New synthetic routes to α-amino acids and γ-oxygenated α-amino acids. Reductive denitration and oxidative transformations of γ-nitro-α-amino acids

Article abstract of DOI:10.1039/a707067e

Transformation of γ-nitro-α-amino acid derivatives into α-amino acids by reductive denitration, into the γ-oxo-α-amino acids by ozonolysis of the corresponding amino acid ester nitronate derivatives, and into γ-hydroxy-α-amino acid derivatives by subsequent reduction of the oxo functionality, can be achieved in good yields. As the γ-nitro-α-amino acid derivatives are prepared from N,O-protected dehydroalanines derivable from the corresponding alanine, serine and cysteine derivatives by specific routes, the overall procedures provide a means for selective conversion of these simple α-amino acids into more complex ones.

Full text of DOI:10.1039/a707067e

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New synthetic routes to á-amino acids and ã-oxygenated á-amino
acids. Reductive denitration and oxidative transformations of ã-nitro-
á-amino acids
Maxwell J. Crossley,* Yik M. Fung, Efstathia Kyriakopoulos and
Jeffrey J. Potter
School of Chemistry, The University of Sydney, NSW 2006, Australia
Transformation of ã-nitro-á-amino acid derivatives into á-amino acids by reductive denitration, into
the ã-oxo-á-amino acids by ozonolysis of the corresponding amino acid ester nitronate derivatives,
and into ã-hydroxy-á-amino acid derivatives by subsequent reduction of the oxo functionality, can be
achieved in good yields. As the ã-nitro-á-amino acid derivatives are prepared from N,O-protected
dehydroalanines derivable from the corresponding alanine, serine and cysteine derivatives by specific
routes, the overall procedures provide a means for selective conversion of these simple á-amino acids
into more complex ones.
In the preceding paper, we reported that conjugate addition to a
dehydroalanine 1 of a nitroalkane provides a general synthesis
of γ-nitro-α-amino acids 2 (Scheme 1).1 The nitro group of a
nitroalkane can be transformed into a variety of other func-
tional groups2 and so these γ-nitro-α-amino acids 2 have the
potential to be precursors of a variety of other γ-substituted
α-amino acids.
Nitro groups that are attached to tertiary carbon atoms or to
secondary carbon atoms that are activated by a vicinal electron-
withdrawing group can be reductively denitrated under radical
conditions.3–5 Thus, sequential application of conjugate add-
ition of a nitroalkane to a dehydroalanine 1 (available from
alanine, serine and cysteine, appropriately protected) and reduc-
tive denitration, followed by deprotection steps, affords a means
of selectively converting simple amino acids into more complex
α-amino acids 3 (Scheme 1). We have previously communicated
conversion of nitro groups into carbonyls.7–11 These methods
include a reductive procedure using aqueous TiCl3,8 the
ozonolysis of nitronates,9 and oxidative procedures using per-
manganates.10 Application of this chemistry to γ-nitro-α-amino
acids 2 would give γ-oxo-α-amino acid derivatives 4 which can
be reduced to the protected γ-hydroxy-α-amino acid 5 and sub-
sequently deprotected to give the corresponding amino acids. A
preliminary example of this route was reported in our synthesis
of γ-lactam analogues of β-lactam antibiotics.12
Results and discussion
Reductive denitration of ã-nitro-á-amino acid derivatives
3-Cyclohexylalanine 9, N-Cbz-leucine 12, N-Cbz-glutamic acid
15 and N-phthaloylglutamic acid 18 have been prepared in
good yields by reductive denitration of the corresponding
N-protected γ-nitro-α-amino acid esters 2, followed by depro-
tection steps.
The synthesis of 3-cyclohexylalanine 9, the saturated-ring
analogue of phenylalanine, which uses the reductive denitration
strategy, is outlined in Scheme 2.† Methyl 2-(benzyloxycarb-
onylamino)-3-(1Ј-nitrocyclohexyl)propanoate1 6 was treated
with tributylstannane and 2,2Ј-azobis-(2-methylpropionitrile)
R3
CO2R
R4
H
alanine, serine or cysteine
+
NR1R2
NO2
1
base
R3
R4
CO2R
R3
CO2R
NR1R2
O2N
CO2Me
NHCbz
CO2R
NHCbz
oxidation
i
NO2 NR1R2
O
2
4
7 R = Me
8 R = H
ii
6
reduction
denitration
iii
R3
R4
CO2R
NR1R2
R3
H
CO2R
NR1R2
CO2
NH3
H
OH
3
5
9
Scheme 1
Scheme 2 Reagents and conditions: i, tributylstannane, AIBN, C6H6,
heat, 4 h; ii, NaOH (10%), room temp., 16 h; iii, cyclohexene, 10% Pd/C,
EtOH, heat, 20 min
an example of this synthetic sequence in the conversion of an
-alanine derivative into the corresponding -leucine.6
Modification of the nitro group of γ-nitro-α-amino acids 2
into oxo and hydroxy functionalities also provides a new route
to γ-oxygenated α-amino acids 4 and 5 (Scheme 1). A number
of high-yielding, mild procedures have been reported for the
† All the amino acid derivatives in this work are racemic although for
simplicity only one of the enantiomers is shown in the Schemes.
J. Chem. Soc., Perkin Trans. 1, 1998
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(AIBN) in refluxing benzene3,4 for 4 h which gave methyl
2-(benzyloxycarbonylamino)-3-cyclohexylpropanoate 7 in 65%
yield after the tin compounds were removed by chromato-
graphy. Compound 7 was saponified with 10% aqueous
sodium hydroxide and the resultant N-protected cyclohexyl-
alanine derivative 8 was hydrogenolysed under catalytic hydro-
gen transfer conditions to give racemic 3-cyclohexylalanine 9
in 80% overall yield from the doubly protected compound 7.
Previous syntheses of 3-cyclohexylalanine 9, and compounds
containing this amino acid residue, have involved catalytic
reduction of a phenylalanine derivative.13–16 Unlike these routes,
our new route to 3-cyclohexylalanine 9 should be easily modi-
fied to provide an entry to derivatives with additional ring sub-
stitution by use of substituted nitrocyclohexanes in the initial
conjugate addition to a dehydroalanine derivative.
give 5-ethyl 1-methyl 2-phthalimidopentane-1,5-dioate 17 in
58% yield after column chromatography. Both ester function-
alities were successfully hydrolysed by treatment with base to
give N-phthaloylglutamic acid20 18 in 75% yield.
While the reductive denitration methodology is restricted to
tertiary or activated secondary nitroalkanes, the utility of the
approach outlined in this paper could be extended to include
removal of nitro groups from unactivated secondary positions
by initial conversion of the nitro group into a keto or hydroxy
functionality, both of which can be reductively removed by
selective processes, thereby allowing synthesis of amino acids
with long side chains. Reductive deoxygenation of the second-
ary alcohol21–23 of the corresponding γ-hydroxy-α-amino acid 5
is one such approach. While we have not yet investigated reduc-
tive deoxygenation of such compounds, we now report the effi-
cient conversion of γ-nitro-α-amino acid derivatives 2 into the
corresponding γ-hydroxy-α-amino acid derivatives 5 (Scheme 1)
as is required in the preliminary step.
A new route to N-Cbz-leucine 12 was also developed. Treat-
ment of methyl 2-(benzyloxycarbonylamino)-4-methyl-4-nitro-
pentanoate1 10 under reductive denitration conditions gave N-
Cbz-leucine methyl ester 11 in 67% yield (Scheme 3). Saponifi-
A new synthesis of ã-oxygenated á-amino acids
This methodology is illustrated by syntheses of the 4-oxo-
glutamic acid derivative 19, the 4-hydroxyglutamic acids 21, the
4-oxo- and 4-hydroxy-norvaline derivatives 23–27, the pro-
tected homoserine aldehyde 29 and the aspartic acid derivative
31.
