Asymmetric synthesis of anti-(2S,3S)- and syn-(2R,3S)-diaminobutanoic acid

Article abstract of DOI:10.1039/b306936m

Conjugate addition of homochiral lithium N-benzyl-N-α-methylbenzylamide to tert-butyl (E)-cinnamate or tert-butyl (E)-crotonate and in situ amination with trisyl azide results in the exclusive formation of the corresponding 2-diazo-3-amino esters in >95%

Full text of DOI:10.1039/b306936m

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Asymmetric synthesis of anti-(2S,3S )- and syn-(2R,3S )-
diaminobutanoic acid†
Mark E. Bunnage, Anthony J. Burke, Stephen G. Davies,* Nicholas L. Millican,
Rebecca L. Nicholson, Paul M. Roberts and Andrew D. Smith
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford,
UK OX1 3QY
Received 17th June 2003, Accepted 22nd July 2003
First published as an Advance Article on the web 11th August 2003
Conjugate addition of homochiral lithium N-benzyl-N-α-methylbenzylamide to tert-butyl (E)-cinnamate or
tert-butyl (E)-crotonate and in situ amination with trisyl azide results in the exclusive formation of the corresponding
2-diazo-3-amino esters in >95% de. Amination of the lithium (E)-enolates of tert-butyl (3S,αR)-3-N-benzyl-N-α-
methylbenzylamino-3-phenylpropanoate or tert-butyl (3S,αS)-3-N-benzyl-N-α-methylbenzylaminobutanoate with
trisyl azide gives the (2R,3R,αR)- and (2S,3S,αS)-anti-2-azido-3-amino esters in good yields and in 85% de and >95%
de respectively. Alternatively, tert-butyl anti-(2S,3S,αS)-2-hydroxy-3-N-benzyl-N-α-methylbenzylaminobutanoate
may be converted selectively to tert-butyl anti-(2S,3S,αS)-2-azido-3-N-benzyl-N-α-methylbenzylaminobutanoate by
aziridinium ion formation and regioselective opening with azide. Deprotection of tert-butyl (2S,3S,αS)-2-azido-3-
aminobutanoate via Staudinger reduction, hydrogenolysis and ester hydrolysis furnishes anti-(2S,3S)-diamino-
butanoic acid in 98% de and 98% ee. The asymmetric synthesis of the diastereomeric syn-(2R,3S)-diaminobutanoic
acid (98% de and 98% ee) was accomplished via functional group manipulation of tert-butyl anti-(2S,3S,αS)-2-
hydroxy-3-N-benzyl-N-α-methylbenzylaminobutanoate in a protocol involving azide inversion of tert-butyl (2S,3S)-
2-mesyloxy-3-N-Boc-butanoate and subsequent deprotection.
Introduction
2,3-Diamino acids are a naturally occurring and diverse set of
bioactive compounds that have attracted considerable com-
mercial and academic interest.1 This simple, polyfunctional
motif can be incorporated into peptide chains and utilised to
stabilise specific conformations,2 and can be used in the prepar-
ation of 3-amino-2-azetidinones, a medically important class of
β-lactam antibiotics.3 Furthermore, they can be utilised in the
production of imidazolines for use as amide bond replace-
ments in peptidomimetic design,4 although the interest in these
diamino acids resides primarily with their occurrence in a
number of peptide antibiotics. For instance (S)-2,3-diamino-
propanoic acid 1 is a component of the neurotoxin (S)-2-N-
oxalyl-2,3-diaminopropanoic acid,5 as well as capreomycin,6
and the antifungal dipeptides Sch37137 and A19009.7 A family
of 2,3-diamino acids bearing a C(3)-stereogenic centre have
also been identified, with (2S,3S)-2,3-diaminobutanoic acid 2 a
component of a variety of peptide antibiotics including laven-
domycin,8 glumamycin,9 antrimycin,10 and cirratiomycin,11 and
has been shown to occur with its C(2)-epimer, syn-(2R,3S)-3,
in the antibiotics amphomycin12 and aspartocin.13 Further
examples include (2S,3R)-2,3-diamino-4-phenylbutanoic acid
4, the amino acid of aminodeoxybestatin,14 while (2R,3S)-2,3-
diamino-3-phenylpropanoic acid 5 has been considered as an
alternative sidechain of the anticancer drug Taxol (Fig. 1).15
A range of methodologies for the asymmetric synthesis of this
class of amino acid have been reported, with perhaps the most
popular involving manipulation of pre-existing stereodefined
functionality within material available from the chiral pool. For
instance, Mitsunobu reaction16 or functional group transform-
ations of either threonine17 or serine18 derivatives have been
applied to the synthesis of 2,3-diaminoacids, while Rapoport et
al. have shown that the (2S,3S)- and (2S,3R)-diastereoisomers of
Fig. 1 Homochiral 2,3-diaminoacids.
2,3-diamino-4-phenylbutanoic acid may be prepared by alkyl-
ation of an aspartic acid derivative.19 An alternative route to this
molecular class has been reported by Merino et al., who have
shown that the addition of Grignard reagents to nitrones derived
from -serine offers an efficient route to protected syn- or anti-3-
substituted 2,3-diaminoacids.20 A variety of other syntheses of
this class of diamino acid have also been reported, including the
preparation of the four diastereoisomers of N,N-protected 2,3-
diaminobutanoic acid using an asymmetric Rh()-phosphine-
catalysed hydrogenation of diastereomeric enamides,21 azide
opening of cis-3-alkylaziridene-2-carboxylates,22 application of
an asymmetric Strecker reaction,23 epoxidation of 1-tolylthio-1-
nitroalkenes and trapping with ammonia,24 and the application
of Sharpless asymmetric aminohydroxylation to α,β-unsaturated
enones and subsequent functional group manipulation.25 Pre-
vious work from this laboratory has demonstrated that the
conjugate addition of homochiral lithium amides derived from
α-methylbenzylamine to α,β-unsaturated acceptors and sub-
sequent deprotection offers an efficient and versatile route for the
asymmetric synthesis of a range of β-amino acid derivatives. Fur-
thermore, this methodology allows for the synthesis of anti-α-
alkyl-β-amino esters26 and anti-α-hydroxy-β-amino esters27 by
elaboration of β-amino ester enolates through reaction with
either an alkyl halide or oxaziridine respectively (Scheme 1).
† This is one of a number of contributions from the current members
of the Dyson Perrins Laboratory to mark the end of almost 90 years of
organic chemistry research in that building, as all its current academic
staff move across South Parks Road to a new purpose-built laboratory.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 0 8 – 3 7 1 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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procedure in 17% yield and in >95% de, consistent with the
stereochemical integrity of the C(3) stereocentre arising from
diastereoselective conjugate addition remaining intact during
this transformation. As Evans et al. have demonstrated that
the use of potassium enolates minimises the extent of diazo
transfer in the reaction of trisyl azide with oxazolidinone enol-
ates,31 application of this protocol to generate the potassium
β-amino enolate of (3S,αR)-6 was attempted. Deprotonation
of (3S,αR)-6 with KDA and amination with trisyl azide gave
essentially exclusive azido transfer, furnishing an insepar-
able diastereoisomeric mixture of anti-(2R,3R,αR)- and syn-
(2S,3R,αR)-2-azido-3-amino esters 7 in 64% yield but in only
55% de, indicating that although the use of the potassium enol-
ate in this reaction manifold has the desired effect upon mini-
misation of diazo-transfer, it also has a detrimental effect upon
reaction diastereoselectivity (Scheme 2). In the crotonate series,
application of this amination protocol via generation of the
lithium (E)-β-amino enolate of tert-butyl (3S,αS)-3-N-benzyl-
N-α-methylbenzylaminobutanoate 9 (>95% de) by treatment
with LDA and subsequent reaction with trisyl azide gave, at
70% conversion, the desired anti-(2S,3S,αS)-2-azido-3-amino
ester 10 in 32% yield (43% yield based upon recovered starting
material) and in >95% de, and the (3S,αS)-2-diazo-3-amino
ester 11 in 9% yield (>95% de) respectively. Attempts to
improve the yield of anti-(2S,3S,αS)-2-azido-3-amino ester 10
via the use of an alternative electrophilic azide source was
examined, but reaction with the lithium (E)-β-amino enolate of
(3S,αS)-9 with diphenylphosphoryl azide gave exclusively the
(3S,αS)-2-diazo-3-amino ester 11 in 64% yield (>95% de).32 In
each case, the C(2)–C(3) anti relative configuration within the
2-azido-3-amino esters 7 and 10 was assigned by analogy to the
known anti-selectivity noted upon hydroxylation of β-amino
enolate 6 (Scheme 2).
