Synthesis of structure and function diverse α-D-diazoacetates, α-D-diazoacetamides, α-D-diazoketones, and the antibiotic α-D-azaserine

Article abstract of DOI:10.1055/s-0032-1318136

Using 0.1 mol% to 1 mol% potassium carbonate in an acetonitrile-deuterium oxide mixture acts as a 'privileged' reaction system, which at ambient temperature affords, via a one-pot-one-cycle procedure, α-D-diazoacetates, α-D-diazoacetamides, or α-D-diazoke

Full text of DOI:10.1055/s-0032-1318136

PAPER
▌903
paper
Synthesis of Structure and Function Diverse α-D-Diazoacetates, α-D-Diazo-
acetamides, α-D-Diazoketones, and the Antibiotic α-D-Azaserine
Synthesis of α-D-Carbonyl Compounds
Sean P. Bew,* Polly-Anna Ashford, Dominika U. Bachera
School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
Fax +44(1603)593002; E-mail: s.bew@uea.ac.uk
Received: 28.10.2012; Accepted after revision: 08.01.2013
material.8 Mezzetti et al. generated optically active N-
Abstract: Using 0.1 mol% to 1 mol% potassium carbonate in an
benzhydryl 13C- and 15N-aziridines by reacting N-benzhy-
acetonitrile–deuterium oxide mixture acts as a ‘privileged’ reaction
dryl imines with 13C-5 or 15N-6 in the presence of catalytic
quantities of RuCl(PNNP)PF6 [PNNP = (1R,2R)-N,N-
system, which at ambient temperature affords, via a one-pot–one-
cycle procedure, α-D-diazoacetates, α-D-diazoacetamides, or α-D-
diazoketones from the corresponding nondeuterated form. The pro- bis[2-(diphenylphosphino)benzyl]cyclohexane-1,2-di-
tocol is inexpensive, employs readily available materials, does not
require harsh reaction conditions, requires two hours for comple-
tion, and affords the desired products in good yields and with excel-
al. used labelled alkyl α-D-diazoacetates, e.g. 5, to probe
lent levels of deuterium incorporation. Exemplifying our protocol
the first isotope labelled synthesis of N-Boc-α-D-azaserine with
amine)] allowing them to investigate and probe mechanis-
tic aspects surrounding aziridine formation.9 Baldwin et
enzyme mechanisms,10 to investigate thermal stereomuta-
tions,11 and for the asymmetric synthesis of deuterated cy-
≥95% D-incorporation is reported.
clopropanes using deuterated 2.12 The tert-butyl ester
Key words: isotope, deuterium-labelled compounds, diazoester,
azaserine
analogue of 4 was employed by Golding et al. for the syn-
thesis of deuterated cyclopropanes.13 Shafer et al. used 4-
nitrophenyl 14C-diazoacetate for its attachment to
chymotrypsin14 and Galletti et al. synthesised 4-(1-deu-
Deuterium-labelled compounds are very important enti-
teroalkylidine)azetidin-2-one 7 in 51% yield by reacting
ties widely employed in analytical, biological, organic,
benzyl ester 9 with 3-acetoxyazetidin-2-one and titani-
material, medicinal and physical organic chemistry.1 Ex-
um(IV) chloride.15 The copper-promoted cycloaddition of
emplifying their utility, they are used for the analysis of
acetylides with α-D-diazocarbonyl compounds generating
agrochemicals and drug metabolites,2 the development of
