Highly enantioselective and practical cinchona-derived phase-transfer catalysts for the synthesis of α-amino acids

Article abstract of DOI:10.1002/1521-3773(20020816)41:16<3036::AID-ANIE3036>3.0.CO;2-3

A new class of naphthalene-based dimeric cinchona alkaloids 1 are very efficient and practical phase-transfer catalysts in the alkylation of a glycine derivative. The mild reaction conditions and the high catalytic efficiency (high yields and ee values) could make these alkaloids practical catalysts in the industrial synthetic process for natural and nonnatural chiral α-amino acids.

Full text of DOI:10.1002/1521-3773(20020816)41:16<3036::AID-ANIE3036>3.0.CO;2-3

COMMUNICATIONS
[
12] Comprehensive Organometallic Chemistry II, Vol. 6, Pergamon,
Oxford, 1995, chap. 5, p. 109.
R
R
R
13] The deprotonation[ analogy can be used to consider the fragments
14]
[
ꢀ
{(cod)Pt} and {m
3
-S} isolobal with CH
2
and with CH . Since {Fe(CO)
3
}
R
þ
2þ
is isolobal with CH , {Re(CO)
3
} is isolobal with CH . The thiocar-
bonylphosphorane can be split homolytically into S- and CPR
is isolobal with CH. The planar ring can be considered as a (CH)
3
, which
1
2
3
þ
5
which is bonded through all five atoms to {Mn(CO)
3
} (isolobal with
CH2 ).
þ
X
[
14] R. Hoffmann, Angew. Chem. 1982, 94, 725 ± 738; Angew. Chem. Int.
Ed. Engl. 1982,21, 711 ± 724.
N+
R =
O
X = Cl or Br
Y = H or allyl
N
Y
CD
Scheme 1.
Highly Enantioselective and Practical
Cinchona-Derived Phase-Transfer Catalysts for
the Synthesis of a-Amino Acids**
preparation of new symmetrical dimeric cinchona-alkaloid-
derived catalysts (Scheme 2), which have a naphthalene
moiety as a ligand, and their application to the catalytic
enantioselective phase-transfer alkylation of glycine deriva-
tive 11 (see Tables 1 and 2).
Hyeung-geun Park,* Byeong-Seon Jeong, Mi-
Sook Yoo, Jeong-Hee Lee, Mi-kyoung Park, Yeon-
Ju Lee, Mi-Jeong Kim, and Sang-sup Jew*
R
R
R
R
Phase-transfer catalysis (PTC) is one of the most useful
methods for practicalsynthesis, because of its operational
simplicity and mild reaction conditions, which enable this
method to be applied to industrial processes.[ Recently, PTC
has been applied extensively to asymmetric synthesis by using
1]
R
R
4
5
6
[2]
chiralquaternary ammonium s at ls .
Chiralphase-transfer
R
R
R
catalysts derived from the cinchona alkaloids have been
R
developed and successfully applied to various useful organic
reactions.[
1d,e,3]
7
8
Since the first cinchona alkaloid-type phase-
[4]
transfer catalysts 1 were introduced by O©Donnell et al.,
more efficient catalysts 2 have been developed independently
R
R
R'
R'
by Lygo et al.[ and Corey et al. by the introduction of the N-
5]
[6]
9
-anthracenylmethyl group instead of the N-benzylgroup in 1
9
10
(
Scheme 1).
Based on the fact that the introduction of a bulky subunit at
N1 of cinchona alkaloids leads to an enhancement of the
stereoselectivity, we recently reported the efficient catalysts 3
R =
R' =
Br
N+
O
by the formation of the meta-dimer, using benzene as a ligand
N+
Scheme 1).[ The enhancement of the stereoselectivity is a
7]
(
O
result of the screening effect between each cinchona unit
CD), which can make the substrate approach from only one
direction. As part of our program to develop practical
catalysts that can be used in industrial processes, we further
investigated more optimaldimeric cata yl sts by modifying the
ligand, that is, the benzene group in 3. We report herein the
N
N
Br
HCN
(
HCD
Scheme 2.
New dimeric quaternary ammonium salts 4±10 were
prepared in two steps from (ꢀ)-hydrocinchonidine (for 4±9)
or (þ)-hydrocinchonine (for 10) and the corresponding
bis(bromomethyl)naphthalenes, which can be easily prepared
by the allylic bromination of the dimethylnaphthalenes.