Having demonstrated that trisyl azide allows the incorpor-
ation of nitrogen in the 2-position of lithium (E)-β-amino enol-
ates, the efficiency of a tandem conjugate addition–amination
protocol was next examined. Thus, conjugate addition of
homochiral lithium N-benzyl-N-α-methylbenzylamide to tert-
butyl cinnamate, tert-butyl crotonate or methyl crotonate
generated the requisite (Z)-β-amino enolates, and subsequent
addition of trisyl azide, gave, in each case, the 2-diazo-3-amino
esters 8, 11 and 12 in >95% de, consistent with the stereo-
chemical integrity of the C(3) stereocentre from conjugate
addition remaining intact (Scheme 3). Although this tandem
conjugate addition–amination protocol allows for three
component coupling and the diastereoselective synthesis of
Scheme 1 Reagents and conditions: (i). lithium (R)-N-benzyl-N-α-
methylbenzylamide, THF, Ϫ78 ЊC; (ii). NH4Cl (aq); (iii). (Ϫ)-camphor-
sulfonyloxaziridine, THF, Ϫ78 ЊC to rt; (iv). LDA, THF, Ϫ78 ЊC;
(v). MeI, Ϫ78 ЊC to rt.
The extension of this methodology to the synthesis of 2,3-
diamino acids via amination of the enolates of β-amino esters
with an electrophilic nitrogen source is described herein, with
application to the synthesis of anti-(2S,3S)- and syn-(2R,3S)-
diaminobutanoic acid. Part of this work has been the subject of
a preliminary communication.28
Results and discussion
Amination of ꢀ-amino ester enolates: asymmetric synthesis of
anti-2-azido-3-amino esters
Initial investigations concentrated upon an evaluation of the
diastereoselectivity observed upon the amination of crotonate
and cinnamate derived β-amino enolates, with trisyl azide used
as an electrophilic nitrogen source for the installation of
azide at C(2) within β-amino esters.29 Treatment of tert-butyl
(3S,αR)-3-N-benzyl-N-α-methylbenzylamino-3-phenylpropan-
oate 6 (>95% de)30 with LDA and subsequent reaction of the
lithium (E)-β-amino enolate of (3S,αR)-6 with trisyl azide gave
a mixture of two distinct components. The major isolated
product from the reaction was the desired anti-(2R, 3R, αR)-2-
azido-3-amino ester 7 in 57% yield and 85% de, indicating that
the amination procedure proceeded with high levels of selectiv-
ity upon formation of the new stereogenic centre at C(2). The
(3R,αR)-2-diazo-3-amino ester 8 was also isolated from this
Scheme 2 Reagents and conditions: (i). LDA, THF, Ϫ78 ЊC; (ii). KOtBu, iPr2NH, n-BuLi, THF; (iii). trisyl azide, Ϫ78 ЊC then AcOH;
(iv). diphenylphosphoryl azide, Ϫ78 ЊC then AcOH.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 0 8 – 3 7 1 5
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(2S,3S,αS)-2-azido-3-amino ester 10 in hand from both
amination and double inversion protocols, reduction to the cor-
responding anti-(2S,3S,αS)-2,3-diamino ester 14 by application
of the Staudinger reaction was followed,37 giving diamine
(2S,3S,αS)-14 in 91% yield and in 98% de. N-Deprotection
via hydrogenolysis and subsequent ester hydrolysis, followed
by purification by ion exchange chromatography, gave anti-
(2S,3S)-2,3-diaminobutanoic acid 2 {[α]2D6 ϩ12.3 (c 0.37, 6 M
HCl]; lit.38 [α]2D2 ϩ10.3 (c 1.0, 6 M HCl)} in 98% de and 98% ee,
having spectroscopic data consistent with that of the literature.
This assignment serves to confirm not only the sense of asym-
metric induction upon amination of the (E)-β-amino enolate
of (3S,αS)-9 with trisyl azide, but also the regioselectivity of
nucleophilic attack during the double inversion protocol
(Scheme 4).
Scheme 3 Reagents and conditions: (i). lithium (R)- or (S)-N-benzyl-
N-α-methylbenzylamide, THF, Ϫ78 ЊC; (ii). trisyl azide, Ϫ78 ЊC;
(iii). AcOH.
homochiral 2-diazo-3-amino esters, it is not applicable for the
synthesis of 2-azido-3-amino esters.
Although the synthesis of anti-2-azido-3-aminobutanoates
may be achieved with high levels of diastereoselectivity by enol-
ate amination with trisyl azide, an alternative strategy for the
synthesis of this motif was devised. It was envisaged that in situ
aziridinium ion formation following neighbouring group
participation of the C(3)-amino substituent onto an activated
form of the known anti-2-hydroxy-3-amino ester 13,27 coupled
with subsequent regioselective ring opening would install
the desired C(2)-amino functionality with overall retention of
configuration (Fig. 2).
Scheme 4 Reagents and conditions: (i). DEAD (2 eq.), PPh3 (2 eq.),
diphenylphosphoryl azide (15 eq.), THF, rt; (ii). hydrazoic acid
(4.5 eq.), PPh3 (4.3 eq.), DEAD (4.3 eq.), benzene, rt; (iii). PPh3, THF–
H2O, rt; (iv). Pd(OH)2 on C, EtOH, H2 (5 atm), 55 ЊC; (v). TFA, rt then
1 M HCl(aq) then Dowex 50X8-200.
The efficiency of this double inversion protocol using phthal-
imide as the nitrogen source was similarly investigated, with
reaction of anti-2-hydroxy-3-amino ester (2R,3R,αR)-13 (98%
de) with phthalimide in the presence of PPh3 and DEAD giving
(2R,3R,αR)-2-phthalimido-3-amino ester 15 in 42% yield and
98% de. Deprotection with hydrazine39 gave diamine (2R,3R,
αR)-14, which was characterised as its 3,5-dinitrobenzoyl deriv-
ative 16 (Scheme 5). Although this approach allows for the
synthesis of the anti-2,3-diamino ester 14, the use of diphenyl-
phosphoryl azide or hydrazoic acid as the nitrogen source in
this double inversion protocol are much more efficient pro-
cedures, allowing the synthesis of the target diamino acid in
good yield.
Fig. 2
The regioselectivity of aziridinium ion ring opening has been
investigated by a variety of research groups,33 with mono-
substituted aziridinium ions generally undergoing nucleophilic
attack at the least sterically hindered position,34 although this
regioselectivity is dependent upon the nature of the nucleo-
phile.35 Chuang and Sharpless have also recently demonstrated
that ring opening at the benzylic C(3)-position of C(2)-ester
and C(3)-aryl bis-substituted aziridinium ions is favoured,
giving β-aryl-α,β-diamino esters in good yields and with high
selectivity.36 To investigate the efficiency of the proposed double
inversion protocol, it was envisaged that Mitsunobu activation
of anti-2-hydroxy-3-amino ester (2S,3S,αS)-13 would result
in aziridinium formation, with displacement using an azide
source giving the anti-2-azido-3-amino ester. Thus, treatment
of (2S,3S,αS)-13 (98% de) with PPh3, DEAD and diphenyl-
phosphoryl azide gave selectively the anti-(2S,3S,αS)-2-azido-
3-amino ester 10, in 71% isolated yield and 98% de, with
identical spectroscopic properties to that prepared from
azidation of the lithium (E)-enolate of (3S,αS)-9. A similar
reaction with hydrazoic acid as the nitrogen nucleophile gave
(2S,3S,αS)-10 in 84% isolated yield and 98% de. With anti-
Asymmetric synthesis of syn-2-azido-3-amino esters
Having demonstrated an efficient asymmetric synthesis of anti-
(2S,3S)-2,3-diaminobutanoic acid via either enolate amination
or functional group manipulation, synthesis of the diastereo-
isomeric syn-(2R,3S)-2,3-diaminobutanoic acid was attempted.