Me
Me
CO2Me
Me
CO2R
NHCbz
i
NO2 NHCbz
10
Me
11 R = Me
12 R = H
ii
The route to 4-hydroxyglutamic acids 21 is outlined in
Scheme 5 and involves oxidation of dimethyl 2-(benzyloxycarb-
Scheme 3 Reagents and conditions: i, tributylstannane, AIBN, C6H6,
heat, 4 h; ii, NaOH (10%), room temp., 16 h
MeO2C
CO2Me
NHCbz
MeO2C
CO2Me
i
cation of the ester 11 afforded a 91% yield of N-Cbz-leucine17
12. The carbamate protecting group can be removed under a
variety of mild conditions.18 This synthesis was the foundation
on which our recent stereoselective conversion of an -alanine
derivative into the corresponding -leucine derivative was
based.6 Previous syntheses of leucine have centred on the intro-
duction of the functional groups by reactions on isobutyl
halides, 3-methylbutyraldehyde and 4-methylpentanoic acid
derivatives.19 The present method differs in approach in that the
amino acid functional groups are already in place and it is the
side-chain which is elaborated in the procedure.
O
NO2 NHCbz
13
19
ii
HO2C
CO2
NH3
MeO2C
CO2Me
NHCbz
iv
OH
OH
21
20
The synthesis of glutamic acid derivatives follows a similar
approach to that outlined above. Reductive denitration of
dimethyl 2-(benzyloxycarbonylamino)-4-nitropentane-1,5-di-
oates1 13 with tributylstannane and AIBN gave the denitrated
diester 14 in 65% yield (Scheme 4). Base hydrolysis of the
iii
20a more polar isomer
20b less polar isomer
Scheme 5 Reagents and conditions: i, N-Benzyltrimethylammonium
hydroxide, MeOH, stirred for 10 min, cooled to Ϫ78 ЊC and treated
with O3–O2, Me2S, warmed to room temp. and stirred overnight; ii,
NaBH4, MeOH, Ϫ20 ЊC, stirred for 30 min, then HCl–MeOH; iii,
HPLC (µ-Porasil column); iv, H2, 10% Pd/C, HCl–MeOH, for 1 h, then
LiOH, stirred at 70 ЊC overnight
RO2C
CO2Me
NO2 NR1R2
13 R = Me, R1 = Cbz, R2 = H
16 R = Et, R1R2 = Phth
i
onylamino)-4-nitropentane-1,5-dioates 13 which are readily
available by conjugate addition of methyl nitroacetate to methyl
2-(benzyloxycarbonylamino)acrylate.1 With a minor modifi-
cation, the McMurry, Melton and Padgett method of form-
ation of carbonyls by the ozonolysis of nitronate anions9 has
proved to be most useful in conversion of the nitro adducts
to the corresponding ketone. N-Benzyltrimethylammonium
hydroxide was used as the base to generate the nitronate in
place of the recommended sodium methoxide, and the yield of
pure dimethyl 2-(benzyloxycarbonylamino)-4-oxopentane-1,5-
dioate 19 from nitro compound 13 was 69%. When sodium
methoxide was substituted as the base, prolonged reaction
times were required in larger scale preparations, and this often
resulted in the formation of substantial amounts of hydrolysed
by-products. The ozonolysis method was also found best in our
related studies leading to the synthesis of amino acids contain-
ing an azetidine ring.24
RO2C
CO2Me
NR1R2
14 R = Me, R1 = Cbz, R2 = H
17 R = Et, R1R2 = Phth
ii
HO2C
CO2H
NR1R2
15 R1 = Cbz, R2 = H
18 R1R2 = Phth
Scheme 4 Reagents and conditions: i, tributylstannane, AIBN, C6H6,
heat, 4 h; ii, NaOH (10%), room temp., overnight
diester 14 gave N-Cbz-glutamic acid 15 in 71% yield after
recrystallisation. The N-phthaloylglutamic acid, 18, was syn-
thesised in a similar way (Scheme 4). The mixture of diastereo-
meric nitro diesters1 16 was reductively denitrated as above to
Treatment of the ketone 19 with NaBH4 in anhydrous
methanol at Ϫ20 ЊC, followed by decomposition of the excess
1124
J. Chem. Soc., Perkin Trans. 1, 1998

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borohydride with methanolic HCl, gave the alcohols 20a and
20b as a 1:1 diastereomeric mixture in 93% yield (Scheme 5).
Addition of methanolic HCl to decompose the excess reagent
and use of a low reaction temperature were essential for high
yields. Substantial hydrolysis of the products was observed
when these conditions were not employed. The two diastereo-
mers were readily separated by normal phase HPLC but the
absolute stereochemistry [(2RS,4RS) or (2RS,4SR)] of each
could not be assigned directly. As is illustrated in the follow-
ing synthesis of 4-hydroxynorvaline derivatives, an indirect
method for assigning relative stereochemistry is available by
conversion of the compounds to the corresponding γ-butyro-
lactones; in this case the erythro-(2RS,4SR)-isomer would
give the trans-disubstituted butyrolactone while the threo-
(2RS,4RS)-isomer would give the cis-disubstituted isomer.
Deprotection of the 2-(benzyloxycarbonylamino)-4-hydroxy-
pentane-1,5-dioic acid diesters 20 was carried out in high
yield by hydrogenolysis over palladium on carbon, under acid
catalysis, to give dimethyl 4-hydroxyglutamate hydrochloride
which was then warmed overnight with aqueous lithium
hydroxide and carefully acidified to pH 3 to afford 4-hydroxy-
glutamic acid 21. This amino acid was obtained as a 1:1
mixture of diastereomers in 92% yield after purification of the
product by ion-exchange chromatography on Dowex-1-
acetate.25,26 The alternate deprotection sequence proved to be
unsatisfactory as base hydrolysis of the dimethyl esters 20 with
aqueous sodium or lithium hydroxide, followed by acidification,
gave a mixture of the diacid 21 and the corresponding lactones.
4-Hydroxyglutamic acid has been isolated from the green
parts of the plants, Phlox decussa27 and Linaria vulgaris28 and
has been synthesised in a low yield as a diastereomeric mixture
by Benoiten and Bouthillier29 and Hanafusa and co-workers30
using malonic ester methodology.
The transformation of a dehydroalanine into 4-hydroxy-
glutamic acids 21 establishes a new route for construction of
the 4-hydroxy-2-amino acid skeleton. Incorporation of stereo-
control into the sequence by asymmetric reduction of the
prochiral ketone functionality and through the use of an
enantiomerically pure asymmetric dehydroalanine as starting
material would greatly improve the usefulness of the method-
ology and is addressed in other work.6,31
The synthetic route to 4-hydroxynorvaline derivatives 24–27
follows that used to synthesise 4-hydroxyglutamic acid 21 and is
outlined in Scheme 6. Methyl 2-(benzyloxycarbonylamino)-4-
nitropentanoates 22, readily available by the addition of nitro-
ethane to methyl 2-(benzyloxycarbonylamino)acrylate,1 were
converted by ozonolysis of the corresponding nitronate into the
4-oxo derivative 23 in 84% yield.
H
CbzHN
H'
Me
O
O
H
H
24
H
H
CbzHN
O
CbzHN
Me
H'
O
O
H
H
O
H
H
Me
H'
25
Fig. 1 Conformations of the lactones 24 and 25
Treatment of methyl 2-(benzyloxycarbonylamino)-4-oxo-
pentanoate 23 with NaBH4 in anhydrous methanol at Ϫ20 ЊC,
followed by decomposition of the excess borohydride with
methanolic HCl, gave the corresponding cis- and trans-4-
hydroxyamino acid lactones, 24 and 25 respectively, as a 1:1
mixture in quantitative yield. Gelin and Chignac have reported
the preparation of γ-lactones by similar reduction of 4-oxo-
carboxylic acid esters.32 From a synthetic viewpoint, formation
of lactone products instead of the hydroxy esters is of little
consequence as hydrolysis of the lactones 24 and 25 would give
the same acids as those arising from hydrolysis of the corre-
sponding 4-hydroxy esters 26 and 27. Lactone formation has a
practical value, however, as it allows assignment of the relative
stereochemistry of the products and, by interconversion, the
related acyclic 4-hydroxy esters.
