Silyl Ethers as
Homoenols**
Oleg L. Epstein, Sejin Lee, and Jin Kun Cha*
The presence of heteroatom substituents on cyclopropanes
enhances their reactivity toward electrophiles. Ring-opening
reactions of cyclopropanols and siloxy derivatives have been
[
1]
extensively investigated. An interesting variation involves
the addition of other functionalities (e.g.,vinyl or ethynyl) to
cyclopropanols,which offers unique composite groups for the
[
2,3]
formation of CꢀC bonds.
The use of a cyclopropanol,
which could be viewed as a “homoenol” or “homoenolate”
equivalent,in the nucleophilic addition to a carbonyl
compound or an acetal,has been limited primarily to 1-
alkoxy-1-siloxycyclopropanes. Little was known about the
cognate homologous aldol or Mukaiyama reaction of parent
[
4]
[
5,6]
cyclopropanols or siloxycyclopropanes.
We report herein
an expedient entry to seven-membered carbocycles by the
Kulinkovich cyclopropanation of acetal-tethered esters and a
subsequent Lewis acid mediated ring expansion of the
resulting cyclopropyl silyl ethers.
In an initial experiment,cyclopropanol 2a was first
prepared in 84–89% yield by the Kulinkovich cyclopropana-
[
7,8]
tion
of commercially available methyl 5,5-dimethoxyval-
erate (1) with ethylmagnesium bromide (Scheme 1). Follow-
ing silylation (96%),treatment of the resulting siloxycyclo-
Scheme 1. Annulation of seven-membered carbocycles. TBS=tert-
butyldimethylsilyl, OTf=trifluoromethanesulfonate.
[*] Dr. O. L. Epstein, Dr. S. Lee, Prof. J. K. Cha
Department of Chemistry
Wayne State University
Detroit, MI 48202 (USA)
Fax: (+1)313-577-8822
E-mail: jcha@chem.wayne.edu
[**] This work was supported by NSF (CHE02-09321) and NIH
(GM 35956).
4
988
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 4988 –4991

Angewandte
Chemie
propane 3a with TiCl afforded 4-methoxycycloheptanone
taining the reaction mixture at low temperature (ꢀ788C;
condition B). Unfortunately, 1,2- and 1,3-diastereoselectivity
was surprisingly low (entries 1–4). Enantioselective syn-
thesis was achieved,albeit in modest selectivity,by means of a
4
(4a) in 86% yield. The yield (63%) was lower when the
[
9]
corresponding trimethylsilyl (TMS) ether was employed. The
use of a silyl ether proved to be necessary: cyclopropanol 2a
was quickly converted into 5 and its hemiacetal at ꢀ788C
nonracemic C -symmetric acetal (entry 5). The stereochem-
2
[
10]
upon exposure to TiCl ,but 5 gave only trace amounts of 4a
istry of the major product 4 f was secured by X-ray analysis.
4
under several different conditions. This observation is in
contrast to the interesting synthesis developed by Minbiole
and co-workers of oxepanes from the respective endocyclic
acetals. These results suggest that the siloxycyclopropane is
indeed the actual nucleophile that adds to the oxocarbenium
ion intermediate.
Diastereoselectivity by a resident stereocenter was next
examined with 3b–e under two different conditions (Table 1).
Both yields and stereoselectivity were improved by main-
(R,R)-(+)-Hydrobenzoin was chosen as a chiral auxiliary
primarily because of its commercial availability and ease of
removal. At present,the origin for the observed 1 3, -diaster-
[
6]
[11]
eofacial selectivity is unclear.
Regioselectivity was also examined: it is the less-substi-
tuted CꢀC bond of the three-membered ring that reacts with
[
12]
the oxocarbenium ion (entries 6–8). It is interesting to note
[
13a]
that the major products 4h and 4i,obtained from 3h
and
[
13b]
3i,
are diastereomeric (Table 1).
Table 1: Diastereo- and regioselectivity of seven-membered-ring formation.
