Novel CuX2-mediated cyclization of acid-base salts of (L)-cinchonidine or (D)-/(L)-α-methylbenzylamine and 2,3-allenoic acids in an aqueous medium. An efficient entry to optically active β-halobutenolides

Article abstract of DOI:10.1039/b008818h

The treatment of 1:1 salts of 2,3-allenoic acid-chiral base with CuX₂ (4 equiv.) in an aqueous medium, i.e. acetone-H₂O (2:1), at 60-65 °C afforded β-halobutenolides with high enantiopurities in good to excellent yields.

Full text of DOI:10.1039/b008818h

Novel CuX -mediated cyclization of acid–base salts of (
L)-cinchonidine or
2
(D)-/(
L
)-a-methylbenzylamine and 2,3-allenoic acids in an aqueous medium. An
efficient entry to optically active b-halobutenolides
Shengming Ma* and Shulin Wu
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
54 Fenglin Lu, Shanghai 200032 People’s Republic of China. E-mail: masm@pub.sioc.ac.cn
3
Received (in Cambridge, UK) 1st November 2000, Accepted 16th January 2001
First published as an Advance Article on the web 15th February 2001
6
The treatment of 1+1 salts of 2,3-allenoic acid–chiral base
with CuX (4 equiv.) in an aqueous medium, i.e. acetone–
nization of 2,3-allenoic acids, the reaction afforded (+)-3a in
9
2
95% yield with 98% ee, the corresponding b-chlorobutenolide
H
2
O (2+1), at 60–65 °C afforded b-halobutenolides with high
(+)-3b was also obtained in 90% yield with 99% ee by using
enantiopurities in good to excellent yields.
2 2
CuCl instead of CuBr (Scheme 2).
Polysubstituted butenolides are a class of compounds of current
interest due to their potential broad range of biological
activities1 and abundant occurrence in natural products.2
However, the methods for the highly stereoselective synthesis
of optically active butenolides are limited.3 In this paper, we
,4
2
wish to report a highly efficient CuX -mediated cyclization of
the salts formed between chiral bases and 2,3-allenoic acids.
The method provides a novel route to b-halobutenolides with
high enantiopurity, important building blocks for polysub-
stituted butenolides.5
With the standard aqueous reaction conditions in hand, a
series of b-bromobutenolides with high optical purity were
prepared and the results are summarized in Table 1. It is
obvious: (1) the yields are from good to excellent; and (2) the
efficiency of the chirality transfer process is almost 100% since
the %ee of the products from the resolved salts are similar to
those from the released free 2,3-allenoic acids (Scheme
Recently, we have developed several methodologies for the
5,6
synthesis of b-halobutenolides from 2,3-allenoic acids. The
interesting point of these reactions is that the starting 2,3-alle-
noic acids are a class of compounds with chirality when
properly substituted. Thus, it would be possible to use a cheap
optically active base to resolve 2,3-allenoic acids and transfer
the axial chirality in allenes into central chirality in butenolides
in a highly stereoselective manner. One major issue here is the
use of the salt of an optically active base with 2,3-allenoic acids
directly as the starting point, the release of 2,3-allenoic acids
from the salts would not be necessary, which makes this strategy
more attractive.
3
),indicating that the chirality of (
impact on the chirality transfer of the allene moiety. Similar
results were obtained for all substrates using CuCl in place of
CuBr to afford b-chlorobutenolides. The absolute configura-
L
)-cinchonidine has almost no
2
2
tion of the chiral centers in the products 3c and 3d were
determined by X-ray diffraction using the bromine atoms as the
reference.10 The absolute configuration of other products are
based on these X-ray studies and further confirmed by the study
of their CD spectra.11
The resolution of racemate 2-methyl-4-phenylbuta-2,3-dien-
oic acid 1a with 0.5 equiv. of ( )-cinchonidine, a readily
L
Furthermore, it is interesting to observe when we used (S)-
available and relatively cheap base, afforded a salt which could
(
+)-a-methylbenzylamine as the resoluting agent, the salt
be readily recrystallized in ethyl acetate to afford the optically
2
0
7
2
(2)-4a was obtained and its treatment with CuBr afforded the
active salt (+)-2a in 43% yield with [a] = +85.4°. Release of
D
opposite enantiomers (R)-(2)-3a (98% ee) and (R)-(2)-3b
the acid from the corresponding salt (+)-2a by the treatment
(
98% ee) in 90% and 93% yields, respectively (Scheme 4).
2 4
with dilute H SO afforded S-(+)-1a, indicating the (S)-
By using (R)-(2)-a-methylbenzylamine instead of its S-
configuration of the allene moiety according to the Lowe–
enantiomer, the corresponding salt (+)-4a afforded the same
Brewster rule (Scheme 1).8
Luckily, when (+)-2a was treated with CuBr
enantiomer as with (
L
)-cinchonidine, i.e. (S)-(+)-3a and (S)-
2
in an aqueous
(
(
+)-3b in 92 (98% ee) and 90% yield (97% ee), respectively
Scheme 4).
In conclusion, we have developed an efficient aqueous
medium (acetone–H
methodology recently developed by ourselves for the halolacto-
2
O (2+1)), at 60–65 °C for 3 h, a
synthesis of highly optically active b-halobutenolides. The
current methodology will show its utility in organic synthesis
due to the ready availability of starting materials with different
substitution patterns,7 direct cyclization from the salts, and
availability of both enantiomers.
,12
Scheme 1
Scheme 3
DOI: 10.1039/b008818h
Chem. Commun., 2001, 441–442
This journal is © The Royal Society of Chemistry 2001
441

