β3-Amino acids by nucleophilic ring-opening of N-nosyl aziridines

Article abstract of DOI:10.1016/S0040-4020(01)00731-1

N-Nosyl aziridines can be easily prepared from 1,2-amino alcohols derived from α-amino acids. Nucleophilic ring-opening of N-nosyl aziridines with cyanide ions followed by hydrolysis of the corresponding nitriles lead to N-nosyl β³-amino acids, which can be readily converted into a variety of derivatives bearing adequate functionality for peptide synthesis. The proposed methodology is simple, efficient, and amenable to large-scale preparations.

Full text of DOI:10.1016/S0040-4020(01)00731-1

TETRAHEDRON
Pergamon
Tetrahedron 57 @2001) 7665±7674
b3-Amino acids by nucleophilic ring-opening of N-nosyl aziridines
p
p
Á
Jaume Farras, Xavier Ginesta, Peter W. Sutton, Joan Taltavull, Frank Egeler, Pedro Romea,
Âp
Á
Felix Urpõ and Jaume Vilarrasa
 Á
Departament de Quõmica Organica, Universitat de Barcelona, Marti i Franques 1-11, 08028 Barcelona, Catalonia, Spain
Received 12 March 2001; revised 15 May 2001; accepted 12 July 2001
AbstractÐN-Nosyl aziridines can be easily prepared from 1,2-amino alcohols derived from a-amino acids. Nucleophilic ring-opening of
N-nosyl aziridines with cyanide ions followed by hydrolysis of the corresponding nitriles lead to N-nosyl b3-amino acids, which can be
readily converted into a variety of derivatives bearing adequate functionality for peptide synthesis. The proposed methodology is simple,
ef®cient, and amenable to large-scale preparations. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
It is well known that although ring strain renders aziridines
susceptible to ring-opening reactions, extremely strong
nucleophiles or acid catalysis are required in the case of
non-activated aziridines @XˆH, alkyl, or aryl in Scheme
1). Therefore, it becomes imperative to introduce sub-
stituents which can stabilize the negative charge on the
nitrogen atom @XˆCOR, CO2R, SO2R) to increase the
reactivity of aziridine rings towards nucleophiles.11
Despite being less abundant than their a analogues,
b-amino acids are present in nature as components of a
vast array of metabolites1 and have been considered pre-
cursors of b-lactam antibiotics.2 They are also building
blocks of b-peptides, which have recently attracted much
attention owing to their ability to fold into de®ned three-
dimensional structures.3,4 Thus, it is not surprising that
development of new synthetic pathways to gain access to
enantiomerically pure b-amino acids is nowadays an area of
active research.5±7 In this context, we have recently
disclosed a synthesis of a N,N-disubstituted cyclo-b3-tetra-
peptide derived from b-homophenylalanine which has been
identi®ed as a potential molecular scaffold suitable for
combinatorial chemistry8 and, therefore, it was crucial to
be provided with a large supply of the aforementioned
b3-amino acid.9 Taking into account that homologation of
the parent a-amino acids is one of the most powerful
strategies for this purpose,5,6 we envisioned that the use
of N-@p-nitrobenzenesulfonyl)aziridines, readily available
from a-amino acids, might constitute a convenient approach
to the synthesis of b3-amino acids and their N-alkyl
derivatives, assuming that the strong electron-withdrawing
p-nitrobenzenesulfonyl group @Ns, nosyl) should facilitate
@i) the nucleophilic ring-opening of the aziridine, @ii) the
subsequent N-alkylation reaction, and @iii) its ®nal removal.
According to these ideas, we herein disclose a convenient
and highly ef®cient methodology to transform a-amino
acids into their b3-counterparts using N-nosyl aziridines as
key intermediates.8,10 Such a strategy allows access to
N-alkyl and/or N-protected b3-amino acids in a straight-
forward manner.
The p-toluenesulfonyl group @XˆTs) is probably the proto-
type of this kind of substituent and several strategies for the
preparation of enantiomerically pure N-@p-toluenesulfonyl)-
aziridines have been already reported.12 Unfortunately, later
removal of the tosyl group is often troublesome and requires
long reaction times and the use of harsh reductive con-
ditions.13 Therefore, other more easily removable sulfon-
amido groups, like the strong electron-withdrawing nosyl
group, may be considered as synthetic equivalents of the
tosyl group and preferred for its easier manipulation in the
deprotection step.14 We have found that such N-nosyl aziri-
dines can be easily prepared in one-pot procedure using
1,2-amino alcohols as starting materials which, in turn, are
commercially available or readily accessible from natural
a-amino acids in enantiomerically pure form.15 Subsequent
nucleophilic ring-opening of these aziridines with cyanide
ions, followed by hydrolysis of the intermediate nitriles,
lead to the target N-nosyl b3-amino acids in good yields
@see Scheme 2 and Table 1).
As shown in Scheme 2, a variety of N-nosyl b3-amino acids
were prepared from 1,2-amino alcohols 1 according to this
Keywords: amino acids and derivatives; aziridines; homologation; sulfon-
amides.
p
Corresponding authors. Tel.: 134-93-402-1248; fax: 134-93-339-7878;
e-mail: jfarras@qo.ub.es; promea@qo.ub.es; furpi@qo.ub.es
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020@01)00731-1

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J. Farras et al. / Tetrahedron 57 /2001) 7665±7674
7666
Scheme 2. @a) NsCl, CH2Cl2/pyridine, 2±4 h, then 2 M KOH; @b) NaCN, CH3CN/H2O, 24 h; @c) conc. HCl/HOAc, re¯ux, 4 h.
which gave a complex mixture probably as a consequence
of the additional activation introduced by the phenyl group.
Table 1. Preparation of N-nosyl b3-amino acids from 1,2-amino alcohols
R
Amino alcohol
Amino acid
Yielda @%)
Hydrolysis of the N-nosyl b-amino nitriles proved to be
strongly dependent on their structure. For instance, heating
of 3b and 3e in conc. HCl at re¯ux for 15 h gave on cooling
the corresponding N-nosyl b3-amino acids 4b and 4e as
highly pure crystalline products in 92 and 86% yields,
respectively. This procedure, however, was not general
because in the other cases the hydrolysis was partial and
signi®cant amounts of intermediate amides and other by-
products were generated, or the ®nal acids did not precipi-
tate on cooling. Fortunately, when the hydrolysis was
performed in a re¯uxing mixture of conc. HCl and HOAc,
N-nosyl b3-amino acids 4a±e were obtained in excellent
yields after puri®cation through a short silica gel column.
Overall yields for the transformation of 1,2-amino alcohols
into N-nosyl b3-amino acids are summarized in Table 1.
1
2
3
4
5
Me
Bn
1a
1b
1c
1d
1e
4a
4b
4c
4d
4e
75
65
60
60
60
iBu
iPr
t-Bu
a
Overall yield of pure 4 from 1.
strategy. Preparation of aziridines 2 was initially trouble-
some because reaction of 1 with 2.2 equiv. of p-nitro-
phenylsulfonyl chloride @NsCl) in pyridine was not
complete, even at 1008C; longer reaction times led to
undesirable decompositions and all our attempts to isolate
the corresponding dinosylated amino alcohols resulted in
low yields. Finally, reaction of 1 with an excess of NsCl
@3 equiv.) in CH2Cl2/pyridine at rt for 2±4 h, followed by
treatment with aqueous 2 M KOH smoothly afforded 2. This
experimental procedure is highly appealing because the
reaction can be run in one-pot at multi-gram scale and
gives in excellent yields @.90%) the corresponding
N-nosyl aziridines, which can be used in the next step
without further puri®cation.
Once we had a general, ef®cient and easily amenable to a
large scale @5±50 mmol) methodology available for the
homologation of natural a-amino acids to N-nosyl
b3-amino acids 4, we turned our attention to their trans-
formation into the corresponding Boc, Fmoc, and
Cbz-derivatives that incorporate the usual protecting groups
required for peptide synthesis. Taking into account that
these groups can be removed under various conditions,13b,c
we envisioned that protection of the carboxylic group as an
allylic ester would constitute a general approach appropriate
for our purposes.17 On the other hand, although removal of
the nosyl group may be carried out with either thiophenol or
b-mercaptoethanol, our own experience suggested that the
use of mercaptoacetic acid would be more convenient
because the thioether formed as co-product can be easily
removed by just washing the reaction mixture with a
saturated aqueous solution of NaHCO3.8,14 In order to test
Having in hand the desired N-nosyl aziridines we next
evaluated their nucleophilic ring-opening process promoted
by cyanide ions. After a careful optimization, it was found
that simple stirring of a mixture of crude N-nosyl aziridines
2 and NaCN in CH3CN/H2O16 afforded in high yields
@70±88% from 1) the desired N-nosyl b-amino nitriles 3
that, once again, could be used in the next step without
further puri®cation. According to NMR spectra of 3, the
aforementioned conditions produced a regioselective ring-
opening of the heterocycle except for phenyl aziridine 2f,
Scheme 3. @a) Allyl bromide, K2CO3, DMF, 17 h, then HSCH2CO2H, DBU, 5 h; @b) Boc2O, Na2CO3, H2O/dioxan, 08C±rt, 16 h; @c) FmocCl, Na2CO3, H2O/
dioxan, 08C±rt, 23 h; @d) BnOCOCl, Na2CO3, H2O/dioxan, 08C±rt, 17 h; @e) 1 M LiOH, MeOH, 17 h; @f) Bu3SnH, Pd@PPh3)4, CH2Cl2, 10 min.

