Enantioselective synthesis of β-amino acids Part 13. Diastereoselective alkylation of dianions derived from chiral analogs of β-aminopropanoic acid containing the α-phenylethyl group

Article abstract of DOI:10.1002/hlca.200290004

Inexpensive acryloyl chloride was converted in 91% overall yield to two derivatives of β-alanine, (R,R,R)-and (R,R,S)-6, containing two chiral auxiliaries. C-Alkylation of (R,R,R)- and (R,R,S)-6 via a dianion derivative, was performed by direct metallation with 2.2 equiv. of lithium hexamethyldisilazane (LHMDS) in THF at - 78°. C-Alkylation of (R,R,S)-6-Li₂ ('matched' pair of chiral auxiliaries) afforded the mono-alkylated products 8-11 in 29-96% yield and 54-95% stereoselectivity. Employment of LiCl as an additive generally increased stereoselectivities, whereas the effect of HMPA as a cosolvent was erratic. Chemical correlation of the major diastereoisomer from the alkylation reactions with (S)-α-alkyl-β-alanine (12-15) showed that addition of the electrophile preferentially takes place on the enolate's Si-face. This conclusion is also supported by molecular-modeling studies (ab initio HF/3-21G), which indicate that the lowest-energy conformation for (R,R,S)-6-Li₂ presents the more sterically hindered Re-face of the enolate. The theoretical studies also predict a determining role for N-Li-O chelation in (R,R,S)-6-Li₂, giving rise to an interesting 'ion-triplet' configuration for the dilithium dianion.

Full text of DOI:10.1002/hlca.200290004

Helvetica Chimica Acta Vol. 85 (2002)
4189
Enantioselective Synthesis of b-Amino Acids
Part 13
Diastereoselective Alkylation of Dianions Derived from Chiral Analogs of
b-Aminopropanoic Acid Containing the a-Phenylethyl Group
by VÌctor Manuel Gutie¬rrez-GarcÌa, Gloria Reyes-Rangel, Omar Munƒoz-Munƒiz, and Eusebio Juaristi*
¬
¬
Departamento de QuÌmica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico
¬
¬
Nacional, Apartado Postal 14-740, 07000 Mexico, D.F., Mexico
(tel.: (52-55) 5747-3722; fax: (52-55) 5747-7113; e-mail: juaristi@relaq.mx)
Dedicated to Professor Dieter Seebach, in appreciation for his example as a person and as a scientist.
Inexpensive acryloyl chloride was converted in 91% overall yield to two derivatives of b-alanine, (R,R,R)-6
and (R,R,S)-6, containing two chiral auxiliaries. C-Alkylation of (R,R,R)- and (R,R,S)-6 via a dianion
derivative, was performed by direct metallation with 2.2 equiv. of lithium hexamethyldisilazane (LHMDS) in
THF at À788. C-Alkylation of (R,R,S)-6-Li2 (−matched× pair of chiral auxiliaries) afforded the mono-alkylated
products 8 11 in 29 96% yield and 54 95% stereoselectivity. Employment of LiCl as an additive generally
increased stereoselectivities, whereas the effect of HMPA as a cosolvent was erratic. Chemical correlation of the
major diastereoisomer from the alkylation reactions with (S)-a-alkyl-b-alanine (12 15) showed that addition of
the electrophile preferentially takes place on the enolate×s Si-face. This conclusion is also supported by
molecular-modeling studies (ab initio HF/3-21G), which indicate that the lowest-energy conformation for
(R,R,S)-6-Li2 presents the more sterically hindered Re-face of the enolate. The theoretical studies also predict a
determining role for NÀLiÀO chelation in (R,R,S)-6-Li2, giving rise to an interesting −ion-triplet× configuration
for the dilithium dianion.
Introduction. Because of the enormous importance of amino acids and peptides in
stereospecific biological interactions [1], a truly remarkable amount of research has
been dedicated to the asymmetric synthesis of chiral amino acids [2]. Among the
methods available for the preparation of enantiomerically enriched a-amino acids,
those making use of chiral derivatives of glycine [3] have been particularly successful.
Among these, Seebach×s chiral imidazolidinone A represents a prominent substrate and
pioneering concept (Scheme 1) [4].
More recently, motivated by the efficiency of the a-phenylethylamino moiety as a
chiral auxiliary [5] and by the advantageous effect of C2-symmetric substrates in
asymmetric synthesis [6], we successfully explored −open-chain× glycinamides of type B
and C as substrates in the preparation of enantiomerically pure a-amino acids [7].
During the last few years, the preparation of b-amino acids has emerged as an
important and challenging synthetic endeavor, partly because they are components of a
variety of natural products, such as taxol [8], the dolastatins [9], and many others [10].
Furthermore, a number of open-chain [11] or cyclized [12] b-amino acids display
interesting pharmacological properties and give rise to stabilized helical peptides with
enhanced resistance to enzymatic degradation [13].

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Scheme 1. Seebach×s Imidazolidinone A as a Convenient Precursor in the Stereoselective Synthesis of a-Amino
Acids
O
HO
O
N
N
1. Base
2. RX
H2N
O
Ph
A
O
N
N
H3O+
HO
O
R
R
O
H2N
Ph
O
O
Me
N
Ph
N
Ph
Ph
N
N
O
O
O
O
H3C
Ph
B
C
Much of the work regarding the stereoselective preparation of b-amino acids has
been reviewed [14]. Recently, the potential of chiral derivatives of b-aminopropanoic
acid, such as D, E, 1, and 2 was explored [15][16]. In particular, the alkylation of (R,R)-1
at À788 in THF with lithium hexamethyldisilazane (LHMDS) afforded diastereoselec-
tivities of 56 80% in 28 65% yield. The addition of LiCl or hexamethylphosphor-
triamide (HMPA) had no significant effect on yield or stereoselectivity. The major
diastereoisomer in this reaction was (R,R,R)-3 after deprotection (Scheme 2) [16].
