Asymmetric synthesis of functionalized aza-cyclic amino acids with quaternary stereocenters by a phase-transfer-catalyzed alkylation strategy

Article abstract of DOI:10.1021/ol047921p

(Chemical Equation Presented) Practical asymmetric synthesis of functionalized aza-cyclic α-amino acid derivatives possessing quaternary stereocenters has been achieved by the phase-transfer-catalyzed alkylation of 2 or 3 using chiral quaternary ammonium

Full text of DOI:10.1021/ol047921p

ORGANIC
LETTERS
2005
Vol. 7, No. 2
191-193
Asymmetric Synthesis of Functionalized
Aza-Cyclic Amino Acids with Quaternary
Stereocenters by a
Phase-Transfer-Catalyzed Alkylation
Strategy
Takashi Ooi, Takashi Miki, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502, Japan
maruoka@kuchem.kyoto-u.ac.jp
Received October 8, 2004 (Revised Manuscript Received December 6, 2004)
ABSTRACT
Practical asymmetric synthesis of functionalized aza-cyclic
by the phase-transfer-catalyzed alkylation of 2 or 3 using chiral quaternary ammonium bromide 1 as catalyst. Subsequent reduction and
alkylation of the 3-keto carbonyl moiety of 4 proceeded with complete diastereochemical control to afford the corresponding -hydroxy aza-
cyclic -amino acid derivatives having stereochemically defined consecutive quaternary carbon centers.
r-amino acid derivatives possessing quaternary stereocenters has been achieved
â
r
As a family of nonproteinogenic amino acids, aza-cyclic
R-amino acids with quaternary stereogenic carbon centers
have attracted a particular interest in the various fields of
science, mainly for the following reasons: (1) their confor-
mational constraints offer an important tool for evaluating
the relationship between peptide conformation and biological
activity,1 (2) they are found as a component of biologically
active natural products with therapeutic potential,2 and (3)
they serve as valuable chiral building blocks in organic
synthesis and also constitute a core structure of effective
catalysts for asymmetric bond formation reactions.3 Since
these amino acids are not available from natural sources,
considerable research efforts have been made to develop
useful methods for their synthesis,4-6 and the recently
introduced asymmetric intramolecular ring-closure of pro-
tected R-amino acids utilizing memory of chirality is a
representative example.7 Unfortunately, however, almost all
the previous studies have relied on the use of stoichiometric
amount of external/internal chirality,4,5,7 and hence, catalytic
asymmetric construction of the requisite stereocenters of aza-
(1) For example, see: (a) Ward, P.; Ewan, G. B.; Jordan, C. C.; Ireland,
S. J.; Hagan, R. M.; Brown, J. R. J. Med. Chem. 1990, 33, 1848. (b) Bisang,
C.; Weber, C.; Inglis, J.; Schiffer, C. A.; van Gunsteren, W. F.; Jelesarov,
I.; Bosshard, H. R.; Robinson, J. A. J. Am. Chem. Soc. 1995, 117, 7904.
(2) (a) Long, R. D.; Moeller, K. D. J. Am. Chem. Soc. 1997, 119, 12394.
(b) Trancard, D.; Tout, J.-B.; Giard, T.; Chichaoui, I.; Cahard, D.;
Plaquevent, J.-C. Tetrahedron Lett. 2000, 41, 3843. (c) Gutie´rrez-Rodr´ıguez,
M.; Garc´ıa-Lo´pez, M. T.; Herranz, R. Tetrahedron 2004, 60, 5177.
(3) (a) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450. (b)
Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J.
Am. Chem. Soc. 2004, 126, 4790.
(4) For a comprehensive review, see: Cativiela, C.; D´ıaz-de-Villegas,
M. D. Tetrahedron: Asymmetry 2000, 11, 645 and valuable sets of
references therein.
10.1021/ol047921p CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/30/2004

