Practical Asymmetric Synthesis of Vicinal Diamines through the Catalytic Highly Enantioselective Alkylation of Glycine Amide Derivatives

Article abstract of DOI:10.1002/anie.200352658

Phase-transfer catalysis (PTC) by a designer chiral quaternary ammonium bromide facilitated the direct, highly enantioselective introduction of a wide variety of substituents including cycloalkyl side chains at the α position of the prochiral glycine amid

Full text of DOI:10.1002/anie.200352658

Communications
In organic synthesis, there has also been considerable interest
in this class of compounds because of their use as chiral
ligands and auxiliaries in asymmetric synthesis.[2] Accordingly,
numerous efforts have been made toward their stereoselec-
tive preparation, and a number of useful methodologies have
been elaborated.[3] Unfortunately, however, only a few
practical and general procedures are available even for the
asymmetric synthesis of monosubstituted vicinal diamines.[4]
Although the reduction of amides derived from natural a-
amino acids is probably one of the most straightforward
methods for the synthesis of optically active monosubstituted
vicinal diamines,[5] critical structural limitations on the avail-
ability of a-amino acids (existing chiral pool) and possible
partial racemization encountered in the formation of the
amide constitute severe drawbacks. The direct stereoselective
introduction of the required side chain onto glycine amides
has emerged as a powerful strategy to overcome this intrinsic
problem. However, the successful catalytic asymmetric func-
tionalization of prochiral glycine amide derivatives has never
been reported, and all previous examples have been diaster-
eoselective transformations involving substrates with chiral
auxiliaries.[6] Herein we report the first highly enantioselec-
tive phase-transfer catalytic (PTC) alkylation of protected
glycine amides 1 with the designer chiral quaternary ammo-
nium salt 4 as the catalyst.[7] The chiral ammonium enolate
generated from 1b and 4c was found to be very reactive and
underwent smooth alkylation even with less reactive secon-
dary alkyl halides, thereby facilitating the practical catalytic
asymmetric synthesis of a broad range of optically active
monosubstituted vicinal diamines (Scheme 1).
First, we examined the feasibility of the stereoselective
alkylation of prochiral glycine amide derivatives under phase-
transfer catalytic conditions by using the benzophenone Schiff
base 1a of N-benzylglycinamide as a representative sub-
strate[8] and the N-spiro chiral quaternary ammonium bro-
mide 4a as the catalyst. Treatment of 1a with benzyl bromide
(1.2 equiv) and 4a (2 mol%) in toluene/aqueous KOH (50%)
(3:1) at 08C for 10 h gave only a trace amount of the
corresponding alkylation product 2a (R = CH2Ph). In con-
trast, the reaction proceeded smoothly under similar con-
Asymmetric Catalysis
Practical Asymmetric Synthesis of Vicinal
Diamines through the Catalytic Highly
Enantioselective Alkylation of Glycine Amide
Derivatives**
Takashi Ooi, Daiki Sakai, Mifune Takeuchi,
Eiji Tayama, and Keiji Maruoka*
Optically active vicinal diamines are of great medicinal
importance, as they are incorporated in a variety of com-
pounds that display a broad spectrum of biological activity.[1]
[*] Prof. K. Maruoka, Dr. T. Ooi, D. Sakai, M. Takeuchi, E. Tayama
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto, 606-8502 (Japan)
Fax: (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was partially supported by the Uehara Memorial
Foundation and a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science, and Technology,
Japan. M.T. thanks the Japan Society for the Promotion of Science
for a Research Fellowship for Young Scientists.
Scheme 1. Practical synthesis of a wide range of optically active vicinal
diamines through the asymmetric phase-transfer catalytic alkylation of
1 in the presence of the catalyst (S,S)-4. RX=primary, secondary,
allylic, or benzylic alkyl halide.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
5868
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DOI: 10.1002/anie.200352658
Angew. Chem. Int. Ed. 2003, 42, 5868 –5870

Angewandte
Chemie
Table 1: Asymmetric synthesis of optically active vicinal diamines by the catalytic enantioselective
phase-transfer alkylation of 1b.[a]
ditions with the catalyst 4b, which has the
substituent 3,5-di-tert-butylphenyl, to fur-
nish 2a (R = CH2Ph) almost quantitatively
with 36% ee. This result suggested that the
steric effect of the 3,3’ aromatic substituent
of the catalyst is more important than the
electronic effect of this group on the reac-
tivity. Compound 2a (R = CH2Ph) was
obtained with higher enantioselectivity
(69% ee) when 4c, which is sterically more
hindered, was employed. We then focused
on screening the amide substituent, based
on these initial results. The diphenylmethyl
(Dpm) derivative 1b was a good substrate,
and the phase-transfer catalytic benzylation
of 1b in the presence of 4c afforded the
desired a-amino amide 2b (R = CH2Ph) in
98% yield with 92% ee (Table 1, entry 1).
