Syntheses of trans -SCH-A and cis -SCH-A via a stereodivergent cyclopropanation protocol

Article abstract of DOI:10.1021/ol101295t

(Figure Presented) A highly diastereoselective cyclopropanation protocol has been employed in the syntheses of trans-SCH-A and cis-SCH-A. This strategy encompasses a stereodivergent procedure for the preparation of syn- and anti-cyclopropane diastereoisom

Full text of DOI:10.1021/ol101295t

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3152-3155
Syntheses of trans-SCH-A and
cis-SCH-A via a Stereodivergent
Cyclopropanation Protocol
Krist´ına Csatayova´, Stephen G. Davies,* James A. Lee, Kenneth B. Ling,
Paul M. Roberts, Angela J. Russell, and James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, UniVersity of Oxford,
Mansfield Road, Oxford OX1 3TA, U.K.
steVe.daVies@chem.ox.ac.uk
Received May 5, 2010
ABSTRACT
A highly diastereoselective cyclopropanation protocol has been employed in the syntheses of trans-SCH-A and cis-SCH-A. This strategy
encompasses a stereodivergent procedure for the preparation of syn- and anti-cyclopropane diastereoisomers in high dr from a common
allylic carbamate precursor.
The cyclopropane motif is found in a wide range of natural
products and biologically significant molecules,1 with the
conversion of an olefin into a cyclopropane using the
Simmons-Smith reaction being one of the most widely used
methods to access this structural unit.2,3 Diastereoselective
cyclopropanation relying upon delivery of the incoming
methylene group by the binding of an allylic functional group
to the zinc reagent4 has been a common strategy for the
stereoselective synthesis of cyclopropanes.5 As part of an
ongoing research program directed toward the chemo- and
stereoselective functionalization of allylic amines at the
olefin,6 we became interested in the potential of allylic
amines and their derivatives as substrates for cyclopropa-
nation. Within this area, we have recently reported the
stereodivergent cyclopropanation of allylic carbamate 1,
which gave either syn-2 in >99:1 dr and 67% isolated yield
(1) For instance, see: (a) Patai, S.; Rappoport, Z. The Chemistry of the
Cyclopropyl Group; Wiley & Sons: New York, 1987. (b) Donaldson, W. A.
Tetrahedron 2001, 57, 8589. (c) Faust, R. Angew. Chem., Int. Ed. 2001,
40, 2251.
(4) (a) Arai, I.; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107,
8254. (b) Kaye, P. T.; Molema, W. E. Chem. Commun. 1998, 2479. (c)
Marsh, E. A.; Hemperly, S. B.; Nelson, K. A.; Heidt, P. C.; Deusen, S. V.
J. Org. Chem. 1990, 55, 2045. (d) Morikawa, T.; Sasaki, H.; Hanai, R.;
Shibuya, A.; Taguchi, T. J. Org. Chem. 1994, 59, 97. (e) Evans, D. A.;
Burch, J. D. Org. Lett. 2001, 3, 503. (f) Tanaka, K.; Uno, H.; Osuga, H.;
Suzuki, H. Tetrahedron: Asymmetry 1994, 5, 1175. (g) Imai, T.; Mineta,
H.; Nishida, S. J. Org. Chem. 1990, 55, 4986.
(2) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1959, 81, 4256
.
(3) New classes of highly reactive zinc carbenoids have been developed,
and the substrate scope of the reaction has become immensely broad. See:
(a) Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39, 8621. (b)
Charette, A. B.; Beauchemin, A.; Francoeur, S. J. Am. Chem. Soc. 2001,
123, 8139. (c) Lorenz, J. C.; Long, J.; Yang, Z.; Xue, S.; Xie, Y.; Shi, Y.
J. Org. Chem. 2004, 69, 327. (d) Charette, A.; Beauchemin, A. Org. React.
2001, 58, 1. (e) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B.
Chem. ReV. 2003, 103, 977. (f) Voituriez, A.; Zimmer, L. E.; Charette,
(5) Competing formation of a zinc-complexed ammonium ylide often
thwarts cyclopropanation. For example, see: (a) Wittig, G.; Schwarzenbach,
K. Liebigs Ann. Chem. 1961, 650, 1. (b) Aggarwal, V. K.; Fang, G. Y.;
Charmant, J. P. H.; Meek, G. Org. Lett. 2003, 5, 1757.
A. B. J. Org. Chem. 2010, 75, 1244
.
10.1021/ol101295t  2010 American Chemical Society
Published on Web 06/16/2010