pyrazoles was reported by Ready et al. who reacted 8 with
sensitive mass spectrometry and NMR spectroscopy
α-deuterated α-diazo benzyl ester (95% D-incorporation)
probes,3 used in reaction mechanism and kinetic studies,
9 in the presence of a copper(I) cyanide–lithium chloride
and employed within new innovative materials i.e. optical
complex, affording pyrazole 10 with a slightly disappoint-
fibres, non-linear optics and OLEDs.4 An interesting re-
ing 73% D-incorporation.16 Finally, Nakanishi et al. re-
cent application has focused on generating selectively
ported the synthesis and applications of 3-([1-
deuterated (at metabolic ‘soft spots’) pharmaceuticals and
14C]diazoacetoxy)-trans-retinal as a photoaffinity label of
investigating their potential to display enhanced metabol-
bacteriorhodopsin.17
ic stability.5
We required a generic, efficient, straightforward, high
Diazocarbonyl species are also important chemical enti-
yielding synthesis of α-D-diazoesters, α-D-diazoamides,
ties with an impressive chemical ‘pedigree’.6 Structure
and α-D-diazoketones (Figure 1).18 Critical for our appli-
and function diverse isotope labelled i.e. D-, 13C-, 14C-, or
cation these had to be afforded with excellent and repro-
15N-α-diazoesters have found applications in agrochemi-
ducible levels of D-incorporation.
cal, medicinal, and mechanistic synthetic chemistry. Sub-
H/D Exchange at a carbon atom is probably the most im-
portant synthetic route to high value (both chemical and
monetary) deuterated compounds. In some instances H/D
exchange proceeds without the need for a catalyst. How-
ever in many cases non-catalysed H/D-exchange reactions
utilise high temperatures e.g. 100–400 °C;19 sealed and
pressurised reactors (using expensive D2); a stoichiomet-
ric quantity of a strongly basic20 or acidic reagent;21 or in
conjunction with D2 require expensive platinum or pyro-
phoric Raney nickel. A consequence of these aggressive
reagent/reaction conditions is an imposed chemical limi-
tation on the types of substrates amenable to H/D ex-
change, a fact that precludes substrates, e.g. α-diazoesters,
that are sensitive to high temperatures or strongly basic or
acidic reaction conditions.
stantiating the general importance of isotope-labelled α-
diazoesters (Scheme 1), Unny et al. executed the synthesis
of 14C-labelled D-threo-chloramphenicol (1) using, as the
key starting material, ethyl [1-14C]-dichloroacetate (gen-
erated by passing Cl2 through a solution of ethyl [1-14C]-
diazoacetate).7 Johnson required 14C-labelled γ-cyhalo-
thrin (the unlabelled version is an active constituent of the
pyrethroid family of insecticides) for metabolism and
environmental studies, a key 14C-labelled γ-cyhalothrin
intermediate employed 1-(1,1-dichloro-2,2,2-trifluoro-
ethyl)-3-methylbut-2-enyl 14C-diazoester 3 as the starting
SYNTHESIS 2013, 45, 0903–0912
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DOI: 10.1055/s-0032-1318136; Art ID: SS-2012-N0840-OP
© Georg Thieme Verlag Stuttgart · New York