Me
N
OH
H2N
N
N
Ph
Ph
SO2
O
Me
O
O
Ph
E [15b]
D [15a]
Me
O
Me
Ph
Cbz
Ph
N
OMe
N
N
Ph
Ph
Me
Ph
1 [16]
2 [16]

Helvetica Chimica Acta Vol. 85 (2002)
4191
Scheme 2. Stereoselectivity of Enolate (R,R)-1-Li Alkylations and Chemical Correlation of Major Product with
a-Substituted b-Amino Acids of Known Configuration [16]
O
Me
O
Me
Cbz
Ph
Cbz
Ph
LHMDS / THF
N
N
Ph
N
N
Ph
RX, –78°
R
Me
Ph
Me
Ph
(R,R,R)-3
RX = MeI, PhCH2Br
(R,R)-1
1. 35 atm H2
Pd(OH)2/MeOH, 65°
O
H2N
OH
2. 6N HCl, 90°
3. Dowex
R
(R)-Amino acid
Motivated by the elegant work of Myers [17], Berkowitz [18], McIntosh [19],
Seebach [20], and others [21], who have demonstrated the highly stereoselective
alkylation of chiral dianions, we examined the stereoselectivity of alkylation of the
chiral, b-alanine-derived dianion (R,R)-4-Li2 (Scheme 3) [22].
Scheme 3. Stereoselectivity of Dianion (R,R)-4-Li2 Alkylations and Chemical Correlation of the Major
Diastereoisomer to a-Substituted b-Amino Acids of Known Configuration [22]
O
Me
Cbz
1. LDA (2.2 equiv.), THF
2. BuLi (2.2 equiv.), –78°
N
H
N
Ph
Me
Ph
(R,R)-4
OLi Me
N
O
Me
Ph
1. RX, –78°
2. H3O+
Cbz
Cbz
N
Li
Ph
N
H
N
Ph
R
Me
Ph
Me
(R,R)-4-Li2
(R,R,S)-5
O
1. H2 (1 atm.), 10% Pd/C
H2N
OH
MeOH, r.t.
R
2. 4N aq. HCl, 90°
3. Dowex
(S)-Amino acid
In general, both higher yields and stereoselectivities were observed in the C-
alkylation of the dianion (R,R)-4-Li2 relative to the enolate (R,R)-2-Li2. Also, the
major diastereoisomeric products (R,R,R)-3 and (R,R,S)-5 were found with opposite
configurations at the newly created stereogenic center. Considering that stereo-
induction in (R,R)-4-Li2 (Scheme 3) is of unlike topicity (i.e., (R)-configured auxiliary

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Me
OLi Me
N
Ph
Me
OLi Me
N
Ph
Ph
N
Li
Ph
N
Li
Me
Ph
Me
Ph
(R,R,R)-6-Li2
(R,R,S)-6-Li2
favors reaction on the Si-face [23]), and that the same applies to (S)-2-Li (i.e., (S)-
configured auxiliary favors addition to the Re-face [23]), we deemed it of interest to
determine the stereoselective alkylation of (R,R,R)-6-Li2 and (R,R,S)-6-Li2. According
to Masamune×s theory [24], one might expect the all-(R)-configured dianion to
correspond to a −matched× pair of auxiliaries, whereas the (R,R,S) diastereoisomeric
dianion could be anticipated as a −mismatched× combination of auxiliaries1).
Results and Discussion. Synthesis of Diastereoisomeric Derivatives of b-Alanine
Containing Two Chiral Auxiliaries. Diastereoisomers (R,R,R)-6 and (R,R,S)-6 were
prepared from acryloyl chloride via a sequential reaction with bis[(R)-1-phenylethyl]-
amine [26] to furnish (R,R)-7 in 93% yield, followed by conjugate addition of (R)- or
(S)-1-phenylethylamine (Scheme 4). The desired products were purified by flash
chromatography (FC) and isolated in excellent yield.
Scheme 4. Preparation of Diastereoisomeric b-Alanine Derivatives (R,R,R)- and (R,R,S)-6
Me Me
O
Me
Ph
N
H
Ph
O
N
Ph
Cl
Et3N / CH2Cl2
93%
Me
Ph
(R,R)-7
Me
Me
O
Me
Ph
NH2
*
(R) or (S)
Ph
N
H
N
Ph
*
EtOH, ∆
Me
Ph
98%
(R,R,R)-6 or
(R,R,S)-6
Stereoselectivity of C-Alkylation of (R,R,R)-6 and (R,R,S)-6. C-Alkylation of
(R,R,R)- and (R,R-S)-6 proceeded best with 2.2 equiv. of LHMDS as the base. The
resulting dianion was treated with the electrophile at À788. Results of the methylation
reaction, in the absence of additives, are summarized in Table 1.
For comparison, the methylation of (R,R)-4-Li2 (Scheme 3) under similar
conditions afforded a diastereoisomer ratio (dr) of 73 :27 [22]. Thus, the comparable
1
)
For an example of double stereo-induction in chiral derivatives of glycine, see [25].

Helvetica Chimica Acta Vol. 85 (2002)
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Table 1. Stereoselectivity of the Methylation of Dianions (R,R,R)- and (R,R,S)-6-Li2 in the Absence of Additives
Substrate
dra)
Yield [%]
(R,R,R)-6
(R,R,S)-6
83 : 17
62 : 38
67
60
a) Diastereoisomer ratio determined by NMR integration of appropriate signals of 8.
selectivities reported in Table 1 indicate that the b-alanine derivative (R,R,S)-6
corresponds to the −matched× pair of chiral auxiliaries (dr 83 :17), whereas (R,R,R)-6
could be seen as the corresponding −mismatched× combination. This result was not
anticipated in the light of the stereo-induction found previously for the chiral enolate 2-
Li [16] and suggests that the influence of the phenylethyl group is not the same in
(R,R,R)-6-Li2 and (R,R,S)-6-Li2 relative to 2-Li. Probably, the reactive intermediates
are present in different conformations upon approach of the electrophile (vide infra).
