Catalytic diastereoselective Pauson-Khand reaction: an efficient route to enantiopure cyclopenta[c]proline derivatives.

Article abstract of DOI:10.1021/ol026826i

Cyclopenta[c]proline derivatives were synthesized in a stereocontrolled manner and in good yields via catalytic Pauson-Khand reactions. The starting materials, optically pure enyne amino acid derivatives, can be easily prepared by an alkenylboronic acid-mediated Mannich-type reaction. [reaction: see text]

Full text of DOI:10.1021/ol026826i

ORGANIC
LETTERS
2002
Vol. 4, No. 23
4077-4080
Catalytic Diastereoselective
Pauson−Khand Reaction: an Efficient
Route to Enantiopure
Cyclopenta[c]proline Derivatives
Biao Jiang* and Min Xu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Science, 354 Fenglin Road,
Shanghai 200032, P. R. China
jiangb@pub.sioc.ac.cn
Received August 30, 2002
ABSTRACT
Cyclopenta[c]proline derivatives were synthesized in a stereocontrolled manner and in good yields via catalytic Pauson−Khand reactions. The
starting materials, optically pure enyne amino acid derivatives, can be easily prepared by an alkenylboronic acid-mediated Mannich-type
reaction.
Fused bicyclic amino acids are a very interesting class of
heterocyclic amino acids and have received considerable
attention with regard to the development of new drugs.1 The
structural features of a wide variety of natural products such
as palauamine, which has a core structure of 3-azabicyclo-
[3,3,0]-octane, have also attracted a great deal of interest.2
Over the past few years, many efficient methods have been
developed for the asymmetric construction of such a skeleton
using a chiral cyclic template to obtain the key azabicyclic
systems successfully.3 The Pauson-Khand reaction has been
considered a valuable and convergent method for the
synthesis of cyclopentanone derivatives.4 Our research goal
is to establish a practical strategy for obtaining a chiral
bicyclic core, which could provide access to a large number
of natural products. The Co2(CO)8-catalyzed Pauson-Khand
reaction may be a good route to chiral azabicycles. There
have been many reports on the stereoselectivity of the
intramolecular Pauson-Khand reaction by incorporating
chirality in the cyclization precursor using stoichiometric
dicobaltoctacarbonyl.5 However, to the best of our knowl-
edge, few reports have addressed the catalytic asymmetric
synthesis of cyclopenta[c]proline using chiral enyne amino
acids. In this communication, we report the first efficient
catalytic approach using intramolecular Pauson-Khand
reactions for the diastereoselective synthesis of cyclopenta-
[c]proline derivatives.
Recently, a new practical approach to unsaturated amino
acids, by reacting alkenyl boronic acid with glyoxylic acid
and amines, was reported by Petasis.6 This prompted us to
investigate the stereocontrolled synthesis of enyne amino acid
(1) (a) Ager, D. J.; Fotheringham, I. G. Curr. Opin. Drug DiscoVery
DeV. 2001, 4, 800. (b) Petersen, M.; Sauter, M. Chimia 1999, 53, 608.
(2) (a) Dilley, A. S.; Romo, D. Org. Lett. 2001, 3, 1535. (b) Mourabit,
A. A.; Potier, P. Eur. J. Org. Chem. 2001, 237. (c) Overman, L. E.; Rogers,
B. N.; Tellew, J. E.; Trenkle, W. C. J. Am. Chem. Soc. 1997, 119, 7159.
(d) Starr, J. T.; Koch, G.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
8793.
(3) (a) Kopach, M. E.; Fray, A. H.; Meyers, A. I. J. Am. Chem. Soc.
1996, 118, 9876. (b) Tsunoda, T.; Ozaki, F.; Shirakata, N.; Tamaoka, Y.;
Yamamoto, H.; Itoˆ, S. Tetrahedron Lett. 1996, 37, 2463.
(4) For recent reviews on the Pauson-Khand reaction, see: (a) Brum-
mond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263. (b) Fletcher, A. J.;
Christie, S. D. R. J. Chem. Soc., Perkin Trans. 1 2000, 1657. (c) Chung,
Y. K. Coord. Chem. ReV. 1999, 188, 297. (d) Geis, O.; Schmalz, H. G.
Angew. Chem., Int. Ed. 1998, 37, 911.
(5) (a) Alcarde, B.; Planco, C.; Sierra, M. A. J. Org. Chem. 1998, 63,
6786. (b) Mukai, C.; Kim, J. S.; Sonobe, H.; Hanaoka, M. J. Org. Chem.
1999, 64, 6822. (c) Carretero, J. C.; Adrio, J. J. Am. Chem. Soc. 1999, 121,
7411. (d) Magnus, P.; Fielding, M. R.; Wells, C.; Lynch, V. Tetrahedron
Lett. 2002, 43, 947.
10.1021/ol026826i CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/19/2002