Previous investigations from within this laboratory have shown
that Mitsunobu inversion of 2-hydroxy-3-amino ester (2S,3S,
αS)-13 may be controlled efficiently by neighbouring group
participation of a C(3)-N-benzoyl group upon treatment with
PPh3 and DEAD and hydrolysis of the resultant oxazoline.40 In
order to install nitrogen functionality at C(2) with inversion of
configuration, aziridinium ion formation from C(3)-N-partici-
pation, or oxazoline formation from participation of an N-acyl
fragment had to be prevented. It was predicted that a protecting
group combination of N-Boc at C(3), coupled with C(2)-
hydroxy activation via mesylation would allow direct SN2
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 0 8 – 3 7 1 5
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Scheme 7 Reagents and conditions: (i). NaN3 (4.6 eq.), DMF, 55 ЊC;
(ii). Pd(OH)2 on C, H2 (5 atm), rt; (iii). diphosgene, toluene, activated
charcoal, rt.
acid (2R,3S)-3 as its dihydrochloride salt {[α]2D5 Ϫ34.5 (c 1.15,
6 M HCl); lit.38 (i). [α]2D2 Ϫ38.1 (c 1.0, 6 M HCl), (ii). lit.25
[α]2D5 Ϫ34.3 (c 1.0, 6 M HCl)} in 98% de and 98% ee, with NMR
spectroscopic properties consistent with those reported in the
literature (Scheme 8).42
Scheme 5 Reagents and conditions: (i). DEAD (2 eq.), PPh3 (2 eq.),
phthalimide (7.5 eq.), THF, rt; (ii). hydrazine monohydrate (3.5 eq.),
EtOH, 0 ЊC then AcOH, 0 ЊC to rt; (iii). 3,5-dinitrobenzoyl chloride,
NEt3, DCM, rt.
displacement at C(2) with azide.41 The 2-hydroxy-3-amino ester
(2S,3S,αS)-13 was first N-debenzylated and trapped in situ with
Boc2O, giving anti-(2S,3S)-2-hydroxy-3-N-Boc ester 17 in 89%
yield and 98% de. Mesylate (2S,3S)-18 (98% de) was sub-
sequently isolated in 78% yield by treatment of 3-N-Boc ester
(2S,3S)-17 with methanesulfonyl chloride and NEt3 (Scheme
6).
Scheme 8 Reagents and conditions: (i). Pd/C, H2 (5 atm), EtOAc, rt;
(ii). TFA, rt overnight then 1 M HCl(aq), rt.
In conclusion, the asymmetric synthesis of anti-(2S,3S)-
and syn-(2R,3S)-2,3-diaminobutanoic acid has been completed
via a strategy involving the conjugate addition of lithium
(S)-N-benzyl-N-α-methylbenzylamide to tert-butyl crotonate.
As both enantiomers of N-benzyl-N-α-methylbenzylamine are
readily available in homochiral form, all four stereoisomers of
2,3-diaminobutanoic acid should be readily available by appli-
cation of this synthetic strategy, which represents a general and
efficient route to this class of compound. Furthermore, the
identification of methodology for the asymmetric synthesis of
α-diazo-β-amino esters with excellent diastereoselectivity has
also been achieved. The application of this methodology for the
synthesis of libraries of homochiral 2,3-diamino acids, and the
utilisation of homochiral aziridinium ions for natural product
synthesis is currently underway within our laboratory.
Experimental
Scheme 6 Reagents and conditions: (i). Pd(OH)2 on C, H2 (5 atm),
Boc2O (3.7 eq.), EtOAc, rt; (ii). MeSO2Cl (1.1 eq.), NEt3 (1.5 eq.),
DCM, 0 ЊC (30 min) then rt.
General experimental
Melting points were determined using either Gallenkamp or
Koffler hot stage apparatus and are uncorrected. Specific
rotations were recorded using a Perkin-Elmer 241 polarimeter
with a thermally jacketed 10 cm cell; [α] values are given in units
of 10Ϫ1 deg cm2 gϪ1. IR spectra were obtained on a Perkin-
Elmer 781 or Perkin-Elmer 1750 spectrophotometer with solu-
tion spectra generally being recorded in chloroform using
0.1 mm or 1.0 mm NaCl cells, with selected peaks reported in
Attempted displacement of mesylate (2S,3S)-18 with sodium
azide gave, at 75% conversion, a 66 : 33 mixture of two separ-
able components, identified as the syn-2-azido-3-N-Boc ester
(2R,3S)-19 (the product of direct azide displacement) in 48%
isolated yield and 98% de (64% yield based on recovered start-
ing material), and trans-oxazolidinone (4S,5R)-20 (the product
of neighbouring group N-Boc participation) in 25% isolated
yield and 98% de. The (4S,5R)-configuration within trans-
oxazolidinone 20 was confirmed by the preparation of an
authentic sample of the epimeric cis-oxazolidinone from the
known 2-hydroxy-3-amino ester (2S,3S,αS)-13 via hydro-
genolysis to amino alcohol (2S,3S)-21 (quantitative yield,
98% de) and subsequent treatment with diphosgene, giving
cis-(4S,5S)-22 in 98% de and in 83% yield (Scheme 7).
1
cmϪ1. H NMR spectra were recorded on Varian Gemini 200,
Bruker AC200, Bruker WH300, Bruker DPX-400 Bruker
AM-500 or Bruker AMX-500 spectrometers with 13C NMR
spectra recorded with DEPT editing as necessary. Chemical
shifts (δC) are quoted in ppm and referenced using residual
solvent peaks with coupling constants (J) measured in Hertz.
Mass spectra were recorded on a VG MASSLAB VG 20–250
instrument using the chemical ionisation (CI) technique, or on
a Waters 2790-Micromass LCT electrospray ionisation mass
Subequent N-Boc deprotection and ester hydrolysis of syn-2-
azido-3-N-Boc ester (2R,3S)-19 gave the desired syn-diamino
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 0 8 – 3 7 1 5
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spectrometer operating at a resolution of 5000 full width
half height. Positive ion spectra were calibrated relative to PEG
with tetraoctylammonium bromide as the internal lock mass.
Elemental analyses were performed by the Dyson Perrins
Laboratory analytical department. Flash column chromato-
graphy was performed on silica gel (Kieselgel 60), with tlc per-
formed on Merck aluminium sheets coated with 0.2 mm silica
gel 60 F254. THF was distilled from sodium–benzophenone
ketyl under an atmosphere of dry nitrogen. For moisture sensi-
tive reactions, standard vacuum line techniques were used,
using glassware that was flame dried and cooled under nitrogen.
Reactions involving lithium amides were performed under an
atmosphere of dry nitrogen and reaction diastereoselectivities
were determined by integration of the appropriate peaks in the
1H NMR spectrum of the crude reaction product.
(2H, AB system, JAB 15.0, NCH2Ph), 1.44 (3H, d, obscured,
C(α)Me), 1.43 (9H, s, CO2C(CH3)3); δC (126 MHz; CDCl3)
165.7 (C(1)), 143.8, 142.1, 140.1 (Ph: Cipso), 129.0, 128.4, 128.1,
128.0, 127.8, 127.2, 126.8, 126.5, 126.1 (Ph: Cortho, Cmeta, Cpara),
81.1 (CO2C(CH3)3); 61.5, 57.0 (C(3), C(α)H), 51.2 (NCH2Ph),
28.5 (CO2C(CH3)3), 10.7 (C(α)Me); m/z (CI) 442 (MHϩ, 10%).
Preparation of tert-butyl (2S,3S,ꢁS )-2-azido-3-(N-benzyl-
N-ꢁ-methylbenzylamino)butanoate 10
n-BuLi (1.6 M, 1.6 ml, 2.6 mmol) was added dropwise to a
stirred solution of diisopropylamine (0.4 ml, 2.57 mmol) in
THF (5 ml) at 0 ЊC. After 20 minutes, the solution was cooled to
Ϫ78 ЊC before the addition of (3S,αS)-9 (0.6 g, 1.7 mmol) in
THF (5 ml) and stirred for 1 h before the addition of trisyl azide
(709 mg, 2.6 mmol) in THF (4 ml). After 2 min, AcOH (0.6 ml,
10.5 mmol) in anhydrous THF (3 ml) was added and the reac-
tion mixture was warmed to rt overnight. After concentration
in vacuo, the residue was treated with saturated aqueous sodium
bicarbonate (20 ml), extracted with DCM (3 × 30 ml), dried
and concentrated in vacuo. Purification by flash chromato-
graphy on silica gel (1% Et2O : petrol) gave 10 as a colourless oil
(0.21 g, 32%); found: C, 70.2; H, 7.4; N, 14.1%; C23H30N4O2
requires C, 70.1; H, 7.6; N, 14.2%; [α]2D3 Ϫ77.4 (c 1.9, CHCl3);
tert-Butyl
(3S,αS)-3-(N-benzyl-N-α-methylbenzylamino)-
butanoate 9,30 tert-butyl (3R,αS)-3-(N-benzyl-N-α-methyl-
benzylamino)-3-phenylpropanoate 630 and tert-butyl (2S,3S,
αS)-3-(N-benzyl-N-α-methylbenzylamino)-2-hydroxybutano-
ate 1327 were prepared according to their respective literature
procedures.
