Design and synthesis of novel C2-symmetric chiral piperazines and an application to asymmetric acylation of σ-symmetric 1,2-diols

Article abstract of DOI:10.1021/ol0626387

(Chemical Equation Presented) A novel alicyclic chiral C ₂-symmetric piperazine, (S,S)-7, is designed and synthesized from L-proline. Benzoylation of a series of cyclic and acyclic meso-1,2-diols with a catalytic amount of (S,S)-7 and CuCl₂ provided optically active monobenzoates with high enantioselectivity.

Full text of DOI:10.1021/ol0626387

ORGANIC
LETTERS
2006
Vol. 8, No. 26
6139-6142
Design and Synthesis of Novel
C2-Symmetric Chiral Piperazines and an
Application to Asymmetric Acylation of
σ
-Symmetric 1,2-Diols
Daisuke Nakamura,‡ Kiyomi Kakiuchi,‡ Kenji Koga,‡ and Ryuichi Shirai*,‡,†
Research and Education Center for Materials Science and Graduate School of
Materials Science, Nara Institute of Science and Technology, Takayama, Ikoma-shi,
Nara 630-0192, Japan, and Faculty of Pharmaceutical Sciences, Doshisha Women’s
College of Liberal Arts, Kodo, Kyotanabe-shi, Kyoto 610-0395, Japan
rshirai@dwc.doshisha.ac.jp
Received October 27, 2006
ABSTRACT
A novel alicyclic chiral C2-symmetric piperazine, (S,S)-7, is designed and synthesized from
L-proline. Benzoylation of a series of cyclic and
acyclic meso-1,2-diols with a catalytic amount of (S,S)-7 and CuCl2 provided optically active monobenzoates with high enantioselectivity.
Designing of new chiral ligands to improve enantioselectivity
of organic reactions has become an important issue. Chiral
tertially diamines (1-5) have been used as efficient chiral
inductors, particularly (-)-sparteine (1) and bisoxazoline (3)
have been found to be effective in many asymmetric
transformations.1 Our project has focused on the development
of a new class of C2-symmetric alicyclic chiral diamines. In
this article, we describe the design and the synthesis of a
novelC2-symmetricchiralalicyclictertiarydiamine,(5aS,10aS)-
5a,10a-dimethyldecahydrodipyrrolo[1,2-a:1′,2′-d]pyrazine
((S,S)-7, DMPP), and its application to asymmetric de-
symmetrization of meso-1,2-diols by enantioselective mono-
acylation.
methyl ester at high temperature followed by LiAlH4
reduction. Unfortunately, their experimental procedure was
not reproducible and the product was obtained in low yield
and contained inseparable unidentified impurity. In addition,
their reported 13C NMR spectra indicates ten 13C-signals for
the structure of (S,S)-6 even though it has C2-symmetry,
(1) (a) Nozaki, H.; Aratani, T.; Toraya, T. Tetrahedron Lett. 1968, 4097.
(b) Mukaiyama, T.; Asami, S. Top. Curr. Chem. 1985, 127, 133. (c)
Tomioka, K.; Nakajima, M.; Koga, K. J. Am. Chem. Soc. 1987, 109, 6213.
(d) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113, 9708. (e) Park,
Y. S.; Boys, M.; Beak, P. J. Am. Chem. Soc. 1996, 118, 3757. (f) Hodgson,
D. M.; Lee, G. P. Chem. Commun. 1996, 1015. (g) Bennan, Y. L.;
Hanessian, S. Chem. ReV. 1997, 97, 3161. (h) Park, Y. S.; Beak, P. J. Org.
Chem. 1997, 62, 1574. (i) Hoppe, D. M.; Hense, T. Angew. Chem., Int. Ed.
1997, 36, 2282 and references sited therein. (j) Lucet, D.; LeGall, T.;
Mioskwski, C. Angew. Chem., Int. Ed. 1998, 37, 2580. (k) Li, X.; Schenkel,
L. B.; Kozlowski, M. C. Org. Lett. 2000, 2, 875. (l) Ganguly, B.; Freed, D.
A.; Kozlowski, M. C. J. Org. Chem. 2001, 66, 1103. (m) Xu, Z.; Kozlowski,
M. C. J. Org. Chem. 2002, 67, 3072. (n) Dearden, M. J.; Firkin, C. R.;
Hermet, J.-P. R.; O’Brien, P. J. Am. Chem. Soc. 2002, 124, 1870. (o)
Kozlowski, M. C.; Li, X.; Carroll, P. J.; Xu, Z. Organometallics 2002, 21,
4513. (p) Phuan, P.-W.; Ianni, J. C.; Kozlowski, M. C. J. Am. Chem. Soc.
2004, 126, 15473.
Prior to the synthesis of (S,S)-7, we reinvestigated the
synthesis of (5aS,10aS)-decahydrodipyrrolo[1,2-a:1′,2′-d]-
pyrazine ((S,S)-6, DHPP), which was reported by Breitmeier
and co-worker,2 by intramolecular aminolysis of L-proline
‡ Nara Institute of Science and Technology.
† Present address: Doshisha Women’s College of Liberal Arts.
(2) Zadel, G.; Breitmaier, E. Chem. Ber. 1994, 127, 1323.
10.1021/ol0626387 CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/24/2006

