Aziridine-mediated asymmetric synthesis of quaternary β-amino acids using 2H-azirine 2-carboxylate esters

Article abstract of DOI:10.1016/S0040-4020(02)00727-5

Regioselective hydrogenation of enantiopure 3-substituted and 3,3-disubstituted aziridine 2-carboxylate esters affords β-amino acids and quaternary β-amino acids, respectively, in good yield. The aziridines are prepared via an aza-Darzens reaction of α-br

Full text of DOI:10.1016/S0040-4020(02)00727-5

Tetrahedron 58 (2002) 7135–7143
Aziridine-mediated asymmetric synthesis of quaternary b-amino
acids using 2H-azirine 2-carboxylate esters
a
a
b
Franklin A. Davis,a Jianghe Deng, Yulian Zhang and R. Curtis Haltiwanger
,
*
aDepartment of Chemistry, Temple University, Philadelphia, PA 19122, USA
bGlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA
Received 4 April 2002; accepted 2 May 2002
Abstract—Regioselective hydrogenation of enantiopure 3-substituted and 3,3-disubstituted aziridine 2-carboxylate esters affords b-amino
acids and quaternary b-amino acids, respectively, in good yield. The aziridines are prepared via an aza-Darzens reaction of a-bromoenolates
with enantiopure sulfinimines (N-sulfinyl imines) and by addition of Grignard reagents to 2H-azirine 2-carboxylate esters. q 2002 Elsevier
Science Ltd. All rights reserved.
b-Amino acids, while not as common as a-amino acids, are
present in natural products, such as peptides, and exhibit
important biological properties.1 b-Amino acids also serve
as valuable building blocks for the asymmetric construction
of b-lactam antibiotics,2,3 and are increasingly employed as
chiral building blocks.4 Moreover, novel amino acids are
frequently incorporated into biologically active molecules,
both to enhance bioactivity and to probe mechanisms of
action.5 Indeed substitution of b-amino acids for a-amino
acids can afford peptide analogs (peptidomimetics) with
increased activity and enzymatic stability.6 b-Peptides,
oligomers of b-amino acids,7 have been shown by the
groups of DeGrado, Gillman, and Seebach to adopt to the
same kinds of defined folded structures as proteins.8
However, while a number of methods have been devised
to prepare b-substituted b-amino acids as single enantio-
mers there very few methods to prepare quaternary
examples (b,b-disubstituted b-amino acids).9,10 Of these
methods the addition of enolates to ketosulfinimines
(N-sulfinyl imines) is particularly useful, but limited due
to the facile syn and anti isomerization of some ketosul-
finimines.11,12 The catalytic hydrogenation of 3-substituted
and 3,3-disubstituted aziridine 2-carboxylate esters
described here offers another opportunity for the asym-
metric synthesis of both secondary and quaternary b-amino
acids.
The regio- and stereoselective ring-opening reactions of
aziridine 2-carboxylate esters 1 serve as valuable sources of
structurally diverse a and b-amino acids (Scheme 1).
Activation of the aziridine nitrogen by an electron-with-
drawing group (acyl, sulfonyl), by protonation; or by Lewis
acids promotes either C-2 attack to give b-amino acids or
C-3 attack to give a-amino acids.13 Since ring-opening does
not effect the stereochemistry at C-2 or C-3 the aziridine
stereochemistry is maintained in the amino acid product.
The ring substituents and the reaction conditions determine
stereo- and regioselectivity of the ring-opening.
With C-3 aryl or vinyl substituted aziridines, catalytic
hydrogenation regiospecifically cleaves the benzylic/vinyl
C–N bond in unactivated and sulfonyl-activated aziridine
carboxylates.14–22 The retention product always predomi-
nates for trisubstituted aziridine esters with CH2Cl2 solvent
Scheme 1.
Keywords: asymmetric synthesis; aziridines; b-amino acids; N-sulfinyl imines.
*
Corresponding author. Tel.: þ1-215-204-0477; fax: þ1-215-204-0478; e-mail: fdavis@astro.ocis.temple.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00727-5

7136
F. A. Davis et al. / Tetrahedron 58 (2002) 7135–7143
Scheme 2.
affording the best selectivity.17 In the absence of a C-3
benzylic or vinyl aziridine substituent, hydrogenation
occurs at C-2 for mono- and disubstituted aziridine-2-
carboxylates to give b-amino esters.20,21 Molander has
shown, using samarium(II) iodide as the reductant, and N,N-
dimethylethanolamine (DMEA) as the proton source, that
C-3 alkyl and C-3 aryl aziridines are cleaved a to the
carboxyl group to give b-amino acids in excellent yields.22
In this study it was found that it was not necessary to
activate nitrogen with an electron-withdrawing group and
the trityl group could be used. Although the stereochemistry
was preserved at the b-position, it was not maintained at the
a-position. Similarly, magnesium in methanol affords b-
amino acids from both aryl and alkyl N-sulfonyl activated
aziridines.23 As part of our continuing interest in aziridines
and their application to the asymmetric synthesis of amino
acids,15–19 we report details of the catalytic hydrogenation
of di- and trisubstituted aziridine 2-carboxylates to b-amino
acids.
1. Results and discussion
1.1. Synthesis of aziridines
The N-sulfinylaziridine carboxylate esters were prepared
using the aza-Darzens reaction developed earlier in our
laboratory (Scheme 2).18 This procedure entails treatment,
in one pot, of the appropriate sulfinimine (S )-2 and a-
bromoacetate or tert-butyl a-bromoacetate with LiHMDS at
2788C. Diastereoselectivities were 66–70% and the
isolated yield of the major aziridine diastereoisomers 3
and 5 was 79–82%. The stereochemistry of the major
aziridine isomers were established as (2S,3S) in analogy
Scheme 3.

F. A. Davis et al. / Tetrahedron 58 (2002) 7135–7143
Table 1. Addition of Grignard reagents to 2H-azirine 2-carboxylates (þ)-10 at 2788C
7137
Entry
(þ)-10 R¼
Solvent
Time (h)
Products % yieldb (% de)c
R0MgXa (equiv.)
1
2
3
4
5
6
7
8
10a Me
MeMgBr (3.5)
MeMgBr (10)
EtMgBr (10)
MeMgBr (3.5)
MeMgBr (10)
EtMgBr (3.5)
EtMgBr (10)
n-BuMgCl (3.5)
n-BuMgCl (10)
i-PrMgCl (3.5)
i-PrMgCl (10)
Et2O
THF
THF
Et2O
THF
Et2O
THFd
Et2O
THF
Et2O
THF
3
3
65 (12aþ16a) (67)
30 (12aþ16a) (.92)
53 (13aþ16a) (60)
73 (12bþ16b) (60)
73 (12bþ16b) (.94)
81 (13bþ16b) (25)
93 (13bþ16b) (67)
88 (14b) (.94)
0.5
0.5
0.5c
0.1
0.5
0.3
0.3
0.3
0.3
10b t-Bu
9
10
11
92 (14b) (.94)
79 (15b) (.94)
90 (15b) (.94)
a
3.4 equiv. of R0MgX added at 2788C.
