Asymmetric synthesis of di- and trisubstituted cyclopropanes through an intramolecular ring closure

Article abstract of DOI:10.1055/s-0030-1259535

An asymmetric synthesis of di- and trisubstituted cyclopropanes proceeding through an intramolecular ring closure of activated chiral benzyl alcohols has been developed. The chiral alcohol intermediates are obtained from asymmetric reduction of readily av

Full text of DOI:10.1055/s-0030-1259535

LETTER
535
Asymmetric Synthesis of Di- and Trisubstituted Cyclopropanes through an
Intramolecular Ring Closure
A
symmetr
e
ic Synthesi
f
s
of Cyc
f
lopropan
r
es throu
e
gh
a
Ring
C
y
losure M. Kallemeyn,* Mathew M. Mulhern, Yi-Yin Ku
Chemical Process Research and Development, R450, Global Pharmaceutical Research and Development, Abbott Laboratories,
North Chicago, IL 60064-4000, USA
Fax +1(847)9385932; E-mail: Jeff.Kallemeyn@abbott.com
Received 21 November 2010
tivity
for
the formation
of
aryl-substituted
Abstract: An asymmetric synthesis of di- and trisubstituted cyclo-
propanes proceeding through an intramolecular ring closure of acti-
vated chiral benzyl alcohols has been developed. The chiral alcohol
intermediates are obtained from asymmetric reduction of readily
available 1,4-keto esters and undergo a one-pot activation and ring
closure to provide the ester-functionalized cyclopropanes in high
enantio- and diastereomeric purity. This methodology avoids the
use of hazardous diazo and alkyl zinc reagents commonly employed
in cyclopropanation reactions.
cyclopropanes.15
We desired a direct formation of the synthetically useful
aryl-ester cyclopropanes and envisioned that 4-aryl-4-oxy
butanonic esters 1, which are readily available by Friedel–
Crafts acylation of arenes with succinic anhydride,16
could be asymmetrically reduced to the alcohol, 2.17 Acti-
vation of the alcohol and ring closure through the ester
enolate would afford the chiral cyclopropane
3
Key words: cyclopropane, ring closure, asymmetric synthesis,
(Scheme 1). This approach would be amenable to large-
scale reactions by avoiding the use of hazardous diazo or
alkylzinc reagents commonly employed in cyclopro-
panantion reactions. Several key questions would need to
be answered during the method development, firstly the
level of the enantiospecificity observed during the ring
closure where SN1 and SN2 pathways may be competitive
in the displacement of the benzylic leaving group. Addi-
tionally, the factors that influence the diastereoselectivity
of the ring closure to afford trans- or cis-substituted prod-
ucts would need to be understood.
asymmetric reduction, stereoselectivity
Chiral cyclopropanes are prevalent in a wide array of nat-
ural products and pharmaceuticals.1 A number of method-
ologies have been developed to rigorously control the
enantio- and diastereoselective formation of the cyclopro-
pane ring from simple starting materials.2,3 Some of the
best developed enantioselective cyclopropanation meth-
ods are limited for the formation of ester-substituted cy-
clopropanes. For example, cyclopropanation of alkenes
using diazoesters4,5 suffer from low diastereoselectivities,
with the exception of recently developed Co-porphyrin
catalysts,6,7 whereas cyclopropanation of allylic alcohols
with Simmons-Smith reagents8 require subsequent oxida-
tion of the primary alcohol to the ester. The formation of
ester-substituted cyclopropanes by 1,4-additions using
chiral sulfur ylides do provide high stereoselectivities
when stoichiometric chiral reagents are used9,10 while cat-
alytic versions of this reaction have a limited scope.11,12
O
OH
chiral
reduction
OR
OR
Aryl
Aryl
O
O
1
2
1) activation
2) ring closure
O
Aryl
OR
An alternative approach to the asymmetric cyclopropana-
tion of alkenes is to form the ester-substituted cyclopro-
pane ring through an intramolecular ring closure.2 Until
recent work by Taylor and coworkers on displacement of
benzylic mesylates by intramolecular allylation to form
alkenyl-substituted cyclopropanes,13 no extensive study
on the electronic and steric factors that influence the dia-
stereo- and enantioselectivity of the ring closure has been
reported.14 Feringa and coworkers have recently demon-
strated the synthesis of disubstituted cyclopropanes
through a conjugate addition enolate-trapping ring clo-
sure, however, this method suffers from low enantioselec-
3
Scheme 1
To investigate the feasibility of the stereoselective cyclo-
propane formation through an intramolecular ring closure,
methyl (1a), isopropyl (1b), and tert-butyl (1c) esters
were prepared from the commercially available 4-(4¢-bro-
mophenyl)-4-oxobutanoic acid. The reduction of the aro-
matic ketone catalyzed by 10 mol% of (R)-Me-CBS
afforded the chiral alcohols in high yields and enantiopu-
rities (Table 1).17 The lower yield in the reduction of 1a
was due to formation of the g-lactone 4. Only a minor
amount of 4 was observed during reduction of 1b and
none with 1c.
SYNLETT 2011, No. 4, pp 0535–0538
x
x.
x
x.
2
0
1
1
Advanced online publication: 08.02.2011
DOI: 10.1055/s-0030-1259535; Art ID: S08910ST
© Georg Thieme Verlag Stuttgart · New York