Further alkylation studies were then carried out with the better substrate (R,R,S)-6 in
the absence or presence of additives (Table 2).
In the absence of additives, methylation proceeded with the highest stereo-
selectivity (dr 83 :17; Entry 1, Table 2). For comparison, alkylation with EtI afforded a
moderate stereoselectivity (dr 74 :26, Entry 15), and BnBr and PrI gave the poorest
results (dr 68 :32 and 62 :38, Entries 8 and 20, respectively).
The addition of −inert× salts to reaction media has been found to affect the
stereoselectivity of alkylation reactions [27 29]. As can be seen from Entries 5 7, 12
14, 18, 19, and 23 25, stereoselectivities increased with LiCl as an additive.
Concomitantly, both methylation and benzylation proceeded in higher yields in the
presence of LiCl. Nevertheless, the opposite was true with EtI and PrI as electrophiles
(Entries 18, 19, and 23 25). Addition of polar HMPA as a cosolvent led to erratic
trends in the alkylation reactions. For example, stereoselectivities decreased in the
methylation reaction, although the observed yields went up2) (Entries 2 4 in Table 2).
In contrast, stereoselectivities for the benzylation reaction (Entries 10 and 11)
increased in the presence of three or 6 equiv. of HMPA, but yields remained low.
Finally, both selectivity and yield tended to decrease in the presence of HMPA in the
reaction with EtI and PrI (Entries 16, 17, 21, and 22)3).
Configuration of the Diastereoisomeric Products 8 10. The absolute configuration
at the new stereogenic center of (R,R,S)-6-Li2 (Table 2) was ascertained by chemical
correlation with a-substituted b-amino acids of known configuration, (S)-12 (S)-14
(Scheme 5). In the case of 11, debenzylation and hydrolysis afforded the b-amino acid
‡
2
)
)
The idea behind HMPA is that it solvates Li , thus generating free anions instead of ion pairs or
aggregates [30].
3
It is to be expected that our seemingly contrasting observations will be better understood when the
knowledge of salt and solvent effects on Li enolates is more advanced [30].

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Table 2. Stereoselectivity for the Alkylation of (R,R,S)-6-Li2. Effect of LiCl and HMPA additives.
Entry
RX
Additive (equiv.)
dra)
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
MeI
MeI
MeI
MeI
MeI
MeI
MeI
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
EtI
EtI
EtI
EtI
EtI
83 : 17
79 : 21
74 : 26
60 : 40
92 : 8
67
87
94
68
86
71
89
42
29
44
34
84
81
96
74
76
54
39
60
62
58
27
54
29
63
HMPA (1)
HMPA (3)
HMPA (6)
LiCl (1)
LiCl (3)
LiCl (6)
91 : 9
89 : 11
68 : 32
68 : 32
85 : 15
89 : 11
92 : 8
HMPA (1)
HMPA (3)
HMPA (6)
LiCl (1)
LiCl (3)
LiCl (6)
95 : 5
92 : 8
74 : 26
65 : 35
58 : 42
87: 13
87: 13
62 : 38
60 : 40
54 : 46
67: 33
80 : 20
69 : 31
HMPA (1)
HMPA (3)
LiCl (1)
LiCl (3)
PrI
PrI
PrI
PrI
PrI
PrI
HMPA (1)
HMPA (3)
LiCl (1)
LiCl (3)
LiCl (6)
a) Diastereoisomer ratio.
15, previously unknown in enantiomerically pure form. Given the similar spectroscopic
behaviors of 8, 10, and 11, we tentatively also assigned the (S)-configuration to 15.
The major diastereomers 8 11 were purified by FC and subjected to hydrogenolytic
debenzylation with 20% Pd(OH)2 in MeOH under 600 psi H2 pressure at 658 for 12 h.
Given the poor stability of the debenzylated products, the crude mixtures were filtered
over Celite, concentrated, and hydrolyzed immediately with 6n HCl in a sealed ampoule at
908. Final purification was achieved with Dowex ionic resin or by silica-gel column
chromatography to give the free amino acids 12 15 (Table 3).
Molecular-Modeling Studies. In order to rationalize the observed stereoinduction
by the chiral bis(1-phenylethyl)amino auxiliary in (R,R,S)-6-Li2, we resorted to semi-
empirical PM3 [31] as well as ab initio HF/3-21G [32] calculations. First of all, a search
for low-energy conformations of the starting chiral amide (R,R)-4 (Scheme 3) was
undertaken at the PM3 level by means of the PC Spartan-Pro program [31], which
makes use of Monte Carlo stochastic methods [33]. This conformational search

Helvetica Chimica Acta Vol. 85 (2002)
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Scheme 5. Chemical Correlation of Alkylated Products 8 11 (major diastereoisomers) with a-Substituted b-
Amino Acids 12 15
H2 (600 psi),
20% Pd(OH)2
Me
Me
O
Me
O
(S)
(S)
(R)
Ph
N
H
N
Ph
H2N
N
Ph
MeOH, 65°
R
R
(R)
Me
Ph
Me
Ph
quant.
8 R = Me
6N HCl
90°
13 – 65%
9 R = CH2Ph
10 R = Et
O
11 R = Pr
H2N
OH
R
(S)-12 R = Me
(S)-13 R = CH2Ph
(S)-14 R = Et
(S)-15 R = Pr
Table 3. Chemical Correlation of Alkylated Derivatives 8 11 with a-Substituted b-Amino Acids 12 15
Substrate
Reaction time [h]
Yield [%]
[a]2D8
Product
8 RˆMe
9 RˆPhCH2
10 RˆEt
8a)
14
48
12
63
13
55
60
‡ 14.2
À 15.5
‡ 5.6
(S)-12
(S)-13
(S)-14
(S)-15
11 RˆPr
À 3.2
a) 4n HCl was used in the hydrolysis reaction.
afforded nine structures corresponding to local minima within a 10 kcal/mol energy
threshold. These nine low-energy conformers were used as starting geometries for
optimizing (R,R,S)-6-Li2 by means of HF/3-21G. All studies converged into a global
energy minimum F, which is shown in the Figure.