The two lactone isomers were separated by normal phase
HPLC. The structures of the lactones 24 and 25 were assigned
unequivocally by use of 1H NMR spectroscopy on the basis of
the chemical shifts of the two geminal protons, 3- and 3Ј-H on
the 2,4-disubstituted-γ-butyrolactones, and on the magnitude
of the vicinal coupling constants of these ring protons.33 The
more polar isomer (3-H resonance at δ 2.86, 3Ј-H resonance at
δ 1.79; J2,3 12.2, J3,4 10.8 Hz) has the cis-stereochemistry 24. The
less polar compound (3-H resonance at δ 2.47, 3Ј-H resonance
at δ 2.33) has the trans-stereochemistry 25. In lactone 24 and
related cis-2,4-disubstituted-γ-butyrolactones the coupling con-
stants J2,3 and J3,4 are larger than in the trans-2,4-disubstituted-
γ-butyrolactones, and are characteristic of quasi-axial–quasi-
axial interactions indicating that the conformation shown in
Fig. 1, in which both the C-2 and C-4 substituents are in quasi-
equatorial positions, is strongly preferred. The proton 3-H is
thus in a quasi-axial position and, as expected, it resonates 1.07
ppm downfield of the quasi-equatorial proton 3Ј-H in the
1H NMR spectrum. For the trans-2,4-disubstituted-γ-butyro-
lactone 25, the difference in the chemical shifts of the protons,
3- and 3Ј-H is small (0.14 ppm) and the vicinal coupling con-
stants to these protons are similar in magnitude, observations
that are consistent with there being two accessible conformers
(Fig. 1) that are in fast exchange on the NMR timescale so that
3- and 3Ј-H have similar magnetic environments.
NHCbz
O
NHCbz
O
Me
CO2Me
NHCbz
ii
O
Me
Me
O
O
24
25
23
i
iv
Me
CO2Me Me
NHCbz
CO2Me
NHCbz
Me
CO2Me
iii
OH
OH
NO2 NHCbz
Incomplete lactonisation occurred in several runs of this
reaction to give a small amount (0–20%) of the erythro-4-
hydroxy-2-amino acid ester 27 in addition to the lactones; in
these cases the yield of the trans-isomer 25 was reduced by an
equivalent amount. The corresponding threo-isomer 26 was
never detected under these reaction conditions presumably
because cyclisation of the threo-alcohol 26 to form the cis-
lactone 24 is more favourable as both the C-2 and C-4 substitu-
ents in 24 can occupy quasi-equatorial positions.
22
26
27
Scheme 6 Reagents and conditions: i, N-Benzyltrimethylammonium
hydroxide, MeOH, stirred for 10 min, cooled to Ϫ78 ЊC and treated
with O3–O2, Me2S, warmed to room temp. and stirred overnight; ii,
NaBH4, MeOH, Ϫ20 ЊC, stirred for 1 h, cooled to Ϫ40 ЊC, HCl–MeOH;
iii, N-benzyltrimethylammonium hydroxide, MeOH, stirred for 10 min,
cooled to Ϫ78 ЊC and treated with O3–O2, then NaBH4 at Ϫ78 ЊC, at
4 ЊC for 10 min, cooled to Ϫ78 ЊC and HCl–MeOH added until pH < 3;
iv, C6H6, heat
J. Chem. Soc., Perkin Trans. 1, 1998
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The 4-hydroxy acid esters, 26 and 27, were prepared in good
yield by direct reduction, NaBH4 at 4 ЊC, of the intermediate
ozonide obtained by ozonolysis of the nitronate derived from
22 (Scheme 6). The isomers were separated easily by flash
column chromatography to afford the threo-isomer 26 in 39%
yield and the erythro-isomer 27 in 31% yield, together with 17%
yield of the corresponding trans-lactone 25; the structures of
the acyclic 4-hydroxy acid esters were assigned by conversion of
the less polar isomer into the corresponding cis-lactone 24 upon
heating in refluxing benzene, thereby establishing that it was the
threo-isomer 26.
No further investigation was undertaken into the deprotec-
tion of either the lactones 24 and 25 or esters 26 and 27 as they
were prepared primarily as precursors for the synthesis of cyclic
hydroxamates of biological interest as will be described separ-
ately.34 The free 4-hydroxynorvalines should be accessible under
conditions similar to those used for the deprotection of the
esters 20 leading to the free 4-hydroxyglutamic acids 21.
Homoserine aldehyde (2-amino-4-oxobutanoic acid) is a syn-
thetically useful precursor of a range of other 4-hydroxy-2-
amino acids through reactions that involve addition to the
formyl group.35 The methodology that we have introduced in
this paper allows a new synthesis of this compound in protected
form 29 as is shown in Scheme 7.
lactone 30 was isolated in 12% yield. When the reaction mix-
ture was held at Ϫ78 ЊC for 1 h after addition of the NaBH4,
and worked up in methanolic HCl, the major product proved
to be the aspartic acid derivative, dimethyl 2-(benzyloxycarb-
onylamino)butane-1,4-dioate 31, which was obtained in 30%
yield (Scheme 7). The problems in the conversion of primary
nitroalkanes into aldehydes arise as a result of over-oxidation
of the reaction intermediates. This was overcome by applying
pyridine as an additive to the reaction. The use of pyridine in
ozonolysis has been reported to favour the formation of alde-
hydes rather than ozonides or peroxides.36,37 Thus treatment
of the nitronate of 28, generated by the addition of N-benzyl-
trimethylammonium hydroxide to a methanolic solution of
the nitro intermediate, with ozone in the presence of 1 equiv.
of pyridine, followed by reduction with dimethyl sulfide, gave
the protected homoserine aldehyde 29 in 50% yield (Scheme 7).
Conclusions
A number of studies have shown the value of dehydroalanines
in the synthesis of more complex α-amino acids,1,6,12,20,38–48 and
the work described in this paper is a further example of this
fact. Conjugate addition of nitroalkanes to a dehydroalanine
derivative followed by reductive denitration of the resultant
γ-nitro-α-amino acid derivative provides a new route for syn-
thesis of proteinogenic (leucine and glutamic acid derivatives)
and non-proteinogenic α-amino acids. A new method for the
synthesis of γ-oxygenated α-amino acids has also been estab-
lished. The method involves transformation of γ-nitro-α-amino
acid derivatives into the corresponding γ-oxo-α-amino acids
and γ-hydroxy-α-amino acids, the γ-oxo-α-amino acids being
obtained by ozonolysis of the corresponding amino acid nitro-
nate derivatives, and the γ-hydroxy derivatives by subsequent
reduction of the oxo functionality. As dehydroalanines can
be prepared in specific routes from alanine,49 serine50–52 or
cysteine53,54 the route allows the conversion of these simple
amino acids into more complex amino acids. In an extension
of this work, convenient routes to γ-lactams and azetidines of
biological interest have been established that involve other
transformations of γ-nitro-α-amino acid derivatives12,24 and
stereocontrol which avoids the formation of racemic α-amino
acids has been achieved through the use of a chiral dehydro-
alanine precursor.6,31
H
CO2Me
NHCbz
O2N
CO2Me
NHCbz
i
O
28
29
iii
ii
NHCbz
O
CO2Me
NHCbz
MeO2C
O
30
31
Scheme 7 Reagents and conditions: i, N-Benzyltrimethylammonium
hydroxide, MeOH, stirred for 10 min, pyridine, cooled to Ϫ78 ЊC,
treated with O3–O2 for 15 min, Me2S at Ϫ78 ЊC, left to stand over-
night at room temp.; ii, N-benzyltrimethylammonium hydroxide,
MeOH, stirred for 10 min, cooled to Ϫ78 ЊC, treated with O3–O2 for
30 min, NaBH4 at Ϫ78 ЊC, raised temp. to 0 ЊC, HCl–MeOH; iii,
N-benzyltrimethylammonium hydroxide, MeOH, stirred for 10 min,
cooled to Ϫ78 ЊC and treated with O3–O2, NaBH4 at Ϫ78 ЊC, after 1 h
raised temp. to 0 ЊC, HCl–MeOH
Experimental
General experimental details have been reported previously.1
Infrared spectra were recorded either on a Perkin-Elmer 1600
FTIR, a Digilab FTS-50 or a Perkin-Elmer 710B spectro-
photometer from neat liquid films (sodium chloride plates) or
Conversion of methyl 2-(benzyloxycarbonylamino)-4-nitro-
butanoate1 28 to the aldehyde 29 requires oxidative cleavage
of the nitrogen᎐carbon bond. Two relatively straightforward
methods have been reported for the conversion of primary
nitroalkanes into aldehydes. Kornblum and co-workers have
reported the conversion of 1-nitrodecane into decanal by
potassium permanganate oxidation in 92% yield.10 With the
ozonolysis method, McMurry and co-workers reported the
conversion of 1-nitrooctane into octanal in 65% yield.9 In order
to avoid over-reaction in the latter case, however, it was found
necessary to control the amount of ozone introduced into
the reaction. Optimum yields of octanal were obtained when
exactly 1 equiv. of ozone was used.