Preparation of (2R,3R,ꢁR)-tert-butyl 2-azido-3-(N-benzyl-
N-ꢁ-methylbenzylamino)-3-phenylpropanoate 7
νmax (film) 2108 (N ), 1735 (C᎐O); δ (200 MHz; CDCl3) 7.46
᎐
3
H
n-BuLi (1.5 M, 0.6 ml, 0.90 mmol) was added dropwise to a
stirred solution of diisopropylamine (97 mg, 0.96 mmol)
in THF (10 ml) at 0 ЊC. After 20 minutes, the solution was
cooled to Ϫ78 ЊC before the addition of (3S,αR)-6 (250 mg,
0.60 mmol) in THF (3 ml) and stirred for 1 h before the addi-
tion of trisyl azide (279 mg, 0.90 mmol) in THF (4 ml). After
2 min, AcOH (166 mg, 2.77 mmol) in anhydrous THF (2 ml)
was added and the reaction mixture was warmed to rt over-
night. After concentration in vacuo, the residue was treated with
saturated aqueous sodium bicarbonate (20 ml), extracted with
DCM (3 × 30 ml), dried and concentrated in vacuo. Purification
by flash chromatography on silica gel (5% Et2O : petrol) gave
7 as a colourless oil (158 mg, 57%); found: C, 73.9; H, 6.75;
N, 12.0%; C28H32N4O2 requires C, 73.7; H, 7.1; N, 12.3%;
[α]2D5 Ϫ15.6 (c 1.03, CHCl3); νmax (CHCl3) 2115 (N3), 1733
(2H, m, Ph), 7.41–7.27 (8H, m, Ph), 4.01 (1H, q, J 6.8, C(α)H ),
3.92 (2H, br s, NCH2Ph), 3.61 (1H, d, J 4.9, C(2)H ), 3.52 (1H,
m, C(3)H ), 1.45 (9H, s, CO2C(CH3)3), 1.38 (3H, d, J 6.8,
C(α)Me), 1.12 (3H, d, J 6.7, C(4)H3); δC (126 MHz; CDCl3)
168.5 (C(1)), 143.4, 141.5 (Ph: Cipso), 128.4, 128.2 128.1, 127.8,
126.8, 126.7 (Ph: Cortho, Cmeta, Cpara), 82.3 (CO2C(CH3)3), 67.4
(C(2)), 58.7 (C(α)H), 53.9 (C(3)H), 50.2 (NCH2Ph), 27.9
(CO2C(CH3)3), 16.4 (C(α)Me), 13.1 (C(4)); m/z (CI) 395 (MHϩ,
8%). Further elution gave (3S,αS)-11 (58 mg, 9%) and
recovered starting material (0.10 g, 26%).
Preparation of tert-butyl (3S,ꢁS )-2-diazo-3-(N-benzyl-
N-ꢁ-methylbenzyl)aminobutanoate 11
n-BuLi (1.6 M, 3.3 ml, 5.3 mmol) was added dropwise to a
stirred solution of (S)-N-benzyl-N-α-methylbenzylamine (1.2
g, 5.6 mmol) in THF (10 ml) at Ϫ78 ЊC. After 1 hour, tert-butyl
(E)-crotonate (500 mg, 3.5 mmol) in THF (5 ml) was added and
stirred for a further 2 hours before the addition of trisyl azide
(1.7 g, 5.6 mmol) in THF (5 ml) at Ϫ78 ЊC. After 2 min, acetic
acid (1 ml) in anhydrous THF (5 ml) was added, and the mix-
ture allowed to warm to rt overnight. After dilution with DCM
(40 ml) and neutralisation with saturated aqueous sodium
bicarbonate (20 ml), the solution was partitioned between H2O
and DCM (3 × 40 ml), dried and concentrated in vacuo. Purifi-
cation by flash chromatography on silica gel (3% Et2O : petrol)
gave 11 as a yellow oil (0.38 g, 29%); found: C, 72.55; H, 7.9;
N, 10.9%; C23H29N3O2 requires C, 72.8; H, 7.65; N, 11.1%;
[α]2D3 Ϫ53.7 (c 1.45, CHCl3); νmax (film) 2081 (N ), 1687 (C᎐O);
(C᎐O); δ (300 MHz; CDCl ) 7.43–7.25 (15H, m, Ph), 4.47 (1H,
᎐
H
3
d, J 7.7, C(2)H ), 4.15 (1H, q, J 6.9, C(α)H ), 4.05 (1H, d, J 7.7,
C(3)H), 3.88, 3.73 (2H, AB system, JAB 14.6, NCH2Ph), 1.39
(9H, s, CO2C(CH3)3), 1.21 (3H, d, J 6.9, C(α)Me); δC (126 MHz;
CDCl3) 168.2 (C(1)), 143.8, 140.7, 137.1 (Ph: Cipso), 129.7, 128.5,
128.2, 128.1, 128.0 (Ph: Cortho, Cmeta, Cpara), 82.6 (CO2C(CH3)3],
65.0, 63.1 (C(3), C(2)), 58.2 (C(α)H), 51.6 (NCH2Ph), 27.9
(CO2C(CH3)3), 15.9 (C(α)Me); m/z (CI) 457 (MHϩ, 100%).
Further elution gave the more polar diazo compound (3R,αR)-
8 as a pale yellow oil (45 mg, 17%).
Preparationoftert-butyl(3R,ꢁR)-3-(N-benzyl-N-ꢁ-methylbenzyl-
amino)-2-diazo-3-phenylpropanoate 8
᎐
2
n-BuLi (1.5 M, 0.5 ml, 0.74 mmol) was added dropwise to
a stirred solution of (R)-N-benzyl-N-α-methylbenzylamine
(166 mg, 0.78 mmol) in THF (10 ml) at Ϫ78 ЊC. After 1 hour,
tert-butyl (E)-cinnamate (100 mg, 0.490 mmol) in THF (5 ml)
was added and stirred for a further 2 hours before the addition
of trisyl azide (227 mg, 0.74 mmol) in THF (5 ml) at Ϫ78 ЊC.
After 2 min, acetic acid (147 mg, 2.45 mmol) in anhydrous THF
(3 ml) was added, and the mixture allowed to warm to rt over-
night. After dilution with DCM (30 ml) and neutralisation with
saturated aqueous sodium bicarbonate (20 ml), the solution
was partitioned between H2O and DCM (3 × 40 ml), dried and
concentrated in vacuo. Purification by flash chromatography on
silica gel (5% Et2O : petrol) gave 8 as a yellow oil (162 mg, 75%);
found: C, 76.2; H, 7.2; N, 9.3%; C28H31N3O2 requires C, 76.2; H,
7.1; N, 9.5%; [α]2D5 ϩ94.1 (c 0.92, CHCl3); νmax (CHCl3) 2098
δH (200 MHz; CDCl3) 7.60–7.15 (10H, m, Ph), 4.14 (1H, q,
J 6.9, C(3)H ), 4.02 (1H, q, J 6.9, C(α)H ), 3.85, 3.70 (2H, AB
system, JAB 15.4, NCH2Ph), 1.49 (9H, s, CO2C(CH3)3), 1.39
(3H, d, J 6.9, C(4)H3), 1.32 (3H, d, J 6.9, C(α)Me); δC (50 MHz;
CDCl3) 166.1 (C(1)), 144.8, 142.4 (Ph: Cipso), 128.1, 127.7,
127.4, 126.8, 126.2 (Ph: Cortho, Cmeta, Cpara), 80.8 (CO2C(CH3)3],
59.3 (C(3)), 51.2 (C(α)H), 50.4 (NCH2Ph), 28.4 (CO2C(CH3)3),
18.4, 17.6 (C(4)H3, C(α)Me); m/z (CI) 380 (MHϩ, 24%).