Table 1. Synthesis of 1,6-Enyne Amino Esters by the Reaction of Alkenylboronic Acids with N-Propargylamines and Glyoxylic Acid
a Resulting mixture was esterified with diazomethane. b Resulting mixture was esterified with benzyl alcohol. c Reaction was carried out by mixing the
three starting materials in CH2Cl2 for 12 h at rt. d Isolated yields. e Reaction was carried out by mixing the three starting materials in CH2Cl2 for 24 h at rt
in the presence of triethylamine. f Diastereomer ratio was determined by HPLC.
derivatives using the reaction of propargylamines, phenyl-
vinyl boronic acids, and glyoxylic acid. To test the reactivity
of the propargylamine, the synthesis of racemic enyne amino
acid esters was first studied. The reaction of N-propargyl-
benzylamine, glyoxylic acid, and (E)-phenylvinyl boronic
acid 1a in dichloromethane for 12 h and then esterification
with diazomethane gave racemic 1,6-enyne amino ester 4a
in 95% yield (Table 1, entry 1). This result turned our
attention to the asymmetric synthesis of enyne amino acid
using a chiral propargylamine as a substrate. Thus, treatment
of (S)-N-propargyl-R-methylbenzylamine 2b with (E)- or (Z)-
phenylethenyl boronic acid 1 and glyoxylic acid gave enyne
amino acid with two isomers in a ratio of 1.5:1, which could
be easily separated by standard chromatography (entries 2
and 5). To our delight, the reaction of (S)-N-propargyl-2-
phenylglycinol 2c gave enyne lactone in 91% yield with two
isomers in a ratio of 1.5:1. We found that the minor
diastereoisomer could be easily converted into the major one
by treatment with triethylamine. Finally, the highly dia-
stereoselective synthesis of enyne amino acid derivatives was
carried out in one pot by mixing chiral N-propargylamines,
glyoxylic acid, phenylethenyl boronic acid, and 2 molar equiv
of triethylamine at room temperature for 12 h. All of the
reactions diastereoselectively gave the enyne amino acid
derivatives in excellent yields (Table 1). In particular, chiral
N-propargyl-2-phenylglycinol only gave a single isomer. To
determine the stereochemistry of the new chiral carbon, the
enyne 4d was recrystallized from hexane and dichloro-
methane. X-ray analysis of compound 4d revealed that the
absolute configuration at the R-carbon was R (Figure 1).
Thus, the use of (S)-N-propargyl-2-phenyl glycinol as a chiral
Figure 1. X-ray crystallography of compounds 4d and 12.
Org. Lett., Vol. 4, No. 23, 2002
4078