The most-salient feature of F is the −ion-triplet× configuration [34] of the dilithium
salt. From the calculated lowest-energy conformation of (R,R,S)-6-Li2, it can be
assumed that the enolate×s Si-face is less-hindered towards an electrophilic approach
relative to the Re-face, which is syn to the phenyl rings. Such a predicted mode of
addition of the electrophile (on the Re-face) should, thus, lead to the preferential
formation of the (S)-configured stereogenic center, as experimentally observed
(Table 2).
Conclusions. C-Alkylation of (R,R,S)-6, a chiral b-alanine derivative containing
the bis(1-phenylethyl)amine and N-(1-phenylethyl)amine chiral auxiliaries, was

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Helvetica Chimica Acta Vol. 85 (2002)
Figure. Ab initio HF/3-21G Conformation of Minimum Energy for (R,R,S)-6-Li2 (F) representing an −ion-
triplet× configuration [34]
accomplished in moderate to good yields via the dianion (R,R,S)-6-Li2. Stereo-
selectivities in the alkylation with various alkyl halides in the presence of one to three
equivalents of LiCl as an additive varied from 67:33 to 95 :5. Assignment of the (S)-
configuration at the newly created stereogenic center was achieved by chemical
correlation with known (S)-a-substituted b-amino acids. This configuration for the
main alkylation product can be rationalized by ab initio calculations of the
conformation of (R,R,S)-6-Li2, which exhibits a relatively unhindered Si-face with
respect to the enolate.
Experimental Part
General. Flasks, stirring bars, and hypodermic needles used for the generation and reactions of
organolithiums were dried for ca. 12 h at 1208 and allowed to cool in a desiccator over anhydrous CaSO4.
Anh. solvents were obtained by distillation from benzophenone/ketyl radical [35]. BuLi was titrated according
to [36]. TLC: MerckDC-F 254 plates, detection by UV light. Flash (FC) [37] and column chromatography (CC):
Merck silica gel (0.040 0.063 mm). Melting points: Mel Temp apparatus, not corrected. 1H-NMR spectra: Jeol
Eclipse-400 (400 MHz), Bruker Ultra Shield (300 MHz), and Jeol GSX-270 (270 MHz) spectrometers;
13C-NMR spectra: Jeol Eclipse-400 (100 MHz), Bruker Ultra Shield (75 MHz), and Jeol GSX-270 (67.5 MHz);
chemical shifts d in ppm relative to Me4Si as internal reference, coupling constants J in Hz. High-resolution mass
¬
spectra (HR-MS) were obtained at the Instituto de QuÌmica, UNAM, Mexico. Elemental analyses were
obtained from Galbraith Laboratories, Inc., Knoxville, TN.
N,N-Bis[(1R)-1-phenylethyl]prop-2-enamide ((R,R)-7). To a soln. of 1.5 g (16.6 mmol) of acryloyl chloride
in 25 ml of anh. CH2Cl2 at 08 under N2 was added dropwise via cannula 3.73 g (16.6 mmol) of N,N-bis[(1R)-1-
phenylethyl]amine. The resulting mixture was stirred at 08 for 1 h. At this point, 2.33 ml (1.68 g, 16.6 mmol) of
Et3Nwas added via syringe, the mixture was allowed to come to r.t., and stirred overnight. The resulting
suspension was treated with 25 ml of H2O, extracted with CH2Cl2 (3 Â 20 ml), the combined extracts were dried
(Na2SO4), filtered, and concentrated. The crude product was purified by FC (hexane/AcOEt 8,5 :1,5) to afford

Helvetica Chimica Acta Vol. 85 (2002)
4197
4.32 g (93%) of (R,R)-7 as a clear oil. [a]D28 ˆ ‡215.0 (c ˆ 1.0, CHCl3). 1H-NMR (CDCl3, 400 MHz): 1.75 (br.,
6 H); 4.72 5.03 (br., 1 H); 5.42 (dd, J ˆ 10.3, 2.2, 1 H); 5.83 6.08 (br., 1 H); 6.12 (dd, J ˆ 16.8, 10.3, 1 H); 6.29
(dd, J ˆ 16.5, 2.2, 1 H); 6.80 7.50 (m, 10 H). 13C-NMR (CDCl3, 100 MHz): 17.6; 20.7; 52.5; 126.9; 127.3; 128.3;
‡
130.6; 141.1; 166.8. MS (70 eV): 279 (M ), 174, 120, 106, 77. Anal. calc. for C19H21NO (279.38): C 81.68, H 7.58;
found: C 81.81, H 7.81.
N,N-Bis[(1R)-1-phenylethyl]-3-{[(1R)-1-phenylethyl]amino}propanamide ((R,R,R)-6). A mixture of
2.52 g (9.0 mmol) of (R,R)-7 and 1.64 g (13.5 mmol) of (R)-1-phenylethylamine were dissolved in 130 ml
EtOH, and the resulting mixture was heated to reflux for 36 h. Solvent removal at reduced pressure and FC
(hexane/AcOEt 7:3) afforded 3.6 g (98%) of (R,R,R)-6 as a clear oil. [a]2D8 ˆ ‡135.2 (c ˆ 1.0, CHCl3). 1H-NMR
((D6)DMSO, 1008, 300 MHz): 1.27 (d, J ˆ 6.5, 3 H); 1.69 (d, J ˆ 7.0, 6 H); 2.35 (ddd, J ˆ 15.1, 6.8, 6.8, 1 H); 2.51
(ddd, J ˆ 15.1, 6.7, 6.7, 1 H); 2.59 (br., 1 H); 2.67 (dd, J ˆ 6.6, 6.6, 2 H); 3.71 (q, J ˆ 6.6, 1 H); 5.13 (q, J ˆ 7.0,
2 H); 7.10 7.34 (m, 15 H). 13C-NMR ((D6)DMSO, 1008, 75 MHz): 19.5; 24.8; 36.6; 44.5; 53.9; 58.2; 127.2; 127.3;
‡
127.4; 128.2; 128.3; 128.6; 128.9; 142.5; 147.1; 172.4. MS (20 eV): 401 ([M ‡ 1] ), 295, 191, 120, 105. HR-MS:
‡
‡
401.2583 ([M ‡ 1] , C27H33N2O ; calc. 401.2593).