Preparation of methyl (3S,ꢁS )-2-diazo-3-(N-benzyl-N-ꢁ-methyl-
benzylamino)butanoate 12
n-BuLi (1.5 M, 3.4 ml, 5.1 mmol) was added dropwise to
a stirred solution of (S)-N-benzyl-N-α-methylbenzylamine
(1.1 g, 5.4 mmol) in THF (10 ml) at Ϫ78 ЊC. After 1 hour,
methyl (E)-crotonate (340 mg, 3.4 mmol) in THF (5 ml) was
added and stirred for a further 2 hours before the addition of
(N ), 1674 (C᎐O); δ (300 MHz; CDCl3) 7.54–7.13 (15H, m,
᎐
2
H
Ph), 4.96 (1H, s, C(3)H ), 4.06 (1H, q, J 6.7, C(α)H ), 3.84–3.61
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 0 8 – 3 7 1 5
3712

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trisyl azide (1.6 g, 5.1 mmol) in THF (5 ml) at Ϫ78 ЊC. After 20
min, acetic acid (1 ml) in anhydrous THF (5 ml) was added, and
the mixture allowed to warm to rt overnight. After dilution
with DCM (40 ml) and neutralisation with saturated aqueous
sodium bicarbonate (20 ml), the solution was partitioned
between H2O and DCM (3 × 40 ml), dried and concentrated
in vacuo. Purification by flash chromatography on silica gel
(10% Et2O : petrol) gave 12 as a yellow oil (0.59 g, 52%); found:
C, 71.5; H, 6.7; N, 12.45%; C20H23N3O2 requires C, 71.2; H, 6.8;
N, 12.5%; [α]2D1 Ϫ69.9 (c 1.1, CHCl3); νmax (film) 2083 (N2), 1696
δH (500 MHz; CDCl3) 7.44 (2H, m, Ph), 7.35–7.20 (8H, m, Ph),
4.04 (1H, q, J 6.9, C(α)H ), 3.89 (2H, s, NCH2Ph), 3.27 (1H, d,
J 4.2, C(2)H ), 3.25–3.24 (1H, m, C(3)H ), 1.39 (9H, s,
CO2C(CH3)3), 1.37 (3H, d, J 6.9, C(α)Me), 1.13 (3H, d, J 6.8,
C(4)H3); δC (126 MHz; CDCl3) 174.4 (C(1)), 144.1, 142.0, (Ph:
Cipso), 128.5, 128.1, 128.0, 126.7, 126.6, (Ph: Cortho, Cmeta, Cpara),
80.7 (CO2C(CH3)3), 59.2 (C(2)), 57.7 (C(α)H), 55.0 (C(3)),
50.9 (NCH2Ph), 28.0 (CO2C(CH3)3), 15.3 (C(α)Me), 13.1
(C(4)); m/z (CI) 369 (MHϩ, 100%).
(C᎐O), 1602 (Ph); δ (200 MHz; CDCl3) 7.47–7.20 (10H, m,
᎐
H
Preparation of (2S,3S )-2,3-diaminobutanoic acid 2
Ph), 4.11 (1H, q, J 6.7, C(α)H ), 4.01 (1H, q, J 6.9, C(3)H ), 3.83,
3.70 (2H, AB system, JAB 15.2, NCH2Ph), 3.70 (3H, s, OMe),
1.32 (6H, app d, J 6.9, C(4)H3 and C(α)Me); δC (126 MHz;
CDCl3) 167.2 (C(1)), 144.9, 142.2 (Ph: Cipso), 128.1, 127.6,
127.4, 126.8, 126.4 (Ph: Cortho, Cmeta, Cpara), 59.4 (C(3)), 51.6
(NCH2Ph), 51.2 (C(α)H), 50.6 (OMe), 18.9, 17.7 (C(4),
C(α)Me); m/z (Electrospray) 338 (MHϩ, 100%).
Pd(OH)2 on C (0.1 g) was added to a stirred solution of
(2S,3S,αS)-14 (0.22 g, 0.6 mmol) in EtOH and the mixture
stirred for 19 hours under H2 (4 atm) at 55 ЊC. Filtration
through Celite, concentration in vacuo and trituration (hexane–
Et2O) gave tert-butyl (2S,3S)-2,3-diaminobutanoate as colour-
less feathers (0.1 g, 88%); mp 129–130 ЊC; νmax (KBr) 3362
(N–H), 1739 (C᎐O), 1575 (N–H, deformation), 1166 (C–N);
᎐
δH (500 MHz; CDCl3) 3.92 (1H, d, J 3.8, C(2)H ), 3.82–3.77
(1H, m, C(3)H ), 1.47 (9H, s, CO2C(CH3)3), 1.21 (3H, d, J 6.7,
C(4)H3); δC (126 MHz; CDCl3) 171.2 (C(1)), 82.8 (CO2C-
(CH3)3), 55.6 (C(2)), 48.9 (C(3)), 28.0 (CO2C(CH3)3), 13.0
(C(4)); m/z (CI) 175 (MHϩ, 100%), 119 (MHϩ Ϫ C4H8, 97%).
TFA (5 ml) was added to tert-butyl (2S,3S)-2,3-diamino-
butanoate (85 mg, 0.5 mmol) at 0 ЊC and warmed to rt over-
night. Concentration in vacuo, followed by the addition of
1.0 M HCl (5 ml) and stirring at rt for 4.5 h prior to concen-
tration in vacuo, gave the hydrochloride salt as a white powdery
solid (65 mg). Purification by ion exchange chromatography
(Dowex 50X8–200) gave (2S,3S)-2 as a white solid (45 mg,
78%); mp 201–202 ЊC (decomp.); [α]2D2 ϩ12.3 (c 0.37, 6 M HCl)
lit.22 [α]2D2 ϩ10.3 (c 1.0, 6 M HCl); νmax (KBr) 3293 (N–H, NH2),
2987–2152 (N–H, NH3ϩ), 1651(N–H deformation, NH3ϩ),
1578 (C᎐O, CO Ϫ); δH (200 MHz; 2 M DCl) 3.70 (1H, d,
Preparation of tert-butyl (3S,ꢁS )-2-diazo-3-(N-benzyl-
N-ꢁ-methylbenzylamino)butanoate 11 from diphenylphosphoryl
azide quench of the enolate derived from tert-butyl (3S,ꢁS )-
3-(N-benzyl-N-ꢁ-methylbenzylamino)butanoate 9
n-BuLi (1.1 M, 1.2 ml, 1.4 mmol) was added dropwise to a
stirred solution of diisopropylamine (0.2 ml, 1.4 mmol) in THF
(4 ml) at 0 ЊC. After 20 minutes, the solution was cooled to
Ϫ78 ЊC before the addition of (3S,αS)-9 (0.3 g, 0.85 mmol) in
THF (5 ml) and stirred for 1.75 h before the addition of di-
phenylphosphoryl azide (0.4 ml, 1.7 mmol) in THF (3 ml).
After 30 min, AcOH (0.2 ml) in anhydrous THF (3 ml) was
added and the reaction mixture was warmed to rt overnight.
After concentration in vacuo, the residue was treated with sat-
urated aqueous sodium bicarbonate (20 ml), extracted with
DCM (3 × 30 ml), dried and concentrated in vacuo. Purification
by flash chromatography on silica gel (10% Et2O : petrol) gave
11 as a colourless oil (0.21 g, 64%).
᎐
2
J 6.1, C(2)H ), 3.40–3.30 (1H, m, C(3)H ), 0.74 (3H, d, J 7.0,
C(4)H3); δC (126 MHz; DMSO-d6) 167.9 (C(1)), 54.6 (C(2)),
46.9 (C(3)), 14.1 (C(4)) {for the DCl salt of (2S,3S)-2}; m/z
(CI) 119 (MHϩ, 100).
Preparation of (2S,3S,ꢁS )-10 by treatment of (2S,3S,ꢁS )-13
with diphenylphosphoryl azide
Preparationoftert-butyl(2R,3R,ꢁR)-2-phthalimido-3-(N-benzyl-
N-ꢁ-methylbenzylamino)butanoate 15
Diphenylphosphoryl azide (2.9 ml, 13.5 mmol) was added to
a solution of (2S,3S,αS)-13 (0.33 g, 0.9 mmol), PPh3 (0.47 g,
1.8 mmol) and DEAD (0.31 g, 1.8 mmol) in THF (10 ml) and
the reaction was stirred at rt for 40 h. Concentration in vacuo
and purification by flash chromatography on silica gel (25%
Et2O : petrol) gave 10 (0.25 g, 71%) as a colourless oil.