room temperature for several days. The resulting diketo-
piperazine 8a3 was purified by silica gel column chroma-
tography and recrystallization. Reduction of 8a with LiAlH4
and bulb-to-bulb distillation gave pure (S,S)-6, with only five
13C NMR signals as expected, in high yield.
With the chiral diamine (S,S)-6 in hand, synthesis of a
variety of subsutituted chiral diamines, which may have
enhanced potential as the chiral ligand for asymmetric
catalyst, was investigated here. Diastereoselective alkylation
of 8a via potassium enolate with Romo’s method4 gave the
monoalkylated products 8b-d in good yield. Then, an
introduction of the same alkyl group on another bridgehead
carbon center was attempted to obtain C2-symmetric cis-
dialkylated products. However, obtaining C-methylation of
monomethyl diketopiperazine 8b by conventional methods
with LDA or KHMDS as the hindered base and iodomethane
in THF was unsuccessful. It was assumed that the methyl
group on the bridgehead interfered with the approach of the
amide base, therefore we employed lithium diethylamide
(LDEA), a more accessible base than the hindered LDA, to
give the desired chiral cis-dimethyl isomer 9b in good yield
as sole diastereomer (Table 1). Unfortunately, synthesis of
cis-diallyl (9c) and cis-dibenzyl (9d) analogues was unsuc-
cessful to give undesired achiral trans-isomers predomi-
nantly, presumably due to severe steric hindrance between
the first alkyl group on the bridgehead center and the
electrophile.
Figure 1. Chiral tertially diamines.
which should give five 13C-signals. It is implied that the
product obtained by Breitmeier’s procedure may not be
chemically and/or optically pure. Therefore, we modified the
procedure of the multigram scale preparation of (S,S)-6 as
follows (Scheme 1). L-Proline methyl ester hydrochloride,
Scheme 1. Modified Synthesis of (S,S)-6
Finally, reduction of 8b with LiAlH4 gave the chiral
diamine (S,S)-7, which was purified as dipicrate and regener-
ated by neutralization in 67% yield from 8b (Scheme 2).
Acylation of alcohol is one of the most essential reactions
in organic synthesis and many asymmetric acylations have
been developed for preparation of small chiral compounds
well suited for further manipulation of the optically active
molecules. Enzymatic acylation of racemic alcohols by
kinetic optical resolution and desymmtetrization of prochiral
diols have been extensively studied5 and almost established
as potential methods for the preparation of certain chiral
alcohol variants. Recently, catalytic asymmetric acylation of
alcohols with achiral acylating agents has emerged in
obtained by thionyl chloride in methanol, was neutralized
with sodium bicarbonate (powder) in dichloromethane and
the resulting precipitate was filtered and the filtrate was
concentrated in vacuo. Then, the neat residue was stirred at
Table 1. Diastereoselective Alkylation of Diketopiperazine
entry
diketopiperazine
base
RX
Mel
Mel
Mel
Mel
AllylBr
BnBr
yield (%)a
cis:transb
1
2
3
4
5
6
8b (R ) Me)
8b
8b
8b
8c (R ) allyl)
8d (R ) Bn)
KHMDS
LDA
LDA + HMPA
LDEA
LDEA
LDEA
N.R.
N.R.
N.R.
75
65
78
1:0
1:8c
0:1
1
a Yield of dialkylated product (cis and/or trans) from 8b-d. b Ratio was obtained by H NMR of the crude mixture. c Inseparable mixture of epimers.
6140
Org. Lett., Vol. 8, No. 26, 2006