N,N-Bis[(1R)-1-phenylethyl]-3-{[(1S)-1-phenylethyl]amino}propanamide ((R,R,S)-6). The procedure de-
scribed for (R,R,R)-6 was followed, with 5.7 g (20.0 mmol) of (R,R)-7 and 3.7 g (30.6 mmol) of (S)-1-
phenylethylamine. Yield: 7.8 g (98%), clear oil. [a]2D8 ˆ ‡98.5 (c ˆ 1.0, CHCl3). 1H-NMR ((D6)DMSO, 1008,
400 MHz): 1.24 (d, J ˆ 6.7, 3 H); 1.68 (d, J ˆ 7.0, 6 H); 2.31 (ddd, J ˆ 15.1, 6.7, 6.7, 1 H); 2.50 (ddd, J ˆ 15.0, 6.6,
6.6, 1 H); 2.60 (ddd, J ˆ 11.7, 6.6, 6.6, 1 H); 2.70 (ddd, J ˆ 11.7, 6.6, 6.6, 1 H); 3.66 (q, J ˆ 6.5, 1 H); 5.13 (q, J ˆ 7.1,
2 H); 7.11 7.32 (m, 15 H). 13C-NMR ((D6)DMSO, 1008, 100 MHz): 19.2; 24.6; 36.2; 44.1; 53.4; 57.7; 126.8;
‡
126.9; 127.1; 127.8; 128.2; 128.5; 142.1; 146.8; 172.0. MS (15 eV): 401 ([M ‡ 1] ), 295, 191, 120, 105. HR-MS:
‡
401.2602 ([M ‡ 1] , C27H33N2O; calc. 401.2593).
General Procedure for the Reaction of the b-Alanine-Derived Dianion (R,R,S)-6-Li2 with Electrophiles. To a
soln. of 0.2 g (0.5 mmol) (R,R,S)-6 in 10 ml of anh. THF under N2 and at À788 was added dropwise 2.2 equiv. of
LHMDS. The resulting soln. was stirred for 1 h at À788. The alkylating agent (1.1 equiv.) was added with
continuous stirring, and the mixture was stirred at À788 for 3 4 h and quenched with aq. NH4Cl soln. The
product was extracted with AcOEt (3 Â 10 ml), the combined org. extracts were dried (Na2SO4), filtered, and
concentrated. Diastereoisomer separation was accomplished by FC [37] (hexane/AcOEt 80 :20) and CC
(CH2Cl2/MeOH/NH4OH 9 :0.5 :0.05).
(2S)-N,N-Bis[(1R)-1-phenylethyl]-2-methyl-3-{[(1S)-1-phenylethyl]amino}propanamide ((R,R,S,S)-8).
Prepared and purified according to the general alkylation procedure. Yield: 67 94% (cf. Table 2). [a]D28
ˆ
1
‡112.2 (c ˆ 1.0, CHCl3). H-NMR ((D6)DMSO, 1008, 300 MHz): 0.76 (d, J ˆ 6.5, 3 H); 1.21 (d, J ˆ 6.6, 3 H);
1.67 (d, J ˆ 7.0, 6 H); 2.36 (dd, J ˆ 11.4, 6.0, 1 H); 2.72 (dd, J ˆ 11.2, 7.3, 1 H); 2.84 (ddq, J ˆ 6.5, 6.5, 6.5, 1 H);
3.65 (q, J ˆ 6.5, 1 H); 5.11 (q, J ˆ 7.0, 2 H); 7.16 7.32 (m, 15 H). 13C-NMR ((D6)DMSO, 1008, 75 MHz): 14.7;
18.3; 23.4; 37.5; 50.9; 52.4; 56.8; 125.7; 125.8; 125.9; 126.1; 126.8; 127.0; 127.4; 127.8; 127.9; 138.6; 141.1; 145.7;
‡
175.0. HR-MS: 415.2751 ([M ‡ 1] , C28H35N2O; calc. 415.2749).
(2S)-N,N-Bis[(1R)-1-phenylethyl]-3-{[(1S)-1-phenylethyl]amino}-2-(phenylmethyl)propanamide
((R,R,S,S)-9). Prepared and purified according to the general alkylation procedure. Yield: 29 96% (cf.
Table 2). [a]2D8 ˆ ‡76.5 (c ˆ 1.0, CHCl3). 1H-NMR ((D6)DMSO, 1008, 400 MHz): 1.16 (br., 3 H); 1.24 (d, J ˆ 6.6,
3 H); 1.60 (br., 3 H); 2.57 (dd, J ˆ 11.5, 5.3, 1 H); 2.70 2.78 (m, 2 H); 2.81 (dd, J ˆ 11.4, 7.7, 1 H); 3.34
(dddd, J ˆ 6.6, 6.6, 6.6, 6.6, 1 H); 3.67 (q, J ˆ 6.5, 1 H); 4.56 (br., 1 H); 5.20 (br., 1 H); 6.94 7.40 (m, 20 H).