cyclic R-amino acids remains to be investigated.6 We report
herein our own approach to this problem based on the phase-
transfer-catalyzed, highly enantioselective alkylation of cyclic
R-amino-â-keto esters 2 or 3 with C2-symmetric chiral
quaternary ammonium salt 18 as catalyst (Scheme 1). This
Table 1. Optimization of the Reaction Conditions in the
Phase-Transfer-Catalyzed Benzylation of 2 with (S,S)-1 as
Catalysta
Scheme 1
% eec
conditions % yieldb (config)d
entry
base
KOHe
K2CO3
sat. K2CO3
solvent
toluene
1
2
3
4
5
6
7
rt, 40 min
rt, 40 h
rt, 6 h
31f
88
94
89
91
92
84
87 (R)
88 (R)
88 (R)
84 (R)
87 (R)
89 (R)
94 (R)
g
mesitylene rt, 26 h
m-xylene
o-xylene
o-xylene
rt, 7 h
rt, 2 h
0 °C, 3 h
a Unless otherwise specified, the reaction was carried out on a 0.3 mmol
scale with 1.2 equiv of benzyl bromide and 5 equiv of base in the presence
of 1 mol % of (S,S)-1 in 2 mL of solvent under the given reaction conditions.
b Isolated yield. c Enantiopurity of 4a was determined by HPLC analysis
using a chiral column (DAICEL Chiralcel OD) with hexane-2-propanol as
solvent. d For determination of the absolute configuration, see the Supporting
Information. e Finely powdered. f 2 was partially decomposed. g 1.5 mL of
saturated aqueous K2CO3 was used.
enables the preparation of various optically active 3-oxo-
proline- and 3-oxopipecolic acid-chimeras 4 and 5, which
can further be functionalized onto the 3-keto carbonyl to give
3-hydroxy aza-cyclic R-amino acid derivatives possessing
stereochemically defined consecutive quaternary carbon
centers.
Initially, we chose 3-oxoproline derivative 2 as a repre-
sentative substrate and examined its benzylation under phase-
transfer conditions using chiral quaternary ammonium bro-
mide (S,S)-1, a promising catalyst for the alkylation of simple
â-keto esters.8a Attempted reaction of 2 with benzyl bromide
(1.2 equiv) in the presence of powdered KOH (5 equiv) and
1 mol % of (S,S)-1 in toluene at room temperature resulted
in nearly instantaneous consumption of the starting 2, but
the desired alkylation product 4a was obtained in only 31%
isolated yield with 87% ee (entry 1 in Table 1). Although
promising enantioselectivity was observed, this result ap-
parently indicated the instability of 2 under strongly basic
conditions. Thus, we changed the base to K2CO3 and found
that the benzylation of 2 under otherwise similar conditions
afforded 4a in 88% yield after stirring for 40 h and its
enantiomeric excess was revealed to be 88% ee (entry 2).
Here, use of saturated aqueous K2CO3 was also effective and
the reaction in toluene-saturated K2CO3 (volume ratio ) 4:3)
at room temperature reached completion in 6 h without
sacrificing the chemical yield and the enantioselectivity (entry
3). We then examined the solvent effect, and interestingly,
o-xylene was identified as a solvent of choice for this system,
providing a substantial enhancement of the reaction rate
(entries 4-6). This observation prompted us to conduct the
reaction at 0 °C, where 2 was consumed within 3 h and 4a
was obtained in 84% yield with 94% ee (entry 7).
This optimized reaction condition was used to further
investigate the applicability of the present method for the
synthesis of various aza-cyclic quaternary amino acid deriva-
tives. As shown in Table 2, a series of benzylic bromides
with substituents of different electronic properties were
employable, allowing the preparation of diverse chimeras
of 3-oxoproline and phenylalanine derivatives (entries 1-4).
Construction of quaternary carbon centers having allylic
substituents on 2 can also be achieved in a similar manner
(entries 5 and 6). The catalytic asymmetric quaternization
of homologous substrate 3, 3-oxopipecolic acid derivative,
appeared feasible with 2 mol % of (S,S)-1, and a uniformly
high level of enantioselectivity was attained (entries 7-10).
The optically active R-alkyl-R-amino-â-keto ester 4 thus
obtained can further be functionalized by taking advantage
of the presence of the 3-keto carbonyl moiety. For instance,
simple treatment of 4a with NaBH4 in MeOH gave rise to
6, a protected chimera of 3-hydroxyproline and phenyl-
alanine, as a single diastereomer in a quantitative yield
(5) Recent representative examples: (a) Glaeske, K. W.; West, F. G.
Org. Lett. 1999, 1, 31. (b) Abella´n, T.; Manchen˜o, B.; Na´jera, C.; Sansano,
J. M. Tetrahedron 2001, 57, 6627. (c) Gil, A. M.; Bun˜uel, E.; D´ıaz-de-
Villegas, M. D.; Cativiela, C. Tetrahedron: Asymmetry 2003, 14, 1479.
(d) Tamura, O.; Yanagimachi, T.; Ishibashi, H. Tetrahedron: Asymmetry
2003, 14, 3033. (e) Le Nguyen, B. K.; Langlois, N. Tetrahedron Lett. 2003,
44, 5961. (f) Andrei, M.; Efskind, J.; Viljugrein, T.; Ro¨mming, C.; Undheim,
K. Tetrahedron: Asymmetry 2004, 15, 1301. (g) Bashiardes, G.; Safir, I.;
Barbot, F.; Laduranty, J. Tetrahedron Lett. 2004, 45, 1567. (h) Khasanov,
A. B.; Ramirez-Weinhouse, M. M.; Webb, T. R.; Thiruvazhi, M. J. Org.
Chem. 2004, 69, 5766.
(6) For rare examples involving catalytic asymmetric bond formation,
see: (a) multistep synthesis via Sharpless epoxidation: Brennan, C. J.;
Pattenden, G.; Rescourio, G. Tetrahedron Lett. 2003, 44, 8757. (b) based
on phase-transfer-catalyzed alkylation of R-amino acid Schiff base (enan-
tiomeric excess was not determined): Belokon, Y. N.; Bhave, D.;
D’Addario, D.; Groaz, E.; North, M.; Tagliazucca, V. Tetrahedron 2004,
60, 1849.
(7) (a) Kawabata, T.; Kawakami, S.; Majumdar, S. J. Am. Chem. Soc.
2003, 125, 13012. See also: (b) Brewster, A. G.; Jayatissa, J.; Mitchell,
M. B.; Schofield, A.; Stoodley, R. J. Tetrahedron Lett. 2002, 43, 3919.
(8) (a) Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi, M.; Takeuchi, M.;
Maruoka, K. Angew. Chem., Int. Ed. 2003, 42, 3796. See also: (b) Ooi, T.;
Doda, K.; Maruoka, K. Org. Lett. 2001, 3, 1273. (c) Ooi, T.; Taniguchi,
M.; Kameda, M.; Maruoka, K. Angew. Chem., Int. Ed. 2002, 41, 4542.
192
Org. Lett., Vol. 7, No. 2, 2005