upon treatment with Zn(CH2I)2 (the Wittig-Furukawa
reagent, derived from Et2Zn and CH2I2) or anti-3 in >99:1
dr and 70% isolated yield upon treatment with
F3CCO2ZnCH2I (Shi’s carbenoid, derived from Et2Zn, CH2I2,
and TFA) (Scheme 1).7
allylic carbamate 8, followed by deprotection of the
nitrogen atom. It was envisaged that if a p-silyloxymethyl
group was incorporated in the C(3)-aryl substituent it
would remain inert during the synthesis while allowing
for the p-cyano group within 4 and 5 to be revealed (Figure
2).
Scheme 1. Stereodivergent Cyclopropanation of 1
Figure 2. Retrosynthetic analyses of 4 and 5.
In this manuscript, we report the application of this
methodology to the synthesis of the melanin-concentrating
hormone receptor 1 (MCH-R1) antagonist trans-SCH-A
4, which was developed by Schering-Plough,8 and its
epimer cis-SCH-A 5. In their synthesis of trans-SCH-A
4, Schering-Plough effected the Simmons-Smith cyclo-
propanation of an allylic alcohol, followed by oxidation
of the alcohol to give the corresponding ketone. Subse-
quent diastereoselective reductive amination was then
carried out to install the nitrogen atom.8a To date, there
have not been any other syntheses of trans-SCH-A 4
reported, although an elegant synthesis of cis-SCH-A 5,
involving an intramolecular R-lithiated aziridine cyclo-
propanation process, has recently been reported by Hodg-
son et al. (Figure 1).9
A series of C(3)-phenyl-substituted allylic carbamates
15-17 were selected as model systems in which to screen
both the effects of C(3)-aryl substitution and ring size on
the stereochemical outcome of our stereodivergent cyclo-
propanation protocol. Allylic carbamates 15-17 were pro-
duced in two steps from the corresponding cyclic enones
9-11 via treatment with PhLi to give alcohols 12-14
followed by bismuth-catalyzed SN′ substitution of 12-14
with benzyl carbamate10 to give 15-17 in 55-68% overall
yield (Scheme 2).
Scheme 2. Synthesis of Allylic Carbamates 15-17
In accordance with our previous studies concerning the
stereodivergent cyclopropanation of allylic carbamate 1,
treatment of 16 with Zn(CH2I)2 gave syn-19 in 84%
yield and >99:1 dr. Similar treatment of 16 with
F3CCO2Zn(CH2I)2 gave anti-22 in 99% yield and >99:1
dr (Scheme 3). The relative configuration within syn-19
Figure 1. Structures of trans-SCH-A 4 and cis-SCH-A 5.
(8) (a) McBriar, M. D.; Guzik, H.; Xu, R.; Paruchova, J.; Li, S.; Palani,
A.; Clader, J. W.; Greenlee, W. J.; Hawes, B. E.; Kowalski, T. J.; O’Neill,
K.; Spar, B.; Weig, B. J. Med. Chem. 2005, 48, 2274. (b) McBriar, M. D.;
Guzik, H.; Shapiro, S.; Xu, R.; Paruchova, J.; Clader, J. W.; O’Neill, K.;
Hawes, B.; Sorota, S.; Margulis, M.; Tucker, K.; Weston, D. J.; Cox, K.
Bioorg. Med. Chem. Lett. 2006, 16, 4262. (c) Kowalski, T. J.; Spar, B. D.;
Weig, B.; Farley, C.; Cook, J.; Ghibaudi, L.; Fried, S.; O’Neill, K.; Del
Vecchio, R. A.; McBriar, M.; Guzik, H.; Clader, J.; Hawes, B. E.; Hwa, J.
Eur. J. Pharmacol. 2006, 535, 182. (d) Kanuma, K.; Omodera, K.;
Nishiguchi, M.; Funakoshi, T.; Chaki, S.; Nagase, Y.; Iida, I.; Yamaguchi,
J.; Semple, G.; Tran, T.-A.; Sekiguchi, Y. Bioorg. Med. Chem. 2006, 14,
3307. (e) McBriar, M. D.; Guzik, H.; Shapiro, S.; Paruchova, J.; Xu, R.;
Palani, A.; Clader, J. W.; Cox, K.; Greenlee, W. J.; Hawes, B. E.; Kowalski,
T. J.; O’Neill, K.; Spar, B. D.; Weig, B.; Weston, D. J.; Farley, C.; Cook,
J. J. Med. Chem. 2006, 49, 2294.
Our strategy for the syntheses of trans-SCH-A 4 and
cis-SCH-A 5 involved elaboration of the requisite dias-
tereoisomers of cyclopropane 6, which could in turn be
accessed via the stereodivergent cyclopropanation of
(6) (a) Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.;
Russell, A. J.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751. (b) Aciro,
C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson,
J. E. Org. Biomol. Chem. 2008, 6, 3762. (c) Bond, C. W.; Cresswell, A. J.;
Davies, S. G.; Fletcher, A. M.; Kurosawa, W.; Lee, J. A.; Roberts, P. M.;
Russell, A. J.; Smith, A. D.; Thomson, J. E. J. Org. Chem. 2009, 74, 6735.
(d) Bagal, S. K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.;
Scott, P. M.; Thomson, J. E. Org. Lett. 2010, 12, 136.
(9) Hodgson, D. M.; Humphreys, P. G.; Miles, S. M.; Brierley, C. A. J.;
Ward, J. G. J. Org. Chem. 2007, 72, 10009.
(7) Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson,
J. E. Chem. Commun. 2007, 4029.
(10) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2007, 46, 409.
Org. Lett., Vol. 12, No. 14, 2010
3153

