Stereoselective palladium-catalyzed cyclopropanation of α,β-unsaturated carboxylic acids derivatized with Oppolzer's sultam

Article abstract of DOI:10.1016/0040-4039(91)80102-C

N-enoyl sultans, derived from α,β-unsaturated carboxylic acids and bornane[10,2]sultam, undergo a stereoselective Pd-catalyzed cyclopropanation upon treatment with diazomethane. The stereoselectivity of the reaction is temperature dependent.

Full text of DOI:10.1016/0040-4039(91)80102-C

Telxahedron Letters. Vo132, No 40, pp 5625-5628, 1991
Printed m GreatBritain
0040~,039/91 $3.00 +
Pergamon Press pie
Stereoselective Palladium-Catalyzed Cyclopropanation of ~,13-
Unsaturated Carboxylic Acids Derivatized with Oppolzer's Sultam
Jerk Vallghrda and Uli Hacksell
Department ofOrgantc Pharmaceuucal Chemistry, Uppsala B~ome&cal Centre, Box 574, Uppsala Umvers~ty,
S-751 23 Uppsala, Sweden
Key Words Stereoselectwe cyclopropanauon, bornane[10,2]sultam, Palladmm-catalysls
Abstract. N-enoyl sultams, derived from ot,~-unsaturated carboxyhc acids and bornane[lO,2]sultam, undergo a
stereoselecttve Pd-catalyzed cyclopropanatton upon treatment wzth dtazomethane The stereoselectway of the reacUon ts
temperature dependent
The cyclopropane moiety occurs frequently m natural products of biological importance.1 In ad&tion,
several cyclopropanated synthetic drugs of pharmacological value have been reported, e.g. the potent monoamine
oxidase inhibitor trans-phenylcyclopropylanfine (1),2 and the selective and potent 5-HT1A-receptor agonist 2. 3,4
Compounds such as ! and 2 are readily prepared from the corresponding cyclopropanecarboxylic acid denva-
tives, e.g. by a Curtius rearrangement.3
1
(IR,2S)-2
(-)-3
We hereto describe a highly stereoselective method for the preparation of 2-subsututed derivatives of cyclo-
propanecarboxyhc acid in good yields.5'6 The method ls based on an initial derivatizatIon of or,IS-unsaturated car-
boxyhc acids with Oppolzer's sultam (bornane[10,2]sultam; 3),7 which funcuons as an easily removable, inex-
penswe, and efficient chlml auxlhary. Reaction of the resulting N-enoyl sultam with diazomethane in the presence
of catalytac amounts of Pd(OAc)2s. produces predominantly one cyclopropanated stereoisomer. The stereochemical
purity of the product may be ~eadily increased by recrystallizatxon.9'1° An adchtional advantage of the method Is the
availability of both enantlomers of 3,N which allows the production of cyclopropanecarboxyhc acids of desired
stereochemistry.
A total of eight cyclopropanated derivatwes were prepared. The reqmsxte trans-N-enoyl sultams were
assembled from commercially avadable ~x,[5-unsaturated carboxyhc acids by a two-step sequence - ~: oxalyl
chloride, toluene, 80* C; it. (-)-3, Nail, toluene - without xsolauon of intermediates (route A; Table 1). Commer-
cially available (E)-but-2-enoyl chloride was used for the preparation of N-enoyl sultam 5g. The thlenyl
derivative 4e was prepared by the Heck couphng of 2-1odothiophene with methyl acrylate [cat Pd(OAc)2,
NBu4C1, K2CO3, DMF, 20° C, 3 d.]12 followed by hydrolysis (2M NaOH, MeOH, 20 °C, 20 min).
5625

