Highly enantioselective phase-transfer-catalyzed alkylation of protected α-amino acid amides toward practical asymmetric synthesis of vicinal diamines, α-amino ketones, and α-amino alcohols

Article abstract of DOI:10.1021/ja0459328

Highly enantioselective alkylation of protected glycine diphenylmethyl (Dpm) amide 1 and Weinreb amide 10 has been realized under phase-transfer conditions by the successful utilization of designer chiral quaternary ammonium salts of type 4 as catalyst. P

Full text of DOI:10.1021/ja0459328

Published on Web 03/17/2005
Highly Enantioselective Phase-Transfer-Catalyzed Alkylation
of Protected r-Amino Acid Amides toward Practical
Asymmetric Synthesis of Vicinal Diamines, r-Amino Ketones,
and r-Amino Alcohols
Takashi Ooi, Mifune Takeuchi, Daisuke Kato, Yukitaka Uematsu, Eiji Tayama,
Daiki Sakai, and Keiji Maruoka*
Contribution from the Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502, Japan
Received July 7, 2004; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Abstract: Highly enantioselective alkylation of protected glycine diphenylmethyl (Dpm) amide 1 and Weinreb
amide 10 has been realized under phase-transfer conditions by the successful utilization of designer chiral
quaternary ammonium salts of type 4 as catalyst. Particularly, remarkable reactivity of the chiral ammonium
enolate derived from 1b and 4c allowed the reaction with less reactive simple secondary alkyl halides with
high efficiency and enantioselectivity. An additional unique feature of this chiral ammonium enolate is its
ability to recognize the chirality of â-branched primary alkyl halides, which provides impressive levels of
kinetic resolution and double stereodifferentiation during the alkylation, allowing for two R- and γ-stereo-
centers to be controlled. Combined with the subsequent reduction using LiAlH4 in cyclopentyl methyl ether
(CPME), this system offers a facile access to structurally diverse optically active vicinal diamines.
Furthermore, the optically active R-amino acid Weinreb amide 11 can be efficiently converted to the
corresponding amino ketone by a simple treatment with Grignard reagents. In addition, reduction and
alkylation of the optically active R-amino ketone into both syn and anti R-amino alcohols with almost complete
relative and absolute stereochemical control have been achieved. With (S,S)- and (R,R)-4 in hand, the
present approach renders both enantiomers of R-amino amides including Weinreb amides readily available
with enormous structural variation and also establishes a general and practical route to vicinal diamines,
R-amino ketones, and R-amino alcohols with the desired stereochemistry.
Introduction
chiral phase-transfer catalysis in the asymmetric bond construc-
tion on prochiral glycine amide derivatives has actually remained
Research on the development of useful yet practical methods
for creating chiral nonracemic organic molecules from prochiral
substrates by chiral phase-transfer catalysis is a rapidly growing
area in organic chemistry.1 In particular, extensive studies have
been made on the catalytic asymmetric functionalization of
protected glycine derivatives mainly due to prime value of the
product as optically active R-amino acid derivatives.2 This
process seems to have reached a level of sophistication with
the recent emergence of new catalysts and the modification of
reaction conditions specifically using glycine esters as a key
substrate.3 In turn, little attention has been given to the
advantages of the characteristic property of other glycine
derivatives such as glycine amides, and the effectiveness of
unexplored.4,5 During the course of our effort to expand the
scope of the phase-transfer catalysis of designer chiral quaternary
(3) See, for example: (a) Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto,
Y. J. Org. Chem. 2002, 67, 7418. (b) Kita, T.; Georgieva, A.; Hashimoto,
Y.; Nakata, T.; Nagasawa, K. Angew. Chem., Int. Ed. 2002, 41, 2832. (c)
Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-k.; Lee, Y.-J.;
Kim, M.-J.; Jew, S.-s. Angew. Chem., Int. Ed. 2002, 41, 3036. (d) Arai, S.;
Tsuji, R.; Nishida, A. Tetrahedron Lett. 2002, 43, 9535. (e) Shibuguchi,
T.; Fukuta, Y.; Akachi, Y.; Sekine, A.; Ohshima, T.; Shibasaki, M.
Tetrahedron Lett. 2002, 43, 9539. (f) Sasai, H. Jpn. Kokai Tokkyo Koho
2003, JP2003335780. (g) Lygo, B.; Allbutt, B. Synlett 2004, 326.
(4) For diastereoselective transformation involving substrates with chiral
auxiliaries, see: (a) Oppolzer, W.; Moretti, R.; Zhou, C. HelV. Chim. Acta
1994, 77, 2363. (b) Lo´pez, A.; Pleixats, R. Tetrahedron: Asymmetry 1998,
9, 1967. (c) Abella´n, T.; Na´jera, C.; Sansano, J. M. Tetrahedron: Asymmetry
1998, 9, 2211. (d) Guillena, G.; Na´jera, C. Tetrahedron: Asymmetry 1998,
9, 3935. (e) Na´jera, C., Abella´n, T.; Sansano, J. M. Eur. J. Org. Chem.
2000, 2809. (f) Guillena, G.; Na´jera, C. Tetrahedron: Asymmetry 2001,
12, 181. (g) Kim, H. J.; Lee, S.-k.; Park, Y. S. Synlett 2001, 613. (h) Deng,
W.-P.; Wong, K. A.; Kirk, K. L. Tetrahedron: Asymmetry 2002, 13, 1135.
For the sole example of catalytic asymmetric alkylation with moderate
enantioselectivity, see: (i) Kumar, S.; Ramachandran, U. Tetrahedron:
Asymmetry 2003, 14, 2539.
(1) For reviews, see: (a) Shioiri, T. In Handbook of Phase-Transfer Catalysis;
Sasson, Y., Neumann, R., Eds.; Blackie Academic & Professional: London,
1997; Chapter 14. (b) O’Donnell, M. J. Phases - The Sachem Phase
Transfer Catalysis ReView 1998, Issue 4, 5. (c) O’Donnell, M. J. Phases
- The Sachem Phase Transfer Catalysis ReView 1999, Issue 5, 5. (d)
Shioiri, T.; Arai, S. In Stimulating Concepts in Chemistry; Vogtle, F.,
Stoddart, J. F., Shibasaki, M., Eds.; Wiley-VCH: Weinheim, 2000; p 123.
(e) O’Donnell, M. J. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima,
I., Ed.; Wiley-VCH: New York, 2000; Chapter 10.
(2) For reviews, see: (a) Abella´n, T.; Chinchilla, R.; Galindo, N.; Guillena,
G.; Na´jera, C.; Sansano, J. M. Eur. J. Org. Chem. 2000, 2689. (b)
O’Donnell, M. J. Aldrichimica Acta 2001, 34, 3. (c) Maruoka, K.; Ooi, T.
Chem. ReV. 2003, 103, 3013.
(5) For recent representative examples of a non-PTC system, see: (a) Reyes,
A.; Juaristi, E. Tetrahedron: Asymmetry 2000, 11, 1411. (b) Palomo, C.;
Aizpurua, J. M.; Galarza, R.; Benito, A.; Khamrai, U. K.; Eikeseth, U.;
Linden, A. Tetrahedron 2000, 56, 5563. (c) Guillena, G.; Na´jera, C. J.
Org. Chem. 2000, 65, 7310. (d) Buenadicha, F. L.; Avendan˜o, C.; So¨llhuber,
M. Tetrahedron: Asymmetry 2001, 12, 3019. (e) Caddick, S.; Parr, N. J.;
Pritchard, M. C. Tetrahedron 2001, 57, 6615. (f) Carlier, P. R.; Zhao, H.;
DeGuzman, J.; Lam, P. C.-H. J. Am. Chem. Soc. 2003, 125, 11482.
9
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J. AM. CHEM. SOC. 2005, 127, 5073-5083
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A R T I C L E S
Ooi et al.
Scheme 1. Phase-Transfer-Catalyzed Asymmetric Alkylation of Protected Glycine Amides 1 and 10 Using Chiral Quaternary Ammonium
Bromides 4, and Its Synthetic Utility
ammonium bromides of type 4,6 we considered it important to
address this issue in light of the interest not only in the utility
of optically active R-amino amide itself7 but also in the ample
possibility of accessing other versatile chiral building blocks
through additional appropriate functionalizations. In this Article,
we describe the development of general, highly enantioselective
alkylation of protected glycine diphenylmethyl (Dpm) amide
1b and Weinreb amide 10 by utilizing 4 as an efficient phase-
transfer catalyst (Scheme 1), and we emphasize its characteristic
features.8 The fruitful synthetic opportunity offered by this
achievement has been clearly visualized by the facile transfor-
mation of the resulting alkylation product 2b into the corre-
sponding optically active vicinal diamines 3, and of 11b into
the corresponding R-amino ketones, respectively. The optically
active R-amino ketones thus obtained can further be derivatized
to syn and anti R-amino alcohols with rigorous stereochemical
control. Because both enantiomers of the catalyst 4 are available,
the present approach allows practical asymmetric synthesis of
those valuable chiral compounds with the desired relative and
absolute stereochemistries.
(S,S)-4a6a,b as catalyst. Treatment of 1a with 1.2 equiv of benzyl
bromide and 2 mol % of (S,S)-4a in toluene-50% KOH aqueous
solution (volume ratio ) 3:1) at 0 °C for 10 h gave only a trace
amount of the corresponding alkylation product 2a (R1
)
CH2Ph). In contrast, however, the reaction proceeded smoothly
under similar conditions with (S,S)-4b6c having 3,5-di-tert-
butylphenyl substituent as catalyst, furnishing 2a (R1 ) CH2Ph)
almost quantitatively with 36% ee. This observation suggesting
the importance of the steric effect of the 3,3′-aromatic substituent
of 4 prompted us to conduct the alkylation with sterically more
hindered (S,S)-4c6c as catalyst, leading to the production of 2a
(R1 ) CH2Ph) with promising enantioselectivity (69% ee). We
then investigated the influence of the amide protecting group
(PG) on the reactivity and selectivity, where glycine diphenyl-
methyl (Dpm) amide derivative 1b was identified as a key
substrate and the phase-transfer catalytic benzylation of 1b in
the presence of (S,S)-4c afforded the desired R-amino amide
2ba in 98% yield with 92% ee (entry 1 in Table 1). This
procedure tolerates a variety of primary alkyl halides, and the
representative results are listed in Table 1. It should be noted
that the use of saturated CsOH is beneficial to constantly attain
high chemical yield in the reactions with simple aliphatic alkyl
halides (entries 3 and 4).