DEAD (0.36 g, 2.1 mmol) in anhydrous THF (10 ml) was added
to a stirred solution of (2S,3S,αS)-13 (0.38 g, 1.04 mmol), PPh3
(0.54 g, 2.1 mmol) and phthalimide (2.3 g, 15.6 mmol) in THF
(25 ml) and stirred at rt for 44 h, before being filtered, washed
with petrol, and concentrated in vacuo. Purification by flash
chromatography on silica gel (10% Et2O in petrol) gave 15 as a
colourless foam (0.22 g, 42%); [α]2D2 ϩ76.1 (c 1.7, CHCl3); νmax
Preparation of (2S,3S,ꢁS )-10 by treatment of (2S,3S,ꢁS )-13
with hydrazoic acid
(film) 1776 (C᎐O, imide), 1719 (C᎐O, ester); δ (500 MHz;
᎐
᎐
Hydrazoic acid (0.84 M in benzene, 3.2 ml, 2.7 mmol) was
added to a solution of (2S,3S,αS)-13 (0.23 g, 0.61 mmol) and
PPh3 (0.67 g, 2.6 mmol) in anhydrous benzene (15 ml) before
the addition of a solution of DEAD (0.4 ml, 2.6 mmol) in
anhydrous benzene (2.5 ml) and the reaction mixture was
stirred at rt for 40 min. Concentration in vacuo and purification
by flash chromatography on silica gel (10% Et2O : petrol) gave
10 (0.20 g, 84%) as a colourless oil.
H
CDCl3) 7.83 (2H, m, Ph), 7.71 (2H, m, Ph), 7.44–7.19 (11H, m,
Ph), 4.64 (1H, d, J 6.9, C(2)H ), 4.24 (1H, quintet, J 7.0,
C(3)H ), 4.15 (1H, q, J 6.9, C(α)H ), 3.86, 3.76 (2H, AB system,
JAB, NCH2Ph), 1.40 (9H, s, CO2C(CH3)3 and 3H, d, J 6.9,
C(α)Me), 1.05 (3H, d, J 7.0, C(4)H3); δC (126 MHz; CDCl3)
167.8 (C(1)), 167.1 (NCO), 143.8, 142.0, 131.7 (Ph: Cipso), 134.0,
128.2, 128.1, 127.8, 126.8, 126.5, 123.3 (Ph: Cortho, Cmeta, Cpara),
81.7 (CO2C(CH3)3), 60.4 (C(2)), 56.7 (C(α)H), 53.5 (C(3)),
49.3 (NCH2Ph), 27.8 (CO2C(CH3)3), 18.2 (C(α)Me), 14.2
(C(4)); m/z (CI) 499 (MHϩ, 94%).
tert-Butyl (2S,3S,ꢁS )-2-amino-3-(N-benzyl-N-ꢁ-methylbenzyl-
amino)butanoate 14
PPh3 (0.5 g, 1.9 mmol) was added to a stirred solution of
(2S,3S,αS)-10 (0.5 g, 1.25 mmol) in anhydrous THF (5 ml) at rt
followed by the addition of water (0.8 ml) and stirred at rt
overnight. Concentration in vacuo and purification by flash
chromatography on silica gel (petrol : EtOAc : MeOH, 79 : 20 :
1) gave 14 as a colourless oil (0.42 g, 91%) which solidified
on standing; found: C, 75.1; H, 9.0; N, 7.3%; C23H32N2O2
requires C, 75.0; H, 8.7; N, 7.6%; [α]2D2 ϩ22.9 (c 1.7, CHCl3);
Preparation of tert-butyl (2R,3R,ꢁR)-2-amino-3-(N-benzyl-
N-ꢁ-methylbenzylamino)butanoate 14
Hydrazine monohydrate (30 mg, 0.6 mmol) in EtOH (1 ml) was
added to (2R,3R,αR)-15 (84 mg, 0.17 mmol) in EtOH (10 ml) at
0 ЊC. After 1 h, AcOH was added, and the mixture stirred for
10 min at 0 ЊC and then allowed to warm to rt overnight. Con-
centration in vacuo and purification by flash chromatography
on silica gel (petrol : EtOAc : MeOH, 79 : 20 : 1) gave 14 as a
νmax (KBr) 3379 (N–H), 1714 (C᎐O), 1602 (N–H, deformation);
᎐
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 0 8 – 3 7 1 5
3713

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pale yellow solid (46 mg, 74%) with identical 1H NMR spectro-
scopic properties to that previously obtained.
(C(4)); m/z (CI) 354 (MHϩ, 1%), 254 (MHϩ Ϫ C4H8 Ϫ CO2,
85%).
Preparation of tert-butyl (2R,3S )-2-azido-3-tert-butylcarbonyl-
oxyaminobutanoate 19 and tert-butyl (4S,5R)-4-methyloxa-
zolidin-2-one-5-carboxylate 20
Preparation of tert-butyl (2R,3R,ꢁR)-2-(3,5-dinitrobenz-
oylamino)-3-(N-benzyl-N-ꢁ-methylbenzylamino)butanoate 16
NEt3 (32 mg, 0.32 mmol) was added to a stirred solution of
(2R,3R,αR)-14 (46 mg, 0.125 mmol) and 3,5-dinitrobenzoyl
chloride (58 mg, 0.25 mmol) in anhydrous DCM (15 ml) and
the mixture stirred at rt for 26 h. Concentration in vacuo and
purification by flash chromatography on silica gel (petrol :
EtOAc : MeOH, 79 : 20 : 1) gave 16 as a yellow solid (60 mg,
97%); found: C, 64.2; H, 6.1; N, 9.8%; C30H34N4O7 requires C,
64.1; H, 6.05; N, 10.0%; mp 159–161 ЊC; νmax (KBr) 3359
Sodium azide (607 mg, 9.34 mmol) was added to a solution of
(2S,3S)-18 (715 mg, 2.03 mmol) in DMF (50 ml) and heated at
55 ЊC for 5 h, before cooling to rt and stirring for a further 3 h.
After dilution with water (30 ml) and extraction with DCM
(2 × 30 ml) the combined organic layers were dried, filtered and
concentrated in vacuo before purification by flash chromato-
graphy on silica gel (50% Et2O : petrol) giving 19 (295 mg, 48%)
as a white solid, mp 56.5–59 ЊC; [α]2D6 ϩ50.0 (c 0.3, CHCl3);
(N–H), 1730 (C᎐O, ester), 1673 (C᎐O, amide), 1546, 1345
᎐
᎐
νmax (film) 3365 (N–H), 2116 (N ), 1719 br s (C᎐O, ester and
᎐
3
(NO2); δH (500 MHz; CDCl3) 9.17 (1H, d, J 2.1, C(4)H; C6H3N-
(NO2)2), 8.69 (2H, d, J 2.1, C(2)H, C(3)H; C6H3N(NO2)2),7.50
(2H, d, J 7.2, Ph), 7.43 (2H, t, Ph), 7.33 (1H, t, Ph), 7.09 (2H, d,
J 7.4, Ph), 6.90 (2H, t, J 7.4, Ph), 6.88 (1H, d, J 7.9, CHN-
HCO), 6.70 (1H, t, J 7.4, Ph), 4.30 (1H, dd, J 7.9, 4.9, C(2)H ),
3.97 (1H, q, J 7.0, C(α)H ), 3.86, 3.66 (2H, AB system, JAB 13.2,
NCH2Ph), 3.43–3.40 (1H, m, C(3)H ), 1.53 (3H, d, J 7.0,
C(α)Me), 1.45 (9H, s, CO2C(CH3)3), 1.40 (3H, d, J 7, C(4)H3);
δC (126 MHz; CDCl3) 169.7 (C(1)), 161.9 (NHCO), 148.3,
143.7, 140.0, 137.9 (Ph, Cipso), 129.3, 128.7, 128.3, 127.8, 127.6,
127.3, 126.7, 120.7 (Ph, Cortho, Cmeta, Cpara), 82.9 (CO2C(CH3)3),
56.7 (C(2)), 56.0, 52.2 (C(α)H, C(3)), 51.1 (NCH2Ph), 28.0
(CO2C(CH3)3), 15.2 (C(α)Me), 11.8 (C(4)); m/z (CI) 563 (MHϩ,
39%).