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J. Farras et al. / Tetrahedron 57 /2001) 7665±7674
7667
Scheme 4. @a) Allyl bromide, K2CO3, DMF, 18 h; @b) MeI, K2CO3, DMF, 17 h; @c) BuI, K2CO3, DMF, 19 h; @d) HSCH2CO2H, DBU, DMF, 17 h.
the aforementioned hypotheses, b3-amino acid 4b was
chosen as a model and we focused our initial efforts on
the preparation of the derivatives 9±11 shown in Scheme
3. As expected, one-pot reaction of 4b with allyl bromide
and K2CO3, followed by treatment with mercaptoacetic acid
and DBU, in non-dried DMF furnished the key amino ester
5 in 66% yield. Reaction of 5 with Boc2O, FmocCl, and
BnOCOCl led almost quantitatively to the corresponding
derivatives 6±8. Finally, removal of the allyl group using
LiOH/MeOH or Bu3SnH/Pd@PPh3)4 provided 9±11 in 99,
58, and 84% yields, respectively.
4b was chosen as a model and converted to the key allylic
ester 12 @see Scheme 4). As expected, reaction of 12 with
either MeI or BuI smoothly furnished the alkylated deriva-
tives 13 and 14 in almost quantitative yields. Finally,
cleavage of nosyl group with mercaptoacetic acid and
DBU afforded the corresponding N-alkyl b3-amino esters
15 and 16 in good yields.
This approach has been fully exploited for the preparation of
building block 17 which is useful for the solid phase syn-
thesis of the previously reported scaffold 18 @see Scheme 5)
to be used in combinatorial chemistry.8
Once established how to ef®ciently obtain N-protected
b3-amino acids we faced the preparation of their N-alkyl-
ated derivatives. These substrates are interesting because
substitution on the nitrogen atom may play an important
role in the conformational behavior of b-peptides.18
Unfortunately, according to our experience, N-alkylation
of Boc-b3-amino esters is often troublesome and a careful
selection of the conditions is necessary to reach good yields.
In this context, the stability of the nosyl group to both acid
and basic media, as well as the activation that it introduces
into the NH moiety, suggested that a strategy based on the
use of N-nosyl b3-amino acids could be more appro-
priate.19,20 In order to verify such hypotheses, amino acid
In this case, the protection of the carboxyl function, the
N-alkylation and the removal of the nosyl group were
carried out in one-pot procedure, to furnish 19 in 80%
yield @see Scheme 6). Finally, the protection of the amino
group @98% yield) and the selective cleavage of the COO-
Allyl group afforded the desired Fmoc b3-amino acid 17 in
54% yield after recrystallization.
In summary, the methodology described in this paper
provides a simple, ef®cient, and practical procedure for
the homologation of natural a-amino acids to N-nosyl
b3-amino acids easily amenable to large-scale preparations.
Scheme 5.
Scheme 6. @a) Allyl bromide, K2CO3, DMF, 13 h, then HSCH2CO2H, DBU, 2.5 h; @b) FmocCl, Na2CO3, H2O/dioxan, 08C±rt, 24 h; @c) Bu3SnH, Pd@PPh3)4,
CH2Cl2, 2.5 h.

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J. Farras et al. / Tetrahedron 57 /2001) 7665±7674
7668
The stability of the nosyl group towards acids and bases, the
activation that it introduces into the NH moiety, and the
availability of smooth deprotection procedures confer to
such N-nosyl amino acids a great synthetic utility. N-alkyl-
ation and transformation of N-nosyl b3-amino acids into a
variety of derivatives bearing the adequate functionality for
peptide synthesis illustrate their potentiality.
NaCN @1.47 g, 30 mmol, 1.5 equiv.) was added in one
portion to a suspension of crude aziridines 2 in 4:1
CH3CN/H2O @100 mL) and the resulting mixture stirred
vigorously at room temperature for 24 h. The ®nal solution
was partitioned in CH2Cl2 @250 mL) and a saturated aqueous
solution of NH4Cl @250 mL). The aqueous layer was further
extracted with CH2Cl2 @3£50 mL), the organic portions
were combined, dried @Na2SO4) and the solvent removed
to afford the crude nitriles 3 as dark brown solids or viscous
oils @3a: 86% from 1; 3b: 88%; 3c: 77%; 3d: 70%; 3e: 70%)
that were used without further puri®cation in the next step.
Analytical samples were puri®ed by ¯ash chromatography
@CH2Cl2/CH3OH 98:2) to afford pure nitriles 3 as solids.
3. Experimental
Melting points were taken on an electrothermal apparatus
and have not been corrected. Speci®c rotations were deter-
mined at 208C on a Perkin±Elmer 241 MC polarimeter. IR
spectra were recorded on either a Perkin±Elmer 681 or a
Nicolet 510 FT spectrometer and only the more repre-
Crude nitriles 3 in 4:1 conc. HCl/HOAc @200 mL) were
heated at re¯ux for 4 h. After cooling, the solution was
extracted with CH2Cl2 @5£200 mL), dried @Na2SO4) and
the solvent removed. The residue was puri®ed by ¯ash
chromatography @CH2Cl2/CH3OH 95:5) to furnish pure
N-p-nitrobenezenesulfonyl b3-amino acids 4.
1
sentative frequencies @cm21) are reported. H @300 MHz)
and 13C NMR @75.4 MHz) spectra were recorded on a
Varian Unity Plus 300 spectrometer; H NMR @500 MHz)
1
spectra were recorded on a Varian Unity Inova 500 spectro-
meter; chemical shifts @d) are quoted in ppm and referenced
to internal TMS for 1H NMR and CDCl3 @d 77.0) or CD3OD
@d 49.0) for 13C NMR; data are reported as follows: s,
singlet; d, doublet; t, triplet; q, quartet; hep, heptuplet; m,
multiplet; br, broad; where appropriate, 2D techniques were
also used to assist in structure elucidation. High-resolution
mass spectra @HRMS) were obtained from the Centro
de Apoio Cienti®co Tecnoloxico a Investigacion @C.A.C.
T.I.), Universidad de Vigo. Elemental analyses were
3.1.1. )S)-N-p-Nitrobenzenesulfonyl-2-methylaziridine
)2a). White solid; Rfˆ0.50 @CH2Cl2); mp 86±888C; [a]Dˆ
124.5 @cˆ1.0 in CHCl3); IR @KBr): n 3105, 2975, 2935,
1
1609, 1532, 1355, 1331, 1304, 1156; H NMR @CDCl3,
300 MHz) d 8.40 @2H, d, Jˆ9.0 Hz, ArH), 8.16 @2H, d,
Jˆ9.0 Hz, ArH), 3.05±2.90 @1H, m, NCH), 2.74 @1H, d,
Jˆ7.0 Hz, NCHaHb), 2.13 @1H, d, Jˆ4.9 Hz, NCHaHb),
1.31 @3H, d, Jˆ5.6 Hz, CH3); 13C NMR @CDCl3,
75.4 MHz) d 150.6, 144.3, 129.1, 124.3, 36.8, 35.5, 16.8;
HRMS @FAB): calcd for [M1H]1 C9H11N2O4S: 243.0440;
found: 243.0442.
Á
obtained by the Servei de Microanalisi @CID-CSIC,
Barcelona). Flash chromatography was performed on SDS
silica gel @35±70 mm). Analytical thin-layer chroma-
tography was carried out on Merck Kieselgel 60 F254 plates.
The following solvents and reagents were puri®ed and dried
according to standard procedures: CH2Cl2, DMF, and
pyridine. All other reagents were used as received. The
following compounds have been reported previously:
@S)-N-p-nitrobenzenesulfonyl-2-benzylaziridine @2b) and
@S)-3-[p-nitrobenzenesulfonyl]amino-4-phenylbutanoic acid
@4b).8
3.1.2. )S)-N-p-Nitrobenzenesulfonyl-2-isobutylaziridine
)2c). White solid; Rfˆ0.50 @CH2Cl2); mp 35±378C; [a]Dˆ
19.3 @cˆ1.0 in CHCl3); IR @KBr): n 3100, 2980, 2880,
1
1610, 1530, 1360, 1340, 1310, 1165; H NMR @CDCl3,
300 MHz) d 8.39 @2H, d, Jˆ9.1 Hz, ArH), 8.16 @2H, d,
Jˆ9.1 Hz, ArH), 3.00±2.90 @1H, m, NCH), 2.74 @1H, d,
Jˆ7.2 Hz, NCHaHb), 2.12 @1H, d, Jˆ4.7 Hz, NCHaHb),
1.75±1.55 @1H, m, CH@CH3)2), 1.40±1.35 @2H, m,
CH2CH@CH3)2), 0.92 @3H, d, Jˆ6.6 Hz, CH3), 0.91 @3H, d,
Jˆ6.7 Hz, CH3); 13C NMR @CDCl3, 75.4 MHz) d 150.6,
144.2, 129.2, 124.2, 40.3, 40.0, 34.8, 26.8, 22.7, 21.9;
HRMS @FAB): calcd for [M1H]1 C12H17N2O4S:
285.0909; found: 285.0900.