Treatment of the nitro adduct 28 with sodium tert-butoxide
followed by potassium permanganate and boric acid, condi-
tions similar to those employed in the preparation of decanal,10
gave less than 10% of the desired aldehyde 29. Application of
McMurry’s ozonolysis method9 for the oxidation also proved
to be unsatisfactory. Treatment of the intermediate ozonide,
derived by treatment of the nitronate obtained from 28 with
ozone at Ϫ78 ЊC, with NaBH4 and allowing the reaction mix-
ture to rise immediately to room temperature gave a complex
mixture from which 2-(benzyloxycarbonylamino)-γ-butyro-
1
as chloroform solutions as indicated. H NMR spectra were
recorded on a Varian EM-390 (90 MHz), a Varian XL-100 (100
MHz), a Bruker AC-200F (200 MHz), a Bruker AMX-400 (400
MHz) or a Bruker AMX-600 (600 MHz) spectrometer.
Analytical high performance liquid chromatography (HPLC)
was carried out on a system consisting of a Waters model
6000A pump, U6K injector, a Waters model 440 ultraviolet
detector (set at a wavelength of 254 nm) and a Waters model
R401 refractive index detector. Preparative HPLC was per-
formed with a Waters model 510EF pump, U6K injector, a
Waters model 481 ultraviolet detector (set at a wavelength of
254 nm) and a Waters model R403 refractive index detector.
The columns used were Whatman Partisil 5 (analytical) 4.6 mm
ID × 25 cm, Brownlee LiChrosorb Si-100 (5 µm) (analytical)
4.6 mm ID × 25 cm, Waters µ-Porasil (semi-preparative) 7.8 mm
ID × 30 cm, Whatman Partisil M9 10/50 (semi-preparative) 9.4
mm ID × 50 cm and Whatman Partisil 10 (preparative) 22.0
mm ID × 50 cm.
Ozone was generated from industrial grade oxygen with a
Wallace and Tiernan laboratory ozonator, model BA-023.
1126
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Methyl 2-(benzyloxycarbonylamino)-3-cyclohexylpropanoate 7
A solution of methyl 2-(benzyloxycarbonylamino)-3-(1Ј-nitro-
cyclohexyl)propanoate1 6 (348 mg, 0.96 mmol) and tributyl-
stannane (0.32 cm3, 350 mg, 1.2 mmol) in dry benzene (12 cm3)
was treated with 2,2Ј-azobis-(2-methylpropionitrile) (AIBN)
(32.8 mg, 0.20 mmol) and heated at reflux for 4 h, allowed
to cool and concentrated under reduced pressure to a yellow
oil. Chromatography over silica (light petroleum) eluted the
organotin compounds, and further elution with ether–light
petroleum (3:1) gave methyl 2-(benzyloxycarbonylamino)-3-
cyclohexylpropanoate 7 (185 mg, 65%) as an oil (Found: Mϩ,
319.1775. C18H25NO4 requires M, 319.1783); νmax(film)/cmϪ1
3300 (NH) and 1710br (C᎐O ester and urethane); δ (90 MHz;
2-(Benzyloxycarbonylamino)-4-methylpentanoic acid (N-Cbz-
leucine) 12
Methyl 2-(benzyloxycarbonylamino)-4-methylpentanoate 11
(250 mg, 0.90 mmol) was treated with aqueous sodium hydrox-
ide (10%; 20 cm3) and warmed gently until the reaction mixture
became homogeneous. The reaction mixture was allowed to
stand at room temperature for 16 h and was then acidified with
aqueous hydrochloric acid (3 mol dmϪ3) and extracted with
ether (3 × 30 cm3). The combined ethereal extracts were washed
with water, dried and concentrated under reduced pressure to
leave a yellow oil (217 mg, 91%) which was recrystallised from
ether–light petroleum to give 2-(benzyloxycarbonylamino)-4-
methylpentanoic acid 12 as needles; mp 54–55 ЊC (lit.,17 mp
52–55 ЊC); δH(90 MHz; CDCl3) 0.87 [6 H, d, J 6.0, C(CH3)2],
1.30–1.93 (3 H, m, 4-H, 3-Ha and Hb), 3.80–4.10 (1 H, br s,
OH), 4.42–4.70 (1 H, m, 2-H), 5.10 (2 H, s, CH2Ar), 5.16–5.41
(1 H, br s, NH) and 7.25 (5 H, s, ArH).
᎐
H
CDCl3) 0.70–1.90 (13 H, m, cyclohexyl H, 3-Ha and Hb), 3.70
(3 H, s, OCH3), 4.15–4.50 (1 H, m, 2-H), 5.12 (3 H, br s, NH
and CH2Ar) and 7.32 (5 H, s, ArH); m/z (EI) 319 (Mϩ, 3%), 260
(59) and 184 (11).
2-(Benzyloxycarbonylamino)-3-cyclohexylpropanoic acid
(N-Cbz-3-cyclohexylalanine) 8
Dimethyl 2-(benzyloxycarbonylamino)pentane-1,5-dioate
(N-Cbz-glutamic acid dimethyl ester) 14
Methyl 2-(benzyloxycarbonylamino)-3-cyclohexylpropanoate 7
(380 mg, 1.2 mmol) was treated with aqueous sodium hydroxide
(10%, 20 cm3) and warmed gently until the reaction mixture
became homogeneous. The reaction mixture was allowed to
stand at room temperature for 16 h and was then acidified
with aqueous hydrochloric acid (3 mol dmϪ3) and extracted
with ether (3 × 30 cm3). The combined ethereal extracts were
washed with water (30 cm3), dried and concentrated under
reduced pressure to leave a yellow solid. Two recrystallisations
from hexane–ethyl acetate gave 2-(benzyloxycarbonylamino)-3-
cyclohexylpropanoic acid 8 (293 mg, 81%) as prisms; mp 115–
116.5 ЊC (lit.,39 mp 114–116 ЊC); νmax(film)/cmϪ1 3600–2500br
Dimethyl
2-(benzyloxycarbonylamino)-4-nitropentane-1,5-
dioates1 13 (367 mg, 1.04 mmol) and tributylstannane (332
mg, 1.04 mmol, 1.1 equiv.) in dry benzene (20 cm3) were treated
with AIBN (32.8 mg, 0.20 mmol) and heated at reflux for 4 h,
allowed to cool and concentrated under reduced pressure to an
orange oil. The crude residue was purified by flash column
chromatography over silica (light petroleum) to remove the tin
compounds. Further elution with ethyl acetate–light petroleum
(2:3) gave dimethyl 2-(benzyloxycarbonylamino)pentane-1,5-
dioate 14 (207 mg, 65%) as a colourless viscous oil [Rf 0.48
analytical TLC, silica 60, 0.25 mm layer, ethyl acetate–light
petroleum (2:3)]. A small sample was further purified for
elemental analysis by semi-preparative normal phase HPLC
[Whatman Partisil M9 10/50, ethyl acetate–light petroleum
(1:3), flow rate 3.0 cm3 minϪ1] (Found: C, 58.1; H, 6.3; N, 4.7.
C15H19NO6 requires C, 58.2; H, 6.2; N, 4.5%); νmax(liquid film)/
cmϪ1 3340 (NH), 3029 (aromatic CH), 2954 (CH), 2848 (CH)
(OH), 3450 (NH) and 1710br (C᎐O acid and urethane); δ (100
᎐
H
MHz; CDCl3) 0.78–2.16 (13 H, m, cyclohexyl H, 3-Ha and Hb),
4.22–4.62 (1 H, br m, 2-H), 5.14 (2 H, s, CH2Ar), 5.08–5.52
(1 H, br s, NH), 7.38 (5 H, s, ArH) and 7.42–8.08 (1 H, br s,
CO2H); m/z (CI-CH4) 306 (Mϩ ϩ 1, 12%), 304 (Mϩ Ϫ 1, 5), 262
(Mϩ Ϫ CO2, 46) and 119 (100).
and 1740–1700br (C᎐O ester); δ (600 MHz; CDCl ) 1.95–2.03
᎐
H
3
(1 H, m, 3-Ha), 2.19–2.26 (1 H, m, 3-Hb), 2.35–2.47 (2 H, m,
4-H), 3.68 (3 H, s, OCH3), 3.76 (3 H, s, OCH3), 4.39–4.44 (1 H,
m, 2-H), 5.12 (2 H, s, CH2Ar), 5.20–5.28 (1 H, m, NH) and
7.30–7.44 (5 H, m, ArH); δC(50 MHz; CDCl3) 27.62 (CH2),
29.89 (CH2), 51.79 (CH2), 52.52 (OCH3), 53.28 (CH), 67.06
(CH2Ar), 128.09 (ArC), 128.19 (ArC), 128.51 (ArC), 136.11
(ipso ArC), 155.88 (NHCO2), 172.26 (CO) and 173.08 (CO);
m/z (EI) 309 (Mϩ, 1.3%), 206 (10), 108 (19), 107 (10), 92 (11)
and 91 (100).
