Mechanistic switch leading to highly efficient chirality transfer in Pd(0)-catalyzed coupling-cyclization of aryl iodides with 1:1 acid-base salts of 2,3-allenoic acids and L-(-)-cinchonidine or D-(+)-/L-(-)-α-methylbenzylamine. Enantioselective synthesis

Article abstract of DOI:10.1039/b109645a

An efficient methodology provides an easy access to highly optically active polysubstituted butenolides starting from aryl halides and 1:1:salts of optically active 2,3-allenoic acid-base via an oxidative addition-coordinative cyclization-reductive elimin

Full text of DOI:10.1039/b109645a

Mechanistic switch leading to highly efficient chirality transfer in
Pd(0)-catalyzed coupling–cyclization of aryl iodides with 1+1 acid–base
salts of 2,3-allenoic acids and
L
-(2)-cinchonidine or
D
-(+)-/ -(2)-a-methylbenzylamine. Enantioselective synthesis of highly
L
optically active 3-aryl polysubstituted butenolides†
Shengming Ma* and Zhangjie Shi
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, PR China. E-mail: masm@pub.sioc.ac.cn;
Fax: (+86)21-64166128
Received (in Cambridge, UK) 23rd October 2001, Accepted 11th January 2002
First published as an Advance Article on the web 13th February 2002
An efficient methodology provides an easy access to highly
optically active polysubstituted butenolides starting from
aryl halides and 1:1+salts of optically active 2,3-allenoic
acid–base via an oxidative addition–coordinative cycliza-
tion–reductive elimination mechanism, which led to the high
efficiency of this chirality isomerization reaction.
dinative cyclization–reductive elimination mechanism (Scheme
2), the chirality of allene moiety can be transferred into the
chiral center in butenolides highly efficiently.
Thus, the 1+1 salt Sa-(+)-2aA was prepared from Sa-(+)-1a
and (i-Pr)2NEt and its Pd(0)-catalyzed reaction with PhI
afforded S-(+)-3a in 62% yield and 91% ee (eqn. 1)!
Chirality transfer processes involving the disappearance of an
original chirality and the establishment of a new chirality is one
of the best ways to obtain optically active compounds from the
easily available optically active starting materials provided that
the chirality can be ‘remembered’ in the corresponding
transition state(s) or intermediate(s) therein. In this paper, we
wish to report an efficient chirality transfer process, i.e., the
Pd(0)-catalyzed coupling–cyclization of aryl iodides with 1+1
(1)
Furthermore, when the 1+1 acid–base salt Sa-(+)-2a was used
directly instead of Sa-(+)-1a as the starting material, the
reaction afforded S-(+)-3a in 95% yield and a remarkable 87%
ee at rt! No reaction was observed in the absence of TBAB
probably due to the low solubility of Sa-(+)-2a in toluene. It was
observed that the reaction temperature was important. When the
reaction was carried out at 5 °C, S-(+)-3a was isolated in 90%
yield and 91% ee (entry 1, Table 1), while at a higher
temperature, both the yields and ee were considerably lower.
In order to study the detail of this chirality transfer process,
we synthesized 2-(n-propyl)-4-(4A-bromophenyl)-2,3-butadie-
acid–base salts of 2,3-allenoic acids and
L-(2)-cinchonidine or
D
-(+)-/ -(2)-a-methylbenzylamine, which provides an effi-
L
cient entry to highly optically active 3-aryl polysubstituted
butenolides.
Highly optically active polysubstituted butenolides are a
class of important compounds with potential biological activ-
ities,1,2 but the synthesis of these compounds has rarely been
reported.3 Recently, among our efforts devoted towards the
synthesis of heterocyclic compounds from functionalized
allenes,4 we have established a Pd(0)/Ag+-cocatalyzed cou-
pling–cyclization reaction of organic halides with 2,3-allenoic
acids to afford racemic polysubstituted butenolides.5
It occurred to us that it would be possible to synthesize
optically active butenolides with high ee value starting from
2,3-allenoic acids with high enantiopurity and organic halides.
The most formidable challenge in this reaction is the chirality
transfer ability of the possible intermediates from the chiral
allenoic acids.
noic acid 1f and its corresponding -(2)-cinchonidine salt Sa-
L
(+)-2f. The corresponding reaction under the comparable
reaction conditions afforded S-(+)-3g (eqn. 2).
The reaction of Sa-(+)-1a6–8 with PhI under the catalysis of
Pd(0) was studied (Scheme 1). The results are somewhat
disappointing as well as encouraging since the highest ee of
(+)-3a9 observed was 60% indicating that the p-allyl palladium
species5 did partially ‘remember’ the chirality in 2,3-allenoic
acids (Scheme 1).
(2)
In order to increase the efficiency of chirality transfer, we
reasoned that if we could make the mechanistic switch from a p-
allyl palladium mechanism5 to an oxidative addition–coor-
Scheme 1
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b1/b109645a/
Scheme 2
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CHEM. COMMUN., 2002, 540–541
This journal is © The Royal Society of Chemistry 2002