13C-NMR ((D6)DMSO, 1008, 100 MHz): 18.3; 19.5; 24.3; 37.7; 45.7; 51.2; 53.5; 54.9; 58.2; 126.4; 126.8; 128.5;
‡
‡
128.6; 129.7; 140.5; 146.7; 174.3. HR-MS: 491.3066 ([M ‡ 1] , C34H39N2O ; calc. 491.3062).
(2S)-N,N-Bis[(1R)-1-phenylethyl]-2-ethyl-3-{[(1S)-1-phenylethyl]amino}propanamide ((R,R,S,S)-10).
Prepared and purified according to the general alkylation procedure. Yield: 39 76% (cf. Table 2). [a]D28
ˆ
‡107.9 (c ˆ 1.0, CHCl3). 1H-NMR ((D6)DMSO, 1008, 300 MHz): 0.74 (t, J ˆ 7.5, 3 H); 1.27 (d, J ˆ 6.6, 3 H); 1.45
(ddq, J ˆ 7.1, 7.0, 2.5, 2 H); 1.72 (d, J ˆ 7.0, 6 H); 2.51 (dd, J ˆ 11.4, 5.4, 1 H); 2.78 (dd, J ˆ 11.4, 7.5, 1 H); 2.91
(dddd, J ˆ 6.5, 6.5, 6.5, 6.5, 1 H); 3.69 (q, J ˆ 6.6, 1 H); 4.90 5.28 (br., 2 H); 6.97 7.38 (m, 15 H). 13C-NMR
((D6)DMSO, 1008, 75 MHz): 10.7; 18.2; 23.1; 23.2; 44.0; 49.5; 52.9; 57.1; 125.7; 126.8; 126.9; 127.4; 142.0; 145.7;
‡
‡
174.1. HR-MS: 429.2894 ([M ‡ 1] , C29H37N2O ; calc. 429.2906).
(2S)-N,N-Bis[(1R)-1-phenylethyl]-3-{[(1S)-1-phenylethyl]amino}-2-propylpropanamide ((R,R,S,S)-11).
Prepared and purified according to the general alkylation procedure. Yield: 27 63% (cf. Table 2). [a]D28
ˆ
‡107.5 (c ˆ 1.0, CHCl3). 1H-NMR ((D6)DMSO, 1008, 300 MHz): 0.75 (t, J ˆ 7.3, 3 H); 1.0 1.19 (m, 2 H); 1.22
(d, J ˆ 6.5, 3 H); 1.35 (ddt, J ˆ 8.9, 6.2, 3.6, 2 H); 1.67 (d, J ˆ 7.0, 6 H); 2.45 (dd, J ˆ 11.5, 5.4, 1 H); 2.72 (dd, J ˆ
11.5, 7.6, 1 H); 2.92 (dddd, J ˆ 6.5, 6.5, 6.5, 6.5, 1 H); 3.64 (q, J ˆ 6.6, 1 H); 4.70 5.44 (br., 2 H); 6.90 7.37

4198
Helvetica Chimica Acta Vol. 85 (2002)
(m, 15 H). 13C-NMR ((D6)DMSO, 1008, 75 MHz): 13.4; 18.2; 19.3; 19.9; 23.3; 32.6; 42.5; 49.8; 52.2; 57.1; 125.8;
‡
‡
126.9; 127.5; 141.0; 145.7; 174.2. HR-MS: 443.3058 ([M ‡ 1] , C30H39N2O ; calc. 443.3062).
(S)-3-Amino-2-methylpropanoic Acid ((S)-12). A hydrogenation flask was loaded with 0.46 g (0.86 mmol)
of (R,R,S,S)-8, 0.05 g 20% Pd(OH)2, and 25 ml EtOH containing 5 drops of AcOH. The flask was pressurized to
33 atm of H2, heated to 658, and shaken for 12 h. The mixture was filtered over Celite and concentrated in vacuo
to afford 0.27 g (quant.) of the deprotected amine, which was transferred to a glass ampoule, dissolved in 7.0 ml
6n HCl soln., and heated to 908 for 12 h. The crude product was washed with CH2Cl2 (3 Â 20 ml), the aq. phase
was concentrated, and the residue was adsorbed to acidic Dowex 50W-X4. The resin was washed with distilled
H2O until neutral, then with 0.1n aq. NH4OH soln. Evaporation of the basic filtrate afforded 0.06 g (63%) of (S)-
12. [a]2D8 ˆ ‡14.2 (c ˆ 1.3, 1n aq. HCl); lit. [a]D28 ˆ À14.2 (c ˆ 0.42, H2O) for (R)-12 [38].
(S)-3-Amino-2-(phenylmethyl)propanoic Acid ((S)-13). According to the procedure described for the
preparation of (S)-12, 0.58 g (1.1 mmol) of (R,R,S,S)-9 was hydrogenolyzed (0.06 g 20% Pd(OH)2) and then
hydrolyzed (12 ml 6n aq. HCl, 12 h) to give (S)-13 in 13% yield. [a]2D8 ˆ À15.5 (c ˆ 1.0, 1n aq. HCl); lit. [a]2D8
À11.0 (c ˆ 1.0, 1n aq. HCl) [39].
ˆ
(S)-3-Amino-2-ethylpropanoic Acid ((S)-14). According to the procedure described for the preparation of
(S)-12, 0.45 g (1.0 mmol) of (R,R,S,S)-10 was hydrogenolyzed (0.09 g 20% Pd(OH)2) and then hydrolyzed
(12 ml 6n aq. HCl, 48 h) to give (S)-14 in 55% yield. [a]2D8 ˆ ‡5.6 (c ˆ 1.0, H2O); lit. [a]2D8 ˆ ‡4.6 (c ˆ 1.0, H2O)
wrong sign in [40]!).