Isolated yield of both aziridines.
b
c
d
Determined by 1H NMR of the crude reaction mixture.
After 0.5 h at 2788C the reaction mixture was warmed to 2158C for 10 min.
with our previous results as well as the 7 Hz J2,3 coupling
constant, which is indicative of a cis arrangement of the
protons.18 Attempts to use the one pot procedure for
preparation of the 2-methyl aziridine carboxylate esters 7/8
failed. More successful was the addition of sulfinimine
(S)-(þ)-2a to the preformed lithium enolate of methyl
a-bromo acetate. However the de was low (33%) and the
yield of the major diastereoisomer (2R,3S )-7 was 55%
(Scheme 2).
As can be seen from the results summarized in Table 1,
addition of Grignard reagents to 2H-azirine (S )-(þ)-10a
(R¼Me) gave mixtures of 3,3-disubstitued aziridines 12a
and 16a that could not be separated (Table 1 entries 1 and 2).
The best selectivity, .90% de, was observed in THF solvent
(Table 1 entry 2). The tert-butyl ester, (S)-(þ)-10b gave
selectivities in excess of .94% de for addition of the
methyl, n-butyl, and isopropyl Grignard reagents in THF
1
(Table 1, entries 5, 9, and 11). By H NMR only a single
diastereoisomer was detected in these examples, but the 13C
NMR suggest that there may be a trace of the other isomer
present. Addition of EtMgBr in THF to (S )-(þ)-10b
afforded an inseparable mixture of 13b/16b in 67% de and
a combined yield of 93% (Table 1, entry 7). The reasonable
assumption is made that syn addition of RMgX to (S )-(þ)-
10b affords aziridines 12b, 13b, and 14b as the major
products (Scheme 3). Earlier studies had shown that
Grignard reagents add exclusively syn to the methyl and
tert-butyl ester moieties in 2H-azirine 2-carboxylates.17
However, attempts to confirm this assumption by NOESY
experiments proved inconclusive.
To prepare quaternary b-amino acids via aziridine hydro-
genation it is necessary to have 3,3-disubstituted aziridines.
While it is possible to prepare such aziridines by addition of
a-haloenolates to ketosulfinimines, it is only practical when
there is a large difference in size between the two keto
groups.18 When the groups are similar in size sulfinimines
exist as inseparable mixtures of E/Z isomers and addition
of organometallic reagents leads to poor diastereoselec-
tivities.24 An alternative method for preparing 3,3-disub-
stituted aziridines 2-carboxylates is the addition of Grignard
reagents to 2H-azirine 2-carboxylate esters.17 Indeed we
found that Grignard reagents add syn to the ester group or
from the more hindered face of the C–N double bond. We
attributed this to pre-chelation of the organometallic reagent
with the carboxyl group.
1.2. Synthesis of b-substituted b-amino acids
Because of the generally held perception that N-activation is
necessary for aziridine ring-opening, hydrogenation studies
were first conducted on the N-tosyl aziridines (2)-17a
and (þ)-18a. These aziridines were prepared in .90% yield
by m-chloroperbenzoic acid (m-CPBA) oxidation of
(2S,3S)-(þ)-3 and (2R,3S)-(þ)-7 (Scheme 4). However,
we soon discovered N-activation was not necessary and that
the NH aziridines, (þ)-17b and (2)-18b, prepared from 3a
and 7 using the MeMgBr protocol, readily open to give the
Treatment of aziridines 3b and 5b with 2 equiv. of MeMgBr
readily removed the N-sulfinyl group, which afforded the
NH aziridines in 70–84% yield after chromatography
(Scheme 3). Swern oxidation25 of 9 at 2788C gave the
2H-azirines (S )-(þ)-10 in 60–62% yield. Results of the
addition of 3.4 equiv. of Grignard reagents to (þ)-10 are
summarized in Table 1.
Scheme 4.

7138
F. A. Davis et al. / Tetrahedron 58 (2002) 7135–7143
Scheme 5.
parent b-amino acids (Scheme 4). Importantly, this means
that the sometimes harsh conditions (HBr/PhOH) necessary
to remove N-tosyl groups may not always be required.26
Hydrogenations were conducted by treating the aziridines
with the appropriate catalysis for 8 h under 1 atm of H2
(balloon). In the absence of H2 aziridine ring-opening was
not observed (Scheme 5). The b-amino acids were isolated
by flash chromatography and these results are summarized
in Table 2.
became more sterically demanding the de increased to a
maximum of 70% for tert-butyl alcohol (Table 2 entries
6–8 and 11). While use of chiral alcohols failed to improve
the de’s, a double diastereodifferentiation effect was noted
for (R) and (S)-2-butanol (e.g. 56 vs 32% de, respectively,
Table 2 entries 9 and 10). It is clear from these results that
the alcohol solvent is, in some manner, altering the catalysts
surface, with the more hindered alcohols providing the best
selectivity.
As noted in Table 2 Raney-nickel proved to the best
catalysts for NH or N–Ts aziridine ring-opening. Aziridine
(2)-17a (Z¼Ts) gave the corresponding b-amino acids
(S )-(þ)-19 in near quantitative yield (Table 2, entries 2 and
3). 2-Methylaziridine (2R,3S)-(þ)-18a gave two separable
diastereoisomers (2S,3S )-(þ)-20a and (2R,3S )-(2)-21a.
The absolute configuration of the major diastereoisomer
was determined by X-ray crystallography to have the
(2S,3S ) stereochemistry which indicates ring-opening
occurs with retention of configuration (Fig. 1). The
retention/inversion diastereoselectivity for (þ)-18a was
dependent on the alcohol solvent (Table 2). As the alcohol
1.3. Quaternary b-amino acids
Hydrogenation of aziridines 12, 14, and 15 with Raney-Ni
in ethanol under an atmosphere of H2 gave quaternary,
b,b-disubstituted b-amino acids (S )-22 in good to excellent
yields and .92% ee (Scheme 6). As noted earlier the
diastereoselection for the addition of Grignard reagents to
2H-azirines (S)-(þ)-10b (Scheme 3) was estimated to be
.94%. In support of this value is the fact that the de’s of the
Mosher amides of 22 were .92% de.
In summary, methodology is presented for the synthesis of
quaternary, b,b-disubstituted b-amino acids via hydro-
genation of 3,3-disubstituted aziridine 2-carboxylates. The
aziridines were prepared by addition of Grignard reagents to
2H-azirine 2-carboxylates.