Quite interestingly, the present system consisting of glycine
amide derivative 1b and the chiral catalyst 4c exhibited
remarkable reactivity, enabling the catalytic asymmetric alkyl-
ation of the glycine anion equivalent with less reactive secondary
alkyl halides.4a,9,10 For instance, reaction of 1b with 2-iodo-
propane (5 equiv) under otherwise similar conditions gave rise
to 2be in 82% yield with 82% ee (entry 5). Here, use of
mesitylene in place of toluene enhanced the enantioselectivity
to 90% ee, and increase of the catalyst loading to 5 mol % led
Results and Discussion
1. Highly Enantioselective Alkylation of Protected r-
Amino Acid Amides: Asymmetric Synthesis of Vicinal
Diamines. We started examining the feasibility of stereoselective
alkylation of prochiral glycine amide derivatives under typical
liquid-liquid phase-transfer conditions with benzophenone
Schiff base of glycine benzyl amide 1a as a representative
substrate and N-spiro chiral quaternary ammonium bromide
(6) (a) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
2000, 122, 5228. (b) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 5139. (c) Ooi, T.; Tayama, E.; Maruoka, K. Angew. Chem.,
Int. Ed. 2003, 42, 579. See also ref 2c.
(7) See, for example: (a) Rockwell, A.; Melden, M.; Copeland, R. A.; Hardman,
K.; Decicco, C. P.; DeGrado, W. F. J. Am. Chem. Soc. 1996, 118, 10337.
(b) Kaljuste, K.; Tam, J. P. Tetrahedron Lett. 1998, 39, 9327. (c) Liu, G.;
Kozmina, N. S.; Winn, M.; von Geldern, T. W.; Chiou, W. J.; Dixon, D.
B.; Nguyen, B.; Marsh, K. C.; Opgenorth, T. J. J. Med. Chem. 1999, 42,
3679. (d) Fray, M. J.; Burslem, M. F.; Dickinson, R. P. Bioorg. Med. Chem.
Lett. 2001, 11, 567.
(9) For a diastereoselective approach, see: (a) McIntosh, J. M.; Leavitt, R.
K.; Mishra, P.; Cassidy, K. C.; Drake, J. E.; Chadha, R. J. Org. Chem.
1988, 53, 1947. (b) Seebach, D.; Hoffmann, M. Eur. J. Org. Chem. 1998,
1337.
(10) For O’Donnell’s recent contribution using elegant boron alkylation
chemistry, see: O’Donnell, M. J.; Drew, M. D.; Cooper, J. T.; Delgado,
F.; Zhou, C. J. Am. Chem. Soc. 2002, 124, 9348. See also: O’Donnell, M.
J.; Cooper, J. T.; Mader, M. M. J. Am. Chem. Soc. 2003, 125, 2370.
(8) Preliminary communication of this study: Ooi, T.; Sakai, D.; Takeuchi,
M.; Tayama, E.; Maruoka, K. Angew. Chem., Int. Ed. 2003, 42, 5868.
9
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Alkylation of Protected
R
-Amino Acid Amides
A R T I C L E S
Table 1. Catalytic Enantioselective Phase-Transfer Alkylation of 1ba
a Unless otherwise specified, the reaction was carried out with 5 equiv of R1X in the presence of a catalytic amount of (S,S)-4c under the given reaction
conditions. b Isolated yield. c Enantiopurity was determined by HPLC analysis of the alkylated imine using a chiral column [DAICEL Chiralcel OD (entry
1), Chiralcel OD-H (entry 2), and Chiralpak AD (entries 3-10)] with hexane-2-propanol as solvent. d Absolute configuration was determined by comparison
of the HPLC retention time with the authentic sample independently synthesized. e With 1.2 equiv of R1X. f Use of 10 equiv of iodocyclohexane.
Scheme 2. Complete Protonation of Deuterium Labeled 1b-d3
under the Typical Asymmetric Alkylation Conditions
Scheme 3. Attempt for Stereoselective Alkylation of 1b with
Racemic 1-Bromo-1-phenylethane
to improvement of the chemical yield (entries 6 and 7). Various
cycloalkyl side chains can also be introduced in satisfactory
chemical yields with excellent enantioselectivities using 2-10
mol % of (S,S)-4c as catalyst (entries 8-10), greatly expanding
the scope of this method.
tunately afforded a nearly equimolar mixture of two dia-
stereomers, and the enantiomeric excess of each isomer was
determined to be 61% and 33% ee, respectively, as shown in
Scheme 3.
Although the origin of the observed high reactivity is unclear,
we conducted the following experiment to gain an insight into
it. Deuterium labeled 1b-d3 was prepared and exposed to the
typical asymmetric alkylation conditions, which furnished the
product 2bf with complete protonation (Scheme 2). This result
suggests that the initial generation of the cesium enolate by the
deprotonation of 1b would be in equilibrium with the reverse
protonation process and also implies the intervention of the
dianion species as a reactive nucleophile.
Given the vast potential of this new asymmetric methodology,
we next focused our attention on the investigation of the
alkylation with alkyl halides having stereogenic carbon centers,
that is, the possibility of diastereo- and enantioselective alkyl-
ation through kinetic resolution of racemic alkyl halides.11
Initially, we attempted the reaction of 1b with racemic secondary
alkyl halide, 1-bromo-1-phenylethane, under the optimized
phase-transfer conditions using (S,S)-4c as catalyst; this unfor-
To our surprise, however, the alkylation of 1b with â-branched,
racemic primary halide, 1-iodo-2-phenylpropane (5a), was found
to proceed stereoselectively under similar conditions to give
(2R,4R) isomer predominantly [(2R,4R)-2bj/(2R,4S)-2bj ) 91:
9] in an essentially enantiopure form (99% ee) (entry 1 in Table
2). This finding indicates that the emergent diastereochemical
preference toward (2R,4R) isomer would directly reflect an
additional yet distinct ability of the chiral quaternary ammonium
cation of 4c to recognize the chirality of the rather remote
â-carbon of the halide through this alkylation event. Indeed,
(S,S)-4c-catalyzed alkylation of 1b with optically pure (S)-5a
under otherwise identical phase-transfer conditions resulted in
(11) Only a few yet important contributions to the phase-transfer-catalyzed
alkylation of glycinate Schiff base with optically active alkyl halides have
recently been reported. Unfortunately, however, notable double stereo-
differentiation and kinetic resolution have never been demonstrated. See:
(a) Le´pine, R.; Carbonnelle, A.-C.; Zhu, J. Synlett 2003, 1455. (b)
Armstrong, A.; Scutt, J. N. Org. Lett. 2003, 5, 2331.
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A R T I C L E S
Ooi et al.
Table 2. Diastereo- and Enantioselective Alkylation of 1b through Kinetic Resolution of â-Branched Racemic Primary Alkyl Halide 5 under
Phase-Transfer-Catalyzed Conditionsa
% eed (config)e
entry
R1
R2
% yieldb
(2R*,4R*)/(2R*,4S*)c
(2R*,4R*)
(2R*,4S*)
prod.
1
2
3
4
Ph
Me (5a)
Me (5b)
Me (5c)
Bu (5d)
89
80
93
87
91:9
92:8
93:7
80:20
99 (2R,4R)
93 (2R,4S)
2bj
2bk
2bl
p-Me-C6H4
c-Hex
Ph
97
97
98
89
90
83
2bm
a The reaction was carried out with 5 equiv each of 5 and saturated CsOH in the presence of 2 mol % of (S,S)-4c in toluene at 0 °C for 2.5 h. b Isolated
yield. c Determined by 1H NMR analysis. d Enantiopurity was determined by HPLC analysis using a chiral column (DAICEL Chiralpak AD-H) with hexane-
2-propanol or ethanol as solvent. e Relative and absolute configurations were established by the reactions with independently prepared (R)- and (S)-5a.
Scheme 4. Double Stereodifferentiation during the Alkylation of 1b with Optically Pure 1-Iodo-2-phenylpropane (5a)
a very clean formation of (2R,4R)-2bj as a single stereoisomer,
while the reaction of 1b with the (R)-5a in the presence of (S,S)-
4c was sluggish and eventually generated three stereoisomers
including (2S,4S)-2bj in 38% combined yield (Scheme 4). The
observed considerable double stereodifferentiation confirmed
that (S)-5a is a matched halide for the (S,S)-4c-catalyzed
alkylation.12 It is of interest that the degree of the diastereo-
selectivity through the kinetic resolution process was subtly
affected by the electronic property of the substituent R1 of 5
and rather sensitive to the steric demand of R2 as is evident
from other representative results listed in Table 2 (entries 2-4).
With this general asymmetric alkylation protocol in hand,
we next pursued the transformation of 2b to the corresponding
vicinal diamine through simple reduction.13,14 This interest
certainly originated from the great importance of optically active
vicinal diamines as a structural component of various com-
pounds with a broad spectrum of biological activity15 and also
as chiral metal ligands and auxiliaries in asymmetric synthesis.16
An initial attempt was made by acidic hydrolysis of the imine
moiety of 2ba followed by treatment with LiAlH4 in refluxing
THF, giving optically active partially protected vicinal diamine
3a with complete preservation of the enantiomeric excess, but
a considerable amount of intermediary amino amide remained
unreacted. Therefore, we tuned the conditions of the reduction
process and found that 3a was obtained in 96% yield by
performing the reduction in cyclopentyl methyl ether (CPME)
at 100 °C (entry 1 in Table 3). The efficiency of the present
transformation was not affected by the structure of the newly
introduced R-side chain (Table 3). Starting from protected
glycine Dpm amide 1b, this procedure provides a straightfor-
ward yet convenient way to obtain a wide range of optically
active monosubstituted vicinal diamines without being afraid
of partial racemization.
The robustness of our approach was highlighted by applica-
tion to the highly enantioselective quaternization of R-amino
acid diphenylmethyl amide-derived aldimine Schiff base 6,
enabling catalytic asymmetric synthesis of optically active
vicinal diamines possessing quaternary stereogenic centers.
Vigorous stirring of the mixture of 6a, allyl bromide (1.2 equiv),
(14) For a recent excellent review on the stereoselective synthesis of vicinal
diamines, see: (a) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem.,
Int. Ed. 1998, 37, 2581 and references therein. For selected leading
references, see also: (b) Enders, D.; Schiffers, R. Synthesis 1996, 53. (c)
Alexakis, A.; Aujard, I.; Mangeney, P. Synlett 1998, 873. (d) Alvaro, G.;
Grilli, S.; Martelli, G.; Savoia, D. Eur. J. Org. Chem. 1999, 1523. (e)
Yamada, K.; Harwood, S. J.; Gro¨ger, H.; Shibasaki, M. Angew. Chem.,
Int. Ed. 1999, 38, 3504. (f) Demay, S.; Kotschy, A.; Knochel, P. Synthesis
2001, 863. (g) Saravanan, P.; Bisai, A.; Baktharaman, S.; Chandrasekhar,
M.; Singh, V. K. Tetrahedron 2002, 58, 4693. (h) Ashweek, N. J.; Coldham,
I.; Haxell, T. F. N.; Howard, S. Org. Biomol. Chem. 2003, 1, 1532.