Table 1 Highly stereoselective cyclization of (L
)-cinchonidine salts of 2,3-dienoic acidsa
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24, 55954y]; (e) C. M. Lee Gary and M. E. Gast, PCT Int. Appl. WO.
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1 16,055, 1991 [Chem. Abstr., 1992, 116, 59197m].
2
For recent examples, see: (a) Y. Chia, F. Chang and Y. Wu, Tetrahedron
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1
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and E. Valentin, J. Org. Chem., 1998, 63, 2385.
3
4
For a summary of methodologies for the synthesis of racemic
butenolides, see: (a) D. W. Knight, Contemp. Org. Synth., 1994, 287; (b)
S. Ma and Z. Shi, J. Org. Chem., 1998, 63, 6387, and the references cited
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5
335; (d) M. J. Bassindalem, P. Hamley, A. Leitner and J. P. A. Harrity,
Tetrahedron Lett., 1999, 40, 3247.
For some of the representative examples of the stereoselective synthesis
of optically active butenolides, see: (a) A. G. Schultz, M. Dai, S. Khim,
L. Pettus and K. Thakkar, Tetrahedron Lett., 1998, 39, 4203; (b) S. M.
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1
998, 39, 4971, 4975 and 4979; (c) A. van Oeveren and B. L. Feringa,
J. Org. Chem., 1996, 61, 2920; (d) M. Renard and L. Ghosez,
Tetrahedron Lett., 1999, 40, 6237; (e) T. Mukaiyama and K. Suzuki,
Chem. Lett., 1980, 255; (f) S. Tsuboi, J. Sakamoto, H. Yamashita, T.
Sakai and M. Utaka, J. Org. Chem., 1998, 63, 1102; (g) Q. Yu, Y. Wu,
L.-J. Xia, M.-H. Tang and Y.-L. Wu, Chem. Commun., 1999, 129; (h) T.
Berkenbusch and R. Bruckner, Tetrahedron, 1998, 54, 11 471.
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Ma, Z. Shi and Z. Yu, Tetrahedron, 1999, 55, 12137.
5
6
7
S. Ma and S. Wu, J. Org. Chem., 1999, 64, 9314.
Scheme 4
The known resolving process in acetone lacks efficiency and affords the
salts in 27.5% yield with [a]2 = +60°, see: W. Runge and G. Kresze,
5
D
Liebigs Ann. Chem., 1975, 1361.
S. R. Landor, The Chemistry of the Allenes, Academic Press, New York,
Financial support from National NSF of China (No.
9932020) and the Major State Basic Research Development
8
9
2
1
982, vol. 3, pp. 587–590.
Program (Grant No. G2000077500) are greatly appreciated.
Shengming Ma is the recipient of 1999 Qiu Shi Award for
Young Scientific Workers issued by Hong Kong Qiu Shi
Foundation of Science and Technology (1999–2002) and the
Special Starting Grant for Outstanding Young Chemists issued
by National Natural Science Foundation of China
The ee values were determined by HPLC on a Chiralpack AS column
using n-hexane–isopropyl alcohol (65+35) as the eluent. The racemic
butenolides were prepared by starting from the racemic 2,3-allenoic
acids using the method reported in ref. 6.
10 The absolute configuration was determined using Texsan software. The
Bijvoet reflections were collected and refined with Bijvoets not flagged
as redundant. CCDC 152077 and 152078. See http://www.rsc.org/
suppdata/cc/b0/b008818h/ for crystallographic data in .cif format.
(
29525202).
1
1 (a) J. K. Gawronski, A. van Oeveran, H. van der Deen, C. W. Leung and
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Chen, Z. Geng, B. Huang, M. R. Martin, A. I. Mateo, M. Brzostowska,
U. Rychlewska and B. Feringa, Chirality, 1997, 9, 537.
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1
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1
[
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Chem. Commun., 2001, 441–442