536
J. M. Kallemeyn et al.
LETTER
Table 1 (R)-MeCBS-Catalyzed Asymmetric Reduction of 1
Table 2 Effect of Ester Group on Ring Closure
OH
O
OH
1) MsCl, Et3N
OR
OR
0 °C, THF
OR
O
O
2) KOt-Bu
0 °C, THF
Br
Br
Br
2a R = Me
2b R = i-Pr
2c R = t-Bu
O
2a R = Me
2b R = i-Pr
2c R = t-Bu
3a R = Me
(R)-MeCBS
BH3, THF
0 °C, THF
3b R = i-Pr
3c R = t-Bu
OR
+
O
O
Product
3a
Yield (%)
er of 2
96:4
er of 3
96:4
dr (trans/cis)
Br
O
1a R = Me
1b R = i-Pr
1c R = t-Bu
68
89
93
91:9
90:10
93:7
3b
97:3
96:4
Br
4
3c
98:2
98:2
Product
2a
Yield (%)
er
With the chiral alcohols in hand, the influence of the ester
group was evaluated in the ring-closing reaction. Activa-
tion of the alcohols 2a–c with MsCl/Et3N followed by in-
tramolecular ring closure by addition of KOt-Bu readily
afforded the cyclopropane products 3a–c in high diastereo-
selectivities (Table 2). In all cases, the trans-diastereomer
75
84
88
97:3
96:4
98:2
2b
2c
Table 3 Substrate Scope of Disubstituted Cyclopropanes
OH
O
1) MsCl, Et3N
Ot-Bu
0 °C, THF
Ot-Bu
O
2) KOt-Bu
0 °C, THF
R
R
2c–h
3c–h
Product
Yield of 3 (%)
er of 2
er of 3
dr of 3 (trans/cis)
O
Ot-Bu
93
98:2
98:2
93:7
Br
3c
O
Ot-Bu
O
83
89
90
76
84
98:2
97:3
87:13
96:4
92:8
98:2
94:6
93:7
90:10
92:8
95:5
3d
Ot-Bu
96:4
Me
3e
O
Ot-Bu
86:14
86:14
66:34
NC
3f
O
Ot-Bu
MeO
3g
O
S
Ot-Bu
3h
Synlett 2011, No. 4, 535–538 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of Cyclopropanes through a Ring Closure
537
was favored, with slight increase in diastereoselectivity product 3d. For compound 7d, where the substituent is
for the larger tert-butyl ester of 3c. In addition, the enan- phenyl, only moderate diastereoselectivity is observed.
tiospecificity for this reaction was high with <0.5% To test the influence of the chiral center in the 2-position
isomerization observed. The tert-butyl ester was chosen on the ring closure, the diastereomers of 6c were separated
for additional studies as it provided the highest yield, and independently subjected to the ring-closing reaction.
enantio-, and diastereoselectivities.
Both diastereomers of 6c formed 7c with high enan-
tiospecificity and diastereoselectivity. The convergence
of both diastereomers of 6c to the single product 7c is con-
sistent with the formation of an enolate intermediate and
demonstrates that the diastereomeric mixtures of the
chiral alcohols 6 can be directly used without affecting the
diastereoselectivity of the ring-closure reaction.
A number of electronically distinct aryl groups were eval-
uated in the ring-closing reaction (Table 3). High yields
and diastereoselectivities were observed for a range of
aryl groups. High enantioselectivities were observed for
substrates containing electronically deficient or neutral
arenes, however, lower enantioselectivities were observed
for substrates containing electron-rich arenes or hetereo-
cycles. These results are consistent with competing SN2
and SN1 reaction pathways where the benzylic cation in-
termediate of the SN1 pathway is more stabilized in elec-
tron-rich arenes resulting in higher amounts of
isomerization.
Table 5 Substrate Scope of Trisubstituted Cyclopropanes
OH
R
O
1) MsCl, Et3N
0 °C, THF
Ot-Bu
Ot-Bu
R
O
2) KOt-Bu
0 °C to r.t., THF
6a–d
7a–d
With the high enantiospecificities and diastereoselectivi-
ties observed in the ring closure to form disubstituted cy-
clopropanes, we desired to extend this methodology to the
formation of chiral trisubstituted cyclopropanes. The ste-
reoselective preparation of trisubstituted cyclopropanes
containing an ester functional group is highly dependent
on the nature of the substituent, with acceptable selectivi-
ty and scope when donor–acceptor carbenes are used,5 but
a limited scope exists for the incorporation of alkyl sub-
stituents.18 Asymmetric reduction of 4-phenyl-4-oxobu-
tanoic esters 5a–d containing methyl, benzyl, isopropyl,
and phenyl substituents in the 2-position afforded chiral
alcohols 6a–d as a mixture of diastereomers (Table 4).
Product
Yield of 7 er of 6
(%)
er of 7
95:5
94:6
97:3
91:9
dr of 7
(trans/cis)
7a
R = Me
69
95
77
95
95:5
94:6
97:3
93:7
96:4
7b
R = Bn
97:3
91:9
65:35
7c
R = i-Pra
7d
R = Ph
a Major diastereomer of 6c. Minor diastereomer of 6c (er 89:11) af-
forded 7c with er 89:11 and dr 92:8.
Table 4 (R)-MeCBS Catalytic Asymmetric Reduction of 5
O
R
OH
R
In conclusion, we have developed an intramolecular ring-
closing reaction to form di- and trisubstituted cyclopro-
panes in high enantio- and diastereoselecitivies from
readily accessible starting materials. This methodology
opens access to broad classes of ester-substituted cyclo-
propanes which have proven difficult to prepare stereo-
selectively while avoiding hazardous reagents typically
employed in cyclopropanation reactions.
(R)-MeCBS
(10 mol%)
Ot-Bu
Ot-Bu
O
O
BH3⋅THF
0 °C, THF
5a–d
6a–d
Product
Yield
(%)
dr
er
er
er
(major) (minor) (combined)
6a
R = Me
89
89
83
95
52:48
51:49
51:49
51:49
97:3
97:3
97:3
95:5
93:7
95:5
94:6
93:7
93:7
6b
R = Bn
92:8
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
6c
R = i-Pr
89:11
90:10
Acknowledgment
6d
R = Ph
This work was supported by Abbott Laboratories. We would like to
thank Dr. Chong Chen and Dr. Clifford Mitchell for assistance with
the SFC chiral analyses and Chris Ling for HRMS analysis.
The mixture of diastereomers 6a–d were subjected to the
MsCl activation and the KOt-Bu ring-closure reactions to
afford the desired cyclopropane products 7a–d in moder-
ate to high yields with high enantiospecificty (Table 5).
For compounds 7a–c, substituted with methyl, benzyl, or
isopropyl groups, high diastereoselectivities are also ob-
served, comparable or better to that of the disubstituted
References
(1) Salaun, J.; Baird, M. S. Curr. Med. Chem. 1995, 2, 511.
(2) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B.
Chem. Rev. 2003, 103, 977.
(3) Pellissier, H. Tetrahedron 2008, 64, 7041.
Synlett 2011, No. 4, 535–538 © Thieme Stuttgart · New York