(15) Michalson, E. T.; Szmuszkovicz, J. Prog. Drug. Res. 1989, 33, 135.
(16) Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 497.
(12) For double asymmetric induction, see: (a) Horeau, A.; Kagan, H. B.;
Vigneron, J. P. Bull. Chim. Soc. Fr. 1968, 3795. (b) Masamune, S.; Choy,
W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1.
(13) (a) Buono, G.; Triantaphylides, C.; Peiffer, G.; Petit, F. Synthesis 1982,
1030. (b) Brunner, H.; Schmidt, M.; Unger, G.; Scho¨nenberger, H. Eur. J.
Med. Chem. Chim. Ther. 1985, 20, 509. (c) Rossiter, B. E.; Eguchi, M.;
Miao, G.; Swingle, N. M.; Herna´ndez, A. E.; Vickers, D.; Fluckiger, E.;
Patterson, R. G.; Reddy, K. V. Tetrahedron 1993, 49, 965. (d) Modin, S.
A.; Andersson, P. G. J. Org. Chem. 2000, 65, 6736.
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Alkylation of Protected
R
-Amino Acid Amides
A R T I C L E S
Table 3. Facile Conversion of 2b to Optically Active Vicinal Diamines 3a
a The hydrolysis was conducted by the simple treatment of 2b with 1 N HCl in THF, and the subsequent reduction was carried out with 4 equiv of LiAlH4
in CPME at 100 °C. b Isolated yield. c Enantiopurity was determined by HPLC analysis.
Table 4. Catalytic Enantioselective Quaternization of R-Amino Acid-Derived Dpm Amide Aldimine Schiff Base 6a
a Unless otherwise noted, the reaction was carried out with 1.2 equiv of R2X and 5 equiv of CsOH‚H2O in the presence of 2 mol % of (S,S)-4c in toluene
at 0 °C for the given reaction time. b Isolated yield. c Enantiopurity was determined by HPLC analysis using a chiral column (DAICEL Chiralpak AD-H)
with hexane-2-propanol or hexanes-ethanol as solvent. d Absolute configuration was determined by X-ray crystallographic analysis after conversion to the
dipeptide with N-benzyloxycarbonyl-L-alanine. e With 5 equiv of R1X. f Use of mesitylene as solvent.
CsOH‚H2O (5 equiv), and (S,S)-4c (2 mol %) in toluene at 0
°C for 3 h gave rise to the desired R,R-dialkyl-R-amino amide
7aa in 93% yield with 93% ee (entry 1 in Table 4). As we
expected, reactions with simple primary and secondary alkyl
halides, iodobutane and iodocyclopentane, also proceeded
smoothly to afford the corresponding quaternization products
7ab and 7ac, respectively, with excellent asymmetric induction
(entries 2 and 3). In addition, alkylation of phenylalanine-derived
6b appeared feasible under similar conditions (entry 4). The
enantiomerically enriched quaternary R-amino amide 7 thus
obtained can be cleanly transformed into the corresponding
partially protected diamine as demonstrated in the preparation
of 9 having a sterically congested quaternary carbon center,
which is not readily accessible by ordinary asymmetric meth-
odologies (Scheme 5).
2. Highly Enantioselective Alkylation of Protected Glycine
Weinreb Amides: Asymmetric Synthesis of r-Amino Ke-
tones and r-Amino Alcohols. To further explore the possibility
and advantage of the phase-transfer-catalyzed alkylation of
R-amino acid amide derivatives, we next chose protected
glycine-derived Weinreb amide 10 as an intriguing substrate.17
If direct stereoselective introduction of the requisite R-substituent
on 10 becomes feasible, unique reactivity of the Weinreb amide
moiety toward organometallic reagents makes it a reliable and
practical entry to a broad range of optically active R-amino
ketones, particularly those not obtainable from natural R-amino
acids.18,19 The potential utility of this approach is tightly
(17) O’Donnell, M. J.; Drew, M. D.; Pottorf, R. S.; Scott, W. L. J. Comb. Chem.
2000, 2, 172.
(18) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
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A R T I C L E S
Ooi et al.
Scheme 5. Preparation of Vicinal Diamine 9 from 7ac via Acidic Hydrolysis and Reduction
Table 5. Catalytic Enantioselective Phase-Transfer Alkylation of
Protected Glycine Weinreb Amides 10a
Scheme 6. Transformation of 11b into Protected R-Amino Ketone
12
Table 6. Efficient Conversion of Optically Active Weinreb Amide
11b into the Corresponding R-Amino Ketone 12a
a Unless otherwise specified, the reaction was carried out with 1.1 equiv
of R1X in the presence of 2 mol % of (S,S)-4b in toluene-50% KOH
aqueous solution (volume ratio ) 3:1) at 0 °C. b Isolated yield. c Enan-
tiopurity of 11 was determined by HPLC analysis using a chiral column
[DAICEL Chiralcel OD-H (entries 1-3), Chiralcel OD (entries 4 and 8),
and Chiralpak AD (entries 5-7 and 9)]. d Absolute configuration was
determined by comparison of the HPLC retention time with the authentic
sample. e With (S,S)-4c as catalyst. f Use of saturated CsOH as base.
a Unless otherwise specified, the reaction was carried out with 1.6-2.0
equiv of R2MgX in THF at 0 °C for 20 min and the amino ketone was
isolated as N-tert-butoxycarbonyl derivative. b Isolated yield. c Isolated as
N-benzoate.
sumption, and reexamination of a suitable catalyst in the
allylation revealed that the sterically less demanding 4b was
superior to 4c in this case. Thus, vigorous stirring of 10a with
allyl bromide (1.1 equiv) in toluene-50% KOH aqueous
solution (volume ratio ) 3:1) under the influence of (S,S)-4b
(2 mol %) at 0 °C for 6 h resulted in the formation of the
corresponding alkylation product 11a (R1 ) CH2CHdCH2) in
96% yield with 96% ee (entry 1 vs 2 in Table 5). Further, we
found that the reaction of 10b possessing a benzyl group on
the amide nitrogen under similar conditions afforded 11b (R1
) CH2CHdCH2) more cleanly with higher enantioselectivity
(99%, 97% ee) (entry 3), and general applicability of this system
was investigated with the variety of alkyl halides summarized
in Table 5. All reactions proceeded smoothly in the presence
of 2 mol % of (S,S)-4b with excellent enantioselectivities (entries
4-7), and use of saturated CsOH as a base was again
recommended for the reaction with simple aliphatic alkyl halides
(entries 8 and 9).
associated with the synthetic as well as pharmaceutical impor-
tance of optically active R-amino ketones serving as key
synthetic precursors for optically active R-amino alcohols20 and
also for a number of biologically active molecules.21,22
Although we first applied the 4c-catalyzed phase-transfer
alkylation conditions optimized for 2b to the allylation of 10a,23
it turned out to be unsuccessful in terms of both chemical yield
and enantioselectivity. This consequence was within our as-
(19) For reviews, see: (a) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15. (b)
Mentzel, M.; Hoffmann, H. M. R. J. Prakt. Chem. 1997, 339, 517.
(20) For reviews, see: (a) Ager, D. H.; Prakash, I.; Schaad, D. R. Chem. ReV.
1996, 96, 835. See also: (b) Meester, W. J. N.; van Dijk, R.; van
Maarseveen, J. H.; Rutjes, F. P. J. T.; Hermkens, P. H. H.; Hiemstra, H. J.
Chem. Soc., Perkin Trans. 1 2001, 2909. (c) Hoffman, R. V.; Maslouh,
N.; Cervantes-Lee, F. J. Org. Chem. 2002, 67, 1045. (d) Zhou, Z. H.; Tang,
Y. L.; Li, K. Y.; Liu, B.; Tang, C. C. Heteroat. Chem. 2003, 14, 603. (e)
Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Angew. Chem., Int. Ed. 2004,
43, 882.
(21) For reviews, see: (a) Dondoni, A.; Perrone, D. Synthesis 1993, 1162. (b)
Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chem. ReV. 1995, 95, 1677.
(c) Sardina, F. J.; Rapoport, H. Chem. ReV. 1996, 96, 1825.
(22) For recent examples, see: (a) Lucet, D.; LeGall, T.; Mioskowski, C.; Ploux,
O.; Marquet, A. Tetrahedron: Asymmetry 1996, 7, 985. (b) MaGee, D. I.;
Leach, J. D.; Mallais, T. C. Tetrahedron Lett. 1997, 38, 1289. (c) Hoffman,
R. V.; Tao, J.-H. J. Org. Chem. 1998, 63, 3979.
Having succeeded in developing an asymmetric phase-
transfer-catalyzed alkylation of 10 for the first time, the use-
fulness of the optically active Weinreb amide 11 was demon-
strated by its successful conversion to the corresponding
R-amino ketones (Scheme 6).17-19,24 Reaction of 11b (R1 )
CH2CHdCH2) (97% ee) with PhMgBr (1.6 equiv) in THF at
(23) We chose the allylation of 10a as a model system because of our interest
in the preparation of optically active R-amino acid Weinreb amides not
obtainable from natural sources.
9
5078 J. AM. CHEM. SOC. VOL. 127, NO. 14, 2005

Alkylation of Protected
R
-Amino Acid Amides
A R T I C L E S
Scheme 7. Stereoselective Synthesis of R-Amino Alcohols from 11ba
a Reactions and conditions: (a) PhMgBr (1.6 equiv), THF, 0°C. (b) L-Selectride (2.0 equiv), THF, -78 °C. (c) 10% citric acid, THF, rt. (d) (Boc)2O (3.0
equiv), NaHCO3 aq, 0 °C to rt. (e) 1 N HCl, 0 °C to rt then concentration. (f) NaBH4 (2.0 equiv), MeOH, 0 °C to rt.
Scheme 8. Diastereoselective Alkylation of Protected R-Amino Ketones 13 and 18
0 °C for 20 min and subsequent hydrolysis with 1 N HCl
followed by reprotection of the amine moiety produced R-amino
ketone 12 (R1 ) CH2CHdCH2, R2 ) Ph) quantitatively without
loss of enantiomeric excess (97% ee) (entry 1 in Table 6). As
listed in Table 6, not only aryl amino ketones but also alkyl
amino ketones can be prepared in a similar manner using an
appropriate Grignard reagent (entries 2 and 3), and the structure
of the R-substituent subtly influenced the efficiency of this
transformation (entries 4 and 5), thereby enabling the facile syn-
thesis of structurally diverse optically active R-amino ketones.