3-Cyclohexylalanine 9
A solution of 2-(benzyloxycarbonylamino)-3-cyclohexylprop-
anoic acid 8 (120 mg, 0.39 mmol) in ethanol was treated with
cyclohexene (5 cm3), 10% palladium on charcoal (100 mg) and
heated at reflux for 20 min. The reaction mixture was then
diluted with ethanol (20 cm3) and filtered through a pad of
Celite. The solid residues were washed thoroughly with hot
ethanol and the combined filtrate was concentrated under
reduced pressure to leave a white solid (67 mg), which was
recrystallised from water to give 3-cyclohexylalanine 9 (64 mg,
96%) as needles; mp 237–238 ЊC (lit.,13 mp 229–230 ЊC);
νmax(Nujol)/cmϪ1 3600–2000br (NH3ϩ), 1620, 1590 (CO2Ϫ) and
2-(Benzyloxycarbonylamino)pentane-1,5-dioic acid (N-Cbz-
glutamic acid) 15
ϩ
Dimethyl 2-(benzyloxycarbonylamino)pentane-1,5-dioate 14
(240 mg, 0.77 mmol) was treated with aqueous sodium hydrox-
ide (10%; 2 cm3) and warmed gently until the reaction mixture
became homogeneous. The reaction was allowed to stir at room
temperature overnight and was then acidified with aqueous
hydrochloric acid (3 mol dmϪ3) and extracted with ether (3 × 30
cm3). The combined ethereal extracts were washed with water
(3 × 20 cm3), dried and concentrated under reduced pressure
to leave a yellow oil. The oil was recrystallised from ether–light
petroleum to give 2-(benzyloxycarbonylamino)pentane-1,5-
dioic acid 15 (155 mg, 71%) as a white powder; mp 121–122 ЊC
(lit.,40 mp 120 ЊC); δH(200 MHz; CDCl3–[2H6]DMSO) 1.92–2.52
(4 H, m, 3- and 4-H), 4.28–4.44 (1 H, m, 2-H), 5.12 (2 H, s,
CH2Ar), 5.64–5.76 (1 H, br d, J 8.0, NH) and 7.32–7.40 (5 H,
m, ArH).
1510 (NH3 bend); δH(100 MHz; CD3OD–D2O) 0.74–1.94 (13
H, m, cyclohexyl H, 3-Ha and Hb) and 3.68 (1 H, dd, J 9.0 and
6.0, 2-H).
Methyl 2-(benzyloxycarbonylamino)-4-methylpentanoate
(N-Cbz-leucine methyl ester) 11
A solution of methyl 2-(benzyloxycarbonylamino)-4-methyl-4-
nitropentanoate1 10 (600 mg, 1.85 mmol) and tributylstannane
(0.64 cm3, 700 mg, 1.85 mmol) in dry benzene (15 cm3) was
treated with AIBN (30 mg, 0.18 mmol) and heated at reflux for
4 h, allowed to cool and concentrated under reduced pressure
to a colourless oil. Chromatography over silica (hexane) eluted
the organotin compounds, and further elution with ether gave
methyl 2-(benzyloxycarbonylamino)-4-methylpentanoate 11
(350 mg, 67%) as an oil (lit.,17 oil); νmax(film)/cmϪ1 3350 (NH)
and 1760–1705br (C᎐O ester and urethane); δ (100 MHz;
᎐
H
CDCl3) 0.91 [6 H, d, J 6.0, C(CH3)2], 1.40–1.70 (3 H, m, 4-H, 3-
Ha and Hb), 3.70 (3 H, s, OCH3), 4.22–4.50 (1 H, m, 2-H), 5.10
(3 H, s over br m, NH and CH2Ar) and 7.34 (5 H, s, ArH). This
material was further characterised as the acid 12.
5-Ethyl 1-methyl 2-phthalimidopentane-1,5-dioate 17
5-Ethyl 1-methyl 4-nitro-2-phthalimidopentane-1,5-dioates1 16
(353 mg, 0.97 mmol) and tributylstannane (310 mg, 1.07 mmol,
1.1 equiv.) in dry benzene (20 cm3) were treated with AIBN
J. Chem. Soc., Perkin Trans. 1, 1998
1127

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(35.0 mg, 0.213 mmol) and heated at reflux for 4 h, allowed to
cool and concentrated under reduced pressure to an orange
oil. The crude residue was purified by flash column chrom-
atography over silica (ethyl acetate–light petroleum; 2:3, Rf
0.55) to give 5-ethyl 1-methyl 2-phthalimidopentane-1,5-dioate
17 (180 mg, 58%) as a colourless viscous oil. A small sample
was further purified for elemental analysis by preparative
normal phase HPLC [Whatman Partisil 10, ethyl acetate–light
petroleum (1:3), flow rate 13.5 cm3 minϪ1, tR 43.2 min] (Found:
C, 60.3; H, 5.6; N, 4.5. C16H17NO6 requires C, 60.2; H, 5.4; N,
4.4%); νmax(liquid film)/cmϪ1 2978 (CH), 2950 (CH) and 1778–
Dimethyl 2-(benzyloxycarbonylamino)-4-hydroxypentane-1,5-
dioates 20a and 20b
Sodium borohydride (300 mg, 8.10 mmol) was added to a solu-
tion of dimethyl 2-(benzyloxycarbonylamino)-4-oxopentane-
1,5-dioate 19 (620 mg, 1.90 mmol) in anhydrous methanol (30
cm3) at Ϫ20 ЊC. The reaction mixture was stirred at Ϫ20 ЊC for
30 min, after which time it was acidified with hydrochloric acid
(9 mol dmϪ3) in methanol at that temperature. The volatile
components of the solution were removed under vacuum, and
the residue was extracted three times with chloroform. The
combined extracts were filtered via a short silica gel column
(ethyl acetate), then evaporated to dryness under vacuum to give
a 1:1 diastereomeric mixture of dimethyl 2-(benzyloxycarbonyl-
amino)-4-hydroxypentane-1,5-dioates 20 (580 mg, 93%) as a
colourless oil (Found: C, 55.4; H, 5.7; N, 4.3. C15H19NO7
requires C, 55.4; H, 5.9; N, 4.3%).
The two diastereomers 20 were further separated and purified
by HPLC [µ-Porasil column, light petroleum–ethyl acetate (3:2),
flow rate 3.0 cm3 minϪ1]. The more polar isomer 20 (tR 15.6 min)
was obtained as a colourless oil (Found: Mϩ, 325.1161.
C15H19NO7 requires M, 325.1161); νmax(CHCl3)/cmϪ1 3517w,
3417w, 2983w, 2950w, 1740s, 1735s and 1507m; δH(400 MHz;
CDCl3) 2.17–2.29 (2 H, m, 3- and 3Ј-H), 3.36–3.45 (1 H, br s,
OH), 3.75 (3 H, s, OCH3), 3.77 (3 H, s, OCH3), 4.23–4.30 (1 H,
m, 4-H), 4.54–4.64 (1 H, m, 2-H), 5.12 (2 H, s, CH2Ar), 5.71
(1 H, br d, J 7.3, NH) and 7.30–7.39 (5 H, m, ArH); m/z (EI)
325 (Mϩ, 1%), 293 (0.8), 266 (5), 222 (6), 108 (30), 107 (11), 91
(100) and 79 (10).