Table 2. Hydrogenation of aziridines 17 and 18 for 8 h at rt and with 1 atm
H2
Entry
Aziridine
(Z¼)
Catalyst/solvent
b-Amino acid
(% yield)a (de)b
1
2
3
4
5
6
7
8
17a (Z¼Ts) Pd/C (H2)/THF
No reaction
(S)-19a (88)
(S)-19a (100)
(S)-19b (84)
No reaction
(2S,3S)-20a (60) (20)
(2S,3S)-20a (62) (34)
(2S,3S)-20a (80) (64)
Pd/C (HCO2H)/THF
Raney-Ni/EtOH
Raney-Ni/EtOH
17b (Z¼H)
18a (Z¼Ts) Raney-Ni/THF
Raney-Ni/MeOH
Raney-Ni/EtOH
Raney-Ni/i-PrOH
9
Raney-Ni/(R)-2-BuOH (2S,3S)-20a (72) (56)
10
11
12
Raney-Ni/(S)-2-BuOH
Raney-Ni/t-BuOH
Raney-Ni/t-BuOH
(2S,3S)-20a (60) (32)
(2S,3S)-20a (77) (70)
(2S,3S)-20b (89)c (71)
18b (Z¼H)
Raney-Ni 2800.
a
Isolated yield of major product.
Determined by 1H NMR on the crude product.
Combined yield of inseparable (2S,3S )-20 and (2R,3S)-21.
b
c
Figure 1. ORTEP view of (2S,3S)-(þ)-20.

F. A. Davis et al. / Tetrahedron 58 (2002) 7135–7143
7139
Scheme 6.
2. Experimental
7.28 (d, 2H, J¼8.0 Hz), 7.61 (d, 2H, J¼8.0 Hz); 13C NMR
(CDCl3) d 166.9, 142.2, 142.1, 129.9, 125.5, 82.1, 41.7,
32.6, 29.3, 28.2, 21.8, 20.9, 14.2. Anal. calcd for
C17H25NO3S: C, 63.13; H, 7.79; N, 4.33. Found: C, 63.55;
H, 7.53; N, 4.09.
2.1. General procedure
Column chromatography was performed on silica gel,
Merck grade 60 (230–400 mesh). Analytical and prepara-
tive thin-layer chromatography was performed on precoated
silica gel plates (250 and 1000 mm) purchased from
Analtech Inc. TLC plates were visualized with UV and in
an iodine chamber. THF and diethyl ether were freshly
distilled under argon from a purple solution of sodium and
benzophenone. Elemental and HRMS analyses were
performed in the Department of Chemistry, University of
Pennsylvania, Philadelphia, and Department of Chemistry,
Drexel University, Philadelphia, PA, respectively. Unless
stated otherwise, all reagents were purchased from com-
mercial sources and used without additional purification.
2.1.3. tert-Butyl E-(SS,2S,3R)-(2)-N-p-toluenesulfinyl-3-
n-propylaziridine 2-carboxylate (6b). Purification by
silica gel column chromatography (n-hexane/EtOAc, 10:1)
gave 0.09 g (16%) of a clear oil: [a ]2D0¼2116.7 (c 1.2,
1
CHCl3); IR (neat) 2963, 2932, 2874, 1746, 1457 cm21; H
NMR (CDCl3) d 0.99 (t, 3H, J¼7.5 Hz), 1.31 (s, 3H), 1.46–
1.58 (m, 2H), 1.62–1.88 (m, 2H), 2.40 (s, 3H), 2.97 (m, 1H),
3.07 (d, 1H, J¼4.0 Hz), 7.27 (d, 2H, J¼8.0 Hz), 7.62 (d, 2H,
J¼8.0 Hz); 13C NMR (CDCl3) d 168.2, 143.6, 142.0, 129.8,
125.4, 82.3, 46.0, 35.0, 30.3, 28.2, 21.8, 21.7, 14.1. HRMS
calcd for C17H26NO3S (MþH): 324.1623. Found: 324.1633.
Sulfinimines (S )-(þ)-N-(5-phenylpentylidene)-p-toluene-
sulfinamide (2a) and (S )-(þ)-N-(n-butylidene)-p-toluene-
sulfinamide (2b) were prepared as previously described.27
2.1.4. Methyl Z-(SS,2S,3S)-(1)-N-p-toluenesulfinyl-3-n-
propylaziridine 2-carboxylate (3b). Purification by silica
gel column chromatography (n-hexane/EtOAc, 10:1) gave
0.35 g (79%) of a yellow oil: [a ]2D0¼þ100.5 (c 1.2, CHCl3);
1
2.1.1. (S)-(1)-N-(5-Phenylpentylidene)-p-toluenesulfina-
mide (2a). Purification by flash chromatography (n-hex-
ane/EtOAc, 9:1): (92%) of a yellow oil: [a]2D0¼þ230.8 (c
IR (neat) 2960, 2874, 1749, 1439, 1098 cm21; H NMR
(CDCl3) d 0.97 (t, 3H, J¼7.5 Hz), 1.42–1.78 (m, 4H), 2.40
(s, 3H), 2.76 (m, 1H), 3.18 (d, 1H, J¼7.0 Hz), 3.60 (s, 3H),
7.28 (d, 2H, J¼8.0 Hz), 7.60 (d, 2H, J¼8.0 Hz); 13C NMR
(CDCl3) d 168.1, 142.3, 141.5, 129.8, 125.5, 52.5, 41.6,
31.6, 30.0, 21.7, 20.7, 14.0. HRMS calcd For C14H20NO3S
(MþH): 282.1164. Found 282.1169.
1
1.19, CHCl3); IR (neat) 1621, 1506, 1094 cm21; H NMR
(CDCl3) d 1.65 (m, 4H), 2.40 (s, 3H), 2.51 (m, 2H), 2.60 (t,
2H), 7.19 (m, 5H), 7.27 (d, 2H, J¼7.4 Hz), 7.54 (d, 2H,
J¼2.0 Hz), 8.21 (t, 1H, J¼5.0 Hz); 13C NMR (CDCl3) d
147.6, 142.6, 142.3, 130.4, 129.0, 128.9, 126.4, 125.2, 36.3,
36.2, 31.4, 25.6, 22.1. Anal. calcd for C18H21NOS: C, 72.24;
H, 7.02; N, 4.68. Found: C, 72.33; H, 7.14; N, 4.95.