Based on the results, highly stereoselective synthesis of
R-amino alcohols has been accomplished.25 For example, after
the reaction of 11b (R1 ) CH2CHdCH2) with PhMgBr,
reduction of the resulting Schiff base protected R-amino ketone
13 (R1 ) CH2CHdCH2) with L-Selectride in THF at -78 °C
and subsequent hydrolysis with citric acid and reprotection
furnished syn amino alcohol 14 (R1 ) CH2CHdCH2) exclu-
sively in 82% overall yield, while treatment of the R-amino
ketone hydrochloride 15 (R1 ) CH2CHdCH2) with NaBH4 in
MeOH led to the predominant formation of anti amino alcohol
16 (R1 ) CH2CHdCH2) (85%) (Scheme 7). A similar tendency
was observed in the case of protected Weinreb amide 11b (R1
) CH2R-Np), and both syn and anti amino alcohols were
obtained with excellent diastereoselectivity as also illustrated
in Scheme 7. Since the other enantiomer of 11 is readily
accessible using (R,R)-4b as catalyst, the present method allows
the practical asymmetric synthesis of four possible isomers of
the desired R-amino alcohols starting from protected glycine
Weinreb amide 10b.
Finally, synthetic utility of protected unnatural R-amino
ketones of type 13 was further demonstrated. Reaction of 13
(R1 ) CH2R-Np) with EtMgBr in THF at -78 °C afforded
(2R,3S)-17 as a sole isolable product (89%), and, as expected,
initial derivatization of 18 from 11b (R1 ) CH2R-Np) and
consecutive alkylation with PhMgBr gave rise to (2R,3R)-17
exclusively (53%) (Scheme 8).
Summary and Conclusion
We have developed a phase-transfer alkylation of protected
glycine amide derivatives, diphenylmethyl (Dpm) amide 1b and
Weinreb amide 10b, with high efficiency, enantioselectivity,
and broad generality relying on the use of structurally modifiable
chiral quaternary ammonium bromide 4 as catalyst. This success
opens a door to a new avenue for the preparation of not only
optically active R-amino amides but also other versatile,
stereochemically homogeneous synthetic intermediates such as
vicinal diamines, R-amino ketones, and R-amino alcohols with
unprecedented structural diversity. The simplicity of these new
asymmetric methodologies for actual implementation should be
fully appreciated in their industrial applications.
(24) Recent syntheses of R-amino ketones via nucleophilic R-amino acylation
reactions: (a) Sengupta, S.; Mondal, S.; Das, D. Tetrahedron Lett. 1999,
40, 4107. (b) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001,
3, 1519. (c) Di Gioia, M. L.; Legio, A.; Liguori, A.; Napoli, A.; Siciliano,
C.; Sindona, G. J. Org. Chem. 2001, 66, 7002. (d) Garcia, J.; Nicola`s, E.;
Albericio, F.; Michelotti, E. L.; Tice, C. M. Tetrahedron Lett. 2002, 43,
7495. (e) Va´zquez, J.; Albericio, F. Tetrahedron Lett. 2002, 43, 7499. (f)
Liu, J.; Ikemoto, N.; Petrillo, D.; Armstrong, J. D., III. Tetrahedron Lett.
2002, 43, 8223. (g) Sharma, A. K.; Hergenrother, P. J. Org. Lett. 2003, 5,
2107. See also ref 13.
(25) For the stereoselective synthesis of R-amino alcohols from glycine ester
via reduction-alkylation sequence, see: (a) Polt, R.; Peterson, M. A.;
DeYoung, L. J. Org. Chem. 1992, 57, 5469. (b) Palian, M. M.; Polt, R. J.
Org. Chem. 2001, 66, 7178. (c) Harrison, B. A.; Pasternak, G. W.; Verdine,
G. L. J. Med. Chem. 2003, 46, 677.
Experimental Section
General. Infrared (IR) spectra were recorded on a Shimadzu FT-IR
8200A spectrometer. 1H NMR spectra were measured on a JEOL JNM-
9
J. AM. CHEM. SOC. VOL. 127, NO. 14, 2005 5079

A R T I C L E S
Ooi et al.
FX400 (400 MHz) spectrometer and a JMTC-400/54/SS (400 MHz)
spectrometer. High-performance liquid chromatography (HPLC) was
performed on Shimadzu 10A instruments using 4.6 mm × 25 cm Daicel
Chiralcel OD, OD-H, Chiralpak AD, and AD-H. Optical rotations were
measured on a JASCO DIP-1000 digital polarimeter. For thin-layer
chromatography (TLC) analysis throughout this work, Merck precoated
TLC plates (silica gel 60 GF254, 0.25 mm) were used. The products
were purified by preparative column chromatography on silica gel (E.
Merck 9385). High-resolution mass spectra (HRMS) were performed
on an Applied Biosystems Mariner API-TOF workstation and JEOL
JMS-HX100.
127.5, 127.3, 127.1, 127.0, 127.0, 126.2, 71.3, 56.3, 44.2, 14.4; IR
(liquid film) 3391, 3059, 3028, 2932, 1678, 1622, 1599, 1493, 1447,
1315, 1285, 1028, 765, 696 cm-1. HRMS (ESI-TOF) calcd for
C36H32N2O ([M + H]+): 509.2587. Found: 509.2590. HPLC condi-
tion: DAICEL Chiralpak AD-H, hexane/i-PrOH ) 9:1, flow rate )
1.0 mL/min, tR ) 19.9 (minor) and 23.8 (major) min.
Stereoselective Alkylation of 1b with â-Chiral Primary Alkyl
Halide 5 (Table 2). The reaction was performed in a manner similar
to that of the alkylation with 1-bromo-1-phenylethane, affording the
product 2bj [entry 1, 93.0 mg, 0.178 mmol, 89%, (2R,4R)-2bj/(2R,4S)-
2bj ) 91:9]; (2R,4R)-2bj: 99% ee, [R]33D ) +12.09° (c 2.09, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.58-7.56 (2H, m, ArH), 7.48 (1H, d,
J ) 8.5 Hz, NH), 7.44-7.17 (18H, m, ArH), 7.12-7.09 (3H, m, ArH),
6.97-6.95 (2H, m, ArH), 6.28 (1H, d, J ) 8.5 Hz, Ph2CH), 4.07 (1H,
dd, J ) 5.9, 7.5 Hz, NCHCO), 2.81-2.73 (1H, m, CH3CHPh), 2.18-
2.04 (2H, m, NCHCH2), 0.99 (3H, d, J ) 7.1 Hz, CH3); 13C NMR
(100 MHz, CDCl3) δ 172.4, 169.4, 146.9, 141.7, 141.6, 139.2, 135.3,
130.4, 128.7, 128.7, 128.6, 128.5, 128.5, 128.2, 128.1, 127.6, 127.3,
127.3, 127.2, 127.1, 126.9, 125.8, 64.8, 56.3, 44.3, 36.2, 21.8; IR (neat)
3389, 3059, 3026, 2959, 2924, 1678, 1622, 1493, 1447, 1315, 1287,
1030, 912, 762, 747, 696 cm-1. HRMS (ESI-TOF) calcd for C37H34N2O
([M + H]+): 523.2744. Found: 523.2746. HPLC condition: DAICEL
Chiralpak AD-H, hexane/i-PrOH ) 8:1, flow rate ) 0.5 mL/min, tR )
In experiments requiring dry solvents, ether and tetrahydrofuran
(THF) were purchased from Kanto Chemical Co. Inc. as “dehydrated”.
Benzene and toluene were dried over sodium metal. Dichloromethane
(CH2Cl2) was stored over 4 A molecular sieves. Triethylamine (Et3N)
was stored over potassium hydroxide (KOH) pellets. Cyclopentyl
methyl ether (CPME) was kindly supplied by Zeon Corp., Japan. Other
simple chemicals were purchased and used as such.
Representative Procedure for Asymmetric Alkylation of Glycine
Diphenylmethylamide-Benzophenone Schiff Base 1b under Phase-
Transfer Conditions (Table 1). To a solution of Schiff base 1b (40
mg, 0.10 mmol) and (S,S)-4c (3.2 mg, 0.002 mmol) in mesitylene (1
mL) were added saturated CsOH aqueous solution (30 µL) and
2-iodopropane (50 µL, 0.50 mmol) sequentially at 0 °C under argon
atmosphere, and the reaction mixture was stirred for 5 h. The resulting
mixture was diluted with water and extracted with ether. The organic
phase was washed with brine and dried over Na2SO4. Evaporation of
solvent and purification of the residue by column chromatography on
silica gel (hexane/ethyl acetate ) 5:1 as eluent) afforded the alkylation
1
14.0 (2R,4R) and 18.5 (2S,4S) min. (2R,4S)-2bj: 93% ee; H NMR
(400 MHz, CDCl3) δ 7.51-7.48 (2H, m, ArH), 7.41-7.06 (20H, m,
ArH and NH), 7.00-6.97 (2H, m, ArH), 6.80-6.78 (2H, m, ArH),
6.32 (1H, d, J ) 8.3 Hz, Ph2CH), 3.99 (1H, dd, J ) 5.5, 7.5 Hz,
NCHCO), 2.90-2.81 (1H, m, CH3CHPh), 2.24 (1H, ddd, J ) 5.5, 7.9,
13.9 Hz, NCHCH2), 2.09-2.02 (1H, m, NCHCH2), 1.11 (3H, d, J )
7.1 Hz, CH3); 13C NMR (100 MHz, CDCl3) δ 172.4, 169.8, 146.5,
141.7, 139.2, 135.3, 130.4, 128.6, 128.6, 128.5, 128.5, 128.3, 128.2,
128.0, 127.3, 127.3, 127.2, 127.1, 126.9, 125.7, 64.8, 56.2, 43.2, 36.4,
23.3; IR (neat) 3391, 3059, 3026, 2957, 2924, 1678, 1620, 1493, 1447,
1315, 1287, 1028, 912, 760, 745, 696 cm-1. HRMS (ESI-TOF) calcd
for C37H34N2O ([M + H]+): 523.2744. Found: 523.2746. HPLC
condition: DAICEL Chiralpak AD-H, hexane/i-PrOH ) 8:1, flow rate
) 0.5 mL/min, tR ) 16.0 (2R,4S) and 17.4 (2S,4R) min.