Next, we studied the transformation of
2b (R = CH2Ph) into the corresponding
vicinal diamine. We found that acidic
hydrolysis of the imine functionality of 2b
(R = CH2Ph) followed by treatment with
LiAlH4 in cyclopentyl methyl ether
(CPME)[9] afforded the optically active
partially protected vicinal diamine 3 (R =
CH2Ph) in 96% yield without loss of
enantiomeric excess (Table 1, entry 1).[10]
This procedure facilitates the straightfor-
ward preparation of a variety of optically
active vicinal diamines with primary alkyl
side chains. Representative examples are
shown in Table 1. A saturated aqueous
solution of CsOH was used to ensure
consistently high chemical yields in the
alkylation with less reactive alkyl halides
(Table 1, entries 3 and 4).
Entry
RX
4c
[mol%]
Solvent
Base[b]
t [h]
Yield of
ee [%][d]
Yield of
2b [%][c]
3 [%][c]
1[e]
2[e]
3[e]
PhCH2Br
BuI
2
2
2
toluene
toluene
toluene
KOH
KOH
CsOH
3
2
3
98
99
94
92 (R)
98 (R)
97 (R)
96
88
91
4[e]
2
toluene
CsOH
3
82
98 (R)
92
5
6
7
2
2
5
toluene
mesitylene
mesitylene
CsOH
CsOH
CsOH
5
5
5
82
81
90
82 (R)
90 (R)
90 (R)
>99
8
2
mesitylene
CsOH
3
91
96
97
9[f]
10
mesitylene
CsOH
5
71
95
90
85
10
10
mesitylene
CsOH
3
80
89
[a] Unless otherwise specified, the reaction was carried out with 5 equivalents of RX in the presence of a
catalytic amount of 4c under the reaction conditions given. [b] Aqueous KOH (50%) or saturated,
aqueous CsOH. [c] Yield of the isolated product. [d] Enantiopurity was determined by HPLC analysis of
the alkylated imine on a chiral phase (Daicel Chiralcel OD (entry 1), Chiralcel OD-H (entry 2), and
Chiralpak AD (entries 3–10)) with hexane/2-propanol as the solvent. The absolute configuration of the
major enantiomer (given in brackets) was determined by comparison of the HPLC retention time with
that of an authentic sample that had been synthesized independently. [e] RX: 1.2 equivalents.
[f] Iodocyclohexane: 10 equivalents.
This system, which consists of the amide
1b and the chiral catalyst 4c, is remarkably
reactive, thus enabling the hitherto difficult
catalytic asymmetric alkylation of a glycine
anion equivalent with simple secondary
alkyl halides.[11,12] For instance, the reaction
of 1b with 2-iodopropane (5 equiv) under
otherwise similar conditions gave 2b (R =
Scheme 2. Facile derivatization of optically active 2b (R=iPr) to the corresponding differently pro-
tected diamines 3 (R=iPr), 5, and 6. Boc=tert-butoxycarbonyl.
iPr) in 82% yield with 82% ee (Table 1, entry 5). The use of
mesitylene in place of toluene enhanced the enantioselectiv-
ity to 90% ee, and increasing the catalyst loading to 5 mol%
led to improvement of the chemical yield (Table 1, entries 6
and 7).[13] Moreover, various cycloalkyl side chains could be
introduced in satisfactory chemical yields with excellent
enantioselectivities when 2–10 mol% of 4c was used as the
catalyst (Table 1, entries 8–10). Regardless of the steric
demand of the newly introduced side chain at the a position,
the resulting a-alkyl a-amino amides 2b can be readily
converted into the corresponding optically active partially
protected vicinal diamine 3 in excellent chemical yields, as
shown in Table 1 and Scheme 2, thus greatly expanding the
scope of the present method. Reprotection of the free amine
in 3 gave 5, which could be derivatized further to the partially
protected diamine hydrochloride 6 (91%) by simple hydro-
genolysis (Scheme 2).