(ꢀ)-Hydrocinchonine or (þ)-hydrocinchonine and the bis-
(bromomethyl)naphthalenes were stirred at 1008C in EtOH/
DMF/CHCl (5:6:2) for 6 h, followed by O9-allylation with
allyl bromide and aqueous KOH (50%), to give the corre-
sponding dimeric quaternary ammonium salts 4±10 in 90±
5% overall yields. The enantioselective efficiency of the
[
*] Prof. H.-g. Park, Prof. S.-s. Jew, B.-S. Jeong, M.-S. Yoo, J.-H. Lee,
M.-k. Park, Y.-J. Lee, M.-J. Kim
College of Pharmacy, Seoul National University
San 56-1, Shinlim-Dong, Gwanak-Gu, Seoul 151-742 (Korea)
Fax : (þ 82)2-872-9129
E-mail: hgpk@plaza.snu.ac.kr, ssjew@plaza.snu.ad.kr
3
[
**] This work was supported by grants from Aminogen Co. (Korea)
through the Research Center of New Drug Development of Seoul
NationalUniversity and the Research Institute of Pharmaceutical
Sciences in the College of Pharmacy of Seoul National University.
9
naphthalene-based dimeric catalysts was evaluated by the
enantioselective phase-transfer alkylation of 11: the catalysts
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
3036
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4116-3036 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 16

COMMUNICATIONS
Table 1. Enantioselective phase-transfer-catalyzed benzylation of 11 cata-
lyzed by 4±10.
Table 2. Catalytic enantioselective phase-transfer alkylation of 11 with
various alkyl halides in the presence of 9 (1 mol%).
[
a]
[a]
chiral catalyst,
9 (1 mol %),
O
Ph
Ph
Ph
N
Ph
O
PhCH Br, 50% KOH
Ph
Ph
O
Ph
Ph
RX, 50% KOH
O
2
N
N
N
*
OtBu
OtBu
OtBu
PhCH3/CHCl3 7:3
OtBu
CH2Ph
12g
PhCH3/CHCl3 7:3,
0
°C
R
1
1
12
1
1
Yield [%][b]
ee [%][c]
(
Entry
RX
t [h]
Yield [%][b]
ee [%][c]
(Config.)[
Entry
Catalyst
mol%
T [8C]
t [h]
d]
Config.)[
d]
a
b
c
(CH
3
O)
CH
(CH
2
SO
I
2
12
12
12
70
83
80
94 (S)
97 (S)
> 99 (S)
1
2
3
4
5
6
7
8
9
4
5
6
7
8
9
9
9
9
10
9
5
5
5
5
5
5
5
5
5
5
1
0
0
0
0
0
0
20
ꢀ20
ꢀ40
ꢀ40
0
2
3
92
90
82
88
90
95
95
93
90
88
95
91 (S)
86 (S)
44 (S)
36 (S)
79 (S)
97 (S)
92 (S)
98 (S)
99 (S)
96 (R)
97 (S)
CH
CH
3
2
3
2
)
4
CH
2
I
10
10
3
0.5
0.05
6
20
20
10
Br
d
6
95
97 (S)
e
Br
Br
10
95
96 (S)
f
6
90
95
98 (S)
97 (S)
1
0
1
Br
1
g
10
[
a] The reaction was carried out with benzylbromide (5.0 equiv) and
Br
aqueous KOH (50%, 13.0 equiv) in toluene/chloroform (7:3) under the
given conditions. [b] Yields of isolated products. [c] The enantiopurity was
determined by HPLC analysis of the benzylated imine 12g by using a chiral
column (DAICEL Chiralcel OD) with hexanes/2-propanol (500:2.5) as
solvent; in this case it was established by analysis of the racemate, of which
the enantiomers were fully resolved. [d] The absolute configuration was
determined by comparison of the HPLC retention time with that of an
authentic sample, which was synthesized independently by reported
h
i
10
8
95
90
90
95
90
98 (S)
96 (S)
98 (S)
98 (S)
96 (S)
F
Br
Br
NC
j
10
4
tBu
[
4±7]
procedures.
BnO
BnO
Cl
k
l
(
1±5 mol%) were mixed with ester 11, benzylbromide, and
Br
12
aqueous KOH (50%) in toluene/chloroform (7:3) at ꢀ40 to
208C for 0.05±20 h.