product 2be (R1 ) i-Pr, entry 6) (36 mg, 0.081 mmol, 81%, 90% ee
1
(R)): [R]25 ) +51.3° (c 0.53, CHCl3); H NMR (400 MHz, CDCl3)
D
δ 7.64-7.61 (2H, m, ArH), 7.43-7.17 (17H, m, ArH and NH), 7.02-
6.99 (2H, m, ArH), 6.35 (1H, d, J ) 9.2 Hz, Ph2CH), 3.90 (1H, d, J )
4.4 Hz, NCHCO), 2.27-2.19 (1H, m, CH3CH), 0.98 (3H, d, J ) 6.8
Hz, CH3), 0.82 (3H, d, J ) 6.8 Hz, CH3); 13C NMR (100 MHz, CDCl3)
δ 171.8, 169.9, 141.7, 141.7, 139.3, 135.7, 130.4, 128.6, 128.5, 128.4,
128.1, 127.7, 127.4, 127.3, 127.1, 127.0, 71.4, 56.1, 33.9, 19.7, 18.1;
IR (liquid film) 3389, 3061, 3028, 2963, 2928, 1676, 1620, 1495, 1447,
1315, 1281, 1030, 1001, 756, 698 cm-1. HRMS (ESI-TOF) calcd for
C31H31N2O ([M + H]+): 447.2431. Found: 447.2434. The enantiopurity
was determined by HPLC analysis using chiral column [DAICEL
Representative Procedure for Hydrolysis of the Imine Moiety
of 2b and Subsequent Reduction of the Amide. Facile Conversion
to Optically Active Vicinal Diamine 3 (Table 3). To a solution of
2be (R1 ) i-Pr) (89 mg, 0.20 mmol) (90% ee) in THF (2 mL) was
added 1 N HCl (2 mL) at room temperature, and the mixture was stirred
for 1 h. The aqueous layer was washed with ether and then basified
with 1 M NaOH. Extraction with ethyl acetate and subsequent
evaporation afforded N-free R-amino acid amide as a white solid
quantitatively. Reduction of the amide moiety was then performed with
LiAlH4 (30 mg, 0.80 mmol) in cyclopentyl methyl ether (CPME) (3
mL) at 100 °C for 2 h. The reaction was quenched with sequential
addition of NaF (0.13 g, 3.2 mmol) and water (43 µL, 2.4 mmol) at 0
°C, and stirring was continued for 1 h. The resulting gray precipitate
was filtered off through a pad of Celite, and the filtrate was
concentrated. The residue was purified by column chromatography on
silica gel (short path; ethyl acetate/methanol ) 4:1 as eluent) to give
Chiralpak AD, hexane/i-PrOH ) 20:1, flow rate ) 1.0 mL/min, tR
33.1 (R) and 36.1 (S) min].
)
Asymmetric Alkylation of 1b with Racemic 1-Bromo-1-phenyl-
ethane under Phase-Transfer Conditions (Scheme 3). This alkylation
was conducted in a manner similar to that described above to give the
alkylation product 2bi [75.2 mg, 0.148 mmol, 74%, dr ) 55 (61%
ee):45 (33% ee)]; major diastereomer: 1H NMR (400 MHz, CDCl3) δ
7.58-7.56 (2H, m, ArH), 7.43-7.31 (6H, m, ArH), 7.27-7.18 (11H,
m, ArH), 7.11-7.08 (2H, m, ArH), 6.94 (1H, d, J ) 8.7 Hz, NH),
6.81-6.76 (4H, m, ArH), 6.17 (1H, d, J ) 8.7 Hz, Ph2CH), 4.16 (1H,
d, J ) 5.1 Hz, NCHCO), 3.46-3.39 (1H, m, CH3CHPh), 1.20 (3H, d,
J ) 7.1 Hz, CH3); 13C NMR (100 MHz, CDCl3) δ 170.9, 170.2, 142.4,
141.7, 141.2, 139.1, 135.4, 130.4, 128.9, 128.6, 128.5, 128.4, 128.3,
128.1, 127.8, 127.7, 127.2, 127.1, 127.1, 127.0, 126.4, 72.1, 55.9, 44.7,
18.6; IR (liquid film) 3391, 3059, 3028, 2968, 2928, 1676, 1622, 1599,
1493, 1447, 1315, 1290, 1030, 735, 696 cm-1. HRMS (ESI-TOF) calcd
for C36H32N2O ([M + H]+): 509.2587. Found: 509.2587. HPLC
condition: DAICEL Chiralpak AD-H, hexane/i-PrOH ) 9:1, flow rate
) 1.0 mL/min, tR ) 21.0 (minor) and 22.7 (major) min. Minor
diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.57 (2H, d, J ) 7.1 Hz,
ArH), 7.43-7.04 (22H, m, ArH and NH), 6.35 (1H, d, J ) 8.7 Hz,
Ph2CH), 6.23 (2H, br d, J ) 6.7 Hz, ArH), 4.15 (1H, d, J ) 3.1 Hz,
NCHCO), 3.56-3.50 (1H, m, CH3CHPh), 1.44 (3H, d, J ) 7.1 Hz,
CH3); 13C NMR (100 MHz, CDCl3) δ 171.1, 170.9, 143.2, 141.6, 139.0,
135.2, 130.4, 128.6, 128.5, 128.4, 128.4, 128.2, 128.1, 128.1, 128.0,
3e (R1 ) i-Pr, entry 5) (54 mg, 0.20 mmol, >99%, 90% ee): [R]30
)
D
1
-27.1° (c 1.02, MeOH); H NMR (400 MHz, CDCl3) δ 7.40-7.37
(4H, m, ArH), 7.31-7.25 (4H, m, ArH), 7.21-7.17 (2H, m, ArH),
4.80 (1H, s, Ph2CH), 2.66 (1H, dd, J ) 3.6, 11.2 Hz, CH2), 2.63 (1H,
ddd, J ) 3.6, 5.6, 8.8 Hz, NH2CH), 2.38 (1H, dd, J ) 8.8, 11.2 Hz,
CH2), 1.80 (2H, br, NH2), 1.65-1.57 (1H, m, CH3CH), 0.86 (3H, d, J
) 6.8 Hz, CH3), 0.86 (3H, d, J ) 6.8 Hz, CH3); 13C NMR (100 MHz,
CDCl3) δ 144.2, 143.9, 128.3, 127.2, 127.1, 126.8, 67.6, 57.0, 52.3,
32.1, 19.5, 17.9; IR (KBr) 2972, 2563, 1558, 1396, 746, 704 cm-1
.
HRMS (ESI-TOF) calcd for C18H25N2 ([M + H]+): 269.2012. Found:
269.2020. The preservation of the enantiomeric excess through the
reduction process was confirmed by HPLC analysis of N-benzoate of
the resulting Dpm-protected diamine (see below).
9
5080 J. AM. CHEM. SOC. VOL. 127, NO. 14, 2005

Alkylation of Protected
R
-Amino Acid Amides
A R T I C L E S
1
BzHNCH(i-Pr)CH2NHCHPh2. 90% ee (retained); H NMR (400
MHz, CDCl3) δ 7.76 (2H, d, J ) 7.2 Hz, ArH), 7.50-7.08 (13H, m,
ArH), 6.39 (1H, d, J ) 9.2 Hz, CONH), 4.81 (1H, s, Ph2CH), 4.07
(1H, m, CONHCH), 2.77 (1H, ddd, J ) 6.2, 6.2, 12.8 Hz, CH2), 2.74
(1H, ddd, J ) 4.8, 4.8, 12.8 Hz, CH2), 1.94 (1H, dq, J ) 6.8, 13.6 Hz,
CH3CH), 0.94 (6H, d, J ) 6.8 Hz, CH3). HPLC condition: DAICEL
atmosphere, and the resulting pale-brown solution was stirred for 20
min at the same temperature. The solution was poured into cooled 1 N
HCl quickly, and the mixture was allowed to warm to room temperature.
After being stirred for 20 min, the mixture was concentrated under
reduced pressure and the residue was dissolved in THF or CH3CN (0.1
M). Benzoyl chloride (BzCl, 3 equiv) or (Boc)2O (3 equiv) and solid
NaHCO3 (excess amount) were added to this mixture at 0 °C, which
was stirred for several hours at room temperature. Water was then
added, and the whole mixture was extracted with ether. The combined
extracts were washed with 1 N HCl, saturated NaHCO3 and brine
sequentially, and dried over Na2SO4. Evaporation of solvent and
purification of the crude products by column chromatography on silica
gel (hexane/ethyl acetate or ether as eluent) gave the corresponding
amino ketone 12.
(2R)-N-Boc-2-amino-1-phenylpent-4-en-1-one (12, R1 ) CH2CHd
CH2, R2 ) Ph; Entry 1). 97% ee, [R]20D ) +4.6° (c 1.00, EtOH); 1H
NMR (400 MHz, CDCl3) δ 7.97 (2H, d, J ) 7.2 Hz, ArH), 7.60 (1H,
t, J ) 7.6 Hz, ArH), 7.49 (2H, t, J ) 7.6 Hz, ArH), 5.67 (1H, ddt, J
) 7.2, 10.0, 17.2 Hz, CH2dCH), 5.47 (1H, br d, J ) 7.2 Hz, NH),
5.39-5.34 (1H, m, NCHCO), 5.07 (1H, d, J ) 10.0 Hz, CHdCH2),
5.01 (1H, d, J ) 17.2 Hz, CHdCH2), 2.69 (1H, ddd, J ) 7.2, 7.2, 14.0
Hz, CH2dCHCH2), 2.38 (1H, ddd, J ) 7.2, 7.2, 14.0 Hz, CH2d
CHCH2), 1.45 (9H, s, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 198.2,
155.1, 134.6, 133.5, 132.0, 128.7, 128.4, 118.7, 79.7, 54.7, 37.5, 28.4;
IR (KBr) 3362, 2980, 2930, 1715, 1686, 1641, 1599, 1582, 1501, 1448,
1393, 1367, 1252, 1227, 1171, 1063, 1020, 1001, 920, 856, 781, 700,
691 cm-1. HRMS (ESI-TOF) calcd for C16H21NO3Na ([M + Na]+):
298.1414. Found: 298.1408. HPLC condition: DAICEL Chiralpak AD,
hexane/EtOH ) 50:1, flow rate ) 0.5 mL/min, tR ) 16.7 (R) and 20.6
(S) min.
Chiralpak AD, hexane/EtOH ) 20:1, flow rate ) 0.5 mL/min, tR
)
26.4 (major) and 29.5 (minor) min.
Representative Procedure for Catalytic Asymmetric Quater-
nization of Aldimine Schiff Base 6 under Phase-Transfer Conditions
(Table 4). To a solution of aldimine Schiff base 6a (R1 ) Me) (75
mg, 0.20 mmol), (S,S)-4c (6.2 mg, 0.004 mmol), and iodocyclopentane
(0.12 mL, 1.0 mmol) in mesitylene (2 mL) under argon atmosphere
was added CsOH‚H2O (176.8 mg, 1.0 mmol) in one portion at 0 °C,
and the reaction flask was flushed with argon immediately. After being
stirred for 3 h, the reaction mixture was diluted with water and extracted
with ether. The organic layer was dried over Na2SO4 and concentrated.