1688br (C᎐O phthalimide, ester); δ (400 MHz; CDCl ) 1.21
᎐
H
3
(3 H, t, J 7.0, CH3), 2.35–2.41 (2 H, m, 4-Ha and Hb), 2.44–
2.55 (1 H, m, 3-Ha), 2.63–2.68 (1 H, m, 3-Hb), 3.76 (3 H, s,
OCH3), 4.02–4.13 (2 H, m, OCH2), 4.94 (1 H, dd, J 10.0 and
5.0, 2-H), 7.73–7.78 (2 H, m, ArH) and 7.85–7.90 (2 H, m,
ArH); δC(50 MHz; CDCl3) 14.06 (CH3), 24.18 (CH2), 30.82
(CH2), 51.12 (OCH3), 52.78 (CH), 60.60 (OCH2), 123.55 (ArC),
131.68 (ipso ArC), 134.24 (ArC), 167.46 (CO), 169.23 (CO) and
172.11 (CO); m/z (EI) 319 (Mϩ, 0.4%), 287 (19), 260 (12), 214
(15), 187 (16), 186 (100), 163 (60), 104 (19) and 76 (13).
2-Phthalimidopentane-1,5-dioic acid (N-phthaloylglutamic acid)
18
5-Ethyl 1-methyl 2-phthalimidopentane-1,5-dioate 17 (40 mg,
0.125 mmol) was treated with aqueous sodium hydroxide (10%;
2 cm3) and warmed gently until the reaction mixture became
homogeneous. The reaction was allowed to stir at room temper-
ature overnight and was then acidified with aqueous hydro-
chloric acid (3 mol dmϪ3) and extracted with ether (3 × 30 cm3).
The combined ethereal extracts were washed with water (3 × 20
cm3), dried and concentrated under reduced pressure to leave
a yellow oil. The residue was recrystallised from ether–light
petroleum to give 2-phthalimidopentane-1,5-dioic acid 18 (26
mg, 75%) as a white solid; mp 158–160 ЊC (lit.,20 mp 160–
161 ЊC); δH(200 MHz; CDCl3) 2.04–2.64 (4 H, m, 3- and 4-H),
4.68–4.76 (1 H, m, 2-H), 4.60–5.80 (2 H, br s, OH) and 7.72–
8.00 (4 H, m, ArH).
The less polar isomer 20b (tR 14.8 min) was also obtained as a
colourless oil (Found: Mϩ, 325.1153. C15H19NO7 requires M,
325.1161); νmax(CHCl3)/cmϪ1 3530w, 3427w, 2957w, 2929w,
1740s, 1735s and 1507s; δH(400 MHz; CDCl3) 2.16 (1 H, ddd,
J 14.3, 7.4 and 7.4, 3-H), 2.45 (1 H, ddd, J 14.3, 4.9 and 4.9,
3Ј-H), 3.15–3.23 (1 H, br s, OH), 3.74 (6 H, s, 2 × OCH3), 4.30–
4.37 (1 H, m, 4-H), 4.61 (1 H, ddd, J 7.6, 7.4 and 4.9, 2-H), 5.12
(2 H, s, CH2Ar), 5.61 (1 H, br d, J 7.6, NH) and 7.30–7.39 (5 H,
m, ArH); m/z (EI) 325 (Mϩ, 0.5%), 293 (1), 266 (2), 222 (3), 108
(25), 107 (11), 91 (100) and 79 (10).
4-Hydroxyglutamic acid 21
Dimethyl 2-(benzyloxycarbonylamino)-4-oxopentane-1,5-dioate
19
To a solution of a 1:1 diastereomeric mixture of dimethyl 2-
(benzyloxycarbonylamino)-4-hydroxypentane-1,5-dioates 20
(99 mg, 0.305 mmol) in anhydrous methanol (7 cm3), 10%
palladium on carbon (100 mg) was added, followed by hydro-
chloric acid (8 mol dmϪ3) in methanol (0.1 cm3). The reaction
mixture was stirred under hydrogen for 1 h, after which the
volatile components were removed under vacuum. Dimethyl
4-hydroxyglutamate hydrogen chloride was obtained as a
colourless solid (65 mg) in quantitative yield. Aqueous lithium
hydroxide (0.1064 mol dmϪ3; 9.68 cm3) was added to dimethyl
4-hydroxyglutamate hydrogen chloride (65 mg, 0.34 mmol),
and the mixture was stirred at 70 ЊC overnight. It was then
allowed to cool and acidified to pH 3 with aqueous hydro-
chloric acid (3 mol dmϪ3). The aqueous solution was placed on
a 1 × 20 cm column of Dowex-1-acetate25,26 (10–50 mesh), pre-
viously washed with water. Water (100 cm3) was initially used as
the eluent and the amino acid was then eluted with aqueous
acetic acid (0.5 mol dmϪ3). Evaporation of the eluate afforded a
1:1 diastereomeric mixture of 4-hydroxyglutamic acid 21 (54
mg, 92%), mp 164–165 ЊC, solidified and remelted mp 171–
173 ЊC [lit.,29 mp 166 ЊC, solidified and remelted mp 172–173 ЊC].
N-Benzyltrimethylammonium hydroxide in methanol (40%
w/v; 2.57 cm3, 6.12 mmol) was added to a 1:1 diastereomeric
mixture of dimethyl 2-(benzyloxycarbonylamino)-4-nitro-
pentane-1,5-dioates1 13 (2.09 g, 5.90 mmol) in anhydrous
methanol (20 cm3) and stirred for 10 min to generate the nitro-
nate anion. The methanolic solution was cooled to Ϫ78 ЊC,
then treated with a stream of ozone–oxygen until the reaction
mixture turned light blue. Dimethyl sulfide (1.53 cm3) was
then added to the mixture at Ϫ78 ЊC and the mixture was
allowed to warm to room temperature. The reaction mixture
was left to stand overnight and then evaporated to dryness.
The residue was acidified with aqueous hydrochloric acid
(3 mol dmϪ3) and then extracted three times with chloro-
form. The combined chloroform extracts were washed five
times with water, dried, then evaporated to dryness to give the
product as a yellow oil (1.86 g). The crude product was purified
by flash chromatography over silica (light petroleum–ethyl
acetate; 11:9) to give dimethyl 2-(benzyloxycarbonylamino)-4-
oxopentane-1,5-dioate 19 (1.31 g, 69%) as a colourless oil
(Found: C, 55.7; H, 5.7; N, 4.1. C15H17NO7 requires C, 55.7; H,
5.3; N, 4.3%); νmax(CHCl3)/cmϪ1 3433w, 2958w, 1734s, 1701m
and 1507m; δH(400 MHz; CDCl3) 3.46–3.49 (2 H, m, 3- and
3Ј-H), 3.75 (3 H, s, OCH3), 3.88 (3 H, s, OCH3), 4.70–4.78 (1 H,
m, 2-H), 5.11 (2 H, s, CH2Ar), 5.68 (1 H, br d, J 8.1, NH) and
7.30–7.40 (5 H, m, ArH); m/z (CI) 324 (Mϩ ϩ 1, 88%), 306 (2),
292 (3), 280 (59), 238 (3), 220 (6), 181 (15), 178 (13) and 91
(100); m/z (EI) 264 (0.6%), 236 (0.3), 220 (<1), 217 (9), 115 (7),
108 (8) and 91 (100).
Methyl 2-(benzyloxycarbonylamino)-4-oxopentanoate 23
A
1:1 diastereomeric mixture of methyl 2-(benzyloxy-
carbonylamino)-4-nitropentanoates1 22 (2.22 g, 7.16 mmol) in
anhydrous methanol (20 cm3) was treated with N-benzyl-
trimethylammonium hydroxide in methanol (40% w/v; 3.38
cm3, 8.07 mmol) and stirred for 10 min to generate the nitronate
anion. The mixture was cooled to Ϫ78 ЊC, then treated with a
stream of ozone–oxygen until the mixture turned light blue.