2.1.5. Methyl E-(SS,2S,3R)-(2)-N-p-toluenesulfinyl-3-n-
propylaziridine 2-carboxylate (4b). Purification by silica
gel column chromatography (n-hexane/EtOAc, 10:1) gave
0.08 g (17%) of a yellow oil: [a ]2D0¼2116.8 (c 1.4, CHCl3);
2.1.2. tert-Butyl Z-(SS,2S,3S )-(1)-N-p-toluenesulfinyl-3-
n-propylaziridine 2-carboxylate (5b). Typical pro-
cedure. In a 100 mL, one-necked, round-bottomed flask
equipped with a stirring bar, rubber septum, and argon filled
balloon was placed 0.42 g (2.02 mmol) of sulfinimine
(þ)-2b in THF (40 mL). The reaction mixture was cooled
to 2788C, 0.60 mL (4.04 mmol) of tert-butyl bromoacetate
(Aldrich) was added followed after 10 min by 2.5 mL
(2.5 mmol) of LiHMDS. The reaction mixture was stirred at
2788C for 30 min, quenched with H2O (10 mL), and diluted
with EtOAc (20 mL). The organic phase was separated, and
the aqueous layer was extracted with EtOAc (2£10 mL).
The combined organic phases were washed with brine
(20 mL), dried (Na2SO4), and concentrated. Purification by
silica gel flash chromatography (n-hexane/EtOAc, 10:1)
gave 0.46 g (82%) of a clear oil: [a]2D0¼þ87.7 (c 0.7,
IR (neat) 2960, 2931, 2874, 1747, 1441, 1227, 1099 cm21
;
1H NMR (CDCl3) d 0.92 (t, 3H, J¼7.5 Hz), 1.42–1.55 (m,
2H), 1.65–1.74 (m, 1H), 1.76–1.88 (m, 1H), 2.33 (s, 3H),
2.92 (m, 1H), 3.11 (d, 1H, J¼3.6 Hz), 3.56 (s, 3H), 7.22 (d,
2H, J¼8.0 Hz), 7.54 (d, 2H, J¼8.0 Hz); 13C NMR (CDCl3)
d 169.6, 143.0, 142.2, 130.0, 125.3, 52.8, 46.4, 30.3, 21.8,
21.6, 14.0.
2.1.6. Methyl Z-(SS,2S,3S )-(1)-N-p-toluenesulfinyl-3-(5-
phenylpentyl)aziridine 2-carboxylate (3a). Purification
by flash chromatography (n-hexane/EtOAc, 8:2) afforded
0.40 g (72%) of a yellow oil: [a ]2D0¼þ73.5 (c 1.08, CHCl3);
IR (neat) 3026, 1733, 1374, 1246 cm21; 1H NMR (CDCl3) d
1.45 (m, 1H), 1.55 (m, 1H), 1.66 (m, 2H), 1.74 (m, 2H), 2.38
(s, 3H), 2.61 (t, 2H, J¼5.0 Hz), 2.73 (m, 1H), 3.16 (d, 1H,
J¼7.0 Hz), 3.58 (s, 3H), 7.24 (m, 5H), 7.27 (d, 2H, J¼
7.5 Hz), 7.58 (d, 2H, J¼7.5 Hz); 13C NMR (CDCl3) d 168.5,
142.8, 141.8, 130.4, 129.1, 129.0, 126.4, 125.6, 52.9, 42.1,
36.3, 32.0, 31.6, 27.4, 27.3, 22.1. Anal. calcd for
1
CHCl3); IR (neat) 2965, 2874, 1742, 1154 cm21; H NMR
(CDCl3) d 0.94 (t, 3H, J¼7.0 Hz), 1.30 (s, 3H), 1.42–1.58
(m, 2H), 1.61–1.69 (m, 1H), 1.72–1.78 (m, 1H), 2.40 (s,
3H), 2.70 (dd, 1H, J¼7.0, 13.7 Hz), 3.03 (d, 1H, J¼7.0 Hz),

7140
F. A. Davis et al. / Tetrahedron 58 (2002) 7135–7143
C21H25NO3S: C, 67.92; H, 6.74; N, 3.78. Found: C, 67.53;
H, 6.90; N, 3.70.
NH4Cl (3 mL), diluted with EtOAc (10 mL), and the
organic phase was separated. The aqueous phase was
extracted with EtOAc (2£5 mL), the combined organic
phases were washed with brine (8 mL), dried (Na2SO4), and
concentrated. Purification by silica gel column chroma-
tography (n-hexane/EtOAc, 5:1) gave 0.09 g (77%) of a
white solid; mp: 40–418C; [a]2D0¼þ49.2 (c 1.0, CHCl3); IR
(neat) 3269, 2963, 2932, 2874, 1719, 1157 cm21; 1H NMR
(CDCl3) d 0.81 (b, 1H), 0.92 (t, 3H, J¼7.0 Hz), 1.45 (s, 3H),
1.35–1.50 (m, 3H), 1.55–1.6 (m, 1H), 2.13 (m, 1H), 2.52
(d, 1H, J¼6.5 Hz); 13C NMR (CDCl3) d 170.5, 82.1, 38.9,
35.8, 30.2, 28.5, 21.5, 14.2. HRMS calcd for C10H20NO2
(MþH): 186.1494. Found: 186.1496.
2.1.7. Methyl E-(SS,2S,3R )-(1)-N-p-toluenesulfinyl-3-(5-
phenylpentyl)aziridine 2-carboxylate (4a). Purification by
flash chromatography (n-hexane/EtOAc, 8:2) afforded
0.03 g (6%) of a yellow oil: [a ]2D0¼þ114.4 (c 1.2,
CHCl3); IR (neat) 3026, 2857, 2933, 1734, 1442,
1
1216 cm21; H NMR (CDCl3) d 1.10 (m, 2H), 1.43 (m,
3H), 1.65 (m, 1H), 2.36 (s, 3H), 2.40 (t, 2H, J¼7.6 Hz), 2.69
(m, 1H), 3.00 (d, 1H, J¼3.6 Hz), 3.71 (s, 3H), 7.03 (m, 2H),
7.10 (m, 1H), 7.18 (m, 2H), 7.25 (d, 2H, J¼7.5 Hz), 7.64 (d,
2H, J¼7.5 Hz); 13C NMR (CDCl3) d 169.5, 142.8, 142.5,
142.3, 130.1, 128.7, 128.7, 126.1, 125.8, 53.1, 47.4, 40.4,
36.0, 31.1, 29.1, 27.4, 22.0.