Cl
As shown in Table 1, the 2,7-dimeric catalyst 9 showed the
m
2
95
99 (S)
highest enantioselectivity (S, 97% ee, 08C, 5 mol%) of the six
ꢀ)-hydrocinchonidine catalysts (4±9), whereas 6 and 7 gave
(
poor selectivities (44% ee and 36% ee, respectively). The low
selectivity might arise from the unfavorable conformation as a
result of the severe steric repulsion between the two HCD
units in 6 and 7, which is in agreement with our previous
study.[ Generally, a lower temperature results in higher
enantioselectivities in the case of 9 (Table 1, entries 6±9).
Notably, 9 can conserve its high catalytic efficiency in terms of
both reactivity and enantioselectivity, even when present in a
smaller quantity (1 mol%; Table 1, entry 10). Interestingly,
the molecular structure of 9 markedly resembles that of 3,
except for the distance between the two cinchona alkaloid
units. The naphthalene ligand of 9 is about 2.4 ä longer than
the benzene ligand of 3. The reason for the high enantiose-
lectivity of 9 is not clear, but it is thought that the 2,7-
naphthalene ligand confers a spatial benefit to form a more
favorable conformation by decreasing the steric hindrance
between the two HCD subunits relative to that in the 1,3-
benzene ligand in 3. The optima il gl and was adapted to
prepare the dimeric (þ)-hydrocinchonine catalyst 10 for the
synthesis of the R isomer of 12. As we expected, 10 also
showed very high enantioselectivity (R, 96% ee, ꢀ408C).
Table 2 summarizes the results obtained for the alkylation of
[
a] The reaction was carried out with RX (5.0 equiv) and aqueous KOH
(50%, 13.0 equiv) in the presence of 9 (1 mol%) in toluene/chloroform
(
7:3) at 08C. [b] Yields of isolated product. [c] Determined by chiral HPLC
(
see Supporting Information). [d] The absolute configuration was deter-
mined by comparison of the HPLC retention time with that of an
authentic sample, which was independently synthesized by the reported
procedure.[
7a]
4±7]
practical phase-transfer catalyst for the enantioselective syn-
thesis of naturaland nonnatural a-amino acids.
In conclusion, we have developed a new class of naphtha-
lene-based dimeric cinchona alkaloids as very efficient and
practicalphase-transfer cata yl sts ( 4±10). Among them, the
2
,7-naphthalene-based dimeric catalysts 9 and 10 show
excellent enantioselectivity in the alkylation of 11 to give
S)-12 and (R)-12, respectively. The mild reaction conditions
(
and the high catalytic efficiency could make 9 and 10 practical
catalysts in the industrial synthetic process for natural and
nonnaturalchiral a-amino acids. Applications to various
other types of phase-transfer catalytic reactions with 9 and 10
are currently being studied.
Experimental Section
1
1 with various alkyl halides in the presence of catalyst 9
1 mol%) at 0 8C. The very high enantioselectivities (94±
9% ee) indicate that the catalyst 9 is a very efficient and
(
9
For the detailed synthesis of
Information.
9 and its precursors, see Supporting
Angew. Chem. Int. Ed. 2002, 41, No. 16
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4116-3037 $ 20.00+.50/0
3037

COMMUNICATIONS
General procedure (alkylation): Benzyl bromide (0.1 mL, 0.85 mmol) was
added to a mixture of N-(diphenylmethylene)glycine tert-butylester ( 11;
Facile Syntheses of Copper(i) Alkynyl Clusters
Stabilized by Hexafluoroacetylacetonate
(hfac) Ligands: The Structure of
5
0 mg, 0.17 mmol) and the chiral catalyst 9 (1.7 mg, 0.0017 mmol) in
toluene/chloroform (7:3, 0.75 mL). The reaction mixture was then cooled
08C), aqueous KOH (50%, 0.25 mL) was added, and the reaction mixture
(
[
Cu (hfac) (1-pentynyl) ]**
2
6
11
15
was stirred at 08C untilthe starting materialhad been consumed (10 h).