1128
J. Chem. Soc., Perkin Trans. 1, 1998

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Dimethyl sulfide (2 cm3) was added to the solution at Ϫ78 ЊC
and the mixture allowed slowly to come to room temperature. It
was then left to stand overnight. The volatile components were
removed under vacuum and the residue acidified with aqueous
hydrochloric acid (3 mol dmϪ3), then extracted three times
with chloroform. The combined chloroform extracts were
washed five times with water, dried, then evaporated to dryness
to give the crude product as a yellow oil (2.20 g). The crude
product was purified by flash chromatography over silica (light
petroleum–ethyl acetate; 11:9) to give methyl 2-(benzyloxy-
carbonylamino)-4-oxopentanoate 23 (1.68 g, 84%) as a pale
yellow oil (Found: Mϩ, 279.1108. C14H17NO5 requires M,
279.1107); νmax(CHCl3)/cmϪ1 3436w, 2958w, 1779w, 1719s,
1508s, 1455w and 1439w; δH(400 MHz; CDCl3) 2.15 [3 H, s,
C(O)CH3], 2.98 (1 H, dd, J 18.3 and 4.1, 3-H), 3.21 (1 H, dd, J
18.3 and 4.3, 3Ј-H), 3.72 (3 H, s, OCH3), 4.56 (1 H, ddd, J 8.6,
4.3 and 4.1, 2-H), 5.11 (2 H, s, CH2Ar), 5.77 (1 H, br d, J 8.6,
NH) and 7.29–7.39 (5 H, m, ArH); m/z (EI) 279 (Mϩ, 5%), 249
(1), 220 (6), 176 (10), 108 (40), 107 (16), 92 (15), 91 (100) and 65
(13).
trimethylammonium hydroxide in methanol (40% w/v; 3.20
cm3, 7.61 mmol) and stirred for 10 min to generate the nitronate
anion. The mixture was cooled to Ϫ78 ЊC, then treated with a
stream of ozone–oxygen until the mixture turned light blue.
Sodium borohydride (362 mg, 9.8 mmol) was added to the reac-
tion mixture at Ϫ78 ЊC. The temperature of the resulting solu-
tion was then raised to 4 ЊC and kept at that temperature for 10
min. It was then cooled to Ϫ78 ЊC and methanolic hydrochloric
acid (9 mol dmϪ3) was added until the solution had a pH < 3.
Volatile components of the mixture were removed under
vacuum. The residue was re-dissolved in chloroform, washed
twice with water, then dried and the solvent removed under
vacuum. Purification of the crude product, immediately after
work-up, by flash chromatography over silica (light petroleum–
ethyl acetate; 1:1) gave in order of elution after work-up:– trans-
2-(benzyloxycarbonylamino)-4-methyl-γ-butyrolactone 25 (328
mg, 17%) as
a colourless oil; the threo-isomer methyl
(2RS,4SR)-2-(benzyloxycarbonylamino)-4-hydroxypentanoate
26 (759 mg, 39%) as a colourless oil (Found: C, 60.2; H, 11.0;
N, 5.2. C14H19NO5 requires C, 59.8; H, 11.4; N, 5.0%); δH(400
MHz; CDCl3) 1.21 [3 H, d, J 6.4, -CH(OH)CH3], 1.65 (1 H,
ddd, J 13.9, 11.0 and 3.2, 3-H), 1.89 (1 H, ddd, J 13.9, 10.7 and
3.4, 3Ј-H), 3.39 (1 H, br s, OH), 3.76 (3 H, s, OCH3), 3.79–3.89
(1 H, m, 4-H), 4.59 (1 H, ddd, J 10.7, 7.8 and 3.2, 2-H), 5.13 (2
H, s, CH2Ar), 5.75 (1 H, br d, J 7.8, NH) and 7.29–7.41 (5 H, m,
ArH); and the erythro-isomer methyl (2RS,4RS)-2-(benzyloxy-
carbonylamino)-4-hydroxypentanoate 27 (659 mg, 31%) as a
colourless oil (Found: C, 60.0; H, 11.1; N, 5.0. C14H19NO5
requires C, 59.8; H, 11.4; N, 5.0%); δH(400 MHz; CDCl3) 1.24 [3
H, d, J 6.4, CH(OH)CH3], 1.71–1.79 (1 H, br s, OH), 1.85–1.95
(1 H, m, 3-H), 1.95–2.05 (1 H, m, 3Ј-H), 3.76 (3 H, s, OCH3),
3.92–4.03 (1 H, m, 4-H), 4.41–4.50 (1 H, m, 2-H), 5.12 (2 H, s,
CH2Ar), 5.73 (1 H, br d, J 7.8, NH) and 7.30–7.41 (5 H, m,
ArH).
2-(Benzyloxycarbonylamino)-4-methyl-ã-butyrolactones 24 and
25
Sodium borohydride (50 mg, 1.35 mmol) was added to a solu-
tion of methyl 2-(benzyloxycarbonylamino)-4-oxopentanoate
23 (130 mg, 0.465 mmol) in anhydrous methanol (5 cm3) at
Ϫ20 ЊC. The solution was stirred at Ϫ20 ЊC for 1 h and then
allowed to rise to 0 ЊC. The reaction mixture was cooled to
Ϫ40 ЊC, methanolic hydrochloric acid (9 mol dmϪ3) was then
added to decompose the excess hydride. The volatile com-
ponents were removed under vacuum and the residue extracted
several times with chloroform. The combined extracts were
dried, then filtered via a short silica gel column. After removal
of solvent under vacuum, a 1:1 diastereomeric mixture of 2-
(benzyloxycarbonylamino)-4-methyl-γ-butyrolactones 24 and
25 (108 mg, 93%) was obtained as a colourless oil (Found: C,
62.4; H, 6.0; N, 5.6. C13H15NO4 requires C, 62.6; H, 6.1; N,
5.6%).
The cis- and trans-isomers were further separated and puri-
fied by HPLC [µ-Porasil column, light petroleum–ethyl acetate
(3:1), flow rate 3.0 cm3 minϪ1]. The first band to be eluted was
evaporated to dryness to yield the trans-isomer 25 as a colour-
less oil. The purity of 25 was checked by analytical HPLC
[Brownlee LiChrosorb Si-100 column, light petroleum–ethyl
acetate (7:3), flow rate 1.0 cm3 minϪ1, tR 9.0 min]; νmax(CHCl3)/
cmϪ1 3430w, 2988w, 2936w, 1781s, 1725s and 1513m; δH(400
MHz; CDCl3) 1.42 (3 H, d, J 6.6, CH3), 2.33 (1 H, ddd, J 12.8,
10.6 and 8.3, 3Ј-H) {coupling constants resolved by the use
of tris[3-(2,2,2-trifluorohydroxyethylidene)-(Ϫ)-camphorato]-
europium() shift reagent in a separate experiment}, 2.47 (1 H,
ddd, J 12.8, 7.2 and 4.0, 3-H), 4.47–4.53 (1 H, m, 2-H), 4.75–4.86
(1 H, m, 4-H), 5.13 (2 H, s, CH2Ar), 5.23–5.34 (1 H, br, NH)
and 7.29–7.39 (5 H, m, ArH); m/z (EI) 249 (Mϩ, 11%), 108 (53),
91 (100) and 65 (15).
Conversion of the threo-alcohol 26 into the cis-lactone 24
A solution of threo-methyl 2-(benzyloxycarbonylamino)-4-
hydroxypentanoate 26 (32 mg, 0.11 mmol) in benzene (30 cm3)
was slowly distilled to dryness to leave the cis-lactone 24 (28
mg, 99%) as a colourless oil, which co-chromatographed with
and had an identical 1H NMR to that of 24 obtained by sodium
borohydride reduction of the ketone 23.
Methyl 2-(benzyloxycarbonylamino)-4-oxobutanoate 29
Methyl 2-(benzyloxycarbonylamino)-4-nitrobutanoate1 28 (112
mg, 0.399 mmol) in anhydrous methanol (5 cm3) was treated
with N-benzyltrimethylammonium hydroxide in methanol
(40% w/v; 0.17 cm3, 0.40 mmol) and stirred for 10 min to gener-
ate the nitronate anion. Pyridine (32 mg, 0.41 mmol) was added
to the mixture, which was then cooled to Ϫ78 ЊC. It was treated
with a stream of ozone–oxygen for 15 min after which the solu-
tion turned pale blue. Dimethyl sulfide (0.10 cm3) was then
added to the mixture at Ϫ78 ЊC and the mixture was allowed to
rise slowly to room temperature. The solution was left to stand
overnight after which the volatile components were removed
under vacuum. The residue was acidified with aqueous hydro-
chloric acid (3 mol dmϪ3) and then extracted three times with
chloroform. The combined chloroform extracts were washed
five times with water, dried, filtered, then evaporated to dryness.