Purification of the residue by column chromatography on silica gel
(hexane/ethyl acetate ) 8:1 as eluent) gave the alkylation product 7ac
(R1 ) Me, R2 ) c-Pent; entry 3) (72 mg, 0.16 mmol, 81%) as a white
solid: 1H NMR (400 MHz, CDCl3) δ 8.23 (1H, s, ArCHdN), 8.05
(1H, d, J ) 8.4 Hz, NH), 7.67 (2H, d, J ) 8.4 Hz, ArH), 7.41 (2H, d,
J ) 8.4 Hz, ArH), 7.38-7.34 (2H, m, ArH), 7.31-7.16 (8H, m, ArH),
6.26 (1H, d, J ) 8.0 Hz, Ph2CH), 2.42 (1H, quint, J ) 8.7 Hz,
(CH2)4CH), 1.64-1.51 (3H, m, CH(CH2)4), 1.50 (3H, s, CH3), 1.46-
1.41 (4H, m, CH(CH2)4), 1.08-0.98 (1H, m, CH(CH2)4); 13C NMR
(100 MHz, CDCl3) δ 174.2, 156.6, 142.1, 141.8, 137.0, 134.4, 129.1,
129.0, 128.5, 128.4, 127.3, 127.2, 127.1, 126.9, 69.4, 56.7, 49.6, 27.4,
26.4, 25.3, 25.2, 19.3; IR (liquid film) 3377, 3028, 2955, 2868, 1674,
1595, 1493, 1088, 824, 754, 698 cm-1. HRMS (ESI-TOF) calcd for
C28H30ClN2O ([M + H]+): 445.2041. Found: 445.2034. The enantio-
meric excess of 7ac was determined by HPLC analysis after hydrolysis
of the imine moiety (see Supporting Information 1).
General Procedure for the Synthesis of Schiff Base Protected
r-Amino Ketones (13 or 18) from r-Amino Acid Weinreb Amide
11 (Schemes 8 and 9). To a solution of Weinreb Amide 11 in THF
(0.2 M) was added an ethereal solution of Grignard reagent (1.6-2.0
equiv) at 0 °C under argon atmosphere, and the solution was stirred
for 20 min at the same temperature. The resulting pale-brown solution
was poured into cooled water, and the mixture was extracted with ether.
The combined extracts were washed with brine, dried over Na2SO4,
and concentrated. Purification of the residue by column chromatography
on silica gel with cooling (powdered dry ice, hexane/ether as eluent)
gave the corresponding Schiff base protected R-amino ketone (13 or
18).
(2R)-2-Diphenylmethyleneamino-1-phenylpent-4-en-1-one (13, R1
) CH2CHdCH2). 97% ee, [R]21D ) +23.4° (c 1.00, EtOH); 1H NMR
(400 MHz, CDCl3) δ 7.87-7.84 (2H, m, ArH), 7.67-7.64 (2H, m,
ArH), 7.51 (1H, tt, J ) 1.2, 7.4 Hz, ArH), 7.45-7.36 (6H, m, ArH),
7.32 (2H, tt, J ) 1.2, 7.4 Hz, ArH), 7.12-7.08 (2H, m, ArH), 5.74
(1H, ddt, J ) 7.3, 10.0, 17.2 Hz, CH2dCH), 5.05-4.99 (2H, m, CHd
CH2), 4.87 (1H, dd, J ) 5.8, 7.3 Hz, NCHCO), 2.83-2.69 (2H, m,
CH2dCHCH2); 13C NMR (100 MHz, CDCl3) δ 199.2, 169.7, 139.3,
136.4, 136.1, 134.3, 132.7, 130.2, 128.8, 128.7, 128.6, 128.5, 128.2,
127.9, 127.7, 117.4, 69.4, 39.3; IR (KBr) 3061, 3026, 2961, 2922, 1690,
1616, 1597, 1578, 1491, 1447, 1315, 1290, 1231, 1180, 1074, 1028,
1001, 982, 941, 918, 780, 770, 696 cm-1. HRMS (ESI-TOF) calcd for
C24H22NO ([M + H]+): 340.1696. Found: 340.1705. HPLC condi-
tion: DAICEL Chiralcel OD, hexane/i-PrOH ) 200:1, flow rate )
0.5 mL/min, tR ) 20.3 (S) and 26.3 (R) min.
General Procedure for Asymmetric Alkylation of Glycine Wein-
reb Amide-Benzophenone Schiff Base 10 under Phase-Transfer
Conditions (Table 5). To a mixture of Weinreb amide 10 (0.20 mmol)
and (S,S)-4b (4 mg, 0.004 mmol) in toluene (2 mL) were added 50%
KOH aqueous solution (0.65 mL) and alkyl halide (0.22 mmol) at 0
°C under argon atmosphere, and the mixture was stirred at the same
temperature. After the completion of the reaction was observed via
TLC, the mixture was diluted with water and extracted with ether. The
combined extracts were washed with brine, dried over Na2SO4, and
concentrated. Purification of the crude products by column chroma-
tography on silica gel (hexane/ether as eluent) gave the corresponding
alkylation product 11.
Ph2CdNCH(allyl)CON(OMe)Me (11a, R1 ) CH2CHdCH2;
Entry 2). 96% ee (R), [R]23D ) +25.8° (c 1.00, EtOH); 1H NMR (400
MHz, CDCl3) δ 7.70-7.65 (2H, m, ArH), 7.49-7.42 (3H, m, ArH),
7.38 (1H, m, ArH), 7.33-7.29 (2H, m, ArH), 7.21-7.19 (2H, m, ArH),
5.73 (1H, ddt, J ) 7.2, 10.0, 17.2 Hz, CH2dCH), 5.06-4.98 (2H, m,
CHdCH2), 4.41 (1H, t, J ) 6.8 Hz, NCHCO), 3.27 (3H, s, OCH3),
3.15 (3H, s, NCH3), 2.81 (1H, ddd, J ) 6.8, 7.2, 13.9 Hz, CH2d
CHCH2), 2.64 (1H, ddd, J ) 6.8, 7.2, 13.9 Hz, CH2dCHCH2); 13C
NMR (100 MHz, CDCl3) δ 172.3, 169.4, 139.4, 136.6, 134.7, 130.0,
128.6, 128.3, 128.2, 127.8, 127.8, 117.1, 62.9, 60.9, 38.0, 32.5; IR (KBr)
3061, 2976, 2937, 1670, 1622, 1597, 1576, 1491, 1447, 1385, 1315,
1286, 1178, 1030, 991, 920, 781, 770, 698 cm-1. HRMS (ESI-TOF)
calcd for C20H23N2O2 ([M + H]+): 323.1754. Found: 323.1750. The
enantiopurity was determined by HPLC analysis using chiral column
[DAICEL Chiralcel OD-H, hexane/EtOH ) 50:1, flow rate ) 0.5 mL/
min, tR ) 20.1 (R) and 22.3 (S) min].
(2R)-2-Diphenylmethyleneamino-3-(1-naphthyl)-1-phenylpro-
pan-1-one (13, R1 ) CH2r-Np). 97% ee, [R]19 ) -211.6° (c 1.00,
D
EtOH); 1H NMR (400 MHz, CDCl3) δ 7.89 (2H, d, J ) 8.8 Hz, ArH),
7.78-7.74 (2H, m, ArH), 7.66 (1H, dd, J ) 3.0, 6.2 Hz, ArH), 7.55
(2H, dd, J ) 1.4, 7.4 Hz, ArH), 7.48 (1H, t, J ) 7.4 Hz, ArH), 7.41-
7.15 (10H, m, ArH), 7.01 (2H, m, ArH), 6.27 (2H, br d, J ) 6.4 Hz,
ArH), 5.21 (1H, dd, J ) 4.8, 8.8 Hz, NCHCO), 3.76 (1H, dd, J ) 4.8,
13.7 Hz, NpCH2), 3.69 (1H, dd, J ) 8.8, 13.7 Hz, NpCH2); 13C NMR
(100 MHz, CDCl3) δ 199.5, 169.7, 139.0, 136.3, 135.8, 133.7, 133.6,
General Procedure for Conversion of Schiff Base Protected
Weinreb Amide 11 to r-Amino Ketone 12 (Scheme 7, Table 6). To
a solution of optically active R-amino acid Weinreb amide-benzo-
phenone Schiff base 11 in THF (0.2 M) was added a 0.9 M ethereal
solution of phenylmagnesium bromide (1.6 equiv) at 0 °C under argon
9
J. AM. CHEM. SOC. VOL. 127, NO. 14, 2005 5081

A R T I C L E S
Ooi et al.
132.7, 132.0, 130.0, 128.9, 128.6, 128.4, 128.2, 128.1, 128.0, 127.8,
127.7, 127.1, 125.6, 125.2, 125.2, 123.5, 69.9, 38.1; IR (KBr) 3061,
3024, 2970, 2926, 1686, 1616, 1597, 1576, 1510, 1491, 1447, 1394,
1315, 1288, 1260, 1225, 1178, 1074, 1028, 1001, 984, 943, 912, 847,
800, 777, 694 cm-1. HRMS (ESI-TOF) calcd for C32H26NO ([M +
H]+): 440.2009. Found: 440.1994. HPLC condition: DAICEL Chiral-
pak AD, hexane/i-PrOH ) 20:1, flow rate ) 0.5 mL/min, tR ) 15.5
(R) and 24.3 (S) min.
ddt, J ) 4.6, 7.4, 7.6 Hz, NCH), 3.55 (1H, br, OH), 2.49 (1H, ddd, J
) 7.4, 7.4, 14.0 Hz, CH2dCHCH2), 2.35 (1H, ddd, J ) 7.4, 7.4, 14.0
Hz, CH2dCHCH2); IR (KBr) 3364, 3296, 3071, 1639, 1603, 1580,
1543, 1491, 1456, 1439, 1327, 1298, 1283, 1238, 1157, 1057, 1042,
1028, 968, 914, 864, 766, 704 cm-1. HRMS (ESI-TOF) calcd for
C18H19NO2Na ([M + Na]+): 304.1308. Found: 304.1331. HPLC
condition: DAICEL Chiralcel OD, hexane/i-PrOH ) 10:1, flow rate
) 0.5 mL/min, tR ) 24.6 (1S,2R), 29.5 (1S,2S), 38.6 (1R,2S), and 42.2
(1R,2R) min.
(2R)-2-Diphenylmethyleneamino-1-(1-naphthyl)pentan-3-one (18).