2.1.11. Methyl cis-(2S,3S )-(1)-3-n-propyl 1H-aziridine-
2-carboxylate (9a). Purification by silica gel column
chromatography (n-hexane/EtOAc, 5:1) gave 0.09 g (84%)
of a colorless oil: [a ]D20¼þ64.0 (c 1.06, CHCl3); IR (neat)
2.1.8. Methyl E-(SS,2R,3S )-(1)-N-p-toluenesulfinyl-2-
methyl-3-(4-phenylbutyl) aziridine 2-carboxylate (7). In
a 250 mL, two-necked, round-bottomed flask fitted with a
magnetic stirring bar, a rubber septum, and an argon filled
balloon was placed 13.5 mL (13.5 mmol, 1.0 M in THF) of
LiHMDS in THF (80 mL). The solution was cooled to
2788C, 1.54 mL (13.5 mmol) of methyl a-bromopropio-
nate was added, and after 0.5 h at 2788C a solution of 1.5 g
(5.0 mmol) of (S)-(þ)-2a in THF (20 mL) was added to the
enolate via a cotton-wrapped, double-ended needle over
0.5 h. The reaction mixture was stirred for 0.5 h, quenched
with H2O (10 mL) at 2788C, and diluted with EtOAc
(2£20 mL). The organic phase was washed with brine
(20 mL), dried (MgSO4), and concentrated. Purification by
flash chromatography (n-hexane/EtOAc, 8:2) afforded
1.07 g (55%) of an oil: [a]2D0¼þ43.5 (c 1.7, CHCl3); IR
1
3270, 2969, 2873, 1734, 1202 cm21; H NMR (CDCl3) d
0.91 (t, 3H, J¼7.0 Hz), 1.36–1.62 (m, 4H), 2.22 (m, 1H),
2.64 (d, 1H, J¼6.0 Hz), 3.75 (s, 3H); 13C NMR (CDCl3) d
171.9, 52.7, 39.1, 34.8, 30.3, 21.4, 14.1. HRMS calcd for
C7H14NO2 (MþH): 144.1024. Found: 144.1020.
2.1.12. Methyl Z-(2S,3S )-(1)-3-(5-phenylpentyl) 1H-
aziridine-2-carboxylate (17b). Purification by flash
chromatography (n-hexane/EtOAc, 10:1) afforded 0.11 g
(95%) of a white solid; mp 40–418C; [a]2D0¼þ47.7 (c 1.09,
CHCl3); IR (KBr) 3262, 3026, 2926, 2856, 1730, 1441,
1206 cm21; 1H NMR (CDCl3) d 1.41 (m, 1H), 1.51 (m, 2H),
1.66 (m, 4H), 2.62 (m, 3H), 3.73 (s, 3H), 7.25 (m, 5H); 13C
NMR (CDCl3) d 172.2, 142.9, 129.0, 128.9, 126.4, 53.0,
36.4, 35.1, 31.6, 30.3, 28.5, 28.0; Anal. calcd for
C14H19NO2: C, 72.10; H, 8.10; N, 6.00. Found: C, 71.83;
H, 7.80; N, 5.94.
1
(neat) 2926, 1731, 1453, 1263, 1103, 846 cm21; H NMR
(CDCl3) d 1.10 (m, 2H), 1.32 (m, 1H), 1.47 (s, 3H), 1.51 (m,
3H), 2.41 (s, 3H), 2.49 (t, 2H, J¼8.0 Hz), 2.91 (dd, 1H,
J¼6.5, 1.5 Hz), 3.77 (s, 3H), 7.11 (d, 2H, J¼7.0 Hz), 7.28 (t,
2H, J¼7.5 Hz), 7.30 (d, 2H, J¼7.5 Hz), 7.68 (d, 2H, J¼
8.0 Hz); 13C NMR (CDCl3) d 170.2, 160.5, 144.6, 142.8,
137.4, 130.3, 129.0, 127.9, 126.5, 73.8, 58.3, 53.6,
36.2, 31.5, 31.3, 25.2, 22.2. Anal. calcd for C22H27NO3S:
C, 68.54; H, 7.06; N, 3.63. Found: C, 68.39; H, 7.32; N,
3.63.
2.1.13. Methyl E-(2R,3S)-(2)-2-methyl-3-(5-phenylpentyl)
1H-aziridine-2-carboxylate (18b). Purification by flash
chromatography (n-hexane/EtOAc 7:3) 0.12 g (92%) of an
oil: [a]2D0¼261.6 (c 1.4, CHCl3); IR (neat) 3290, 2933,
1
1724, 1456, 1287, 1207, 1106 cm21; H NMR (CDCl3) d
1.36 (s, 3H), 1.59–1.43 (m, 4H), 1.68 (m, 2H), 2.20 (m, 2H),
2.63 (m, 2H), 3.74 (s, 3H), 7.18 (m, 3H), 7.27 (m, 2H); 13C
NMR (CDCl3) d 176.1, 143.0, 129.0, 128.9, 126.4, 53.3,
44.5, 38.8, 36.4, 31.8, 29.5, 27.8, 14.4. HRMS calcd for
C15H21NO2 (mþNa): 270.1470. Found: 270.1463.
2.1.9. Methyl Z-(SS,2S,3S )-(1)-N-p-toluenesulfinyl-2-
methyl-3-(4-phenylbutyl) aziridine 2-carboxylate (8).
Purification by flash chromatography (n-hexane/EtOAc,
8:2) afforded 0.59 g (21%) of an oil: [a]2D0¼þ32.5 (c 0.097,
CHCl3); IR (neat) 3026, 2933, 2858, 1746, 1730, 1453,
2.1.14. tert-Butyl (S)-(1)-3-n-propyl 2H-azirine-2-car-
boxylate (10b). Typical procedure. In a 50 mL, one-
necked, round-bottomed flask equipped with a stirring bar,
rubber septum, and argon filled balloon was placed 1.85 g
(10.0 mmol) of 9b in DCM (20 mL), and the solution was
cooled to 2788C. In a second 250 mL, one-necked, round-
bottomed flask equipped with a stirring bar, rubber septum
and argon filled balloon was added 11.0 mL (21.9 mmol) of
oxalyl chloride in DCM (80 mL) and the solution was
cooled to 2788C. At this time 3.40 mL (47.8 mmol) of
DMSO was added and after 10 min the solution of 9b was
transferred via a double ended needle to the DMSO solution.
After stirring for 10 min at 2788C, 6.7 mL (49.9 mmol) of
Et3N was added and the reaction mixture was warmed to rt
and stirred for 4 h. The reaction mixture was concentrated,
Et2O (80 mL) was added, and the precipitated salts were
1
1148 cm21; H NMR (CDCl3) d 1.32–1.58 (m, 6H), 1.47
(s, 1H), 2.35 (s, 3H), 2.51 (t, 2H, J¼7.2 Hz), 2.66 (dd, 1H,
J¼5.6 Hz, J¼6.8 Hz), 3.59 (s, 3H), 7.09 (m, 3H), 7.20 (m,
4H), 7.64 (m, 2H); 13C NMR (CDCl3) d 168.9, 141.3, 141.0,
140.7, 128.7, 127.5, 127.4, 124.9, 124.8, 51.5, 50.4, 44.9,
34.8, 30.1, 27.2, 25.7, 20.6, 14.8.
2.1.10. tert-Butyl Z-(2S,3S )-(1)-3-n-propyl 1H-aziridine
2-carboxylate (9b). Typical procedure. In a 50 mL, one-
necked, round-bottomed flask equipped with a stirring bar,
rubber septum, and argon filled balloon was placed 0.20 g
(0.61 mmol) of (þ)-5b in THF (10 mL). The reaction
was cooled to 2788C, 0.40 mL (1.22 mmol) of MeMgBr
(Aldrich) was added and the reaction mixture was stirred for
20 min. At this time the reaction was quenched with sat.