auxiliary gave an amino acid with an (R)-configuration, while
(R)-N-propargyl-2-phenylglycinol gave the (S)-diastereo-
isomer, which was similar to our observation in the prepara-
tion of indoylglycines.7
Table 3. Catalytic Diastereoselective Pauson-Khand Reaction
with a Series of 1,6-Enyne Amino Estersa
The intramolecular Pauson-Khand reaction, a formal [2
+ 2 + 1] cyclization of three components (alkynes, olefin
moieties, and carbon monoxide), has been recognized as one
of the most important methods for constructing cyclo-
pentenone-fused bicyclic compounds.8 The catalytic Pauson-
Khand reaction shows high atom efficiency. Several catalytic
versions have recently been developed, including the use of
catalytic amounts of Co2(CO)8 in conjunction with either
P(OPh)3,9 ultraviolet light,10 or high-pressure carbon mon-
oxide.11
To optimize the reaction conditions, the racemic 1,6-enyne
amino ester 1a was used in catalytic versions of the Pauson-
Khand reaction. The results are summarized in Table 2.
Table 2. Examination of the Intramolecular Pauson-Khand
Reaction with Various Catalytic Systems
Co2(CO)8
coligand,
mol %
time temp yielda
entry (mol %)
solvent
(h)
(°C)
(%)
1
2
3
4
10
10
10
5
P(OPh)3, 30 DME
24
24
4
84
70
70
70
32
40
67
50
CyNH2, 20
Bu3PS, 60
Bu3PS, 30
DME
benzene
benzene
24
a Isolated yield.
Treatment of 4a with 10 mol % Co2(CO)8 and 30 mol %
P(OPh)3 in DME under 1 atm of carbon monoxide gave
cyclopenta[c]proline derivatives 6 in 32% yield (entry 1).
The reactant never disappeared, even when the reaction was
prolonged to 24 h. Switching to cyclohexylamine as a
coligand12 in DME also gave a lower yield (entry 2).
Fortunately, with 10 mol % Co2(CO)8 in the presence of 60
mol % Bu3PS,13 we were pleased to find a significant
improvement in yield, and the cyclic amino ester 6 was
a Reaction was carried out in the presence of 10 mol % Co2(CO)8 catalyst
and 60 mol % Bu3PS as a co-ligand in benzene at 70 °C under 1 atm of
CO. b Isolated yields.
(6) (a) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997,
53, 16463. (b) Petasis, N. A.; Goodman, A.; Zavialov, I. A. J. Am. Chem.
Soc. 1997, 119, 445.
(7) Jiang, B.; Yang, C.-G.; Gu, X.-H. Tetrahedron Lett. 2001, 42, 2545.
(8) For the first report of an intramolecular Pauson-Khand reaction,
see: Schore, N. E.; Croudace, M. C. J. Org. Chem. 1981, 46, 5436.
(9) Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, Y. K. J. Am. Chem. Soc.
1994, 116, 3159.
(10) Pagenkopf, B. C.; Livinghouse, T. J. Am. Chem. Soc. 1996, 118,
2285.
(11) (a) Jeong, N.; Hwang, S. H.; Lee, Y.; Lim, J. S. J. Am. Chem. Soc.
1997, 119, 10549. (b) Rautenstrauch, V.; Megard, P.; Conesa, J.; Kuster,
W. Angew. Chem., Int. Ed. 1990, 29, 1413.
(12) Krafft, M. E.; Bon˜aga, L. V. R.; Hirosawa, C. Tetrahedron Lett.
1999, 40, 9171.
isolated as a single isomer in 67% yield (entry 3). The use
of only 5 mol % Co2(CO)8 gave a poor yield (entry 4).
Consequently, the best result was obtained with 10 mol
% Co2(CO)8 and 1,6-enyne amino ester in the presence of
60 mol % Bu3PS as a coligand in benzene at 70 °C under 1
atm of carbon monoxide. The configuration of cycloaddition
product 6 was established by NMR studies and chemical
correlations. The NOESY spectrum of 6 showed correlation
between H2 and H4, indicating a cis relationship between
the phenyl ring and the carboxyl group. The large value of
(13) Hayashi, M.; Hashimoto, Y.; Yamamoto, Y.; Usuki, J.; Saigo, K.
Angew. Chem., Int. Ed. 2000, 39, 631.
Org. Lett., Vol. 4, No. 23, 2002
4079

J3,4 (9.8 Hz) also confirmed that the product had an exo
that the Pauson-Khand reaction of enyne amino ester
occurred with excellent stereocontrol to give a single isomer
and predominantly exo adducts and allowed the Pauson-
Khand procedure to generate two new chiral centers in one
step without epimerization of the amino chiral carbon.
In summary, this strategy, which involves an alkenyl-
boronic acid-mediated Mannich-type reaction followed by
a Co2(CO)8-catalyzed Pauson-Khand reaction, opens a new
route to enantiopure-fused cyclic chiral amino acids. This
strategy is remarkable for its conciseness and convergence.
Furthermore, the entire process is atom efficient. Due to the
diversity of the starting materials and excellent stereocontrol,
this strategy provides an expeditious route to chiral cyclic
amino acids.
configuration.14
The extension of this catalytic system to the asymmetric
synthesis of chiral bicyclic amino acids is summarized in
Table 3. The reaction of 2(R)-enyne 4b or 4c gave (2R,3S,4R)-
bicyclic amino acid derivatives in good yields and as single
isomers, while the reaction of (2S)-5b or 5c gave (2S,3R,4S)-
adduct (entries 1-4). Remarkably, the reaction of 1,6-enyne
lactone 4d or 5d (entries 5 and 6) gave rigid tricyclic
compounds 11 and 12, respectively, in high yields. Interest-
ingly, the configurations of Pauson-Khand reaction adducts
were only controlled by the direction of the carbonyl group
and were not affected by the configuration of the vinyl part.
The reaction of (R,S)-(Z)-enyne 4e gave the same product 7
as 4b in low yield (33%), while the reaction of (S,S)-(Z)-
enyne 5e gave the same product (8) as 5b (entries 7 and 8).
Comparing the NMR and NOSEY data of 6 with those of 7
shows that the chiral cyclopenta[c]proline derivatives also
had an exo configuration. The absolute configuration of the
exo product was further confirmed by X-ray crystal analysis
of compound 12 (Figure 1). It was particularly interesting
Acknowledgment. We are grateful for the financial
support provided by the Shanghai Municipal Committee of
Science and Technology.
Supporting Information Available: Characterization
data and spectra for compounds 4a, 4d, 4e, 5d, and 6-12.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Adrio, J.; Rivero, M. R.; Carretero, J. C. Chem. Eur. J. 2001, 7,
2435.
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