carbamate); δH (500 MHz; CDCl3), 4.75 (1H, d, J 8.5, CONH ),
4.24 (1H, m, C(3)H ), 4.00 (1H, d, J 2.7, C(2)H ), 1.51 (9H, s,
CO2C(CH3)3), 1.42 (9H, s, NCO2C(CH3)3), 1.21 (3H, d, J 6.8,
C(4)H3); δC (126 MHz; CDCl3) 167.5 (C(1)), 154.7 (NCO2C-
(CH3)3), 83.5 (CO2C(CH3)3), 79.5 (NCO2C(CH3)3), 66.5 (C(2)),
47.6 (C(3)), 28.3 (CO2C(CH3)3), 27.9 (NCO2C(CH3)3), 18.5
(C(4)); m/z (CI) 301 (MHϩ, 100%); HRMS (CIϩ) found,
301.1871; C13H24N4O4 requires 301.1876. Further elution
returned starting material (2S,3S)-18 (182 mg, 25%) followed
by tert-butyl (4S,5R)-4-methyloxazolidin-2-one-5-carboxylate
20 (100 mg, 25%) as a white solid; Rf 0.18 [1 : 1 30–40 ЊC petrol :
EtOAc]; mp 107 ЊC [petrol : EtOAc]; found: C, 53.6; H, 7.25; N,
6.9%; C9H15NO4 requires C, 53.7; H, 7.5; N, 7.0%; [α]2D5 Ϫ22.6
(c 0.5,CHCl3); δH (400 MHz; CDCl3) 6.58 (1H, s, NH ), 4.39
(1H, d, J 5.7, CHCO2C(CH3)3), 3.91–3.94 (1H, m, CHCH3),
1.49 (9H, s, CO2C(CH3)3), 1.39 (3H, d, J 6.2, CHCH3); δC (100
MHz; CDCl3) 167.5 (CO2C(CH3)3), 158.4 (NC(O)O), 83.4
(CO2C(CH3)3), 79.7 (CHCO2C(CH3)3), 52.0 (CHCH3), 27.9
Preparation of tert-butyl (2S,3S )-2-hydroxy-3-tert-butyl-
carbonyloxyaminobutanoate 17
Pd(OH)2 on C (0.31 g) was added to a stirred solution of
(2S,3S,αS)-13 (0.30 g, 0.76 mmol) and di-tert-butyl dicarb-
onate (0.56 g, 2.58 mmol) in EtOAc (10 ml) and the mixture
stirred for 24 hours under H2 (5 atm) at rt. After filtration
through Celite and concentration in vacuo, purification by flash
chromatography on silica gel (10% Et2O : petrol) gave 17 (0.19
g, 89%) as a colourless oil; found: C, 56.85%; H, 9.4; N, 4.95%;
C13H25NO5 requires C, 56.7; H, 9.1; N, 5.1%; [α]2D3 ϩ10.6 (c 2.38,
(CO2C(CH3)3), 21.5 (CHCH3); νmax (KBr) 1764, 1731 (C᎐O);
᎐
HRMS (Electrospray) found, 202.1084; C9H16NO4 requires
202.1079; m/z (CIϩ) 202 (MHϩ, 85%).
Preparation of tert-butyl (2S,3S )-2-hydroxy-3-aminobutanoate
2143 and tert-butyl (4S,5S )-4-methyloxazolidin-2-one-5-
carboxylate 22
CHCl3); νmax (film) 3397 (N–H), 1717 br s (C᎐O, ester and carb-
᎐
Pd(OH)2 on C (250 mg) was added to a stirred solution of
(2S,3S,αS)-13 (500 mg, 1.36 mmol) in degassed MeOH (10 ml)
and stirred at rt under H2 (5 atm) overnight. After filtration
through Celite, concentration in vacuo gave (2S,3S)-21 (238 mg,
quant., identical to a commercially available sample from
Evotec OAI); δH (400 MHz; CDCl3) 4.33 (1H, d, J 2.8, C(2)H ),
3.68–3.63 (1H, m, C(3)H ), 1.52 (9H, s, CO2C(CH3)3), 1.21 (3H,
d, J 6.9, C(4)H3). Diphosgene (0.06 ml, 0.5 mmol) was added
dropwise to a stirred suspension of (2S,3S)-21 (80 mg, 0.45
mmol) and activated charcoal (20 mg) in toluene (5 ml) at rt
before heating at reflux for four hours. After cooling to rt, fil-
tration through Celite and concentration in vacuo, the residue
was washed with NH4Cl(aq) (20 ml) and extracted with EtOAc
(3 × 20 ml). Concentration in vacuo and purification by chrom-
atography on silica (Et2O) gave (4S,5S)-22 as a white solid (81
mg, 83%); mp 103–104 ЊC [petrol : Et2O]; [α]2D5 Ϫ11.6 (c 0.8,
CHCl3); δH (400 MHz; CDCl3) 6.48 (1H, s, NH ), 4.89 (1H, d,
J 8.6, CHCO2C(CH3)3), 4.22 (1H, dq, J 8.6, J 6.4, CHCH3),
1.51 (9H, s, CO2C(CH3)3), 1.25 (3H, d, J 6.4, CHCH3); δC (100
MHz; CDCl3) 166.1 (CO2C(CH3)3), 158.6 (NC(O)O), 83.6
(CO2C(CH3)3), 77.0 (CHCO2C(CH3)3), 50.1 (CHCH3), 28.0
(CO2C(CH3)3), 16.7 (CHCH3); νmax (KBr) 2983 (N–H), 1756,
amate); δH (200 MHz; CDCl3), 4.92 (1H, d, J 8.7, CONH ),
4.20–4.19 (1H, br m, OH ), 4.12–4.06 (1H, m, C(3)H ), 3.06
(1H, d, J 5.2, C(2)H ), 1.49 (9H, s, CO2C(CH3)3), 1.45 (9H, s,
NCO2C(CH3)3), 1.01 (3H, d, J 6.8, C(4)H3); δC (126 MHz;
CDCl3) 172.1 (C(1)), 155.2 (NCO2C(CH3)3), 83.2 (CO2C-
(CH3)3), 79.5 (NCO2C(CH3)3), 72.7 (C(2)), 48.4 (C(3)), 28.4
(CO2C(CH3)3), 28.0 (NCO2C(CH3)3), 14.1 (C(4)); m/z
(Electrospray) 293 (MNH4ϩ, 5%), 276 (MHϩ, 100%).
Preparation of tert-butyl (2S,3S )-2-methanesulfonyloxy-3-tert-
butylcarbonyloxyaminobutanoate 18
Methanesulfonyl chloride (0.24 ml, 3.13 mmol) in DCM (20 ml)
was added dropwise to a stirred solution of (2S,3S)-17 (820 mg,
2.98 mmol) in anhydrous DCM (20 ml) and NEt3 (0.58 ml, 4.17
mmol) at 0 ЊC. After 40 min the solution was warmed to rt and
stirred for a further 24 h before the addition of H2O (20 ml).
The mixture was partitioned between DCM (3 × 30 ml) and
H2O, dried and concentrated in vacuo before purification by
flash chromatography on silica gel (50% Et2O : petrol) to give 18
(870 mg, 78%) as a colourless oil; [α]2D1 Ϫ38.4 (c 0.56, CHCl3);
νmax (film) 3397 (N–H), 1749 (C᎐O, ester), 1709 (C᎐O, carb-
᎐
᎐
1727 (C᎐O); HRMS (Electrospray) found, 202.1083; C H NO
᎐
9
16
4
amate), 1369, 1176 (OSO2); δH (200 MHz; CDCl3), 5.19 (1H, d,
J 2.5, C(2)H ), 4.77 (1H, d, J 8.2, CONH ), 4.36–4.26 (1H, m,
C(3)H ), 3.16 (3H, s, OSO2CH3), 1.50 (9H, s, CO2C(CH3)3), 1.45
(9H, s, NCO2C(CH3)3), 1.10 (3H, d, J 6.9, C(4)H3); δC (126
MHz; CDCl3) 166.2 (C(1)), 154.9 (NCO2C(CH3)3), 83.8 (CO2C-
(CH3)3), 80.1 (NCO2C(CH3)3), 79.6 (C(2)), 47.2 (C(3)), 39.1
(OSO2Me), 28.3 (CO2C(CH3)3), 27.9 (NCO2C(CH3)3), 14.4
requires 202.1079; m/z (CIϩ) 202 (MHϩ, 70%).
Preparation of (2R,3S )-2,3-diaminobutanoic acid 3
Pd on C (42 mg) was added to a stirred solution of (2S,3S)-19
(84 mg, 0.27 mmol) in EtOAc (5 ml) and stirred overnight under
H2 (5 atm) at rt. Filtration through Celite and concentration in
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 0 8 – 3 7 1 5
3714

View Article Online
Aizpurua, F. Cabre, C. Cuevas, S. Munt and J. M. Odriozola,
Tetrahedron Lett., 1994, 35, 2725.