3.1. Preparation of N-p-nitrobenezenesulfonyl b3-amino
acids. General procedure
p-Nitrobenzenesulfonyl chloride @13.3 g, 60 mmol) was
added in one portion to a suspension of amino alcohols 1
@20 mmol) in dry 2:1 CH2Cl2/pyridine @20 mL) at 08C and
the resulting mixture was stirred at room temperature for
2±4 h. It was diluted with CH2Cl2 @300 mL) and washed
with 2 M HCl @3£100 mL), which was subsequently
extracted with CH2Cl2 @50 mL). The organic portions were
combined and carefully shaken @CAUTION: undesirable
emulsions are produced under vigorous shaking) with a
2 M aqueous solution of KOH @6£200 mL) and the aqueous
portions were subsequently extracted with CH2Cl2
@150 mL). The organic portions were combined, dried
@Na2SO4) and the solvent was removed to afford N-@p-nitro-
benzenesulfonyl)aziridines 2 @2a: 98%; 2b: 95%; 2c: 91%;
2d: 91%; 2e: 90%; 2f: 97%) that were used in the next step
without further puri®cation. Analytical samples were puri-
®ed by ¯ash chromatography @CH2Cl2) or recrystallization
@CH2Cl2/hexanes) to afford pure aziridines 2 as white solids.
3.1.3. )S)-N-p-Nitrobenzenesulfonyl-2-isopropylaziridine
)2d). White solid; Rfˆ0.50 @CH2Cl2); mp 73±768C;
[a]Dˆ111.2 @cˆ1.0 in CHCl3); IR @KBr): n 3120, 2980,
1
2890, 1620, 1540, 1360, 1340, 1325, 1175, 950; H NMR
@CDCl3, 300 MHz) d 8.39 @2H, d, Jˆ9.2 Hz, ArH), 8.16
@2H, d, Jˆ9.2 Hz, ArH), 2.75±2.65 @2H, m, NCH and
NCHaHb), 2.22±2.18 @1H, m, NCHaHb), 1.55±1.40 @1H,
m, CH@CH3)2), 0.94 @3H, d, Jˆ6.9 Hz, CH3), 0.84 @3H, d,
Jˆ6.7 Hz, CH3); 13C NMR @CDCl3, 75.4 MHz) d 150.6,
144.1, 129.3, 124.2, 47.0, 33.6, 30.1, 19.5, 19.0; HRMS
@FAB): calcd for [M1H]1 C11H15N2O4S: 271.0753;
found: 271.0762.
3.1.4. )S)-N-p-Nitrobenzenesulfonyl-2-tert-butylaziridine
)2e). White solid; Rfˆ0.55 @CH2Cl2); mp 114±1158C;
[a]Dˆ129.8 @cˆ1.0 in CHCl3); IR @KBr): n 3100, 2980,

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J. Farras et al. / Tetrahedron 57 /2001) 7665±7674
7669
2860, 1605, 1525, 1370, 1345, 1300, 1175; 1H NMR
@CDCl3, 300 MHz) d 8.39 @2H, d, Jˆ9.2 Hz, ArH), 8.17
@2H, d, Jˆ9.2 Hz, ArH), 2.74 @1H, dd, Jˆ7.2, 4.9 Hz,
NCH), 2.63 @1H, dd, Jˆ7.2, 0.5 Hz, NCHaHb), 2.23 @1H,
dd, Jˆ4.9, 0.5 Hz, NCHaHb), 0.83 @9H, s, C@CH3)3); 13C
NMR @CDCl3, 75.4 MHz) d 144.2, 135.5, 129.4, 124.2,
49.7, 31.3, 30.3, 26.2; HRMS @FAB): calcd for [M1H]1
C12H17N2O4S: 285.0909; found: 285.0903.
3.1.9.
)R)-4-Methyl-3-[p-nitrobenzenesulfonyl]amino-
pentanenitrile )3d). Yellowish solid; Rfˆ0.50 @CH2Cl2/
CH3OH 98:2); mp 116±1178C; [a]Dˆ277.6 @cˆ1.0 in
CHCl3); IR @KBr): n 3320, 3120, 2980, 2250, 1610, 1535,
1345, 1340, 1170, 1150; 1H NMR @CDCl3, 300 MHz) d 8.39
@2H, d, Jˆ9.1 Hz, ArH), 8.09 @2H, d, Jˆ9.1 Hz, ArH), 5.13
@1H, br d, Jˆ8.4 Hz, NH), 3.40±3.25 @1H, m, NCH), 2.69
@1H, dd, Jˆ16.9, 5.5 Hz, CHaHbCN), 2.62 @1H, dd, Jˆ16.9,
5.0 Hz, CHaHbCN), 2.00±1.85 @1H, m, CH@CH3)2), 0.88
@3H, d, Jˆ6.7 Hz, CH3), 0.83 @3H, d, Jˆ6.7 Hz, CH3); 13C
NMR @CDCl3, 75.4 MHz) d 150.2, 146.0, 128.3, 124.5,
116.6, 56.3, 31.4, 23.0, 19.1, 18.0; HRMS @FAB): calcd
for [M1H]1 C12H16N3O4S: 298.0862; found: 298.0863.
3.1.5. )S)-N-p-Nitrobenzenesulfonyl-2-phenylaziridine
)2f). White solid; Rfˆ0.50 @CH2Cl2); mp 120±1228C;
[a]Dˆ177.8 @cˆ1.0 in CHCl3); IR @KBr): n 3100, 3030,
1610, 1530, 1520, 1350, 1330, 1310, 1160; 1H NMR
@CDCl3, 300 MHz) d 8.38 @2H, d, Jˆ9.1 Hz, ArH), 8.19
@2H, d, Jˆ9.1 Hz, ArH), 7.40±7.20 @5H, m, ArH), 3.90
@1H, dd, Jˆ7.1, 4.6 Hz, NCH), 3.11 @1H, d, Jˆ7.1 Hz,
NCHaHb), 2.51 @1H, d, Jˆ4.6 Hz, NCHaHb); 13C NMR
@CDCl3, 75.4 MHz) d 150.6, 144.0, 134.1, 129.2, 128.8,
126.4, 124.4, 41.9, 36.6; HRMS @FAB): calcd for
[M1H]1 C14H13N2O4S: 305.0596; found: 305.0594.
3.1.10.
)R)-4,4-Dimethyl-3-[p-nitrobenzenesulfonyl]-
aminopentanenitrile )3e). Yellowish solid; Rfˆ0.55
@CH2Cl2/CH3OH 98:2); mp 137±1388C; [a]Dˆ240.3
@cˆ0.8 in CHCl3); IR @KBr): n 3298, 3110, 2971, 2252,
1610, 1578, 1532, 1351, 1165; 1H NMR @CDCl3,
300 MHz) d 8.38 @2H, d, Jˆ9.1 Hz, ArH), 8.12 @2H, d,
Jˆ9.1 Hz, ArH), 5.30±5.25 @1H, br s, NH), 3.44 @1H, t,
Jˆ5.5 Hz, NCH), 2.64 @1H, dd, Jˆ17.2, 5.5 Hz, CHaHbCN),
2.52 @1H, dd, Jˆ17.2, 5.5 Hz, CHaHbCN), 0.92 @9H, s,
C@CH3)3); 13C NMR @CDCl3, 75.4 MHz) d 150.2, 146.3,
128.4, 124.5, 117,4, 59.2, 35.3, 26.4, 20.7; HRMS @FAB):
calcd for [M1H]1 C13H18N3O4S: 312.1018; found:
312.1011.
3.1.6. )S)-3-[p-Nitrobenzenesulfonyl]aminobutanenitrile
)3a). Yellowish solid; Rfˆ0.40 @CH2Cl2/CH3OH 98:2); mp
155±1578C; [a]Dˆ251.5 @cˆ1.0 in CHCl3); IR @KBr): n
3267, 3110, 2977, 2252, 1609, 1534, 1355, 1312, 1167,
1146; 1H NMR @CDCl3, 300 MHz) d 8.40 @2H, d, Jˆ
9.1 Hz, ArH), 8.09 @2H, d, Jˆ9.1 Hz, ArH), 5.00±4.90
@1H, br s, NH), 3.85±3.70 @1H, m, NCH), 2.68 @1H, dd,
Jˆ16.8, 5.7 Hz, CHaHbCN), 2.57 @1H, dd, Jˆ16.8, 4.4 Hz,
CHaHbCN), 1.30 @3H, d, Jˆ6.7 Hz, CH3); 13C NMR
@CDCl3, 75.4 MHz) d 150.3, 146.1, 128.2, 124.6, 116.1,
46.7, 26.5, 20.7; HRMS @FAB): calcd for [M1H]1
C10H12N3O4S: 270.0549; found: 270.0558.