5626
B
N
'.
. .
O
O
O
4
5
6
An alternative route (route B) to sultana denvauves also appears qmte useful, the couphng between N-
propenoyl sultame 613 and lodobenzene [Pd(OAc)2, K2CO3, DMF, NBu4CI, 20° C, 4 dl produced 5a as a single
stereolsomer m acceptable yield
Table 1 Physical Data ofN-enoyl sultams 5
R
so
O
Comp
5a
R
Yield
%
laid~)
-95.0
nap (° C)
189-190
U%/
~
82
MeO
/
5b
5c
~
84
75
-90 9
-873
156-158
190-192
MeO
"li
~
M e O ~
5 d
81
-65.7
205-206
MeO"
y
MeO
5e
5f
f f f f f f ~
71
78
-92 4
-92 1
213-215
153-158
/Qo~,.~
5 g
77
-99.0
185-187
oll
CH 3-
5 h
84
-65. 9
CH3(CH2)9"
a) 22° C, (c=1 0, CH2CI2)
The cyclopropanauon reacuon was performed w~th dmzomethane (CAUTION)TM m the presence ofcatalyuc
amounts of Pd(OAe)2 In order to find suitable reacnon conditions for th~s reaction, we performed cyclopropa-
nation reactions of 5a at different temperatures The cyclopropanauon was quanmatwe at temperatures between
- 30° C and 28° C At temperatures below - 30° C the reaction became very sluggish and above 30° C the

5627
volatility of diazomethane caused problems. The stereoselectivlty of the reacnon, which was studied by GLC/MS
analysis of the resulung diastereomerlc cyclopropanes, increased with the reaction temperature (Figure 1); the
diastereomeric excess (%de) of the product increased from about 53 to 87 % as a result of an increase m reaction
temperature from -30 to 0* C Thus, it appears that reaction condmons favounng thermodynamic control also
increase stereoselectw~ty. Only a slight change m %de was apparent at h~gher temperatures. Smce the reaction
was easily performed at 0* C, we chose this temperature for experaments with the other substrates (Table 2).
S O 2
y
" ' l ' t
5
0
7
0
In a typical cyclopropanataon experiment, the approprmte N-enoyl sultam derivative and Pd(OAc)2 (0.005
equiv) were dissolved in CH2C12 or C1CH2CH2C1 and an azeotrope of dmzomethane and ether or THF (from 10
eqmv. Dmzogen~) was dasulled into the chilled reactaon vessel The reaction was interrupted after 12 h by addation
of acetic acid. The mixture was extracted with a saturated aqueous NaHCO3 solution and the orgamc layer was
dried (MgSO4) and then filtered through a pad of sdlca gel. The crude products (Ta-7h, table 2) were first
analyzed by GLC/MS to determine the diastereomeric purity which ranged from 67 to 92 %de. Recrystallization
from EtOH provided pure derivatives with diastereomenc purmes ranging from 97.6 to > 99.8 %de in yields of
62 to 73 % (Table 2). Compound 7h was obtained as an oil but the dlastereolsomers were efficiently separated by
flash chromatography.
Fagure 1. Effect of Reactmn Temperature on
Table 2. Asymmemc Cyclopropanatmn of 5.
the cyclopropanation of N- enoyl sultam 5a.
Comp. %dea Yieldb %dec
(%)
[~]ffe mp (°Cy
~ 9 0
7a
7b
7e
7d
7e
7f
86.2
92.1
72.3
66.8
86.5
76.3
90.8
83.2
73
73
63
62
67
67
72
99.2
98.8
97 7
97.6
99.4
99.7
99.4
-233.3
-180.7
-213.1
-185.5
-218.6
-267.5
-120.1
134.5-135
148-148.5
180-182
158-159
121-124
139-140
154-155
70
7g
7h
62~ >99.8
-89.0 50-50.5
50
-40
r
I
I
•
I
I
•
I
-20
0
20
40
60
a) Determmed on thecrude product b) Yield of recrystaUlzed product
c) Determined on recrystalhzed material, d) 22° C, (c=l 0, CH2CI2)
e)Punfied by flash chromatography (StO2, ether/hght petroleum 1:4)
Temperature (°C)
In order to estabhsh the stereochemical outcome of the reaction we converted 7b into the corresponding
carboxylic acid 8 [i: Tffl-PrO)4, PhCH2OH, 140° C, 30 mln; iz: 2M NaOH, H20, MeOH, THF, 20* C, 30 mm;
yield: 81%). The optical rotation produced by 8, [CX]D22 = -195.6° (C 1.0, CHCI3), agreed well with that desclbed
in the literature,3 [~]Dz2 = -196.5° (c 0.5, CHCI3), for the 1R,2R stereolsomer. This stereoisomer may be readdy
converted into the pharmacologxcally interesting (1S,2R)-2 by use of a literature procedure.3 Hydrolysis of 7a,
7c and 7g to the corresponding carboxyhc acid denvatwes by the above procedure and comparisons of their