F. A. Davis et al. / Tetrahedron 58 (2002) 7135–7143
7141
removed by filtration. The organic phase was washed with
H2O (2£30 mL), the aqueous phase was extracted with Et2O
(2£10 mL), the combined organic phases were washed with
brine (30 mL), dried (Na2SO4), and concentrated. Purifi-
cation by silica gel column chromatography (n-hexane/
EtOAc, 20:1) gave 1.10 g (60%) of a yellow liquid:
[a]2D0¼þ67.8 (c 0.5, CHCl3); IR (neat) 2976, 2937, 1725,
2.1.19. tert-Butyl (2S,3R/S )-3-ethyl-3-n-propyl 1H-azir-
idine-2-carboxylate (13b/16b). Chromatographic purifi-
cation (n-hexane/EtOAc, 9:1) gave 0.05 g (93%) of 13b/16b
as a yellow oil: major isomer (2S,3R)-13b: 1H NMR
(CDCl3) d 0.87 (m, 6H), 1.30–1.48 (m, 4H), 1.53–1.63 (m,
2H), 1.41 (s, 9H), 2.26 (b, 1H); 13C NMR (CDCl3) 170.6,
82.0, 47.0, 42.7, 38.0, 28.5, 23.3, 18.8, 14.5, 10.9. Minor
isomer (2S,3S)-16b: 1H NMR (CDCl3) 0.80–0.90 (m, 6H),
1.30–1.48 (m, 4H), 1.53–1.63 (m, 2H), 1.41 (s, 9H), 2.25
(b, 1H); 13C NMR (CDCl3) 170.6, 82.0, 47.0, 42.4, 32.0,
29.2, 23.4, 20.0, 14.4, 9.7.
1
1344, 1168 cm21; H NMR (CDCl3) d 1.07 (t, 3H, J¼
7.5 Hz), 1.45 (s, 3H), 1.61 (s, 1H), 1.80 (m, 2H), 2.33 (s,
1H), 2.79 (m, 1H); 13C NMR (CDCl3) d 172.0, 162.8, 82.0,
30.2, 29.2, 28.7, 18.5, 14.3. HRMS calcd for C10H18NO2
(MþH): 184.1338. Found: 184.1343.
2.1.20. tert-Butyl Z-(2S,3S )-(1)-3-n-butyl-3-n-propyl
1H-aziridine-2-carboxylate (14b). Chromatographic
purification (n-hexane/EtOAc, 10:1) gave 0.06 g (88%) of
a yellow oil: [a]2D0¼þ55.5 (c 0.82, CHCl3); IR (neat) 3271,
2.1.15. Methyl (S)-(1)-3-n-propyl 2H-azirine-2-carboxyl-
ate (10a). Purification by silica gel column chromatography
(n-hexane/EtOAc, 20:1) gave 0.14 g (62 %) of a yellow oil:
[a]2D0¼þ104.7 (c 0.74, CHCl3); IR (neat) 2965, 2879, 1733,
2970, 2933, 2973, 1368, 1229, 1157 cm21 1H NMR
;
1
1340, 1186 cm21; H NMR (CDCl3) d 1.07 (t, 3H, J¼
(CDCl3) d 0.84 (m, 6H), 1.15–1.25 (m, 4H), 1.30–1.45
(m, 6H), 1.41 (s, 9H), 1.50–1.60 (m, 2H), 2.27 (s, 1H); 13C
NMR (CDCl3) d 170.5, 82.0, 46.3, 42.7, 38.6, 30.1, 29.0,
28.5, 23.3, 18.9, 14.5, 14.4. HRMS calcd for C14H27NO2
(MþH): 242.2120. Found: 241.3697.
7.5 Hz), 1.45 (s, 3H), 1.61 (s, 1H), 1.80 (m, 2H), 2.33 (s,
1H), 2.79 (m, 1H); 13C NMR (CDCl3) d 173.0, 162.3, 52.5,
29.0, 28.9, 18.3, 14.1. HRMS calcd for C7H12NO2 (MþH):
142.0868. Found: 142.0867.
2.1.16. Methyl E-(2S,3R)-(1)-3-methyl-3-n-propyl 1H-
aziridine-2-carboxylate (12a). Typical procedure. In a
10 mL, one-necked, round-bottomed flask equipped with a
stirring bar, rubber septum, and argon filled balloon was
placed 0.04 g (0.22 mmol) of 10a in THF (5 mL). The
reaction was cooled to 2788C and 0.025 mL (0.74 mmol) of
MeMgBr was added. The reaction mixture was stirred at
2788C for 20 min, quenched with sat. NH4Cl (2 mL), and
diluted with EtOAc (5 mL). The organic phase was
separated, and the aqueous layer was washed with EtOAc
(2£5 mL). The combined organic phases were washed with
brine (4 mL), dried (Na2SO4), and concentrated. Purifi-
cation by silica gel column chromatography (n-hexane/
EtOAc, 10:1) gave 0.01 g (30%) of a yellow oil:
[a]2D0¼þ90.3 (c 0.058, CHCl3); IR (neat) 3272, 2962,
2.1.21. tert-Butyl Z-(2S,3S )-(1)-3-iso-propyl-3-n-propyl
1H-aziridine-2-carboxylate (15b). Chromatographic
purification (n-hexane/EtOAc, 9:1) gave 0.05 g (79%) of a
yellow oil: [a ]2D0¼þ54.8 (c 0.68, CHCl3); IR (neat) 3266,
2963, 2933, 2874, 1719, 1368, 1225, 1155 cm21; 1H NMR
(CDCl3) d 0.89 (t, 3H, J¼7.5 Hz), 0.93 (d, 3H, J¼7.0 Hz),
1.02 (d, 3H, J¼7.0 Hz), 1.18–1.26 (m, 2H), 1.44–1.50 (m,
1H), 1.46 (s, 3H), 1.58–1.67 (m, 2H), 2.47 (s, 1H); 13C
NMR (CDCl3) d 170.8, 81.9, 49.6, 41.6, 31.9, 28.5, 20.2,
19.0, 18.3, 14.8. HRMS calcd for C13H26NO2 (MþH):
250.1783. Found: 250.1774.
2.1.22. Methyl E-(2S,3S)-(2)-N-p-toluenesulfonyl-3-(5-
phenylpentyl)aziridine 2-carboxylate (17a). Typical pro-
cedure. In a 25 mL, one-necked, round-bottomed flask
equipped with a magnetic stirring bar was placed 0.25 g
(0.67 mmol) of 3a in CHCl3 (10 mL). m-Chloroperbenzoic
acid, 0.39 g (1.35 mmol, 60%, Aldrich) was added to the
solution in small portions and the reaction mixture was
stirred at rt for 30 min. The solution was diluted with DCM
(10 mL), sat. NaHCO3 (10 mL) was added, and the organic
phase was dried (MgSO4) and concentrated. Purification by
flash chromatography (n-hexane/EtOAc, 9:1) afforded
0.26 g (98%) of a colorless oil: [a ]2D0¼235.1 (c 3.75,
1
2875, 1731, 1440, 1210, 1105 cm21; H NMR (CDCl3) d
0.92 (t, 3H, J¼7.0 Hz), 1.30–1.55 (m, 4H), 1.27 (s, 3H),
2.43 (b, 1H), 3.76 (s, 3H); 13C NMR (CDCl3) d 171.8, 52.7,
43.4, 42.2, 41.8, 19.4, 16.9, 14.4. HRMS calcd for
C8H16NO2 (MþH): 158.1181. Found: 158.1175.