3.1.11. )S)-3-[N-p-Nitrobenzenesulfonyl]aminobutanoic
acid )4a). White solid; Rfˆ0.30 @CH2Cl2/CH3OH 95:5);
mp 122±1248C; [a]Dˆ27.1 @cˆ1.0 in EtOH); IR @KBr):
n 3400±2900 @br), 3272, 3116, 2950, 1717, 1610, 1528,
1
1348, 1310, 1170; H NMR @CD3OD, 300 MHz) d 8.38
@2H, d, Jˆ9.0 Hz, ArH), 8.08 @2H, d, Jˆ9.0 Hz, ArH),
3.80±3.65 @1H, m, NCH), 2.44 @1H, dd, Jˆ15.7, 6.6 Hz,
CHaHbCO2), 2.33 @1H, dd, Jˆ15.7, 7.0 Hz, CHaHbCO2),
1.11 @3H, d, Jˆ6.9 Hz, CH3); 13C NMR @CD3OD,
75.4 MHz) d 175.0, 152.2, 149.7, 130.2, 126.2, 49.2, 43.6,
22.7; HRMS @FAB): calcd for [M1H]1 C10H13N2O6S:
289.0494; found: 289.0489.
3.1.7.
)S)-3-[p-Nitrobenzenesulfonyl]amino-4-phenyl-
butanenitrile )3b). Yellowish solid; Rfˆ0.50 @CH2Cl2/
CH3OH 98:2); mp 116±1188C; [a]Dˆ266.7 @cˆ1.0 in
CHCl3); IR @KBr): n 3260, 3110, 2980, 2920, 2240, 1605,
1520, 1345, 1315, 1305, 1160; 1H NMR @CDCl3, 300 MHz)
d 8.15 @2H, d, Jˆ9.0 Hz, ArH), 7.71 @2H, d, Jˆ9.0 Hz,
ArH), 7.20±7.10 @3H, m, ArH), 7.00±6.90 @2H, m, ArH),
5.34 @1H, br d, Jˆ7.2 Hz, NH), 3.75±3.65 @1H, m, NCH),
2.96 @1H, dd, Jˆ14.0, 5.6 Hz, CHaHb), 2.86 @1H, dd, Jˆ
16.9, 5.9 Hz, CHxHy), 2.79 @1H, dd, Jˆ14.0, 9.1 Hz,
CHaHb), 2.69 @1H, dd, Jˆ16.9, 4.1 Hz, CHxHy); 13C NMR
@CDCl3, 75.4 MHz) d 149.9, 145.0, 135.0, 129.0, 128.9,
127.9, 127.5, 124.3, 116.5, 52.3, 39.9, 25.4; HRMS
@FAB): calcd for [M1H]1 C16H16N3O4S: 346.0862;
found: 346.0873.
3.1.12. )S)-5-Methyl-3-[p-nitrobenzenesulfonyl]amino-
hexanoic acid )4c). Yellowish oil; Rfˆ0.30 @CH2Cl2/
CH3OH 95:5); [a]Dˆ12.9 @cˆ0.7 in EtOH); IR @®lm): n
3400±2800 @br), 3290, 3110, 2960, 1715, 1610, 1535, 1355,
1
1165; H NMR @CD3OD, 300 MHz) d 8.38 @2H, d, Jˆ
9.1 Hz, ArH), 8.08 @2H, d, Jˆ9.1 Hz, ArH), 3.75±3.65
@1H, m, NCH), 2.32 @2H, d, Jˆ6.6 Hz, CH2CO2),
1.65±1.45 @1H, m, CH@CH3)2), 1.45±1.32 @1H, m,
CHaHbCH@CH3)2), 1.30±1.20 @1H, m, CHaHbCH@CH3)2),
0.83 @3H, d, Jˆ6.6 Hz, CH3), 0.72 @3H, d, Jˆ6.6 Hz,
CH3); 13C NMR @CD3OD, 75.4 MHz) d 174.6, 151.3,
149.1, 129.4, 125.3, 50.8, 45.7, 41.9, 25.6, 23.3, 21.9;
HRMS @FAB): calcd for [M1H]1 C13H19N2O6S:
331.0964; found: 331.0978.
3.1.8.
)S)-5-Methyl-3-[p-nitrobenzenesulfonyl]amino-
hexanenitrile )3c). Yellowish solid; Rfˆ0.45 @CH2Cl2/
CH3OH 98:2); mp 79±828C; [a]Dˆ259.8 @cˆ1.0 in
CHCl3); IR @KBr): n 3204, 2960, 2265, 1609, 1542, 1434,
1349, 1167, 1092; 1H NMR @CDCl3, 300 MHz) d 8.39 @2H,
d, Jˆ9.1 Hz, ArH), 8.10 @2H, d, Jˆ9.1 Hz, ArH), 5.45±4.25
@1H, br s, NH), 3.70±3.55 @1H, m, NCH), 2.75 @1H, dd,
Jˆ16.9, 5.5 Hz, CHaHbCN), 2.54 @1H, dd, Jˆ16.9, 3.8 Hz,
CHaHbCN), 1.60±1.35 @3H, m, CH2CH@CH3)2), 0.84 @3H, d,
Jˆ6.3 Hz, CH3), 0.66 @3H, d, Jˆ6.3 Hz, CH3); 13C NMR
@CDCl3, 75.4 MHz) d 150.2, 146.1, 128.3, 124.5, 116.5,
48.8, 43.1, 25.6, 24.4, 22.5, 21.4; HRMS @FAB): calcd for
[M1H]1 C13H18N3O4S: 312.1018; found: 312.1009.
3.1.13. )R)-4-Methyl-3-[p-nitrobenzenesulfonyl]amino-
pentanoic acid )4d). White solid; Rfˆ0.30 @CH2Cl2/
CH3OH 95:5); mp 153±1558C; [a]Dˆ144.8 @cˆ1.0 in
EtOH); IR @KBr): n 3400±2900 @br), 3200, 2970, 1725,
1610, 1535, 1350, 1155, 1140; 1H NMR @CD3OD,
300 MHz) d 8.36 @2H, d, Jˆ9.1 Hz, ArH), 8.06 @2H, d,
Jˆ9.1 Hz, ArH), 3.65±3.55 @1H, m, NCH), 2.34 @1H, dd,

Á
J. Farras et al. / Tetrahedron 57 /2001) 7665±7674
7670
1
@®lm): n 3370, 2980, 1710, 1500, 1165; H NMR @CDCl3,
Jˆ15.7, 5.6 Hz, CHaHbCO2), 2.19 @1H, dd, Jˆ15.7, 7.5 Hz,
CHaHbCO2), 1.82 @1H, hepd, Jˆ6.9, 4.9 Hz, CH@CH3)2),
0.87 @3H, d, Jˆ6.9 Hz, CH3), 0.86 @3H, d, Jˆ6.9 Hz,
CH3); 13C NMR @CD3OD, 75.4 MHz) d 174.6, 151.2,
149.2, 129.3, 125.2, 57.8, 37.9, 33.7, 18.9, 18.1; HRMS
@FAB): calcd for [M1H]1 C12H17N2O6S: 317.0807;
found: 317.0805. Anal. Calcd for C12H16N2O6S: C, 45.64;
H, 5.10; N, 8.86. Found: C, 45.64; H, 5.14; N, 8.89.
300 MHz) d 7.34±7.17 @5H, m, ArH), 5.92 @1H, ddt,
Jˆ16.7, 11.3, 5.4 Hz, CH2CHvCH2), 5.40±5.20 @2H, m,
CH2CHvCH2), 5.06 @1H, br d, Jˆ7.2 Hz, NH), 4.62±4.56
@2H, m, CH2CHvCH2), 4.26±4.08 @1H, m, NCH), 2.92
@1H, dd, Jˆ13.2, 6.7 Hz, CHaHbAr), 2.81 @1H, dd, Jˆ
13.2, 7.8 Hz, CHaHbAr), 2.56 @1H, dd, Jˆ15.8, 5.4 Hz,
CHaHbCO), 2.45 @1H, dd, Jˆ15.8, 6.0 Hz, CHaHbCO),
1.40 @9H, s, C@CH3)3); 13C NMR @CDCl3, 75.4 MHz) d
171.2, 155.0, 137.6, 131.8, 129.3, 128.4, 126.4, 118.4,
79.3, 65.2, 48.8, 40.3, 37.6, 28.3; HRMS @FAB): calcd for
[M1H]1 C18H26NO4: 320.1862; found: 320.1867.
3.1.14.
)R)-4,4-Dimethyl-3-[p-nitrobenzenesulfonyl]-
aminopentanoic acid )4e). White solid; Rfˆ0.25
@CH2Cl2/CH3OH 95:5); mp 184±1868C; [a]Dˆ173.0 @cˆ
1.0 in EtOH); IR @KBr): n 3500±2900 @br), 3232, 3110,
2970, 1723, 1607, 1528, 1349, 1335, 1310, 1146, 1074;
1H NMR @CD3OD, 300 MHz) d 8.33 @2H, d, Jˆ9.1 Hz,
ArH), 8.04 @2H, d, Jˆ9.1 Hz, ArH), 3.64 @1H, dd, Jˆ7.8,
4.4 Hz, NCH), 2.49 @1H, dd, Jˆ16.1, 4.4 Hz, CHaHbCO2),
2.05 @1H, dd, Jˆ16.1, 7.8 Hz, CHaHbCO2), 0.92 @9H, s,
C@CH3)3); 13C NMR @CD3OD, 75.4 MHz) d 175.1, 151.2,
149.5, 129.3, 125.1, 61.3, 37.4, 36.1, 26.8; HRMS @FAB):
calcd for [M1H]1 C13H19N2O6S: 331.0964; found:
331.0971. Anal. Calcd for C13H18N2O6S: C, 47.27; H,
5.49; N, 8.48. Found: C, 46.91; H, 5.46; N, 8.25.