produced the corresponding syn-cyclopropanes 29-33 in
>99:1 dr and good isolated yield. Similarly, treatment of
26-28 with F3CCO2Zn(CH2I)2 gave anti-cyclopropanes
36-38 as single diastereoisomers (>99:1 dr) in good isolated
yield. Crucially, however, cyclopropanation of the five-
membered ring substrates 24 and 25 with F3CCO2ZnCH2I
showed improved levels of diastereoselectivity relative to
the C(3)-phenyl-substituted model system (71:29 dr), with
the O-TIPS protected derivative 35 being isolated in 77%
yield and 99:1 dr (Scheme 4). The relative configurations
Scheme 3. Stereodivergent Cyclopropanation of 15-17
Scheme 4. Stereodivergent Cyclopropanation of 24-28
was unambiguously established via single-crystal X-ray
analysis (Figure 3),11 thus the relative configuration within
anti-22 could also be unambiguously assigned. These data
indicate that the addition of a C(3)-aryl substituent does
not adversely affect the sense of diastereoselectivity in
this reaction manifold.
within cyclopropanes 29-38 were assigned by analogy to
the model C(3)-phenyl-substituted systems; these assign-
1
Figure 3. X-ray crystal structure of syn-19 (some H-atoms have
been omitted for clarity).
ments were also supported by H NMR NOE analyses.
With diastereoisomerically pure (g99:1 dr) samples of
both O-TIPS protected cyclopropanes syn-30 and anti-35
in hand, their elaboration toward trans-SCH-A 4 and cis-
SCH-A 5, respectively, was undertaken. Hydrogenolysis
of syn-30 (>99:1 dr) gave primary amine 39 in quantitative
yield, with no products arising from cleavage of the
cyclopropane ring being observed. Coupling of 39 with
carboxylic acid 40 (mediated by EDCI/HOBt) gave amide
41 in 80% yield and >99:1 dr after purification. Subsequent
reduction of the amide functionality within 41 with
LiAlH4, followed by treatment with 4-fluoro-3-trifluo-
romethylphenyl isocyanate, gave urea 43 in 71% isolated
yield (over 2 steps). O-TIPS deprotection of 43 was
achieved upon treatment with 1.7 equiv of TBAF giving
44 in quantitative yield. Oxidation of the primary alcohol
functionality within 44 with MnO2 then gave aldehyde
45 in 73% isolated yield. Subsequent treatment of 45 with
NH4OH and 5.0 equiv of IBX for 11 days completed the
synthesis of trans-SCH-A 4, which was isolated as a single
diastereoisomer (>99:1 dr) in 66% yield (Scheme 5). The
1H NMR spectrum of our sample of trans-SCH-A 4 was
found to be identical to that of an authentic sample
provided by Schering-Plough (now Merck Research
The stereodivergent cyclopropanation protocol was also
found to be applicable to the corresponding five- and seven-
membered ring analouges 15 and 17, affording syn-cyclo-
propanes 18 and 20 as the major products upon treatment
with Zn(CH2I)2 and anti-cyclopropanes 21 and 23 as the
major products upon treatment with F3CCO2Zn(CH2I)2. With
the exception of syn-20 and anti-21, the cyclopropane
products were isolated as single diastereoisomers (>99:1 dr)
in each case (Scheme 3). The relative configurations within
18, 20, 21, and 23 were assigned by analogy to those within
syn-19 and anti-22, and these assignments were further
1
supported by H NMR NOE analyses.
Subsequent studies focused upon the cyclopropanation of
allylic carbamates 24-28, incorporating C(3)-(p-silyloxy-
methyl)phenyl substituents, which were prepared in a directly
analogous manner to the C(3)-phenyl model substrates
15-17. In each case, treatment of 24-28 with Zn(CH2I)2
(11) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 779449.
3154
Org. Lett., Vol. 12, No. 14, 2010