(S)-3-Amino-2-propylpropanoic Acid ((S)-15). According to the procedure described for the preparation
of (S)-12, 0.58 g (1.3 mmol) of (R,R,S,S)-11 was hydrogenolyzed (0.1 g 20% Pd(OH2) and then hydrolyzed
(12 ml 6n aq. HCl, 12 h) to give (S)-15 in 60% yield. [a]2D8 ˆ À3.2 (c ˆ 1.0, 1n aq. HCl). 1H-NMR (D2O,
400 MHz): 0.83 (t, J ˆ 7.3, 3 H); 1.25 (tq, J ˆ 7.3, 7.3, 2 H); 1.44 (ddt, J ˆ 13.2, 6.7, 6.6, 1 H); 1.50 (ddt, J ˆ 13.6, 9.2,
6.9, 1 H); 2.51 (dddd, J ˆ 6.9, 6.7, 6.5, 6.5, 1 H); 2.97 (dd, J ˆ 12.8, 5.1, 1 H); 3.05 (dd, J ˆ 12.8, 8.4, 1 H).
13C-NMR (D2O, 100 MHz): 13.3; 19.6; 32.1; 41.0; 45.1; 181.0.
¬
Financial support from Conacyt, Mexico, grant 33023-E is gratefully acknowledged. We are also grateful to
¬
VÌctor M. Gonzalez and MarÌa Luisa RodrÌguez for recording NMR spectra.
REFERENCES
[1] D. Seebach, Angew. Chem., Int Ed. 1990, 29, 1320; E. Juaristi, −Introduction to Stereochemistry and
Conformational Analysis×, Wiley, New York, 1991; E. L. Eliel, S. H. Wilen, L. N. Mander, −Stereochemistry
of Organic Compounds×, Wiley, New York, 1994; E. Juaristi, An. Quim., Int. Ed. 1997, 93, 135.
[2] −a-Amino Acid Synthesis×, Ed. M. J. O×Donnell, Tetrahedron Symposium-in-Print, Tetrahedron 1988, 44,
5253; R. M. Williams, −Synthesis of Optically Active a-Amino Acids×, Pergamon Press, Oxford, 1989; R. O.
Duthaler, Tetrahedron 1994, 50, 1539; M. Calmes, J. Daunis, Amino Acids 1999, 16, 215; −Asymmetric
Synthesis of Novel Sterically Constrained Amino Acids×, Eds. V. Hruby, V. A. Soloshonok, Tetrahedron
Symposium-in-Print, Tetrahedron 2001, 57, 6329.
[3] U. Schoellkopf, Tetrahedron 1983, 39, 2085; D. Seebach, E. Juaristi, D. D. Miller, C. Schickli, T. Weber,
¬
¬
Helv. Chim. Acta 1987, 70, 237; E. Juaristi, J. L. Leon-Romo, Y. RamÌrez-Quiros, J. Org. Chem. 1999, 64,
2914; R. M. Williams, P. J. Sinclair, D. Zhai, D. Chen, J. Am. Chem. Soc. 1988, 110, 1547; J. F. Dellaria, B. D.
Santarsiero, J. Org. Chem. 1989, 54, 3916; Y. N. Belokon, A. S. Sagyan, S. M. Djamgaryan, V. I. Bakhmutov,
V. M. Belikon, Tetrahedron 1988, 44, 5507; M. Orena, G. Porzi, S. Sandri, J. Org. Chem. 1992, 57, 6532; R.
¬
Chinchilla, L. R. Falvello, N. Galindo, C. Najera, Angew. Chem., Int. Ed. 1997, 36, 995; D. A. Evans, A. E.
Weber, J. Am. Chem. Soc. 1986, 108, 6757; S. Ikegami, H. Uchiyama, T. Hayama, T. Katsuki, M.
Yamaguchi, Tetrahedron 1988, 44, 5333; A. G. Myers, B. H. Yang, H. Chen, J. L. Gleason, J. Am. Chem.
Soc. 1994, 116, 9361.
[4] D. Seebach, R. Imwinkelried, T. Weber, in −Modern Synthetic Methods 1986×, Ed. R. Scheffold, Springer
Verlag, Berlin, 1986, p. 125.
¬
[5] E. Juaristi, J. Escalante, J. L. Leon-Romo, A. Reyes, Tetrahedron: Asymmetry 1998, 9, 715; E. Juaristi, J. L.
¬
Leon-Romo, A. Reyes, J. Escalante, Tetrahedron: Asymmetry 1999, 10, 2441.
[6] H. B. Kagan, T. Dang, J. Am. Chem. Soc. 1972, 94, 6429; J. K. Whitesell, Chem. Rev. 1989, 89, 1581.
[7] A. Reyes, E. Juaristi, Tetrahedron: Asymmetry 2000, 11, 1411.
[8] I. Ojima, S. N. Lin, T. Wang, Curr. Med. Chem. 1999, 6, 927.

Helvetica Chimica Acta Vol. 85 (2002)
4199
[9] R. B. Bates, K. G. Brusoe, J. J. Burns, S. Caldera, W. Cui, S. Gangwar, M. R. Gramme, K. J. McClure, G. P.
Rouen, H. Shadow, C. C. Stessman, S. R. Taylor, V. H. Vu, G. V. Yarick, J. X. Zhang, G. R. Pettit, R.
Bontems, J. Am. Chem. Soc. 1997, 119, 2111.
[10] F. von Nussbaum, P. Spiteller, M. Ruth, W. Steglich, G. Wanner, B. Gamblin, L. Stievano, F. E. Wagner,
Angew. Chem., Int. Ed. 1998, 37, 3292.
[11] J. Tamariz, in −Enantioselective Synthesis of b-Amino Acids×, Ed. E. Juaristi, Wiley, New York, 1997,
pp. 45 66.
[12] −The Organic Chemistry of b-Lactams×, Ed. G. I. Georg, Verlag Chemie, New York, 1993.