3.2.3. )S)-3-tert-Butoxycarbonylamino-4-phenylbutanoic
acid )9). A 1 M aqueous solution of LiOH @30 mL, 30
mmol) was added to a stirred solution of 6 @1.05 g,
3.3 mmol) in CH3OH @50 mL). After 17 h the solution was
concentrated under reduced pressure and the resulting
suspension diluted with EtOAc @100 mL) and washed with
a 0.5 M aqueous solution of citric acid @3£50 mL), which
was subsequently extracted with EtOAc @25 mL). The
organic portions were combined, washed with brine
@50 mL), dried @MgSO4) and the solvent removed to afford
9 @0.91 g, 99%) as a white solid, similar in all respects to a
commercially available sample @Fluka Chimie AG).
3.2. Preparation of N-protected b3-amino acids
3.2.4. Allyl )S)-3-)9H-¯uoren-9-yl)methoxycarbonyl-
amino-4-phenylbutanoate )7). @9H-Fluoren-9-yl)methyl
chloroformate @2.86 g, 11.1 mmol) was added in small
portions to a suspension of 5 @2.02 g, 9.2 mmol) and
Na2CO3 @2.44 g, 23.1 mmol) in 2:1 H2O/dioxan @30 mL)
at 08C and the resulting mixture was stirred at room
temperature for 23 h. The mixture was diluted with
EtOAc @200 mL), washed with a 0.5 M aqueous solution
of citric acid @3£50 mL) and brine @50 mL), dried
@MgSO4) and the solvent removed to afford 7 @3.91 g,
96%) as a creamy solid: Rfˆ0.45 @hexanes/EtOAc 3:1);
mp 114±1158C; [a]Dˆ212.7 @cˆ1.1 in CHCl3); IR
3.2.1. Allyl )S)-3-amino-4-phenylbutanoate )5). Anhydrous
K2CO3 @0.77 g, 5.6 mmol) was added in one portion to a
stirred solution of 4b @2.03 g, 5.6 mmol) and allyl bromide
@0.48 mL, 5.5 mmol) in non-dried DMF @20 mL) at room
temperature. After 17 h mercaptoacetic acid @0.93 mL,
13.4 mmol) was added followed by DBU @8.30 mL,
55.6 mmol) and the mixture stirred for a further 5 h. The
resulting suspension was diluted with EtOAc @50 mL),
washed with a saturated aqueous solution of NaHCO3
@3£50 mL), dried @MgSO4) and the solvent removed to
afford 5 @0.81 g, 66%) as an orange oil: Rfˆ0.42 @CH2Cl2/
MeOH 10:1); [a]Dˆ10.2 @cˆ1.1 in CHCl3); IR @®lm): n
3340, 2900, 1720, 1450, 1140; 1H NMR @CDCl3, 500 MHz)
d 7.29±7.24 @2H, m, ArH), 7.21±7.16 @3H, m, ArH), 5.88
@1H, ddt, Jˆ17.0, 10.5, 5.5 Hz, CH2CHvCH2), 5.29 @1H,
ddd, Jˆ17.0, 3.0, 1.5 Hz, CH2CHvCHaHb), 5.20 @1H, ddd,
Jˆ10.5, 2.5, 1.5 Hz, CH2CHvCHaHb), 4.57±4.54 @2H, m,
CH2CHvCH2), 3.49±3.43 @1H, m, NCH), 2.74 @1H, dd,
Jˆ13.5, 5.5 Hz, CHaHbAr), 2.59 @1H, dd, Jˆ13.5, 8.0 Hz,
CHaHbAr), 2.50 @1H, dd, Jˆ16.0, 4.0 Hz, CHaHbCO), 2.33
@1H, dd, Jˆ16.0, 9.0 Hz, CHaHbCO); 13C NMR @CDCl3,
75.4 MHz) d 171.9, 138.4, 132.0, 129.2, 128.5, 126.5,
118.3, 65.1, 49.6, 43.9, 41.8; HRMS @FAB): calcd for
[M1H]1 C13H18NO2: 220.1337; found: 220.1335.
1
@KBr): n 3300, 3040, 2920, 1710, 1440, 1230; H NMR
@CDCl3, 300 MHz) d 7.80±7.72 @2H, m, ArH), 7.74±7.50
@2H, m, ArH), 7.44±7.10 @9H, m, ArH), 5.90 @1H, ddt,
Jˆ17.1, 10.5, 5.7 Hz, CH2CHvCH2), 5.36±5.20 @3H, m,
CH2CHvCH2 and NH), 4.60±4.57 @2H, m, CH2CHvCH2),
4.46±4.00 @4H, m, CHN and CHCH2O), 3.00±2.75 @2H, m,
CH2Ar), 2.60±2.40 @2H, m, CH2CO); 13C NMR @CDCl3,
75.4 MHz) d 171.1, 155.6, 143.9, 141.3, 137.4, 131.8,
129.3, 128.6, 127.3, 127.0, 126.7, 125.0, 120.0, 118.6,
66.6, 65.3, 49.3, 47.2, 40.2, 37.5; HRMS @FAB): calcd for
[M1H]1 C28H28NO4: 442.2018; found: 442.1997.
3.2.5. )S)-3-)9H-Fluoren-9-yl)methoxycarbonylamino-4-
phenylbutanoic acid )10). To a stirred solution of 7
@3.87 g, 8.8 mmol) in dry CH2Cl2 @60 mL) was added
Pd@PPh3)4 @100 mg, 87 mmol) quickly followed by
Bu3SnH @3.50 mL, 13.0 mmol) and the resulting mixture
stirred under N2 for 10 min. The solution was washed with
2 M HCl @2£30 mL) and brine @30 mL), dried @MgSO4) and
the solvent removed. The residue was dissolved in CH3CN
@150 mL), washed with hexanes @3£150 mL), the solvent
removed and the resulting solid recrystallized from CCl4
to afford 10 @2.03 g, 58%) as a white solid, similar in all
respects to a commercially available sample @Fluka Chimie
AG).
3.2.2. Allyl )S)-3-tert-butoxycarbonylamino-4-phenyl-
butanoate )6). Boc2O @0.96 g, 4.4 mmol) was added in
small portions to a suspension of 5 @0.74 g, 3.4 mmol) and
Na2CO3 @0.90 g, 8.5 mmol) in 2:1 H2O/dioxan @15 mL) at
08C and the resulting mixture was stirred at room tempera-
ture for 16 h. The mixture was diluted with EtOAc @50 mL)
and washed with a 0.5 M aqueous solution of citric acid
@3£50 mL), which was subsequently extracted with
EtOAc @25 mL). The organic portions were combined,
washed with brine @50 mL), dried @MgSO4) and the solvent
removed to afford 6 @1.01 g, 94%) as a yellow oil: Rfˆ0.68
@hexanes/EtOAc 3:1); [a]Dˆ28.7 @cˆ1.1 in CHCl3); IR

Á
J. Farras et al. / Tetrahedron 57 /2001) 7665±7674
7671
3.2.6. Allyl )S)-3-benzyloxycarbonylamino-4-phenyl-
butanoate )8). Benzyl chloroformate @0.70 mL, 5.0 mmol)
was added dropwise to a suspension of 5 @0.91 g, 4.1 mmol)
and Na2CO3 @1.11 g, 10.4 mmol) in 2:1 H2O/dioxan
@15 mL) at 08C and the resulting mixture was stirred at
room temperature for 17 h. The mixture was diluted with
EtOAc @50 mL), washed with a 0.5 M aqueous solution of
citric acid @3£50 mL) and brine @50 mL), dried @MgSO4)
and the solvent removed to afford 8 @1.44 g, 98%) as a
yellow oil: Rfˆ0.55 @hexanes/EtOAc 3:1); [a]Dˆ212.8
@cˆ1.0 in CHCl3); IR @®lm): n 3320, 3000, 1710, 1505,
d, Jˆ5.5 Hz, CH2); 13C NMR @CDCl3, 75.4 MHz) d 170.8,
149.6, 145.9, 136.6, 131.5, 129.1, 128.6, 127.9, 126.9,
124.0, 118.9, 65.5, 52.8, 40.7, 39.1; HRMS @FAB): calcd
for [M1H]1 C19H21N2O6S: 405.1120; found: 405.1102.