Table 1 Enantioselective synthesis of 3-aryl butenolides via the Pd(0)-catalyzed coupling–cyclization reaction of 1+1 acid–base salts of 2,3-allenoic acids
and chiral basesa
1+1 salt
Entry
R1
R2
Base
acid–base Saltb,c
Ar2I
Time (h)
Yield9 (%)
ee (%)d
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
n-Pr
n-Pr
Me
Me
Me
Me
Me
H
A
A
A
A
B
B
C
C
C
A
(+)-2a (97% ee)
(+)-2a (97% ee)
(+)-2b (98% ee)
(+)-2b (98% ee)
(+)-2c (97% ee)
(+)-2c (97% ee)
(2)-2c (98% ee)
(2)-2c (98% ee)
(2)-2c (98% ee)
(+)-2e (97% ee)
Ph
48
48
60
60
72
72
60
60
60
48
90 (S-(+)-3a)
66 (S-(+)-3b)
72 (S-(+)-3c)
75 (S-(+)-3d)
60 (S-(+)-3a)
65 (S-(+)-3b)
66 (R-(2)-3a)
72 (R-(2)-3b)
58 (R-(2)-3e)
55 ((+)-3f)g
91
92
91
91
93
95
96
98
94
94
p-MeC6H4
Ph
p-MeC6H4
Ph
p-MeC6H4
Ph
p-MeC6H4
f
9
10e
Ph
n-Hep
p-EC6H4
Ph
.
a The reaction was carried out using 2 (0.1 mmol), ArI (0.12 mmol), Pd2(dba)3 CHCCl3 (5 mol%), PPh3 (20 mol%), and TBAB (0.1 mmol) in toluene (3 mL).
b A =
L
-(2)-cinchonidine; B =
L
-(2)-a-methylbenzylamine; C =
-(+)-a-methylbenzylamine. c Ee value referring to the allene moiety determined by its
D
conversion to ethyl ester by the treatment of 2 with EtI and i-Pr2NEt in DMF at rt. d Ee values were determined by HPLC with Chiralcel OD column (0.46
cm f 3 25 cm). e MeCN was used as the solvent. f E = CO2Me. g The absolute configuration not determined.
Siddiqui, F. Afshan, Farhana S. Faizi, S. N.-H. Naqvi and R. M. Tariq,
J. Chem. Soc., Perkin Trans. 1, 1999, 2367; D. A. G. Cortez, J. B.
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B. Cass and J. R. Pirani, Phytochmistry, 1998, 49, 2493; H. Ostuka, K.
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Prod., 1998, 64, 534; S. Driol, F. Felluga, C. Forzeto, P. Nitti, G. Pitacco
The absolute configurations of the allene moiety in Sa-(+)-2f
and S-(+)-3g were determined by X-ray diffraction studies of
the single crystals of the corresponding acid Sa-(+)-1f and S-
(+)-3g using bromine atom as the reference.10 The ster-
eochemical outcome indicates that the mechanism may proceed
via a mechanism shown in Scheme 2.
With these standard reaction conditions we studied the
chirality transfer ability of this coupling-cyclization reaction in
detail. The results are listed in Table 1. The following points are
noteworthy: (1) the yields are moderate to good, with the
highest being 90% (entry 1, Table 1); (2) the products 3 were
formed in > 90% ee, although somewhat lower than that of
allene moiety in the 1+1 acid–base salts 2; (3) the efficiency of
and E. Valentin, J. Org. Chem., 1998, 63, 2385; S. Guo, L. Wang and D.
Chen, India J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 1997, 36B,
339.
2 T. S. Brima US 4,968,817, 1990: Chem. Abs. 1991 114 185246yA.
Tanabe Jpn. Kokai Tokyo Koho JP 63,211,276 [88,211,276], 1988:
Chem. Abs. 1989 110 94978qG. C. M. Lee Eur. Pat. EP. 372,940, 1990:
Chem. Abs. 1990 113 191137jY. Ducharme, J. Y. Gauthier, P. Prasit, Y.
Leblanc, Z. Wang, S. Leger and M. Thrien PCT Int. Appl. WO 95,
00,501, 1995: Chem. Abs. 1996 124 55954yC. M, L. Gary and M. E.
Gast PCT Int. Appl. WO. 91 16,055, 1991: Chem. Abs. 1992 116
59197m.
3 For some of the representative examples of the stereoselective synthesis