538
J. M. Kallemeyn et al.
LETTER
(4) Doyle, M. P. In Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005,
341–355.
(5) Davies, H. M. L.; Walji, A. M. In Modern Rhodium-
Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-
VCH: Weinheim, 2005, 301–340.
(6) Chen, Y.; Zhang, X. P. J. Org. Chem. 2007, 72, 5931.
(7) Doyle, M. P. Angew. Chem. Int. Ed. 2009, 48, 850.
(8) Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1.
(9) Pyne, S. G.; Dong, Z.; Skelton, B. W.; White, A. H. J. Org.
Chem. 1997, 62, 2337.
(10) Solladie-Cavallo, A.; Diep-Vohuule, A.; Isarno, T. Angew.
Chem. Int. Ed. 1998, 37, 1689.
(13) Melancon, B. J.; Perl, N. R.; Taylor, R. E. Org. Lett. 2007,
9, 1425.
(14) Cristol, S. J.; Jarvis, B. B. J. Am. Chem. Soc. 1966, 88, 3095.
(15) den Hartog, T.; Rudolph, A.; Macia, B.; Minnaard, A. J.;
Feringa, B. L. J. Am. Chem. Soc. 2010, 132, 14349.
(16) Seed, A. J.; Sonpatki, V.; Herbert, M. R. Org. Synth. 2002,
79, 204.
(17) Hilborn, J. W.; Lu, Z.-H.; Jurgens, A. R.; Fang, Q. K.; Byers,
P.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 2001,
42, 8919.
(18) (a) Feit, B. A.; Elser, R.; Melamed, U.; Goldberg, I.
Tetrahedron 1984, 40, 5177. (b) DeAngelis, A.; Dmitrenko,
O.; Yap, G. P. A.; Fox, J. M. J. Am. Chem. Soc. 2009, 131,
7230. (c) Krawczyk, H.; Wasek, K.; Kedzia, J.;
Wojciechowski, J.; Wolf, W. M. Org. Biomol. Chem. 2008,
6, 308. (d) Haener, R.; Maetzke, T.; Seebach, D. Helv. Chim.
Acta 1986, 69, 1655.
(11) Aggarwal, V. K.; Smith, H. W.; Hynd, G.; Jones, R. V. H.;
Fieldhouse, R.; Spey, S. E. J. Chem. Soc., Perkin Trans. 1
2000, 3267.
(12) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd,
G.; Porcelloni, M. Angew. Chem. Int. Ed. 2001, 40, 1433.
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