3.3.2. Allyl )S)-3-[N-methyl-N-p-nitrobenzenesulfonyl]-
amino-4-phenylbutanoate )13). Anhydrous K2CO3
@552 mg, 4.0 mmol) was added in one portion to a solution
of crude 12 @404 mg, 1.0 mmol) and MeI @0.25 mL,
4.0 mmol) in dry DMF @5 mL) at room temperature. The
resulting mixture was stirred at room temperature under
N2 for 17 h. Removal of the volatiles afforded a brown
solid that was diluted with EtOAc @40 mL), washed with a
0.75 M aqueous solution of citric acid @2£40 mL), and brine
@40 mL) and dried @MgSO4). The solvent was removed to
afford 13 @402 mg, 95%) as a dark oil that was used in the
next step without further puri®cation. An analytical sample
was puri®ed by ¯ash chromatography @CH2Cl2) to afford
pure 13 as a white solid; Rfˆ0.50 @CH2Cl2); mp 112±
1148C; [a]Dˆ212.5 @cˆ0.8 in CHCl3); IR @KBr): n 3040,
1
1240; H NMR @CDCl3, 300 MHz) d 7.36±7.12 @10H, m,
ArH), 5.88 @1H, ddt, Jˆ17.2, 10.2, 5.8 Hz, CH2CHvCH2),
5.40±5.18 @3H, m, NH and CH2CHvCH2), 5.06 @2H, s,
OCH2Ar), 4.60±4.50 @2H, m, CH2CHvCH2), 4.32±4.14
@1H, m, NCH), 2.90 @1H, dd, Jˆ13.4, 6.6 Hz, CHaHbAr),
2.82 @1H, dd, Jˆ13.4, 7.4 Hz, CHaHbAr), 2.56 @1H, dd,
Jˆ16.2, 5.4 Hz, CHaHbCO), 2.47 @1H, dd, Jˆ16.2, 5.4 Hz,
CHaHbCO); 13 C NMR @CDCl3, 75.4 MHz) d 170.9, 155.4,
137.3, 136.3, 131.7, 129.1, 128.3, 128.2, 127.8, 127.7,
124.4, 118.4, 66.4, 65.1, 49.3, 40.1, 37.5; HRMS @FAB):
calcd for [M1H]1 C21H23NO4: 354.1705; found: 354.1717.
1
2980, 1740, 1610, 1525, 1340, 1170; H NMR @CDCl3,
500 MHz) d 8.12 @2H, d, Jˆ9.0 Hz, ArH), 7.62 @2H, d,
Jˆ9.0 Hz, ArH), 7.25±7.15 @3H, m, ArH), 7.10±7.00
@2H, m, ArH), 5.88 @1H, ddt, Jˆ17.2, 10.4, 5.9 Hz,
CH2CHvCH2), 5.30 @1H, dq, Jˆ17.2, 1.5 Hz,
CH2CHvCHaHb), 5.25±5.20 @1H, m, CH2CHvCHaHb),
4.75±4.65 @1H, m, NCH), 4.51 @2H, ddd, Jˆ5.9, 2.8,
1.5 Hz, CH2CHvCH2), 2.85 @3H, s, NCH3), 2.84 @1H, dd,
Jˆ13.9, 6.4 Hz, CHxHy), 2.73 @1H, dd, Jˆ13.9, 8.8 Hz,
CHxHy), 2.65±2.55 @2H, m, CH2); 13C NMR @CDCl3,
75.4 MHz) d 170.0, 149.6, 145.4, 137.1, 131.7, 129.0,
128.7, 128.2, 127.0, 124.0, 118.8, 65.7, 56.8, 38.9, 37.9,
28.8; HRMS @FAB): calcd for [M1H]1 C20H23N2O6S:
419.1277; found: 419.1292.
3.2.7. )S)-3-Benzyloxycarbonylamino-4-phenylbutanoic
acid )11). A 1 M aqueous solution of LiOH @20 mL,
20 mmol) was added to a stirred solution of 8 @778 mg,
2.20 mmol) in CH3OH @20 mL). After 17 h the solution
was concentrated under reduced pressure and the resulting
suspension diluted with EtOAc @50 mL) and washed with a
0.5 M aqueous solution of citric acid @3£50 mL), which was
subsequently extracted with EtOAc @25 mL). The organic
portions were combined, washed with brine @50 mL), dried
@MgSO4) and the solvent removed. The residue was puri®ed
by recrystallization from CCl4/hexanes to afford 11
@580 mg, 84%) as a white solid, similar in all respects to a
commercially available sample @Fluka Chimie AG).
3.3.3. Allyl )S)-3-methylamino-4-phenylbutanoate )15).
Mercaptoacetic acid @114 mL, 1.6 mmol) and DBU
@750 mL, 5.0 mmol) were added to a solution of crude 13
@210 mg, 0.5 mmol) in non-dried DMF @5 mL) under N2 at
room temperature. The resulting mixture was stirred for
19 h, concentrated under reduced pressure and diluted
with EtOAc @30 mL), which was washed with a saturated
solution of NaHCO3 @2£30 mL), and brine @30 mL) and
dried @MgSO4). The solvent was removed to afford a
brown solid that was puri®ed by ¯ash chromatography
@hexanes/EtOAc 1:1) to give 15 @71 mg, 60%) as a yellow
oil; Rfˆ0.45 @hexanes/EtOAc 1:1); [a]Dˆ18.1 @cˆ1.3 in
3.3. Preparation of N-alkylated derivatives
3.3.1. Allyl )S)-3-[p-nitrobenzenesulfonyl]amino-4-
phenylbutanoate )12). Anhydrous K2CO3 @456 mg,
3.3 mmol) was added in one portion to a solution of 4b
@1.092 g, 3.0 mmol) and allyl bromide @0.31 mL,
3.6 mmol) in dry DMF @20 mL) at room temperature. The
resulting mixture was stirred at room temperature under N2
for 18 h. Removal of the volatiles afforded a brown solid
that was diluted with EtOAc @50 mL), washed with a 0.75 M
aqueous solution of citric acid @2£50 mL) and brine
@50 mL), and dried @MgSO4). The solvent was removed to
afford 12 @1.123 g, 93%) as a brown solid that was used in
the next step without further puri®cation. An analytical
sample was puri®ed by ¯ash chromatography @hexanes/
EtOAc 1:1) to afford pure 12 as a yellowish solid: Rfˆ
0.52 @hexanes/EtOAc 1:1); mp 87±908C; [a]Dˆ249.4
@cˆ1.0 in CHCl3); IR @KBr): n 3320, 3270, 3100, 2970,
1735, 1725, 1610, 1525, 1350, 1310, 1160; 1H NMR
@CDCl3, 300 MHz) d 8.13 @2H, d, Jˆ9.0 Hz, ArH), 7.76
@2H, d, Jˆ9.0 Hz, ArH), 7.17±7.08 @3H, m, ArH), 7.00±
6.95 @2H, m, ArH), 5.89 @1H, ddt, Jˆ17.2, 10.4, 5.8 Hz,
CH2CHvCH2), 5.60 @1H, d, Jˆ8.7 Hz, NH), 5.35±5.23
@2H, m, CH2CHvCH2), 4.65±4.50 @2H, m, CH2CHvCH2),
3.90±3.75 @1H, m, NCH), 2.85 @1H, dd, Jˆ13.8, 6.0 Hz,
CHaHb), 2.75 @1H, dd, Jˆ13.8, 8.3 Hz, CHaHb), 2.66 @2H,
1
CHCl3); IR @®lm): n 3040, 2980, 2970, 1740, 1150; H
NMR @CDCl3, 300 MHz) d 7.35±7.15 @5H, m, ArH), 5.91
@1H, ddt, Jˆ17.2, 10.4, 5.8 Hz, CH2CHvCH2), 5.32 @1H,
dq, Jˆ17.2, 1.5 Hz, CH2CHvCHaHb), 5.25±5.20 @1H, m,
CH2CHvCHaHb), 4.60±4.55 @2H, m, CH2CHvCH2),
3.25±3.10 @1H, m, NCH), 2.84 @1H, dd, Jˆ13.4, 6.6 Hz,
CHaHbAr), 2.73 @1H, dd, Jˆ13.4, 6.9 Hz, CHaHbAr),
2.50±2.35 @2H, m, CH2CO), 2.43 @3H, s, NCH3), 1.70±
1.60 @1H, br s, NH); 13C NMR @CDCl3, 75.4 MHz) d
172.0, 138.5, 132.1, 129.3, 128.5, 126.4, 118.3, 65.1, 57.8,
40.1, 38.2, 33.7; HRMS @FAB): calcd for [M1H]1
C14H20NO2: 234.1494; found: 234.1491.