The suspension was diluted with diethyl ether (20 mL), washed with water
Timothy C. Higgs,* Phillip J. Bailey, Simon Parsons,
and Peter A. Tasker*
(
2 î 5 mL), dried over MgSO
Purification of the residue by flash column chromatography on silica gel
hexanes/EtOAc 50:1) afforded the desired product 12g (62 mg, 95%
4
, filtered, and concentrated in vacuo.
(
Whilst the copper(i) alkynyl complexes have been widely
yield) as a colorless oil. The enantioselectivity was determined by chiral
HPLC analysis (DAICEL Chiralcel OD, hexane/2-propanol (500:2.5), flow
[
1]
studied, for their potentialas synthetic reagents,
photophysical( ul minescent) properties,
their
ꢀ
1
rate 1.0 mLmin , 238C, l 254 nm, retention times: R (minor) 12.2 min, S
major) 22.5 min, 97% ee) The absolute configuration was determined by
[2±18]
and the extraor-
(
dinary variety of binding modes exhibited by alkynyl
comparison of the HPLC retention time with the authentic sample
[
14,18±24]
synthesized by the reported procedure.[
4±7]
ligands,
only a few homometallic and homovalent
I
Cu clusters with low nuclearities of 2,3,4, or 6 have been
structurally characterized.[
1,3±15,18±27]
Received: May 6, 2002 [Z19236]
One of the problems in
preparing and isolating high-nuclearity copper(i) complexes
containing terminal alkynyl ligands is the propensity of such
systems to aggregate indiscriminately to yield highly insoluble
polymers or oligomers. One approach to overcoming this
problem is to employ suitable ™capping ligands∫ to protect the
periphery of the cluster. If such ligands were available they
could, in principle, be used to control the size and shape of
clusters by varying the relative concentrations of capping and
interstitial (alkynyl) ligands. To date, this synthetic strategy
has been employed using predominantly neutral ligands,
mostly phosphane-based (for example, PPh3 and
[
1] a) A. Nelson, Angew. Chem. 1999, 111, 1685; Angew. Chem. Int. Ed.
999, 38, 1583; b) Phase-Transfer Catalysis: Mechanism and Synthesis
Ed.: M. E. Halpern), American Chemical Society, Washington, DC,
997; c) Handbook of Phase Transfer Catalysis (Eds.: Y. Sasson, R.
Neumann), Blackie A&M, London, 1997; d) T. Shioiri, S. Arai in
Stimulating Concepts in Chemistry (Eds.: F. Vogtle, J. F. Stoddart, M.
Shibasaki), Wiley-VCH, Weinheim, 2000, pp. 123 ± 143; e) M. J.
O©Donnell in Catalytic Asymmetric Synthesis (Ed.: I. Ojima), Wiley-
VCH, New York, 2000, . 10.
1
(
1
[
2] For recent reports for non-cinchona-derived chiralquaternary ammo-
nium salts, see a) E. V. Dehmlow, S. Schrader, Pol. J. Chem. 1994, 68,
2
199; b) J. JamalEddine, M. Cherqaoui, Tetrahedron: Asymmetry 1995,
6
, 1225; c) E. V. Dehmlow, R. Klauck, S. Duttmann, B. Neumann, H.-G.
[2,3,5±10,12±15,18±22,24]
Ph PCH PPh ),
anionic ligands (for example, 2-Me NCH C H S ).
and in a few cases mono-
2
2
2
Stammler, Tetrahedron: Asymmetry 1998, 9, 2235; d) K. Soai, M.
Watanabe, Chem. Commun. 1990, 43; e) A. Loupy, J. Sansoulet, A.
Zaparucha, C. Merienne, Tetrahedron Lett. 1989, 30, 333; f) A. Loupy,
A. Zaparucha, Tetrahedron Lett. 1993, 34, 473; g) K. I. Rubina, Y. S.
Goldberg, M. V. Shymanska, E. Lukevics, Appl. Organomet. Chem.
ꢀ
[1,25]
2
2
6
4
Herein, we report a very convenient method for the
I
synthesis of homovalent Cu clusters of the type
[
Cu (hfac) (RCꢁC) ]
(hfac ¼ hexafluoroacetylacetonate)
xþy
x
y
1
1
987, 1, 435; h) T. Ooi, M. Kameda, K. Maruoka, J. Am. Chem. Soc.