[
a]
Entry
Substrate
Conditions
Major product
Yield [%]
Diastereoselectivity
1
2
3b: R=Me
A
B
4b
4b
4c
77
91
45
22
1:0.9
1.7:1
1:0.9
3c: R=OTBSA
[
b]
+
6
1
3
4
3d: R =TBSA
4d
4d
4e
58
65
67
1.3:1
1.5:1
2:1
B
1
3e: R =TIPSA
5
3 f
A
B
4 f
4 f
72
84
3:1
3.5:1
2
6
7
3g: R =Me
A
4g
4h
82
76
2.5:1
2.5:1
2
3h: R =(CH ) OTIPSA
2
2
2
8
3i: R =(CH ) OTIPSA
4i
68
3:1
2
2
[
a] Condition A: TiCl (1.2 equiv), ꢀ78!ꢀ208C; condition B: TiCl (2.0 equiv), ꢀ788C. [b]
4
4
Angew. Chem. Int. Ed. 2006, 45, 4988 –4991ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4989

Communications
[
9]
The surprisingly modest diastereoselectivity in the cycli-
nation of 7, the resulting cyclopropanol 8 was converted into
silylene 9 by standard methods. The key cyclization pro-
zation might be attributed to competing stereochemical
pathways that involve chair,boat,and/or twist-boat (not
ceeded cleanly by the action of TiCl to deliver 10 as a single
diastereomer,but as an inconsequential mixture of 10a and
4
[
14]
shown) conformations (Scheme 2). Assuming that a chair-
1
0b. The stereochemistry of 10 was tentatively assigned by
consideration of the most plausible transition state. As
additional support, 10 was converted into 11,which proved
to be identical to the minor isomer from the cyclization of 3d
(
Table 1,entry 3). Together with diastereoselective hydroxy-
[
13b]
cyclopropanation of secondary homoallylic alcohols,
this
diastereoselective approach should be useful in a rapid
increase in molecular complexity by the coupling of two
large segments.
In conclusion,a concise synthesis of multifunctionalized
seven-membered carbocycles has been achieved by sequen-
tial application of the Kulinkovich cyclopropanation of
acetal-tethered esters and the Lewis acid mediated addition
of the resulting cyclopropyl silyl ethers to the oxonium ion
intermediates. Particularly noteworthy is the effective use of a
tert-butylsilylene group for diastereoselective cyclization.
Mechanistic studies and applications in natural product
synthesis will be reported in due course.
Scheme 2. Stereochemical rationale.
like transition state is of lower energy,the configuration of the
major isomers I is tentatively assigned as shown in Table 1.
The minor isomers II could arise from a boatlike transition
a
state; for example,when R = H (e.g., 3d and 3e),the
Received: March 14,2006
Published online: July 3,2006
indicated boat conformation might become competing. At
present,one cannot discount the involvement of a gauche
conformation of the oxocarbenium ion in a chairlike tran-
sition state in the formation of the minor isomers. Elucidation
of important factors that influence diastereocontrol might be
possible by judicious placement of multiple substituents but
must await further investigations.
Toward eventual applications in natural product synthesis,
such as the stereoselective syntheses of skipped polyols,we
developed an effective strategy for diastereoselective cycliza-
tion by relying on di-tert-butylsilylene as a conformational
lock (Scheme 3). Subsequent to the Kulinkovich cyclopropa-
Keywords: carbocycles · cyclopropanation · cyclopropanols ·
.
homoenols
[
1] For reviews,see: a) C. H. DePuy, Acc. Chem. Res. 1968, 1,33;
b) D. H. Gibson,C. H. DePuy, Chem. Rev. 1974, 74,605; c) I.
Ryu,S. Murai, Houben-Weyl,
Houben-Weyl Methods of
Organic Chemistry, Vol. E17c, 1997,p. 1985; d) O. G. Kulinko-
vich, Chem. Rev. 2003, 103,2597; see also: e) H. N. C. Wong,
M. Y. Hon,C. W. Tse,Y. C. Yip,J. Tanko,T. Hudlicky,
Rev. 1989, 89,165; f) H.-U. Reissig,R. Zimmer, Chem. Rev. 2003,
03,1151; g) M. Yu,B. L. Pagenkopf, Tetrahedron 2005, 61,321.
Chem.
1
[
2] For reviews,see: a) B. M. Trost, Top. Curr. Chem. 1986, 133,3;
b) J. Salaün, Top. Curr. Chem. 1988, 144,1; c) B. M. Trost,A.