Scheme 5. Synthesis of trans-SCH-A 4
Laboratories).12,13 An analogous reaction sequence was also
employed for the conversion of anti-35 (99:1 dr) into cis-
SCH-A 5 which was isolated in >99:1 dr and 14% overall
from a common allylic carbamate precursor. This strategy
encompasses the stereodivergent preparation of both the syn-
and anti-cyclopropane diastereoisomers in high dr from the
corresponding cyclic allylic carbamate. Several further
applications of this methodology are ongoing within our
laboratory.
1
yield (over 7 steps). The H and 13C NMR spectroscopic
data for cis-SCH-A 5 were found to be in excellent agreement
with those reported by Hodgson et al.9 The assigned relative
configurations within both trans-SCH-A 4 and cis-SCH-A
1
5 were also confirmed by H NMR NOE analyses.
Acknowledgment. The authors would like to thank the
Oxford Chemical Crystallography Service for the use of their
X-ray diffractometers.
In conclusion, a highly chemo- and diastereoselective
cyclopropanation protocol has been employed in the syn-
theses of trans-SCH-A (in 8 steps and 25% overall yield)
and its epimer cis-SCH-A (in 8 steps and 11% overall yield)
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) Some major discrepancies exist between our 1H NMR data for trans-
SCH-A 4 and the 1H NMR data for trans-SCH-A 4 which were originally
reported by Schering-Plough (see ref 8a).
(13) We would like to thank Dr. J. W. Clader (Merck Research
1
Laboratories) for providing a H NMR spectrum of trans-SCH-A 4.
OL101295T
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