97% ee, [R]25D ) +361.4° (c 1.00, EtOH); 1H NMR (400 MHz, CDCl3)
δ 7.80 (1H, d, J ) 8.4 Hz, ArH), 7.75 (1H, d, J ) 8.4 Hz, ArH), 7.71
(1H, d, J ) 8.4 Hz, ArH), 7.55-7.53 (2H, m, ArH), 7.41-7.34 (2H,
m, ArH), 7.31-7.24 (5H, m, ArH), 7.21 (1H, d, J ) 6.8 Hz, ArH),
7.04 (1H, dt, J ) 1.2, 7.8 Hz, ArH), 6.83 (2H, t, J ) 6.8 Hz, ArH),
5.98 (1H, br, ArH), 4.29 (1H, dd, J ) 3.2, 10.0 Hz, NCHCO), 3.82
(1H, dd, J ) 3.2, 13.5 Hz, NpCH2), 3.35 (1H, dd, J ) 10.0, 13.5 Hz,
NpCH2), 2.84 (1H, dq, J ) 7.2, 18.8 Hz, CH3CH2), 2.53 (1H, dq, J )
7.2, 18.8 Hz, CH3CH2), 1.08 (3H, t, J ) 7.2 Hz, CH2CH3); 13C NMR
(100 MHz, CDCl3) δ 211.1, 169.5, 139.0, 135.2, 133.9, 133.6, 132.2,
130.0, 128.4, 128.3, 128.0, 127.8, 127.7, 127.6, 127.1, 126.7, 125.6,
125.3, 125.1, 123.6, 72.7, 37.1, 33.7, 7.5; IR (KBr) 3057, 2976, 2937,
2905, 1713, 1620, 1597, 1578, 1510, 1491, 1447, 1396, 1379, 1346,
1315, 1286, 1155, 1074, 1028, 945, 914, 799, 779, 696 cm-1. HRMS
(ESI-TOF) calcd for C28H26NO ([M + H]+): 392.2009. Found:
392.1999. HPLC condition: DAICEL Chiralpak AD, hexane/EtOH )
50:1, flow rate ) 0.5 mL/min, tR ) 8.8 (R) and 10.5 (S) min.
General Procedure for Conversion of Schiff Base Protected
r-Amino Ketone 13 to the Corresponding syn-Amino Alcohol 14
(Scheme 8). To a solution of 13 in THF (0.2 M) was added a 1.0 M
THF solution of L-Selectride (2.0 equiv) at -78 °C. After being stirred
for 1 h at the same temperature, the mixture was poured into cooled
saturated NH4Cl. Extractive workup was performed with ether, and
the combined extracts were washed with brine, dried over Na2SO4, and
concentrated. Purification of the residue by column chromatography
on silica gel (hexane/ether as eluent) gave Schiff base protected R-amino
alcohol with a small amount of impurities. A solution of the Schiff
base protected R-amino alcohol in THF (0.1 M) was treated with 10%
aqueous citric acid (the same amount as THF) and stirred for several
hours at room temperature. (Boc)2O (3.0 equiv) and solid NaHCO3
(excess amount) were then added sequentially at 0 °C. After being
stirred for 2 h at room temperature, the resulting mixture was diluted
with water and extracted with ether. The combined extracts were washed
with brine, dried over Na2SO4, and concentrated. The residue was
purified by column chromatography on silica gel (hexane/ether or ethyl
acetate as eluent) to afford syn-amino alcohol 14.
(1R,2R)-N-Boc-2-amino-3-(1-naphthyl)-1-phenylpropan-1-ol (14,
R1 ) CH2r-Np). 97% ee, syn/anti ) 93:7, [R]21 ) -42.6° (c 1.00,
D
1
EtOH); H NMR (400 MHz, DMSO-d6) δ 8.10 (1H, d, J ) 7.6 Hz,
ArH), 7.89 (1H, d, J ) 6.4 Hz, ArH), 7.74 (1H, d, J ) 6.8 Hz, ArH),
7.53-7.23 (9H, m, ArH), 6.42 (1H, d, J ) 8.8 Hz, NH), 5.60 (1H, d,
J ) 4.4 Hz, OCH), 4.69 (1H, s, OH), 3.96 (1H, m, NCH), 3.36 (1H,
dd, J ) 4.0, 13.5 Hz, NpCH2), 2.88 (1H, dd, J ) 9.4, 13.5 Hz, NpCH2),
1.20 (9H, s, C(CH3)3); 13C NMR (100 MHz, DMSO-d6) δ 155.0, 142.8,
135.1, 133.2, 131.6, 128.3, 127.5, 127.2, 126.6, 126.4, 126.4, 125.6,
125.2, 125.1, 123.5, 77.4, 72.8, 56.6, 33.5, 28.1; IR (KBr) 3422, 3061,
2976, 2930, 1686, 1597, 1510, 1497, 1454, 1393, 1367, 1290, 1250,
1169, 1090, 1063, 1022, 912, 860, 800, 779, 735, 702 cm-1. HRMS
(ESI-TOF) calcd for C24H27NO3Na ([M + Na]+): 400.1883. Found:
400.1870. HPLC condition: DAICEL Chiralcel OD, hexane/EtOH )
30:1, flow rate ) 0.5 mL/min, tR ) 23.6 (1S,2R), 28.0 (1R,2S), 32.4
(1S,2S), and 36.2 (1R,2R) min.
General Procedure for anti-r-Amino Alcohol (16) Synthesis from
r-Amino Acid Weinreb Amide 11 (Scheme 8). To a solution of Schiff
base protected Weinreb amide 11 in THF (0.2 M) was added a 0.9 M
ethereal solution of phenylmagnesium bromide (1.6 equiv) at 0 °C under
argon atmosphere, and the resulting pale-brown solution was stirred
for 20 min at the same temperature. The solution was then poured into
cooled 1 N HCl quickly, and the whole mixture was allowed to warm
to room temperature and stirred there for 20 min. The volatiles were
removed under reduced pressure, and the crude 15 was dissolved in
MeOH (0.1 M). NaBH4 (2.0 equiv) was added at 0 °C, and the mixture
was stirred for 1-2 h at room temperature. (Boc)2O (3.0 equiv) and
solid NaHCO3 (excess amount) were then added to the resulting mixture
at 0 °C. After being stirred for 2 h at room temperature, the mixture
was diluted with water and extracted with ether. The combined extracts
were washed with 1 N HCl, saturated NaHCO3 and brine, and then
dried over Na2SO4. Evaporation of solvent and purification of the crude
products by column chromatography on silica gel (hexane/ether or ethyl
acetate as eluent) afforded anti-R-amino alcohol 16.
(1S,2R)-N-Boc-2-amino-1-phenylpent-4-en-1-ol (16, R1 ) CH2CHd
1
CH2). 97% ee, syn/anti ) 2:98, [R]23 ) -13.3° (c 1.00, EtOH); H
D
(1R,2R)-N-Boc-2-amino-1-phenylpent-4-en-1-ol (14, R1 ) CH2CHd
NMR (400 MHz, CDCl3) δ 7.40-7.27 (5H, m, ArH), 5.74 (1H, dddd,
J ) 6.6, 7.4, 8.8, 17.6 Hz, CH2dCH), 5.05 (1H, d, J ) 17.6 Hz, CHd
CH2), 5.04 (1H, d, J ) 8.8 Hz, CHdCH2), 4.91 (1H, br, NH), 4.54
(1H, br, OCH), 3.97 (1H, br, NCH), 3.37 (1H, br, OH), 2.24-2.17
(1H, m, CH2dCHCH2), 2.10-2.02 (1H, m, CH2dCHCH2), 1.45 (9H,
s, C(CH3)3); 13C NMR (100 MHz, CDCl3) δ 156.5, 140.6, 134.6, 128.1,
127.4, 126.3, 117.6, 79.8, 76.2, 56.0, 33.8, 28.4; IR (KBr) 3354, 3071,
2984, 2939, 1688, 1639, 1529, 1458, 1441, 1393, 1367, 1312, 1269,
1252, 1175, 1065, 1018, 995, 912, 881, 854, 764, 704, 675 cm-1. HRMS
(ESI-TOF) calcd for C16H23NO3Na ([M + Na]+): 300.1570. Found:
300.1575. The enantio- and diastereomeric excesses were determined
by HPLC analysis of N-benzoate derivative (see below).
1
CH2). 97% ee, syn/anti ) 99:1, [R]20 ) -15.2° (c 1.00, EtOH); H
D
NMR (400 MHz, CDCl3) δ 7.34-7.25 (5H, m, ArH), 5.79 (1H, ddt, J
) 7.2, 10.6, 16.2 Hz, CH2dCH), 5.10 (1H, d, J ) 16.0 Hz, CHd
CH2), 5.09 (1H, d, J ) 10.6 Hz, CHdCH2), 4.75 (1H, br, NH), 4.69
(1H, dd, J ) 4.4, 4.4 Hz, OCH), 3.79 (1H, br, NCH), 3.25 (1H, br,
OH), 2.34 (1H, ddd, J ) 7.2, 7.2, 14.4 Hz, CH2dCHCH2), 2.15 (1H,
ddd, J ) 7.2, 7.2, 14.0 Hz, CH2dCHCH2), 1.38 (9H, s, C(CH3)3); 13
C
NMR (100 MHz, CDCl3) δ 156.5, 141.6, 134.3, 128.3, 127.6, 126.3,
117.9, 79.7, 76.0, 56.2, 36.2, 28.4; IR (KBr) 3423, 3078, 3030, 2978,
2930, 1692, 1506, 1454, 1393, 1367, 1252, 1171, 1047, 1024, 916,
856, 770, 702 cm-1. HRMS (ESI-TOF) calcd for C16H23NO3Na ([M
+ Na]+): 300.1570. Found: 300.1566. The enantio- and diastereomeric
excesses were determined by HPLC analysis of N-benzoate derivative
(see below).