15 F. M. Rossi, E. T. Powers, R. Yoon, L. Rosenberg and J. Meinwald,
Tetrahedron, 1996, 52, 10279.
16 O. Mitsunobu, Synthesis, 1981, 1.
vacuo gave tert-butyl (2R,3S)-2-amino-3-tert-butylcarbonyloxy-
aminobutanoate (72 mg, 97%) as a white solid; mp 204–207 ЊC;
[α]2D3 Ϫ32.8 (c 0.54, CHCl3); νmax (KBr) 3426 (N–H, carbamate),
3356 (N–H), 1741 (C᎐O, ester) 1720 (C᎐O, carbamate); δ (500
᎐
᎐
H
MHz; CDCl3), 4.96 (1H, d, J 8.0, CONH ), 4.09 (1H, m, C(3)H ),
3.42 (1H, br s, C(2)H ), 1.47 (9H, s, CO2C(CH3)3), 1.42 (9H, s,
NCO2C(CH3)3), 1.16 (3H, d, J 6.8, C(4)H3); δC (126 MHz;
CDCl3) 122.6 (C(1)), 155.1 (NCO2C(CH3)3), 81.8 (CO2C(CH3)3),
79.0 (NCO2C(CH3)3), 58.2 (C(2)), 48.9 (C(3)), 28.4 (CO2C-
(CH3)3), 28.0 (NCO2C(CH3)3), 18.2 (C(4)); m/z (Electrospray)
275 (MHϩ, 53%), 219 (MHϩ Ϫ C4H8, 100). TFA (2.5 ml) was
added to tert-butyl (2R,3S)-2-amino-3-tert-butylcarbonyloxy-
aminobutanoate (30 mg, 0.11 mmol) at 0 ЊC for 10 min and then
warmed to rt overnight. Concentration in vacuo, followed by the
addition of HCl (1.0 M) and stirring for 1.5 h before concen-
tration in vacuo gave (2R,3S)-2,3-diaminobutanoic acid 3 as its
dihydrochloride salt; [α]2D5 Ϫ34.5 (c 1.15, 6 M HCl); lit.38 [α]2D2
Ϫ38.1 (c 1.0, 6 M HCl), lit.25 [α]2D0 Ϫ34.3 (c 1.0, 6 M HCl)}; δH
(400 MHz, D2O) 4.08 (1H, d, J 3.2, CHCO2H), 3.85–3.81 (1H, m,
CHCH3), 1.31 (3H, d, J 6.7, CHCH3).
17 U. Schmidt, K. Mundinger, B. Riedl, G. Haas and R. Lau,
Synthesis, 1992, 1201; J. H. Martin and W. K. Hausmann, J. Am.
Chem. Soc., 1960, 82, 2079.
18 Y. Nakamura, M. Hirai, K. Tamotsu, Y. Yonezawa and C. Shin,
Bull. Chim. Soc. Jpn, 1995, 68, 1369; P. G. Mattingly and M. J.
Miller, J. Org. Chem., 1980, 45, 410; P. G. Mattingly and J. F. Kerwin
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19 P. J. Dunn, R. Häner and H. Rapoport, J. Org. Chem., 1990, 55,
5017.
20 P. Merino, A. Lanaspa, F. L. Merchan and T. Tejero, Tetrahedron:
Asymmetry, 1998, 9, 629.
21 A. J. Robinson, P. Stanislawski and D. Mulholland, J. Org. Chem.,
2001, 66, 4148; A. J. Robinson, C. Y. Lim, L. He, P. Ma and H.-Y. Li,
J. Org. Chem., 2001, 66, 4141.
22 K.-D. Lee, J.-M. Suh, J.-H. Park, H.-J Ha, H. G. Choi, C. S. Park,
J. W. Chang, W. K. Lee, Y. Dong and H. Yun, Tetrahedron, 2001, 57,
8267.
23 K. P. P. Fondekar, F.-J. Volk, S. M. Khaliq-uz-Zaman, P. Bisel and
A. W. Frahm, Tetrahedron: Asymmetry, 2002, 13, 2241.
24 E. Dumez, A. Szeki and R. F. W. Jackson, Synlett, 2001, 8, 1214.
25 H. Han, J. Yoon and K. D. Janda, J. Org. Chem., 1998, 63, 2045.
26 S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin Trans. 1,
1994, 1141.
Further purification by ion exchange chromatography
(Dowex 50X8-200) gave 3 as a white powder (quantitative); [α]2D2
25
Ϫ27.2 (c 0.18, 6 M HCl); [α]D Ϫ28.5 (c 1.7, 6 M HCl); νmax
(KBr) 2971 (N–H, NH3ϩ), 2600–2000 (N–H, NH ), 1654 (C᎐O,
᎐
2
CO H), 1590 (C᎐O, CO Ϫ); δH (200 MHz; 2 M DCl) 4.15 (1H,
᎐
2
2
27 M. E. Bunnage, S. G. Davies, C. J. Goodwin and O. Ichihara,
Tetrahedron, 1994, 50, 3975; M. E. Bunnage, S. G. Davies and C. J.
Goodwin, Synlett, 1993, 731; M. E. Bunnage, S. G. Davies and C. J.
Goodwin, J. Chem. Soc., Perkin Trans. 1, 1993, 1375; M. E.
Bunnage, A. N. Chernega, S. G. Davies and C. J. Goodwin, J. Chem.
Soc., Perkin Trans. 1, 1994, 2373; M. E. Bunnage, A. J. Burke, S. G.
Davies and C. J. Goodwin, Tetrahedron: Asymmetry, 1994, 5, 203;
S. G. Davies, S. W. Epstein, A. C. Garner and A. D. Smith,
Tetrahedron: Asymmetry, 2002, 13, 1555.
d, J 3.4, C(2)H ), 3.66–3.61 (1H, m, C(3)H ), 1.07 (3H, d, J 6.8,
C(4)H3); δH (200 MHz; D2O) 4.19 (1H, d, J 3.5, C(2)H ), 3.93–
3.82 (1H, m, C(3)H ), 1.36 (3H, d, J 6.7, C(4)H3); δC {of HCl
salt) (126 MHz; D2O) 169.8 (C(1)), 54.1 (C(2)), 46.4 (C(3)),
12.9 (C(4)); m/z (CI) 119 (MHϩ, 100%); HRMS (CI) found,
119.0821; C4H10N2O2 requires 119.0821.
28 A. J. Burke, S. G. Davies and C. J. R. Hedgecock, Synlett, 1996, 621.
29 For a review of electrophilic amination procedures see: C. Greck and
J. P. Genet, Synlett, 1997, 741.
30 S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1991, 2, 183.
31 D. A. Evans, T. C. Britton, J. A. Ellman and R. L. Dorow, J. Am.
Chem. Soc., 1990, 112, 4011.
Acknowledgements
We thank Hoechst Marion Roussel for support (A. J. B.)
and New College, Oxford, for a Junior Research Fellowship
(A. D. S.).
32 This observation is in accord with that of Heimgartner and
coworkers who showed that when the lithium enolates derived
from N-methyl-N-phenylcarboxamides were treated with diphenyl-
phosphoryl azide at 0 ЊC the corresponding α-diazoamide was
obtained as the sole reaction product, see: J. M. Villalgordo,
A. Linden and H. Heimgartner, Helv. Chim. Acta, 1996, 79, 213.
33 P. O’Brien and T. D. Towers, J. Org. Chem., 2002, 67, 304.
34 P. F. Richardson, L. J. T. Nelson and K. B. Sharpless, Tetrahedron
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35 K. Weber, S. Kuklinski and P. Gmeiner, Org. Lett., 2000, 2, 647; A. S.
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36 T.-H. Chuang and K. B. Sharpless, Org. Lett., 1999, 1, 1435;
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42 Analysis of the 1H NMR spectra of the anti- and syn-diastereo-
isomers 2 and 3 respectively showed distinct differences in coupling
constants, with the C(2)–C(3) coupling constant in the syn-isomer
being ∼3 Hz, while in the anti-diastereoisomer it is 7 Hz, consistent
with those noted by Janda et al. (see reference 25).
14 R. Herranz, S. Vinuesa, J. Castro-Pichel, C. Perez and M. T. Garcia-
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43 (2S,3S)-tert-Butyl 2-hydroxy-3-aminobutanoate 21 is commercially
available from Evotec OAI.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 7 0 8 – 3 7 1 5
3715