Brandi, J. Am. Chem. Soc. 1984, 106,5041; d) B. M. Trost,D. C.
Lee, J. Am. Chem. Soc. 1988, 110,6556; e) B. M. Trost,D. W. C.
Chen, J. Am. Chem. Soc. 1996, 118,12541.
[
3] a) J.-H. Youn,J. Lee,J. K. Cha, Org. Lett. 2001, 3,2935; b) H.-S.
Oh,H. I. Lee,J. K. Cha, Org. Lett. 2002, 4,3707; c) H.-S. Oh,
J. K. Cha, Tetrahedron: Asymmetry 2003, 14,2911.
[
[
4] I. Kuwajima,E. Nakamura, Top. Curr. Chem. 1990, 155,1.
5] Cf. J. T. Carey,C. Knors,P. Helquist, J. Am. Chem. Soc. 1986,
108,8313.
[
6] During the course of our own investigation,an elegant synthesis
of oxepanes appeared: K. E. OꢀNeil,S. V. Kingree,K. P. C.
Minbiole, Org. Lett. 2005, 7,515.
[
7] a) O. G. Kulinkovich,S. V. Sviridov,D. A. Vasilevskii,T. S.
Pritytskaya, Zh. Org. Khim. 1989, 25,2244; b) O. G. Kulinko-
vich,S. V. Sviridov,D. A. Vasilevskii,
Synthesis 1991,234;
c) O. G. Kulinkovich,A. I. Savchenko,S. V. Sviridov,D. A.
Vasilevski, Mendeleev Commun. 1993,230.
[
8] For reviews,see: a) O. G. Kulinkovich,A. de Meijere, Chem.
Rev. 2000, 100,2789; b) F. Sato,H. Urabe,S. Okamoto, Chem.
Rev. 2000, 100,2835; c) O. G. Kulinkovich, Eur. J. Org. Chem.
2004,4517.
Scheme 3. Diastereoselective cyclization by using di-tert-butylsiylene.
TBAF=tetrabutylammonium fluoride.
[9] Substrates 3d,e were prepared from enantiomerically enriched 7
(> 95% ee) by adaptation of two reported procedures: a) G. P.-J.
4
990 www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 4988 –4991

Angewandte
Chemie
Hareau,M. Koiwa,S. Hikichi,F. Sato, J. Am. Chem. Soc. 1999,
121,3640; b) J. S. Panek,P. Liu, J. Am. Chem. Soc. 2000, 122,
11090; c) M. Tokunaga,J. F. Larrow,F. Kakiuchi,E. N. Jacobsen,
Science 1997, 277,936.
[
10] We thank Dr. Mary Jane Heeg for single-crystal X-ray analysis.
CCDC 280875 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/products/csd/request.
[
[
[
11] Compare with: a) A. Alexakis,P. Mangeney, Tetrahedron:
Asymmetry 1990, 1,477; b) S. E. Denmark,N. G. Almstead, J.
Am. Chem. Soc. 1991, 113,8089; c) T. Sammakia,R. S. Smith, J.
Am. Chem. Soc. 1992, 114,10998.
12] This mode of addition might be considered as a formal “edge”
attack,as conformational constraints preclude “corner” attack:
C. Meyer,N. Blanchard,M. Defosseux,J. Cossy, Acc. Chem. Res.
2003, 36,766.
13] Substrates 3g–i were prepared diastereoselectively by previously
reported methods: a) J. Lee,H. Kim,J. K. Cha, J. Am. Chem.
Soc. 1996, 118,4198; b) L. G. Quan,S.-H. Kim,J. C. Lee,J. K.
Cha, Angew. Chem. 2002, 41,2264; Angew. Chem. Int. Ed. 2002,
41,2160.
[
14] Intervention of competing chair–boat pathways is known for
similar cyclizations: a) A. B. Smith III,K. Minbiole,P. R.
Verhoest,T. J. Beauchamp, Org. Lett. 1999, 1,913; b) J. E.
Dalgard,S. D. Rychnovsky, J. Am. Chem. Soc. 2004, 126,15662;
c) Q. Sun,J. S. Panek, J. Am. Chem. Soc. 2004, 126,2425.
Angew. Chem. Int. Ed. 2006, 45, 4988 –4991ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4991