(1S,2R)-N-Benzoyl-2-amino-1-phenylpent-4-en-1-ol. 85% yield,
1
97% ee, syn/anti ) 2:98, [R]22 ) -39.9° (c 1.00, EtOH); H NMR
D
(400 MHz, CDCl3) δ 7.73-7.70 (2H, m, ArH), 7.51 (1H, tt, J ) 1.2,
7.4 Hz, ArH), 7.43-7.33 (6H, m, ArH), 7.29 (1H, tt, J ) 1.8, 6.8 Hz,
ArH), 6.20 (1H, d, J ) 7.8 Hz, NH), 5.77 (1H, dddd, J ) 6.0, 8.2,
10.5, 16.7 Hz, CH2dCH), 5.10-5.02 (3H, m, CHdCH2 and OCH),
4.50 (1H, dddd, J ) 3.2, 4.8, 7.8, 9.7 Hz, NCH), 3.89 (1H, s, OH),
2.37-2.31 (1H, m, CH2dCHCH2), 2.21 (1H, ddd, J ) 8.2, 9.7, 14.7
Hz, CH2dCHCH2); IR (KBr) 3429, 3314, 3057, 2939, 1634, 1605,
(1R,2R)-N-Benzoyl-2-amino-1-phenylpent-4-en-1-ol. 85% yield,
1
97% ee, syn/anti ) 99:1, [R]20 ) -56.4° (c 1.00, EtOH); H NMR
D
(400 MHz, CDCl3) δ 7.69-7.67 (2H, m, ArH), 7.49 (1H, tt, J ) 1.2,
7.4 Hz, ArH), 7.42-7.24 (7H, m, ArH), 6.42 (1H, br d, J ) 7.6 Hz,
NH), 5.86 (1H, ddt, J ) 7.4, 10.0, 17.2 Hz, CH2dCH), 5.19-5.12
(2H, m, CHdCH2), 4.87 (1H, dd, J ) 4.6, 4.6 Hz, OCH), 4.33 (1H,
9
5082 J. AM. CHEM. SOC. VOL. 127, NO. 14, 2005

Alkylation of Protected
R
-Amino Acid Amides
A R T I C L E S
1580, 1528, 1489, 1454, 1414, 1364, 1342, 1315, 1300, 1286, 1246,
1207, 1195, 1153, 1111, 1076, 1061, 1038, 1022, 1003, 912, 881, 766,
729, 702 cm-1. HRMS (ESI-TOF) calcd for C18H20NO2 ([M + H]+):
282.1489. Found: 282.1500. HPLC condition: see the (1R,2R)-isomer.
(1S,2R)-N-Boc-2-amino-3-(1-naphthyl)-1-phenylpropan-1-ol (16,
R1 ) CH2r-Np). 97% ee, syn/anti ) 2:98, [R]20D ) -100.9° (c 1.00,
EtOH); 1H NMR (400 MHz, DMSO-d6, 82:18 mixture of rotamers) δ
7.84 (1H, d, J ) 8.0 Hz, ArH), 7.73-7.69 (1H, m, ArH), 7.54 (1H, d,
J ) 7.6 Hz, ArH), 7.46-7.25 (9H, m, ArH), 6.76 (0.82H, d, J ) 9.6
Hz, NH), 6.24 (0.18H, d, J ) 10.0 Hz, NH), 5.67 (0.18H, d, J ) 4.4
Hz, OCHPh), 5.62 (0.82H, d, J ) 4.4 Hz, OCHPh), 4.71 (0.82H, m,
OH), 4.59 (0.18H, m, OH), 3.97-3.90 (0.18H, m, NCH), 3.77-3.73
(0.82H, m, NCH), 3.61 (0.18H, d, J ) 13.8 Hz, NpCH2), 3.46 (0.82H,
d, J ) 13.8 Hz, NpCH2), 2.92 (0.82H, dd, J ) 11.0, 13.8 Hz, NpCH2),
2.75 (0.18H, dd, J ) 11.0, 13.8 Hz, NpCH2), 1.12 (9H, s, C(CH3)3);
13C NMR (100 MHz, DMSO-d6) δ 154.6, 143.4, 135.6, 133.2, 131.5,
128.3, 127.5, 126.9, 126.6, 126.4, 126.2, 125.4, 125.1, 125.0, 123.2,
77.1, 75.1, 57.6, 31.7, 28.1; IR (KBr) 3406, 3387, 3061, 3042, 2980,
2934, 2878, 1672, 1531, 1454, 1394, 1367, 1333, 1273, 1252, 1217,
TOF) calcd for C34H32NO ([M + H]+): 470.2478. Found: 470.2465.
The enantiomeric excess was determined after conversion to its
Z-derivative (see below).
(2R,3S)-N-Z-4-Amino-5-(1-naphthyl)-3-phenylpentan-3-ol. 97%
ee, [R]24D ) +32.5° (c 1.00, THF); 1H NMR (400 MHz, DMSO-d6) δ
7.83 (1H, d, J ) 8.0 Hz, ArH), 7.70 (1H, d, J ) 8.0 Hz, ArH), 7.55-
7.09 (16H, m, ArH and NH), 4.86 (1H, d, J ) 13.2 Hz, PhCH2), 4.85
(1H, s, OH), 4.81 (1H, d, J ) 13.2 Hz, PhCH2), 4.00 (1H, dt, J ) 3.2,
8.0 Hz, NCH), 2.99-2.77 (2H, m, NpCH2), 1.84 (2H, br q, J ) 7.2
Hz, CH3CH2), 0.57 (3H, t, J ) 7.2 Hz, CH2CH3); IR (KBr) 3443, 3335,
3059, 3036, 2970, 2936, 1682, 1553, 1448, 1396, 1340, 1267, 1219,
1194, 1132, 1043, 1028, 1003, 968, 910, 773, 758, 704 cm-1. HRMS
(ESI-TOF) calcd for C29H30NO3 ([M + H]+): 440.2220. Found:
440.2209. HPLC condition: DAICEL Chiralpak AD, hexane/EtOH )
4:1, flow rate ) 0.5 mL/min, tR ) 12.2 (2R,3S) and 30.7 (2S,3R) min.
(2R,3R)-2-Diphenylmethyleneamino-1-(1-naphthyl)-3-phenyl-
pentan-3-ol [(2R,3R)-17]. 97% ee, [R]23D ) +247.3° (c 1.00, EtOH);
1H NMR (400 MHz, CDCl3) δ 7.77 (1H, d, J ) 8.4 Hz, ArH), 7.69
(1H, d, J ) 8.4 Hz, ArH), 7.56 (1H, d, J ) 8.4 Hz, ArH), 7.36-7.18
(13H, m, ArH), 7.11 (1H, d, J ) 6.8 Hz, ArH), 6.83 (1H, t, J ) 7.4
Hz, ArH), 6.51 (2H, t, J ) 7.4 Hz, ArH), 5.07 (2H, br, ArH), 4.01
(1H, s, OH), 3.78-3.73 (2H, m, NCH and NpCH2), 3.23 (1H, dd, J )
11.2, 13.6 Hz, NpCH2), 2.32 (1H, dq, J ) 7.2, 7.2 Hz, CH3CH2), 2.18
(1H, dq, J ) 7.2, 7.2 Hz, CH3CH2), 0.83 (3H, t, J ) 7.2 Hz, CH2CH3);
13C NMR (100 MHz, CDCl3) δ 168.2, 144.6, 139.2, 135.1, 133.7, 132.8,
129.7, 128.3, 128.2, 128.2, 127.7, 127.7, 127.0, 126.9, 126.7, 126.6,
126.5, 126.2, 125.4, 125.2, 125.1, 123.5, 79.5, 70.9, 34.1, 30.0, 8.2;
IR (KBr) 3454, 3059, 2968, 2934, 1628, 1597, 1578, 1510, 1491, 1447,
1196, 1171, 1107, 1067, 1040, 1020, 926, 797, 777, 729, 702 cm-1
.
HRMS (ESI-TOF) calcd for C24H27NO3Na ([M + Na]+): 400.1883.
Found: 400.1885. HPLC condition: see the (1R,2R)-isomer.
General Procedure for Diastereoselective Alkylation of Schiff
Base Protected r-Amino Ketones (Scheme 9). To a solution of Schiff
base protected R-amino ketone 13 or 18 (1.0 equiv) in THF (0.2 M)
was added an ethereal solution of Grignard reagent (2-3 equiv) at -78
°C under argon atmosphere. The mixture was stirred for 1 h at the
same temperature and poured into cooled saturated NH4Cl. The whole
mixture was extracted with ether. The combined extracts were then
washed with brine, dried over Na2SO4, and concentrated. The residue
was purified by column chromatography on silica gel (hexane/ether as
eluent) to give the corresponding Schiff base protected R-amino tert-
alcohol 17 as a single diastereomer.
1375, 1313, 1285, 1180, 1074, 1030, 961, 912, 800, 775, 700 cm-1
.
HRMS (ESI-TOF) calcd for C34H32NO ([M + H]+): 470.2478.
Found: 470.2462. HPLC condition: DAICEL Chiralcel OD, hexane/
i-PrOH ) 100:1, flow rate ) 0.5 mL/min, tR ) 20.1 (2S,3S) and 23.1
(2R,3R) min.
(2R,3S)-2-Diphenylmethyleneamino-1-(1-naphthyl)-3-phenyl-
pentan-3-ol [(2R,3S)-17]. 97% ee, [R]24D ) +189.7° (c 1.00, EtOH);
1H NMR (400 MHz, CDCl3) δ 7.72 (1H, d, J ) 8.4 Hz, ArH), 7.64
(1H, d, J ) 8.4 Hz, ArH), 7.53-7.48 (4H, m, ArH), 7.43 (2H, t, J )
8.0 Hz, ArH), 7.39-7.26 (5H, m, ArH), 7.20 (1H, t, J ) 8.0 Hz, ArH),
7.15 (1H, d, J ) 8.4 Hz, ArH), 7.09-7.02 (2H, m, ArH), 6.92 (1H, t,
J ) 7.6 Hz, ArH), 6.68 (2H, br t, J ) 7.2 Hz, ArH), 5.74 (2H, br,
ArH), 3.85 (1H, d, J ) 10.0 Hz, NCH), 3.72 (1H, s, OH), 3.18 (1H,
dd, J ) 10.0, 13.8 Hz, NpCH2), 2.94 (1H, d, J ) 13.8 Hz, NpCH2),
1.79 (1H, dq, J ) 7.2, 7.2 Hz, CH3CH2), 1.73 (1H, dq, J ) 7.2, 7.2
Hz, CH3CH2), 0.68 (3H, t, J ) 7.2 Hz, CH2CH3); 13C NMR (100 MHz,
CDCl3) δ 168.3, 143.1, 139.1, 135.5, 135.4, 133.6, 132.8, 129.9, 128.3,
128.1, 128.0, 127.8, 127.2, 127.0, 126.7, 126.5, 125.8, 125.1, 125.1,
124.9, 123.6, 79.3, 70.4, 34.5, 34.4, 7.8; IR (KBr) 3477, 3057, 3030,
2966, 2932, 2876, 1626, 1597, 1578, 1510, 1491, 1447, 1387, 1313,
1285, 1256, 1178, 1074, 1028, 959, 916, 775, 702 cm-1. HRMS (ESI-
Acknowledgment. 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. is grateful to the Japan
Society for the Promotion of Science for Young Scientists for
a research fellowship.
Supporting Information Available: Preparation of R-amino
acid amide-derived Schiff bases 1, 6, and 10, stereochemical
assignment of 7ac, 14, 16, and 17, characterization of new
1
compounds and their H and 13C NMR spectra; the crystal-
lographic data for dipeptide 19 (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA0459328
9
J. AM. CHEM. SOC. VOL. 127, NO. 14, 2005 5083