999, 121, 6519; i) T. Ooi, M. Kameda, H. Tannai, K. Maruoka,
I
and the structuralcharacterization of the al rgest Cu cluster
Tetrahedron Lett. 2000, 41, 8339; j) T. Ooi, M. Takeuchi, M. Kameda, K.
Maruoka, J. Am. Chem. Soc. 2000, 122, 5228; k) T. Ooi, M. Takeuchi, K.
Maruoka, Synthesis 2001, 1716.
3] M. J. O©Donnell, Aldrichimica Acta 2001, 34, 3.
4] a) M. J. O©Donnell, W. D. Bennett, S. Wu, J. Am. Chem. Soc. 1989, 111,
obtained to date, [Cu (hfac) (1-pentynyl) ]. When hfacH is
2
6
11
15
added dropwise to a suspension of Cu O and anhydrous
2
MgSO in excess alkyne (RCꢁCH, R ¼ n-C H , n-C H , n-
4
3
7
4
9
[
[
C H , n-C H ) an exothermic reaction is observed. After
5
11
6
13
addition of n-hexane, filtration and washing, a lime-green
2353; b) M. J. O©Donnell, S. Wu, J. C. Huffman, Tetrahedron 1994, 50,
4507; c) M. J. O©Donnell, S. Wu, I. Esikova, A. Mi, US Patent 5,554,753
1996; d) M. J. O©Donnell, F. Delgado, C. Hostettler, R. Schwesinger,
solution is obtained which is presumed to contain mononu-
2
ꢀ
clear [Cu(hfac)(h -RCꢁCH)] or similar species containing
Tetrahedron Lett. 1998, 39, 8775; e) M. J. O©Donnell, F. Delgado, R. S.
Pottorf, Tetrahedron 1999, 55, 6347.
more than one neutral 1-alkyne ligand (Scheme 1).
Evaporation and subsequent heating (658C) in vacuo gives
viscous red or orange oils or, more frequently, crystalline
solids containing discrete organometallic complexes of the
type [Cu (hfac) (RCꢁC) ], with yields in the range 20±50%.
[
[
[
5] a) B. Lygo, P. G. Wainwright, Tetrahedron Lett. 1997, 38, 8595; b) B.
Lygo, J. Crosby, J. A. Peterson, Tetrahedron Lett. 1999, 40, 1385; c) B.
Lygo, Tetrahedron Lett. 1999, 40, 1389; d) B. Lygo, J. Crosby, J. A.
Peterson, Tetrahedron Lett. 1999, 40, 8671.
6] a) E. J. Corey, F. Xu, M. C. Noe, J. Am. Chem. Soc. 1997, 119, 12414;
b) E. J. Corey, M. C. Noe, F. Xu, Tetrahedron Lett. 1998, 39, 5347;
c) E. J. Corey, Y. Bo, J. Busch-Peterson, J. Am. Chem. Soc. 1998, 120,
xþy
x
y
In certain cases, partialaerialoxidation of such systems has
generated new [Cu (hfac) (RCꢁC) ]-type clusters with high-
xþy
x
y
1
3000.
er nuclearities. Thus, when 1-pentyne was used as the reagent,
7] a) S.-s. Jew, B.-S. Jeong, M.-S. Yoo, H. Huh, H.-g. Park, Chem.
Commun. 2001, 1244; b) H.-g. Park, B.-S. Jeong, M.-S. Yoo, M.-k.
Park, H. Huh, S.-s. Jew, Tetrahedron Lett. 2001, 42, 4645.
[
Cu (hfac) (pentynyl) ] (orange solid) was isolated which, in
18 10 8
[
*] Dr. T. C. Higgs, Prof. P. A. Tasker, Dr. P. J. Bailey, Dr. S. Parsons
The Department of Chemistry
The King©s Buildings, The University of Edinburgh
West Mains Road, Edinburgh, Lothian, Scotland, EH9 3JJ (UK)
Fax : (þ 44)131-650-6452
E-mail: pat01@holyrood.ed.ac.uk, pat05@holyrood.ed.ac.uk
[
**] This work was supported by Avecia, Seiko-Epson Corporation, and
EPSRC funding. We would like to thank Stephen Boyer of the
Computing and Engineering Department of the University of North
London for performing microanalyses. We would also like to thank
Dr. Mary McPartlin for a stimulating discussion with regard to
interpretation of our crystallographic results.
3038
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4116-3038 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 16