of optically active butenolides, see: (a) A. van Oeveren and B. L.
Feringa, J. Org. Chem., 1996, 61, 2920; (b) M. Renard and L. Ghosez,
Tetrahedron Lett., 1999, 40, 6237; (c) S. Tsuboi, J. Sakamoto, H.
Yamashita, T. Sakai and M. Utaka, J. Org. Chem., 1998, 63, 1102; (d)
Q. Yu, Y. Wu, L. Xia, M. Tang and Y. Wu, Chem. Commun., 1999, 129;
(e) T. Berkenbusch and R. Brckner, Tetrahedron, 1998, 54, 11461.
4 S. Ma and S. Wu, J. Org. Chem., 1999, 64, 9314; S. Ma, Z. Shi and Z.
Yu, Tetrahedron, 1999, 55, 12137; S. Ma, Z. Shi and Z. Yu,
Tetrahedron Lett., 1999, 40, 2393; S. Ma and S. Zhao, J. Am. Chem.
Soc., 1999, 121, 7943; S. Ma and Z. Zhang, Chem. Commun., 2000, 117;
S. Ma and L. Li, Org. Lett., 2000, 2, 941; For a recent highlight, see: A.
S. K. Hashmi, Angew. Chem. Int. Ed., 2000, 39, 3590.
chirality transfer process with
higher than that with -(2)-cinchonidine (compare entries 1, 2
with 6, 7); (4) with -(+)-a-methylbenzylamine, the efficiency
of chirality transfer is even higher, and the products are the
opposite enantiomers of what were formed with both
L-(2)-a-methylbenzylamine is
L
D
L-(2)-a-
methylbenzylamine and
Table 1).
L-(2)-cinchonidine (entries 8–10,
In conclusion, we have developed an efficient enantiose-
lective synthesis of 3-aryl butenolides using the readily
available chiral bases such as
L-cinchonidine,
D
-(+)- and -
L
(2)-a-methylbenzylamine, as the chiral source. Through the X-
ray diffraction study of the structures of S-(+)-1f and S-(+)-3g,
it is concluded that the reaction may proceed via an oxidative–
coordinative cyclization–reductive elimination process.
Financial support from National NSF of China and the Major
State Basic Research Development Program (Grant No.
G2000077500). Shengming Ma is the recipient of the 1999 Qiu
Shi Award for Young Scientific Workers issued by Hong Kong
Qiu Shi Foundation of Science and Technology (1999–2003)
and the Special Starting Grant for Outstanding Young Chemists
issued by Shanghai Municipal Committee of Science and
Technology
5 S. Ma and Z. Shi, J. Org. Chem., 1998, 63, 6387.
6 H.-J. Bestmann and H. Hartung, Chem. Ber., 1966, 99, 1198; H. D.
Venkruijsse and L. Brandsma Synthesis of Acetylenes, Allenes annd
Cumulenes. A Laboratory Manual, Elsevier, Amsterdam, The Nether-
lands, 1981, p. 33.
7 (a) S. Ma and S. Wu, Chem. Commun., 2001, 441; (b) W. Runge and G.
Kresze, Liebigs Ann. Chem., 1975, 1361.
8 S. R. Landor The Chemistry of the Allenes, Academic Press, New York,
1982, vol. 3, pp. 587–590.
9 The absolute configurations of butenolides were determined based on
the reaction mechanism and the absolute configurations of the allene
moieties of the starting 2,3-allenoic acid–base salts.
Notes and references
1 R. D. Larock, B. Riefling and C. A. Fellows J. Org. Chem., 1978, 43,
131 and the references cited therein. For recent examples, see: Y. Chia,
F. Chang and Y. Wu, Tetrahedron Lett., 1999, 40, 7513; S. Takahashi,
K. Maeda, S. Hirota and T. Nakata, Org. Lett., 1999, 1, 2025; B. S.
10 The absolute configurations of (+)-1f and (+)-3g were determined by
SHELXS software. CCDC 157278 and 157279. See http://www.rsc.org/
suppdata/cc/b1/b109645a/ for crystallographic files in .cif or other
format.
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