[13] D. Seebach, M. Overhand, F. Kuhnle, B. Martinoni, L. Oberer, U. Hommel, H. Widmer, Helv. Chim. Acta
1996, 79, 913; D. H. Apella, L. A. Christianson, I. L. Karle, D. R. Powell, S. H. Gellman, J. Am. Chem. Soc.
1996, 118, 13071; S. H. Gellman, Acc. Chem. Res. 1998, 31, 173; D. Seebach, K. Gademann, M. Ernst, D.
Hoyer, Angew. Chem., Int. Ed. 1999, 38, 1223; K. Gademann, T. Kimmerlin, D. Hoyer, D. Seebach, J. Med.
Chem. 2001, 44, 2460.
[14] E. Juaristi, D. Quintana, J. Escalante, Aldrichim. Acta 1994, 27, 3; D. C. Cole, Tetrahedron 1994, 50, 9517; G.
Cardillo, C. Tomasini, Chem. Soc. Rev. 1996, 23, 117; −Enantioselective Synthesis of b-Amino Acids×, Ed. E.
¬
Juaristi, Wiley, New York, 1997; E. Juaristi, H. Lopez-Ruiz, Curr. Med. Chem. 1999, 6, 983.
[15] R. Ponsinet, G. Chassaing, J. Vaissermann, S. Lavielle, Eur. J. Org. Chem. 2000, 83; G. Nagula, V. J. Huber,
C. Lum, B. A. Goodman, Org. Lett. 2000, 2, 3527.
¬
¬
[16] V. M. Gutierrez-GarcÌa, H. Lopez-Ruiz, G. Reyes-Rangel, E. Juaristi, Tetrahedron 2001, 57, 6487.
[17] A. G. Myers, J. L. Gleason, T. Yoon, J. Am. Chem. Soc. 1995, 117, 8488; A. G. Myers, J. L. Gleason, T. Yoon,
D. W. Kung, J. Am. Chem. Soc. 1997, 119, 656; A. G. Myers, P. Schnider, S. Kwoon, D. W. Kung, J. Org.
Chem. 1999, 64, 3322.
[18] D. B. Berkowitz, M. K. Smith, J. Org. Chem. 1995, 60, 1233.
[19] J. M. McIntosh, S. Peters, Synthesis 1999, 635.
[20] D. Seebach, H. Estermann, Tetrahedron Lett. 1988, 28, 3103; D. Seebach, A. Jacobi, M. Rueping, K.
Gademann, M. Ernst, B. Jaun, Helv. Chim. Acta 2000, 83, 2115.
[21] C. Papa, C. Tomasini, Eur. J. Org. Chem. 2000, 1569; M. Beatty, C. Jennings-White, M. A. Avery, J. Chem.
Soc., Perkin Trans. 1 1992, 1637.
¬
ƒ
ƒ
[22] V. M. Gutierrez-GarcÌa, G. Reyes-Rangel, O. Munoz-Muniz, E. Juaristi, J. Braz. Chem. Soc. 2001, 12, 652.
[23] D. Seebach, V. Prelog, Angew. Chem., Int. Ed. 1982, 21, 654.
[24] S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem., Int. Ed. 1985, 24, 1.
[25] J. Yaozhong, L. Guilan, Z. Changyou, P. Huri, W. Lanjun, M. Aiqiao, Synth. Commun. 1991, 21, 1087.
[26] C. G. Overberger, N. P. Marullo, R. G. Hiskey, J. Am. Chem. Soc. 1961, 83, 1374.
[27] A. Loupy, B. Tchoubar, D. Astruc, Chem. Rev. 1992, 92, 1141.
[28] D. Seebach, A. K. Beck, A. Studer, in −Modern Synthetic Methods 1995×, Ed. C. Leumann, VCH
Publishers, Basel, 1995, pp. 1 178.
¬
[29] C. Anaya de Parrodi, E. Juaristi, L. Quintero-Cortes, P. Amador, Tetrahedron: Asymmetry 1996, 7, 1915; E.
¬
¬
Juaristi, J. L. Leon-Romo, Y. RamÌrez-Quiros, J. Org. Chem. 1999, 64, 2914.
[30] E. Juaristi, A. K. Beck, J. Hansen, T. Matt, T. Mukhopadhyay, M. Simson, D. Seebach, Synthesis 1993, 1271;
D. B. Collum, Acc. Chem. Res. 1999, 32, 1035.
[31] PC Spartan-Pro, Version 1.0, Wavefunction, Inc., Irvine, CA, 1999.
[32] Gaussian 98, Revision A.7, Gaussian, Inc., Pittsburg, PA, 1998.
[33] G. Chang, W. C. Guida, W. C. Still, J. Am. Chem. Soc. 1989, 111, 4379.
[34] A. Streitwieser, Acc. Chem. Res. 1984, 17, 353; A. Streitwieser, S. M. Bachrach, A. Dorigo, P. v. R. Schleyer,
in −Lithium Chemistry: A Theoretical and Experimental Overview×, Eds. A. M. Sapse, P. v. R. Schleyer,
Wiley, New York, 1995, pp. 12 15.
[35] H. C. Brown, G. W. Kramer, A. B. Levy, M. M. Midland, −Organic Synthesis via Boranes×, Wiley, New York,
1975, p. 256.
¬
[36] E. Juaristi, A. MartÌnez-Richa, A. GarcÌa-Rivera, J. S. Cruz-Sanchez, J. Org. Chem. 1983, 48, 2603.
[37] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923.
[38] K. Balenovic, N. Bregant, Tetrahedron 1959, 5, 44.
¬
[39] E. Juaristi, D. Quintana, M. Balderas, E. GarcÌa-Perez, Tetrahedron: Asymmetry 1996, 7, 2233.
¬
¬
¬
¬
[40] E. Juaristi, M. Balderas, H. Lopez-Ruiz, V. M. Jimenez-Perez, M. Kaiser-Carril, Y. RamÌrez-Quiros,
Tetrahedron: Asymmetry 1999, 10, 3493.
Received June 7, 2002