Table 2. Asymmetric Benzoylation of meso-1,2-Diols Catalyzed by CuCl2-Chiral Diamines
a Optical purity was determined by chiral HPLC.
succession.6 Matsumura and co-workers reported excellent
asymmetric acylation catalyzed by the complex of CuCl2 and
chiral bisoxazoline. Here, we applied chiral piperazine (S,S)-7
(DMPP) as the ligand to the above-noted asymmetric
acylation.
Benzoylation of meso-1,2-diols with 3 mol % of CuCl2-
chiral diamines, such as (S,S)-6, (S,S)-7, (-)-sparteine, and
bisoxazoline, for comparison, provided optically active
monobenzoates in moderate to excellent enantioselectivity
(Table 2). Desymmetrization of all the meso-diols investi-
gated was achieved in high enantioselectivity with CuCl2-
(S,S)-7 complex, while use of CuCl2-bisoxazoline and
CuCl2-(S,S)-6 exhibited relatively low optical yield. It was
demonstrated that an introduction of two methyl groups on
bridgehead centers of (S,S)-6 greatly enhanced the enantio-
selectivity. Interestingly, CuCl2-(-)-sparteine complex showed
high enantioselectivity giving the antipodes of mono-
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C.-H.; Whitesides, G. M. Enzymes in Synthetic Organic Chemistry;
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(6) For nonenzymatic asymmetric acylation of meso-diols: (a)
Mukaiyama, T.; Tomioka, I.; Shimizu, M. Chem. Lett. 1984, 49. (b)
Mukaiyama, T.; Yanabe, Y.; Shimizu, M. Chem. Lett. 1984, 404. (c)
Ichikawa, J.; Asami, M.; Mukaiyama, T. Chem. Lett. 1984, 949. (d) Ishihara,
K.; Kubota, M.; Yamamoto, H. Synlett 1994, 611. (e) Vedejs, E.; Daugulis,
O.; Diver, S. T. J. Org. Chem. 1996, 61, 430. (f) Oriyama, T.; Imai, K.;
Hosoya, T.; Sano, T. Tetrahedoron Lett. 1998, 39, 397. (g) Oriyama, T.;
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T.; Imai, K.; Ohoishi, K.; Oriyama, T. Chem. Lett. 1999, 265. (i) Trost, B.
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T.; Murakami, S.; Onomura, O. J. Am. Chem. Soc. 2003, 125, 2052. (k)
Kawabata, T.; Stragies, R.; Fukaya, T.; Nagaoka, Y.; Schedel, H.; Fuji, K.
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Scheme 2. Reduction of Dimethyldiketopiperazine
Org. Lett., Vol. 8, No. 26, 2006
6141

benzoates obtained by use of the CuCl2-(S,S)-7 complex.
Although the availability of D-proline is severely limited,
(-)-sparteine could serve as the pseudoenantiomer of (S,S)-
7.
Acknowledgment. This work was supported by Grant-
in-Aid for Scientific Research (C) (No. 18590023) from the
Japan Society for the Promotion of Science.
In conclusion, the synthesis of the novel class of alicyclic
chiral piperazine ligand (S,S)-7 has been developed. It was
also demonstrated that (S,S)-7 is an effective ligand for
copper-catalyzed asymmetric acylation of meso-1,2-diols.
Mechanistic studies of asymmetric acylation and further
application of other asymmetric transformations with (S,S)-7
are currently under investigation.
Supporting Information Available: Synthetic procedure,
spectral and analytical data for (S,S)-6, (S,S)-7, and asym-
metric acylation of meso-1,2-diols. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0626387
6142
Org. Lett., Vol. 8, No. 26, 2006