3.3.4. Allyl )S)-3-[N-butyl-N-p-nitrobenzenesulfonyl]-
amino-4-phenylbutanoate )14). Anhydrous K2CO3 @300
mg, 2.2 mmol) was added in one portion to a solution of

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J. Farras et al. / Tetrahedron 57 /2001) 7665±7674
7672
crude 12 @300 mg, 0.74 mmol) and BuI @0.24 mL,
2.2 mmol) in dry DMF @5 mL) at room temperature. The
resulting mixture was stirred at room temperature under
N2 for 19 h. Removal of the volatiles afforded a brown
solid that was diluted with EtOAc @40 mL), washed with a
0.5 M aqueous solution of citric acid @2£40 mL) and brine
@40 mL) and dried @MgSO4). The solvent was removed to
afford 14 @335 mg, 98%) as a brown oil that was used in the
next step without further puri®cation. An analytical sample
was puri®ed by ¯ash chromatography @CH2Cl2) to afford
pure 14 as a white solid; Rfˆ0.55 @CH2Cl2); mp 53±558C;
[a]Dˆ28.3 @cˆ1.0 in CHCl3); IR @®lm): n 3100, 3030,
2980, 2970, 1740, 1610, 1535, 1350, 1160; 1H NMR
@CDCl3, 500 MHz) d 8.09 @2H, d, Jˆ9.0 Hz, ArH), 7.73
@2H, d, Jˆ9.0 Hz, ArH), 7.15±7.10 @3H, m, ArH), 7.05±
7.00 @2H, m, ArH), 5.75 @1H, ddt, Jˆ17.0, 10.5,
6.0 Hz, CH2CHvCH2), 5.20 @1H, dq, Jˆ17.0, 1.5 Hz,
CH2CHvCHaHb), 5.16 @1H, dq, Jˆ10.5, 1.5 Hz,
CH2CHvCHaHb), 4.40±4.30 @3H, m, NCH and
CH2CHvCH2), 3.18 @2H, t, Jˆ8.0 Hz, NCH2), 2.87 @1H,
dd, Jˆ13.8, 7.2 Hz, CHxHy), 2.80 @1H, dd, Jˆ13.8, 7.5 Hz,
CHxHy), 2.67 @1H, dd, Jˆ16.4, 7.0 Hz, CHaHb), 2.54 @1H,
dd, Jˆ16.4, 7.5 Hz, CHaHb), 1.62±1.48 @2H, m, NCH2CH2),
1.30±1.20 @2H, m, NCH2CH2CH2), 0.87 @3H, t, Jˆ7.5 Hz,
CH3); 13C NMR @CDCl3, 75.4 MHz) d 170.3, 149.6, 146.5,
137.3, 131.6, 129.1, 128.6, 128.3, 126.9, 124.0, 118.8, 65.5,
58.0, 45.6, 40.2, 38.6, 32.8, 20.2, 13.7; HRMS @FAB): calcd
for [M1H]1 C23H29N2O6S: 461.1746; found: 461.1753.
@100 mL), washed with a saturated aqueous solution of
NaHCO3 @3£50 mL), dried @MgSO4) and the solvent
removed to afford 19 @2.32 g, 80%) as an orange oil:
Rfˆ0.38 @CH2Cl2/MeOH 10:1); [a]Dˆ21.1 @cˆ1.1 in
CHCl3); IR @®lm): n 3180, 3030, 2900, 1725, 1440, 1135;
1H NMR @CDCl3, 500 MHz) d 7.31±7.26 @2H, m, ArH),
7.23±7.16 @3H, m, ArH), 5.90 @1H, ddt, Jˆ17.5, 10.5,
5.5 Hz, OCH2CHvCH2), 5.82 @1H, ddt, Jˆ17.0, 10.5,
6.0 Hz, NCH2CHvCH2), 5.31 @1H, ddd, Jˆ17.5, 3.0,
1.5 Hz, OCH2CHvCHaHb), 5.23 @1H, ddd, Jˆ10.5, 3.0,
1.5 Hz, OCH2CHvCHaHb), 5.14 @1H, ddd, Jˆ17.0, 3.5,
1.5 Hz, NCH2CHvCHaHb), 5.06 @1H, ddd, Jˆ10.5,
3.0, 1.5 Hz, NCH2CHvCHaHb), 4.58±4.55 @2H, m,
OCH2CHvCH2), 3.32±3.26 @3H, m, NCH and
NCH2CHvCH2), 2.85 @1H, dd, Jˆ13.5, 6.5 Hz, CHaHbAr),
2.72 @1H, dd, Jˆ13.5, 7.5 Hz, CHaHbAr), 2.42 @2H, d,
Jˆ6.5 Hz, CH2CO), 2.10±1.90 @1H, br s, NH); 13C NMR
@CDCl3, 75.4 MHz) d 171.8, 138.4, 136.6, 132.0, 129.3,
128.4, 126.3, 118.2, 115.8, 64.9, 55.3, 49.5, 40.4, 38.6;
HRMS @FAB): calcd for [M1H]1 C16H22NO2: 260.1650;
found: 260.1642.
3.3.7. Allyl )S)-3-[N-allyl-N-)9H-¯uoren-9-yl)methoxy-
carbonyl)]amino-4-phenylbutanoate )20). @9H-Fluoren-
9-yl)methyl chloroformate @2.30 g, 8.9 mmol) was added
in small portions to a suspension of 19 @2.31 g, 8.9 mmol)
and Na2CO3 @2.37 g, 22.4 mmol) in 2:1 H2O/dioxan
@30 mL) at 08C and the resulting mixture was stirred at
room temperature for 24 h. The mixture was diluted with
EtOAc @150 mL), washed with a 0.5 M aqueous solution of
citric acid @2£50 mL) and brine @50 mL), dried @MgSO4)
and the solvent removed to afford 20 @4.19 g, 98%) as a
light orange oil: Rfˆ0.82 @hexanes/EtOAc 1:1); [a]Dˆ
222.0 @cˆ1.0 in CHCl3); IR @®lm): n 3430, 3040, 2920,
3.3.5. Allyl )S)-3-butylamino-4-phenylbutanoate )16).
Mercaptoacetic acid @112 mL, 1.6 mmol) and DBU
@580 mL, 3.8 mmol) were added to a solution of crude 14
@230 mg, 0.5 mmol) in non-dried DMF @5 mL) under N2 at
room temperature. The resulting mixture was stirred for
17 h, concentrated under reduced pressure and diluted
with EtOAc @30 mL), which was washed with a saturated
solution of NaHCO3 @2£30 mL), and brine @30 mL) and
dried @MgSO4). The solvent was removed to afford a
brown oil that was puri®ed by ¯ash chromatography
@hexanes/EtOAc 1:1) to give 16 @96 mg, 70%) as a yellow
oil; Rfˆ0.45 @hexanes/EtOAc 1:1); [a]Dˆ16.4 @cˆ0.75 in
1
1730, 1690, 1440, 1230; H NMR @CDCl3, 300 MHz; 1:1
rotamers ratio, asterisk denotes one of the rotamers) d 7.82±
7.72 @4H, m, ArH), 7.68±7.52 @4H, m, ArH), 7.12±7.44
@16H, m, ArH), 6.82±6.74 @2H, m, ArH), 5.87 @2H,
ddt, Jˆ17.2, 10.3, 5.7 Hz, OCH2CHvCH2 and
p
OCH2CHvCH2p), 5.52±5.34 @2H, m, NCH2CHvCH2 and
NCH2CHvCH2 ), 5.32±5.27 @4H, m, OCH2CHvCH2
1
p
CHCl3); IR @®lm): n 3040, 2980, 2970, 1740, 1150; H
and OCH2CHvCH2 p), 5.26±4.96 @4H, m, NCH2CHvCH2
NMR @CDCl3, 300 MHz) d 7.35±7.15 @5H, m, ArH), 5.91
@1H, ddt, Jˆ17.2, 10.4, 5.8 Hz, CH2CHvCH2), 5.31 @1H,
dq, Jˆ17.2, 1.5 Hz, CH2CHvCHaHb), 5.23 @1H, dq, Jˆ
10.4, 1.4 Hz, CH2CHvCHaHb), 4.65±4.50 @2H, m,
CH2CHvCH2), 3.35±3.20 @1H, m, NCH), 2.83 @1H, dd,
Jˆ13.5, 6.5 Hz, CHaHb), 2.72 @1H, dd, Jˆ13.5, 7.0 Hz,
CHaHb), 2.65±2.55 @2H, m, CH2), 2.45±2.40 @2H, m,
CH2), 1.50±1.20 @5H, m, CH2CH2 and NH), 0.87 @3H, t,
Jˆ7.5 Hz, CH3); 13C NMR @CDCl3, 75.4 MHz) d 172.0,
138.6, 132.1, 129.3, 128.4, 126.3, 118.3, 65.0, 56.3, 46.7,
40.6, 38.7, 32.2, 20.3, 13.9; HRMS @FAB): calcd for
[M1H]1 C17H26NO2: 276.1964; found: 276.1977.
and NCH2CHvCH2 ), 4.76±4.86 @1H, m, CHCHaHbOp),
4.74±4.64 @1H, m, CHCHaHbOp), 4.58±4.38 @6H, m,
CHCH2O, OCH2CHvCH2 and OCH2CHvCH2 ), 4.28±
p
4.21 @2H, m, CHCH2O and CHCH2Op), 4.18±4.10 @1H,
m, CHN), 3.98 @1H, m, CHNp), 3.64±3.54 @4H, m,
NCH2CHvCH2 and NCH2CHvCH2 ), 3.15 @1H, dd,
p
Jˆ13.0, 8.5 Hz, CHaHbAr), 3.02±2.96 @2H, m, CHaHbAr
and CHaHbCO), 2.68 @1H, dd, Jˆ16.5, 6.0 Hz, CHaHbCO),
2.30±2.18 @2H, m, CH2Arp), 2.16±2.04 @1H, m, CHaHbCO),
2.00±1.87 @1H, m, CHaHbCOp); 13C NMR @CDCl3,
75.4 MHz; 1:1 rotamers ratio) d 170.4, 170.1, 155.1,
154.4, 143.2, 140.6, 140.5, 137.4, 137.3, 133.4, 133.2,
131.2, 128.4, 128.3, 127.6, 127.4, 127.0±126.6, 126.3,
126.1, 125.6, 125.5, 124.1, 123.9, 123.6, 120.0±118.0,
117.4, 116.3, 116.0, 66.0, 65.6, 64.2, 56.9, 55.9, 49.8,
46.4, 38.1, 37.8, 36.5; HRMS @FAB): calcd for [M1H]1
C31H32NO4: 482.2331; found: 482.2331.