Finally, our approach has been successfully extended to
the catalytic asymmetric synthesis of optically active vicinal
diamines with sterically congested quaternary stereogenic
centers. Thus, vigorous stirring of a mixture of the alanine
diphenylmethyl amide derived aldimine Schiff base 7, iodo-
cyclopentane (5 equiv), CsOH·H2O (5 equiv), and 4c
(2 mol%) in mesitylene at 08C for 3 h gave a-amino amide
8 almost quantitatively with 93% ee. Subsequent hydrolysis
and reduction of 8 cleanly produced the corresponding
partially protected diamine 9 (96%),[14] which is not readily
accessible by other asymmetric methodologies (Scheme 3).
Angew. Chem. Int. Ed. 2003, 42, 5868 –5870
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Communications
Ooi, M. Kameda, H. Tannai, K. Maruoka, Tetrahedron
Lett. 2000, 41, 8339; d) T. Ooi, M. Takeuchi, K.
Maruoka, Synthesis 2001, 1716; e) T. Ooi, Y. Uematsu,
M. Kameda, K. Maruoka, Angew. Chem. 2002, 114,
1621; Angew. Chem. Int. Ed. 2002, 41, 1551; f) T. Ooi,
M. Takahashi, K. Doda, K. Maruoka, J. Am. Chem.
Soc. 2002, 124, 7640; g) T. Ooi, M. Taniguchi, M.
Kameda, K. Maruoka, Angew. Chem. 2002, 114, 4724;
Angew. Chem. Int. Ed. 2002, 41, 4542; h) T. Ooi, E.
Tayama, K. Maruoka, Angew. Chem. 2003, 115, 599;
Angew. Chem. Int. Ed. 2003, 42, 579.
[8] For excellent reviews on the use of Schiff bases of
glycine derivatives, see: a) T. Abellµn, R. Chinchilla,
N. Galindo, G. Guillena, C. Nµjera, J. M. Sansano, Eur.
J. Org. Chem. 2000, 2689; b) M. J. O'Donnell, Aldri-
chimica Acta 2001, 34, 3.
[9] Cyclopentyl methyl ether, kindly supplied by Zeon
Corporation, Japan, has a higher boiling point (1068C)
than tert-butyl methyl ether. Both ethers are regarded
as a potential substitute for diethyl ether.
Scheme 3. Catalytic asymmetric synthesis of the vicinal diamine 9, which possesses a
sterically congested quaternary stereogenic center.
In conclusion, we have presented a practical procedure for
the asymmetric synthesis of vicinal diamines based on the
catalytic highly enantioselective alkylation of 1b under phase-
transfer conditions in the presence of the designer chiral
quaternary ammonium bromide 4c. As this substrate–catalyst
combination enables the previously difficult catalytic asym-
metric construction of a-alkyl a-amino amides that contain a
tertiary b carbon center,[15] our approach offers efficient
access to structurally diverse optically active vicinal diamines,
including those with sterically very congested quaternary
a carbon centers.
[10] No loss of enantiomeric excess was observed, as determined by
HPLC analysis.
[11] The catalytic enantioselective preparation of a-amino acid
derivatives that contain a tertiary b carbon atom from glycine
anion equivalents is commonly regarded as extremely difficult.
For a diastereoselective approach, see: a) J. M. McIntosh, R. K.
Leavitt, P. Mishra, K. C. Cassidy, J. E. Drake, R. Chadha, J. Org.
Chem. 1988, 53, 1947; b) W. Oppolzer, R. Moretti, C. Zhou, Helv.
Chim. Acta 1994, 77, 2363; c) D. Seebach, M. Hoffmann, Eur. J.
Org. Chem. 1998, 1337; d) S. D. Bull, S. G. Davies, A. C. Garner,
N. Mujtaba, Synlett 2001, 781. Because of the lowreactivity
observed in reactions with some alkyl halides, such as iodocy-
cloalkanes,[11a] an extra reaction step is sometimes necessary, for
example, alkylation with a reactive secondary allylic halide and
subsequent reduction; see: e) J. M. McIntosh, R. K. Leavitt,
Tetrahedron Lett. 1986, 27, 3839.
[12] An alternative solution to this long-standing problem is based on
elegant boron alkylation chemistry: M. J. O'Donnell, M. D.