2.1.17. Methyl (2S,3R/S )-3-ethyl-3-n-propyl 1H-aziri-
dine-2-carboxylate (13a/16a). 0.03 g (53%) of a yellow
oil. Major isomer (2S,3R )-13a: 1H NMR (CDCl3) d 0.92 (m,
3H), 1.38–1.53 (m, 4H), 2.43 (b, 1H), 3.74 (s, 3H); 13C
NMR (CDCl3) 171.9, 52.7, 41.7, 38.1, 31.9, 23.4, 19.7, 14.5,
CHCl3); IR (neat) 2926, 1751, 1161 cm21 1H NMR
;
(CDCl3) d 1.30 (m, 2H), 1.59 (m, 4H), 2.45 (s, 3H), 2.53
(t, 2H, J¼7.5 Hz), 2.98 (m, 1H), 3.43 (d, 1H, J¼8.0 Hz),
7.12–7.35 (m, 7H), 7.85 (d, 2H, J¼8.5 Hz); 13C NMR
(CDCl3) d 166.3, 145.0, 142.0, 134.1, 129.7, 129.6, 128.3,
128.2, 128.1, 125.7, 52.6, 44.6, 40.9, 35.5, 30.6, 26.5, 26.4,
21.6; Anal. calcd for C21H25NO4S: C, 65.09; H, 6.50; N,
3.61. Found: C, 65.51; H, 6.45; N, 3.11.
1
10.7. Minor isomer (2S,3S )-15a: H NMR (CDCl3) d 0.90
(m, 3H), 1.38–1.53 (m, 4H), 2.41 (b, 1H), 3.74 (s, 3H); 13C
NMR (CDCl3) d 171.9, 47.6, 41.4, 38.1, 29.2, 23.4, 19.7,
14.5, 9.8.
2.1.18. tert-Butyl E-(2S,3R )-(1)-3-methyl-3-n-propyl
1H-aziridine-2-carboxylate (12b). Chromatographic
purification (n-hexane/EtOAc, 9:1) gave 0.04 g (73%) of a
yellow oil: [a ]2D0¼þ54.0 (c 0.74, CHCl3); IR (neat) 3276,
2.1.23. Methyl E-(2R,3S )-(1)-N-p-toluenesulfonyl-2-
methyl-3-(4-phenylbutyl)-aziridine-2-carboxylate (18a).
Chromatographic purification (n-hexane/EtOAc, 9:1) gave
0.28 g (95%) of a yellow oil: [a]2D0¼þ1.0 (c 1.5, CHCl3); IR
1
2967, 1721, 1158 cm21; H NMR (CDCl3) d 0.92 (t, 3H,
J¼7.0 Hz), 1.25 (s, 3H), 1.30–1.35 (m, 1H), 1.47 (s, 9H),
1.41–1.51 (m, 3H), 2.32 (s, 1H); 13C NMR (CDCl3) d
170.6, 42.9, 42.5, 42.2, 28.6, 19.3, 16.7, 14.4. HRMS calcd
for C11H22NO2 (MþH): 200.1650. Found: 200.1642.
(neat) 2929, 1767, 1436, 1331, 1161, 1091, 956, 668 cm21
;
1H NMR (CDCl3) d 1.37–1.43 (m, 1H), 1.45 (s, 3H), 1.56–
1.62 (m, 3H), 2.44 (s, 3H), 2.56 (t, 2H, J¼8.5 Hz), 3.55 (dd,

7142
F. A. Davis et al. / Tetrahedron 58 (2002) 7135–7143
1H, J¼5.0, 2.0 Hz), 3.82 (s, 3H), 7.13–7.30 (m, 7H), 7.79
(d, 2H, J¼8.0 Hz); 13C NMR (CDCl3) d 189.4, 144.8, 142.8,
137.9, 130.2, 129.0, 128.2, 126.5, 53.8, 53.2, 49.6, 36.3,
31.5, 27.9, 27.3, 16.4. HRMS calcd for C22H27NO4S
(Mþ1): 402.1739. Found: 402.1736.
NMR (CDCl3) d 175.0, 144.0, 143.0, 138.9, 130.3, 129.0,
128.9, 127.7, 126.4, 56.8, 52.5, 44.0, 36.3, 32.0, 31.6, 26.1,
22.1, 13.9; Anal. calcd for C22H29NO4S: C, 65.48; H, 7.24;
N, 3.47. Found: C, 65.09; H, 7.35; N, 3.33.
2.1.28. tert-Butyl (R )-(2)-3-amino-3-methyl hexanoate
(22a). Chromatographic purification (n-hexane/EtOAc, 1:1)
gave 0.04 g (71 %) of a yellow oil: [a ]2D0¼22.67 (c 0.52,
2.1.24. Methyl (S )-(1)-3-amino-7-phenylheptanote
(19b). In a 25 mL, two-neck, round-bottomed flask,
equipped with a rubber septum, stirring bar, and hydrogen
filled balloon was placed 0.05 g (0.21 mmol) of 17b in
EtOH (8 mL), and 0.04 g of Raney-Ni (W 2800). The
reaction mixture was stirred for 8 h, the Raney-Ni was
removed by filtration through Celite, and the solution was
concentrated. The residue was extracted with DCM
(3£4 mL), the combined organic phases were washed with
brine (3 mL), dried (Na2SO4), and concentrated. Purifi-
cation by silica gel column chromatography (n-hexane/
EtOAc/MeOH, 12:7:1) gave 0.04 g (84%) of a yellow oil:
[a ]2D0¼þ8.77 (c 0.94, CHCl3); IR (neat) 3380, 3307, 2930,
1
CHCl3); IR (neat) 3366, 2965, 1730, 1374, 1150 cm21; H
NMR (CDCl3) d 0.92 (t, 3H, J¼7.0 Hz), 1.25 (s, 3H), 1.35
(m, 2H), 1.45 (s, 9H), 1.59 (m, 2H), 2.39 (s, 2H), 4.14 (b,
2H); 13C NMR d (CDCl3) 172.0, 81.8, 53.6, 46.4, 44.5, 28.7,
27.0, 17.9, 15.1. HRMS calcd for C11H24NO2 (MþH):