Scheme 2
Table 2. Phase-Transfer-Catalyzed Asymmetric Quaternization
of 2 and 3a
In summary, a concise, catalytic asymmetric synthesis of
functionalized aza-cyclic R-amino acid derivatives possessing
quaternary stereocenters has been accomplished by the phase-
transfer-catalyzed alkylation using chiral quaternary am-
monium bromide 1 as catalyst. Subsequent reduction and
alkylation of the 3-keto carbonyl moiety proceeded with high
diastereoselectivity to afford the corresponding densely
functionalized â-hydroxy-R-amino esters. Further application
of this method to the asymmetric synthesis of biologically
intriguing compounds is being investigated in our laboratory.
a Unless otherwise noted, the reaction was carried out with 1.2 equiv of
RBr in the presence of 1-2 mol % of (S,S)-1 in o-xylene-saturated K2CO3
(volume ratio ) 4:3) at 0 °C for the given reaction time. b Isolated yield.
c Enantiopurity of products was determined by HPLC analysis using a chiral
column. d For determination of the absolute configuration, see the Supporting
Information. e With 3 equiv of allyl bromide.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
(Scheme 2). Moreover, selective alkylation with various
Grignard reagents was found to proceed smoothly to furnish
7 with complete stereochemical control, thereby allowing
the construction of two consecutive stereochemically defined
quaternary stereocenters. The observed diastereoselectivity
could be accounted for by the chelate formation with the
magnesium cation with both the ester and ketone group, and
nucleophilic attack occurs from the side opposite the benzylic
side chain, resulting in the cis-disposition of the hydroxy
and benzyl group.9
Supporting Information Available: Detailed experi-
mental procedure, spectroscopic characterization of new
compounds and stereochemical assignment. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL047921P
(9) (a) Van Emelen, K.; De Wit, T.; Hoornaert, G. J.; Compernolle, F.
Org. Lett. 2000, 2, 3083. (b) Van Emelen, K.; De Wit, T.; Hoornaert, G.
J.; Compernolle, F. Tetrahedron 2002, 58, 4225.
Org. Lett., Vol. 7, No. 2, 2005
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