Drew, J. T. Cooper, F. Delgado, C. Zhou,J. Am. Chem. Soc. 2002,
124, 9348; see also: M. J. O'Donnell, J. T. Cooper, M. M. Mader,
J. Am. Chem. Soc. 2003, 125, 2370.
[13] The attempted reaction of 1b with 2-iodopropane in the
presence of O-allyl-N-(9-anthracenylmethyl)cinchonidinium
bromide (10 mol%),[16] one of the most reliable and most
commonly used catalysts, under otherwise similar conditions
proceeded sluggishly to afford 2b (R = iPr) in 15% yield with
19% ee after 12 h. The use of excess CsOH·H2O as a solid base
and CH2Cl2 as the solvent at À788C to À408C did not lead to the
formation of the product, and 2b (R = iPr) was obtained in
approximately 23% yield, although with only 7% ee, after 5 h at
À208C.
Received: August 15, 2003 [Z52658]
Keywords: alkyl halides · alkylation · asymmetric catalysis ·
.
phase-transfer catalysis · vicinal diamines
[1] E. T. Michalson, J. Szmuszkovicz, Prog. Drug Res. 1989, 33, 135.
[2] See, for example: A. Togni, L. M. Venanzi, Angew. Chem. 1994,
106, 517; Angew. Chem. Int. Ed. Engl. 1994, 33, 497.
[3] For an excellent recent review, see: a) D. Lucet, T. Le Gall, C.
Mioskowski, Angew. Chem. 1998, 110, 2724; Angew. Chem. Int.
Ed. 1998, 37, 2581, and references therein; for selected leading
references, see also: b) A. Alexakis, I. Aujard, P. Mangeney,
Synlett 1998, 873; c) S. Demay, A. Kotschy, P. Knochel, Synthesis
2001, 863; d) P. Saravanan, A. Bisai, S. Baktharaman, M.
Chandrasekhar, V. K. Singh, Tetrahedron 2002, 58, 4693.
[4] For some impressive contributions, see: a) D. Enders, R.
Schiffers, Synthesis 1996, 53, and references therein; b) K.
Yamada, S. J. Harwood, H. Gröger, M. Shibasaki, Angew.
Chem. 1999, 111, 3713; Angew. Chem. Int. Ed. 1999, 38, 3504.
[5] a) G. Buono, C. Triantaphylides, G. Peiffer, F. Petit, Synthesis
1982, 1030; b) H. Brunner, M. Schmidt, G. Unger, H. Schönen-
berger, Eur. J. Med. Chem. 1985, 20, 509; c) B. E. Rossiter, M.
Eguchi, G. Miao, N. M. Swingle, A. E. Hernµndez, D. Vickers, E.
Fluckiger, R. G. Patterson, K. V. Reddy, Tetrahedron 1993, 49,
965.
[14] The absolute configuration of the product 8 was determined to
be R by X-ray crystallographic analysis after conversion into a
dipeptide with N-benzyloxycarbonyl-l-alanine; see Supporting
Information.
[15] For the importance of optically active a-amino amides, see, for
example: a) A. Rockwell, M. Melden, R. A. Copeland, K.
Hardman, C. P. Decicco, W. F. DeGrado, J. Am. Chem. Soc.
1996, 118, 10337; b) K. Kaljuste, J. P. Tam, Tetrahedron Lett.
1998, 39, 9327; c) G. Liu, N. S. Kozmina, M. Winn, T. W.
von Geldern, W. J. Chiou, D. B. Dixon, B. Nguyen, K. C.
Marsh, T. J. Opgenorth, J. Med. Chem. 1999, 42, 3679; d) M. J.
Fray, M. F. Burslem, R. P. Dickinson, Bioorg. Med. Chem. Lett.
2001, 11, 567.
[6] For recent examples, see: a) G. Guillena, C. Nµjera, J. Org.
Chem. 2000, 65, 7310, and references therein; b) H. J. Kim, S.-k.
Lee, Y. S. Park, Synlett 2001, 613.
[7] For the synthetic utility of this type of ammonium salts as chiral
phase-transfer catalysts, see: a) T. Ooi, M. Kameda, K. Maruoka,
J. Am. Chem. Soc. 1999, 121, 6519; b) T. Ooi, M. Takeuchi, M.
Kameda, K. Maruoka, J. Am. Chem. Soc. 2000, 122, 5228; c) T.
[16] E. J. Corey, F. Xu, M. C. Noe, J. Am. Chem. Soc. 1997, 119,
12414.
5870
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 5868 –5870