202.1807. Found: 202.1873.
2.1.29. tert-Butyl (S)-(1)-3-amino-3-n-propyl heptanoate
(22b). Chromatographic purification (n-hexane/EtOAc, 1:1)
gave 0.04 g (78 %) of a yellow oil: [a ]2D0¼þ1.38 (c 0.94,
CHCl3); IR (neat) 3379, 3312, 2959, 2933, 1724,
1
1
2856, 1736, 1602, 1436, 838 cm21; H NMR (CDCl3) d
1367 cm21; H NMR (CDCl3) d 0.90 (m, 6H), 1.20–1.30
1.32–1.48 (m, 4H), 1.58–1.67 (m, 2H), 1.98 (b, 2H), 2.28
(dd, 1H, J¼9.0, 16.0 Hz), 2.48 (dd, 1H, J¼4.0, 16.0 Hz),
2.62 (t, 2H, J¼7.5 Hz), 3.19 (b, 1H), 7.17 (m, 3H), 7.27 (m,
2H); 13C NMR (CDCl3) d 173.4, 142.8, 128.8, 128.7, 126.1,
52.0, 48.7, 42.6, 37.7, 36.2, 31.7, 26.1. HRMS calcd for
C14H22NO2 (MþH): 236.1650. Found: 236.1654.
(m, 6H), 1.30–1.40 (m, 4H), 1.44 (s, 9H), 1.68 (b, 2H), 2.25
(s, 2H); 13C NMR (CDCl3) d 172.3, 81.2, 54.2, 46.4, 43.1,
40.4, 28.5, 26.3, 23.7, 17.3, 15.1, 14.5. HRMS calcd for
C14H30NO2 (MþH): 244.2276. Found: 244.2274.
2.1.30. tert-Butyl (R)-(2)-3-amino-3-iso-propyl-hexanoate
(21c). Chromatographic purification (n-hexane/EtOAc 1:1)
gave 0.04 g (86%) of a yellow oil: [a]2D0¼22.46 (c 0.73,
CHCl3); IR (neat) 3389, 3318, 2961, 2934, 1722, 1457,
2.1.25. Methyl (S )-(2)-3-N-( p-tolylsulfonyl)amino-7-
phenyl heptanoate (19a). Chromatographic purification
(n-hexane/EtOAc, 1:1) gave 0.09 g (88%) of an oil:
[a ]2D0¼210.3 (c 0.8, CHCl3); IR (neat) 3318, 1733, 1100,
904 cm21; 1H NMR (CDCl3) d 1.25 (m, 2H), 1.26 (m, 2H),
1.44–1.51 (m, 2H), 2.40 (m, 2H), 2.42 (s, 3H), 2.50 (t, 2H,
J¼9.0 Hz), 3.50 (m, 1H), 3.60 (s, 3H), 5.12 (d, 1H, J¼
9.0 Hz), 7.10 (d, 2H, J¼8.0 Hz), 7.10–7.29 (m, 5H), 7.73
(d, 2H, J¼8.0 Hz); 13C NMR (CDCl3) d 172.5, 144.0, 142.9,
138.7, 130.3, 129.0, 127.7, 126.4, 52.4, 51.2, 39.2, 36.2,
35.2, 31.4, 26.0, 22.2. Anal. calcd for C21H27NO4S: C,
64.75; H, 6.99; N, 3.60. Found: C, 64.38; H, 7.15; N, 3.43.
1
1367 cm21; H NMR (CDCl3) d 0.89 (m, 9H), 1.28–1.35
(m, 2H), 1.37–1.43 (m, 2H), 1.45 (s, 9H), 1.57 (b, 2H), 1.72
(m, 1H), 2.30 (dd, 2H, J¼13.9, 38.1 Hz); 13C NMR (CDCl3)
d 172.6, 80.8, 56.1, 43.9, 40.6, 35.3, 28.5, 17.3, 17.2, 15.2.
HRMS calcd for C13H28NO2 (MþH): 230.2120. Found:
230.2118.
Acknowledgments
This work was supported by the National Institutes of
Health (GM 51982).
2.1.26. Methyl (2S,3S )-(1)-2-methyl-3-N-(p-tolylsulfo-
nyl)amino-7-phenylheptanoate (20a). Chromatographic
purification (n-hexane/EtOAc, 9:1) gave 0.22 g (80%) of a
yellow oil: [a]2D0¼þ4.00 (c 2.0, CHCl3); IR (neat) 3289,
2936, 1736, 1453, 1328, 1159, 1091 cm21 1H NMR
;
References
(CDCl3) d 1.06 (d, 3H, J¼7.5 Hz); 1.15 (m, 2H), 1.36–
1.46 (m, 4H), 2.41 (s, 3H), 2.45 (t, 2H, J¼7.5 Hz), 2.66 (m,
1H), 3.41 (m, 1H), 3.64 (s, 3H), 5.20 (d, 1H, J¼9.5 Hz),
7.09 (d, 2H, J¼7.0 Hz), 7.10–7.29 (m, 5H), 7.75 (d, 2H,
J¼7.0 Hz), 13C NMR (CDCl3) d 175.9, 143.8, 139.3, 130.2,
129.0, 128.9, 127.6, 126.4, 56.6, 52.5, 42.9, 36.2, 34.3, 31.5,
26.1, 22.2, 14.8. Anal. calcd for C22H29NO4S: C, 65.48; H,
7.24; N, 3.47. Found: C, 65.01; H, 7.60; N, 3.27.
1. For reviews and leading references see (a) Drey, C. N. C. In
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2.1.27. Minor isomer: methyl (2R,3S)-(2)-2-methyl-3-N-
( p-tolylsulfonyl)amino-7-phenylheptanoate acid (21a).
Chromatographic purification (n-hexane/EtOAc, 9:1) gave
0.04 g (15%) of an oil: [a]2D0¼216.6 (c 3.65, CHCl3); IR
(neat) 3263, 2937, 1767, 1471, 1329, 1158, 1091 cm21; 1H
NMR (CDCl3) d 1.06 (d, 3H, J¼7.5 Hz), 1.06–1.48 (m,
6H), 2.42 (s, 3H), 2.47 (m, 2H), 2.52 (m, 1H), 3.38 (m, 1H),
3.61 (s, 3H), 4.92 (d, 1H, J¼9.7 Hz), 7.10 (d, 2H, J¼
8.5 Hz), 7.11–7.73 (m, 5H), 7.76 (d, 2H, J¼8.5 Hz); 13C
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New York, 1983; Vol. 7, p 331 and references cited therein.

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