The crude product was purified by flash chromatography over
silica (light petroleum–ethyl acetate; 1:1) to give methyl 2-
(benzyloxycarbonylamino)-4-oxobutanoate 29 (52 mg, 50%) as
a colourless oil (Found: Mϩ, 265.0950. C13H15NO5 requires
M, 265.0950); νmax(CHCl3)/cmϪ1 3431w, 2957w, 1788m, 1722s,
1510s, 1456m and 1439m; δH(400 MHz; CDCl3) 3.00–3.16 (2 H,
m, 3- and 3Ј-H), 3.74 (3 H, s, OCH3), 4.50–4.59 (1 H, m, 2-H),
5.11 (2 H, s, CH2Ar), 5.72 (1 H, br d, J 8.2, NH), 7.30–7.39
(5 H, m, ArH) and 9.71 (1 H, s, CHO); m/z (EI) 265 (Mϩ, 1.7%),
237 (<1), 206 (3), 162 (4), 108 (30), 107 (13), 91 (100), 87 (10), 86
(18), 85 (19), 84 (24) and 83 (27).
The cis-isomer 24 was also obtained as a colourless oil,
its purity was also checked by analytical HPLC [Brownlee
LiChrosorb Si-100 column, light petroleum–ethyl acetate (7:3),
flow rate 1.0 cm3 minϪ1, tR 9.1 min]; νmax(CHCl3)/cmϪ1 3429w,
2988w, 2936w, 1781s, 1724s and 1513s; δH(400 MHz; CDCl3)
1.46 (3 H, d, J 5.9, CH3), 1.79 (1 H, ddd, J 12.2, 12.2 and 10.8,
3Ј-H), 2.79–2.92 (1 H, m, 3-H), 4.45–4.59 (1 H, m, 2-H), 4.54
(1 H, ddq, J 11.0, 10.8 and 5.9, 4-H), 5.12 (2 H, s, CH2Ar),
5.33–5.45 (1 H, br s, NH) and 7.27–7.40 (5 H, m, ArH); m/z (EI)
249 (Mϩ, 13%), 108 (58), 91 (100) and 65 (10).
Methyl 2-(benzyloxycarbonylamino)-4-hydroxypentanoates 26
and 27
A 1:1 diastereomeric mixture of methyl 2-(benzyloxycarb-
onylamino)-4-nitropentanoates1 22 (2.33 g, 7.53 mmol) in
anhydrous methanol (20 cm3) was treated with N-benzyl-
J. Chem. Soc., Perkin Trans. 1, 1998
1129

View Article Online
5 N. Ono, Nitro Compounds; Recent Advances in Synthesis and
Chemistry, VCH, New York, 1990, ch. 1.
2-(Benzyloxycarbonylamino)-ã-butyrolactone 30
Methyl 2-(benzyloxycarbonylamino)-4-nitrobutanoate1 28 (144
mg, 0.50 mmol) in anhydrous methanol (5 cm3) was treated with
N-benzyltrimethylammonium hydroxide in methanol (40%
w/v; 0.21 cm3, 0.50 mmol) and stirred for 10 min to generate
the nitronate anion. The mixture was cooled to Ϫ78 ЊC, then
treated with a stream of ozone–oxygen for 30 min. Sodium
borohydride (55 mg, 1.5 mmol) was added to the solution at
Ϫ78 ЊC. The temperature of the mixture was allowed to rise to
0 ЊC and hydrochloric acid (8 mol dmϪ3) in methanol was then
added to decompose the excess reagent. The volatile com-
ponents were removed under vacuum and the residue extracted
several times with chloroform. The combined extracts were
washed once with water, dried, filtered and the solvent removed
under vacuum. The residue was purified by flash chrom-
atography over silica (light petroleum–ethyl acetate; 9:11), fol-
lowed by HPLC [µ-Porasil column, light petroleum–ethyl
acetate (3:2), flow rate 3.0 cm3 minϪ1] to give 2-(benzyloxy-
carbonylamino)-γ-butyrolactone 30 (14 mg, 12%) as a colourless
oil (Found: Mϩ, 235.0842. C12H13NO4 requires M, 235.0844);
νmax(CHCl3)/cmϪ1 3429w, 2927w, 1784s, 1723s and 1512m;
δH(400 MHz; CDCl3; 318 K) 2.14–2.27 (1 H, m, 3-H), 2.68–2.82
(1 H, m, 3Ј-H), 4.19–4.30 (1 H, m, 2-H), 4.40–4.44 (2 H, m,
4-H), 5.13 (2 H, s, CH2Ar), 5.27–5.39 (1 H, br, NH) and 7.27–
7.38 (5 H, m, ArH); m/z (EI) 235 (Mϩ, 11%), 108 (65), 107 (16),
92 (9), 91 (100), 86 (10), 65 (11) and 57 (12).
6 M. J. Crossley and C. W. Tansey, Aust. J. Chem., 1992, 45, 479.
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Dimethyl 2-(benzyloxycarbonylamino)butane-1,4-dioate 31
Methyl 2-(benzyloxycarbonylamino)-4-nitrobutanoate1 28 (301
mg, 1.07 mmol) in anhydrous methanol (10 cm3) was treated
with N-benzyltrimethylammonium hydroxide in methanol
(40% w/v; 0.45 cm3, 1.07 mmol) and stirred for 10 min to gener-
ate the nitronate anion. The mixture was cooled to Ϫ78 ЊC,
then treated with a stream of ozone–oxygen for 30 min. Sodium
borohydride (118 mg, 3.21 mmol) was added to the solution at
Ϫ78 ЊC. The temperature of the mixture was held at Ϫ78 ЊC for
24 M. J. Crossley and Y. M. Fung, unpublished results.
25 L. Benoiton, M. Winitz, S. M. Birnbaum and J. P. Greenstein, J. Am.
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34 M. J. Crossley, R. L. Crumbie and Y. M. Fung, unpublished results.
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1 h, allowed to rise to 0 ЊC and hydrochloric acid (8 mol dmϪ3
)
in methanol was then added to decompose the excess reagent.
The volatile components were removed under vacuum and the
residue extracted several times with chloroform. The combined
extracts were washed once with water, dried, filtered and the
solvent removed under vacuum. The residue was purified by
flash chromatography over silica (light petroleum–ethyl acetate;
11:9) and HPLC [µ-Porasil column, light petroleum–ethyl
acetate (4:1), flow rate 3.0 cm3 minϪ1] to give dimethyl 2-
(benzyloxycarbonylamino)butane-1,4-dioate 31 (94 mg, 30%) as
a colourless oil (Found: Mϩ, 295.1041. C14H17NO6 requires M,
295.1056); νmax(CHCl3)/cmϪ1 3435w, 2957w, 1730s, 1509s and
1440m; δH(100 MHz; CDCl3) 2.08–2.32 and 3.02–3.15 (1 H
each, m, 3- and 3Ј-H), 3.67 (3 H, s, OCH3), 3.74 (3 H, s, OCH3),
4.56–4.76 (1 H, m, 2-H), 5.14 (2 H, s, CH2Ar), 5.60–5.95 (1 H,
m, NH) and 7.20–7.40 (5 H, m, ArH); m/z (EI) 295 (Mϩ, 2%),
236 (2), 108 (24), 107 (10) and 91 (100).
43 S. G. Pyne, B. Dikic, P. A. Gordon, B. W. Skelton and A. H. White,
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44 M. J. Crossley, T. W. Hambley and A. W. Stamford, Aust. J. Chem.,
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45 M. J. Crossley and A. W. Stamford, Aust. J. Chem., 1993, 46, 1443.
46 M. J. Crossley and A. W. Stamford, Aust. J. Chem., 1994, 47, 1713.
47 M. J. Crossley and A. W. Stamford, Aust. J. Chem., 1994, 47, 1695.
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Acknowledgements
This work was supported by a grant from the National Health
and Medical Research Council to M. J. C. The award of a
Commonwealth Postgraduate Research Award (to Y. M. F.) is
gratefully acknowledged.
51 R. Andruszkiewicz and A. Czerwinski, Synthesis, 1982, 968.
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Paper 7/07067E
Received 30th September 1997
Accepted 13th January 1998
1130
J. Chem. Soc., Perkin Trans. 1, 1998