3.3.6. Allyl )S)-allylamino-4-phenylbutanoate )19).
Anhydrous K2CO3 @3.74 g, 27.0 mmol) was added in one
portion to a stirred solution of 4b @4.09 g, 11.2 mmol) and
allyl bromide @2.40 mL, 27.7 mmol) in non-dried DMF
@40 mL) at room temperature. After 13 h mercaptoacetic
acid @1.9 mL, 27.3 mmol) was added followed by DBU
@16.5 mL, 110.4 mmol) and the mixture stirred for a further
2.5 h. The resulting suspension was diluted with EtOAc
3.3.8. )S)-3-[N-Allyl-N-)9H-¯uoren-9-yl)methoxycarbo-
nyl)]amino-4-phenylbutanoic acid )17). To a solution of
20 @2.13 g, 4.4 mmol) in dry CH2Cl2 @40 mL) was added

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J. Farras et al. / Tetrahedron 57 /2001) 7665±7674
7673
Chem. Res. 1998, 31, 173±180. @c) Seebach, D.; Matthews,
J. L. Chem. Commun. 1997, 2015±2022. @d) Borman, S.
Chem. & Eng. News 1997, 75 @24), 32±35.
Pd@PPh3)4 @95 mg, 84 mmol) quickly followed by Bu3SnH
@1.31 mL, 4.9 mmol) and the resulting mixture stirred under
N2 for 2.5 h. The solution was washed with 2 M HCl
@2£20 mL) which was subsequently extracted with CH2Cl2
@10 mL). The organic portions were combined, dried
@MgSO4) and the solvent removed. The residue was
dissolved in CH3CN @100 mL), washed with hexanes
@3£80 mL), the solvent removed and the resulting solid
recrystallized from CH3CN to afford 17 @1.05 g, 54%) as a
pale yellow solid: Rfˆ0.47 @hexanes/EtOAc 1:1); mp 134±
1368C; [a]Dˆ234.9 @cˆ1.1 in CHCl3); IR @®lm): n 3500±
5. For recent reviews on the stereoselective synthesis of b-amino
acids, see: @a) Abele, S.; Seebach, D. Eur. J. Org. Chem. 2000,
Â
1±15. @b) Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem. 1999,
6, 983±1004.
6. For recent references on homologation of a-amino acids, see:
@a) Ananda, K.; Gopi, H. N.; Suresh Babu, V. V. J. Pept. Res.
2000, 55, 289±294. @b) Guichard, G.; Abele, S.; Seebach, D.
Helv. Chim. Acta 1998, 81, 187±206. @c) Ellmerer-MuÈller,
1
Â
È
E. P.; Brossner, D.; Maslouh, N.; Tako, A. Helv. Chim. Acta
1998, 81, 59±65. @d) MuÈller, A.; Vogt, C.; Sewald, N.
Synthesis 1998, 837±841. @e) Leggio, A.; Liguori, A.;
Procopio, A.; Sindona, G. J. Chem. Soc., Perkin Trans. 1
1997, 1969±1971. @f) Seebach, D.; Overhand, M.; KuÈhnle,
F. N. M.; Martinoni, B.; Oberer, L.; Hommel, U.; Widmer,
H. Helv. Chim. Acta 1996, 79, 913±941. @g) Caputo, R.;
Cassano, E.; Longobardo, L.; Palumbo, G. Tetrahedron
1995, 51, 12337±12350.
2300, 1690, 1435, 1230; H NMR @CDCl3, 500 MHz; 1:1
rotamers ratio, asterisk denotes one of the rotamers) d 7.79±
7.72 @4H, m, ArH), 7.62 @2H, t, Jˆ7.5 Hz, ArH), 7.53 @2H,
d, Jˆ7.0 Hz, ArH), 7.41±7.10 @16H, m, ArH), 6.77±6.70
@2H, m, ArH), 5.50±5.35 @2H, m, CH2CHvCH2 and
p
CH2CHvCH2p), 5.20±4.92 @4H, m, CH2CHvCH2 and
CH2CHvCH2 ), 4.88±4.74 @1H, m, CHaHbOp), 4.71±4.59
@1H, m, CHaHbOp), 4.50 @1H, dd, Jˆ10.5, 7.0 Hz, CHaHbO),
4.40 @1H, dd, Jˆ10.5, 6.5 Hz, CHaHbO), 4.21 @2H, m,
CHCH2O and CHCH2Op), 4.08±4.02 @1H, m, NCH),
3.95±3.65 @1H, m, NCHp), 3.64±3.48 @4H, m,
7. For very recent leading references on stereoselective synthesis
of b3-amino acids, see: @a) Horstmann, T. E.; Guerin, D. J.;
Miller, S. J. Angew. Chem., Int. Ed. Engl. 2000, 39, 3635±
3638. @b) Nelson, S. G.; Spencer, K. L. Angew. Chem., Int. Ed.
Engl. 2000, 39, 1323±1325. @c) Palomo, C.; Oiarbide, M.;
p
CH2CHvCH2 and CH2CHvCH2 ), 3.13±3.08 @1H, dd,
Jˆ13.0, 8.5 Hz, CHaHbAr), 2.95 @1H, dd, Jˆ16.5, 8.0 Hz,
CHaHbCO), 2.90 @1H, dd, Jˆ13.0, 6.5 Hz, CHaHbAr), 2.68
@1H, dd, Jˆ16.5, 5.5 Hz, CHaHbCO), 2.28±2.14 @2H, m,
CH2Arp), 2.10±2.00 @1H, m, CHaHbCOp), 1.95±1.80 @1H,
m, CHaHbCOp); 13C NMR @CDCl3, 75.4 MHz; 1:1 rotamers
ratio) d 176.8, 176.7, 156.1, 155.3, 144.0, 141.4, 138.1,
134.0, 131.8, 131.6, 131.1, 130.9, 130.3, 130.2, 129.9,
129.8, 129.6, 129.1, 129.0, 127.5, 127.0, 122.6, 122.5,
119.9, 119.7, 117.2, 117.1, 66.9, 66.5, 57.7, 56.5, 50.9,
47.3, 39.0, 38.6, 37.1; HRMS @FAB): calcd for [M1H]1
C28H28NO4: 442.2018; found: 442.2034.
Â
Â
Gonzalez-Rego, M. C.; Sharma, A. K.; Garcõa, J. M.;
Â
Gonzalez, A.; Landa, C.; Linden, A. Angew. Chem., Int. Ed.
Engl. 2000, 39, 1063±1065. @d) Sibi, M. P.; Liu, M. Org. Lett.
2000, 2, 3393±3396. @e) Myers, J. K.; Jacobsen, E. N. J. Am.
Chem. Soc. 1999, 121, 8959±8960. @f) Evans, D. A.; Wu,
L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D. H. B.; Tedrow,
J. S. J. Org. Chem. 1999, 64, 6411±6417. @g) Kim, B. J.; Park,
Y. S.; Beak, P. J. Org. Chem. 1999, 64, 1705±1708. @h) Tang,
T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12±13.
Á Â
8. @a) Sutton, P. W.; Bradley, A.; Farras, J.; Romea, P.; Urpõ, F.;
Vilarrasa, J. Tetrahedron 2000, 56, 7947±7958. @b) Sutton,
Á
P. W.; Bradley, A.; Elsegood, M. R. J.; Farras, J.; Jackson,
Acknowledgements
Â
R. F. W.; Romea, P.; Urpõ, F.; Vilarrasa, J. Tetrahedron Lett.
1999, 40, 2629±2632.
We thank the European Union TMR programme for
support @ERBFMRX-CT96-0011) including a postdoctoral
fellowship to P. W. S. @1998±2000). Financial support from
9. We have followed the nomenclature used by Seebach et al. for
b-amino acids. See, e.g. Ref. 4c.
Â
Ministerio de Educacion y Cultura @DGESIC, grant PM98-
1272) and from Direccio General de Recerca, Generalitat de
Catalunya @fellowship to F. E. and grants 1998SGR00040
and 2000SGR00021) is also gratefully acknowledged.
10. For a previous example, see: Maligres, P. E.; See, M. M.;
Askin, D.; Reider, P. J. Tetrahedron Lett. 1997, 38, 5253±
5256.
Â
11. For reviews on reactivity of aziridines, see: @a) McCoull, W.;
Davis, F. A. Synthesis 2000, 1347±1365. @b) Stamm, H.
J. Prakt. Chem. 1999, 341, 319±331. @c) Atkinson, R. S.
Tetrahedron 1999, 55, 1519±1559. @d) Tanner, D. Angew.
Chem., Int. Ed. Engl. 1994, 33, 599±619. For a recent
example, see: @e) Wu, J.; Hou, X.-L.; Dai, L.-X. J. Org.
Chem. 2000, 65, 1344±1348.
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