5628
optical rotations with data from the hterature3'~5 demonstrated that also these denvatwes have the IR,2R stereo-
chemistry, On the basis of the magmtudes and signs of the optical rotattons obtained from the other four cyclo-
propanated derivatives xt is hkely that also these derivatives have the 1R,2R stereochem~stry. Th~s would xmply
that the sultana auxiliary confers the same sense of re-face selecuvxty m the d~azomethane/Pd(OAc) 2 cyclopro-
panat~on reaction as ~t does m OsO4-catalyzed dxhydroxylattons] 6 Pd-catalyzed catalytm hydrogenations~7 and m
several cycloaddmon reacnons 12.18
S"
HO
O
7b
O
8
Acknowledgment Support for this study was provided by grants from the Swedish Board for Techmcal
Development and the Swedish Natural Science Research Council
References and Notes:
1
2
3
See. e g. Lm, H -W, Walsh, C T. Biochemistry of the cyclopropyl group. In The Chemistry of the
cycIopropyl group, Rappoport, Z. Ed, John Wiley & Sons Ltd, 1987, p 959-1025
Zlrk!e, C L.. Kaiser, C., TedeschL D H., Tedeschl, R E~ Burg~, A J Med Pharm Chem. 1962, 5,
1265-1284
Arvldsson, L-E; Johansson, A M, Hacksell, U., Nxlsson, J L.G, Svensson, K. Hjorth, S.
Magnusson, T., Carlsson, A, Lmdberg. P, Andersson, B, Sanchez, D., Wlkstrom, H ; Sundell, S J
Med Chem. 1988, 31, 92-99
4
5
6
Cornfield, L J., Lambert, G. Arvldssom L -E ; Melhn, C : Vallg~rda, J, Hacksell, U., Nelson, D L. Mot
Pharmacol , 1991, 39, 780-787
For revaews on stereo';electvve cyclopropanataon reacuons, see e g.. Salaun, J. Chem Rev 1989, 89,
1247-1270
All compounds reported hereto gave spectral data consistent with the assigned structures as well as
satisfactory elemental analyses
7
8
9
For a review, see e.g Oppolzer, W. Pure Appl Chem 1990, 62, 1241-1250
Pauhssen, R., Hubert, A J, Teyssle, Ph. Tetrahedron Lett 1972, 1465-1466.
A Pd-catalyzed &azomethane cyclopropananon of styrene substituted with an ephednne-denved oxazohdme
as the chtral auxd~ary has been reported Abdallah, H, Gree. R, Came. R, Tetrahedron Lett 1982, 23,
503-506
10 For other stereoselective cyclopropanat~ons, see e g Doyle, M.P. P~eters, R J. Martin, S F, Austin,
R.E, Oalmann, C J., Muller, P J Am Chem Soc 1991, 113, 1423-1424.
11 Manufactured by Oxford Chlrahty, Oxford, UK. For synthesxs see, e g." Welsmlller, M.C., Towson, J C.,
Davis, F.A Org Synth 1990, 09, 154-157, Towson, J C
A C, Davis, F.A tbtd, 1990, 69, 158-168.
,
Welsmfller, M C. Lal, G S , Sheppard,
12 Jeffery, T Tetrahedron Lett. 1985, 26. 2667-2670
13 Oppolzer, W., Chapms, C, Bernardtelh, G. Helv Chtm Acta, 1984, 67, 1307-1401
14 Black, H T Aldrtchtmlca Acta, 1983, 16, 3-10
15 Mort, A.. Aral, I. Yamamoto, H, Nakai, H., Aral, Y Tetrahedron, 1986, 42, 6447-6458
16 Oppolzer, W., Barras, J -P Helv Chtm Acta, 1987, 70, 1666-1675
1~7 Oppolzer, W, MJ]Js, R 1 , R6gher, M Tetrahedron Lett 1986, 27= L83-186.
[8 See_, e_g C.Jl~ar_~_D P ._K_~m..B. tq~..D_au~ghetty,_l ~_El~ffue~_T A_ Te~r~zbeJtronlztt 1988,29,3555-3558
(Recewed in UK 24 July 1991)