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S. P. Bew et al.
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A limited number of relatively inexpensive deuterated
solvents are available, examples include deuterated chlo-
roform, acetone, methanol, acetonitrile, and dimethyl
sulfoxide. Using these deuterated solvents we may be able
to readily monitor the exchange reaction of 11 (α-H-di-
OH OH
O
N2
14
O
O
C
O
D
NH
Cl
Cl
H
14C
NO2
O
O
F3C
N2
Cl
Cl
1
azoester → α-D-diazoester) in ‘real time’ by H NMR
spectroscopy as it proceeds to 13. Employing acetone-d6
2
3
1
O
(D6 99.9%) as an inexpensive, deuterated, nontoxic, deu-
N2
N2
1
13C
O
terium oxide miscible solvent and 11 allowed H NMR
O
D
spectroscopic monitoring of the reaction via loss of the α-
diazoacetate singlet at δ = 4.80. The H/D-exchange reac-
tion was effective affording 13 with 80% D-incorporation
after only 2.5 hours.
H
4
5
D
O
15N
OBn
N
O
Partially deuterium oxide miscible solvents i.e. tert-butyl
methyl ether, diethyl ether, ethyl acetate, or methyl ethyl
ketone (Table 1) were not particularly effective, affording
moderate levels, i.e. 42–55%, of D-incorporation in 13.
Switching to a completely deuterium oxide miscible sol-
vent generally had a positive effect on the H/D exchange,
methanol-d4 (D4 99.8%) afforded 80% D-incorporation,
propan-2-ol however afforded a lower 59% D-incorpora-
tion. Cyclic ethers such as dioxane and tetrahydrofuran
also afforded lowered levels of D-incorporation i.e. 47%
and 46% respectively (values broadly similar to those of
partially miscible solvents). Using 1H NMR spectroscopy
as our diagnostic tool the application of polar aprotic sol-
vents such as dimethyl sulfoxide-d6 (D6 99.8%), N,N-di-
methylformamide, and acetonitrile-d3 (D3 99.8%) was
investigated, α-D-13 was afforded with variable levels of
D-incorporation i.e. 76%, 79% and 59% respectively.
Thus utilising a deuterium oxide miscible solvent con-
ferred significant rate benefits on the H/D-exchange reac-
tion. Albeit the levels of D-incorporation were reasonable
for such a simple procedure, they were not exemplary. In-
vestigating higher reaction temperatures (30 °C and 35
°C) on the level of H/D exchange in 11 → 13 found no sig-
nificant positive or negative effect.
NH
O
H
O
6
7
O
9
95%
N2
O
Ph
O
N
N
10
73%
OBn
D
Ph
Li
CuCN⋅6LiCl
Ph
D
8
Scheme 1 Reported α-diazoesters and the application of deuterated α-
diazoester 9 in the synthesis of 10
O
O
O
N2
N2
N2
R
RHN
RO
D
D
D
α-D-diazoester
α-D-diazoamide
α-D-diazoketone
Figure 1 Generic α-D-diazoesters, α-D-amides, and α-D-ketones
Previous syntheses of α-D-diazocarbonyl species have fo-
cused on α-D-diazoacetates (no examples of α-D-diazo-
acetamides are in the literature) via H/D-exchange
reactions requiring multiple exposures to excess deuteri-
um oxide (using 99.8% and 100 atom% D2O) and strong
base (i.e., NaOD); a phase-transfer reagent (e.g.,
CTAB);22 or biphasic reaction conditions requiring multi-
ple exposures to deuterium oxide.23 These protocols re-
quire from two-to-three cycles of 12–48 hour reaction
times, a fact that results in accumulated reaction times of
24–144 hours.
O
D
D
H
H
O
N
O
N
N
O
N
O
11
no catalyst
D2O miscible
solvent
Path
B
Path
A
The possibility that stirring 11 in a deuterium oxide mis-
cible solvent with deuterium oxide may afford a conve-
nient route to 13 intrigued us. Thus stirring deuterium
oxide with the enolate of 11 generating in situ a deuterox-
ide anion (Scheme 2) that chemoselectively deprotonates
the weaker C–H bond on 12, i.e. Path A (due to lower
zero-point energies C–D bonds are approximately 3 kJ
mol–1 stronger than C–H bonds24), affording, via succes-
sive deuterate/deprotonate cycles, increased levels of deu-
terium in 13.
OD
D
N
D
O
O
H
D
N
N
O
deuterate/
N
O
O
N
N
O
deprotonate
cycle
13
12
Scheme 2 Uncatalysed H/D-exchange reaction generating 13
Synthesis 2013, 45, 903–912
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of α-D-Carbonyl Compounds
905
Exploiting the use of acetonitrile-d3 (allowed ‘real time’ the H/D-exchange reactions would proceed without the
1H NMR spectroscopic monitoring of 11 to 13) as our pre- need for deuterated acetonitrile, we wanted to exploit and
ferred solvent,25 we considered dovetailing it with a cata- exemplify our results using 1 mol% potassium carbonate
lytic amount of weak base dissolved in deuterium oxide as an extremely inexpensive ‘off-the-shelf’ catalyst. Dis-
(100 equiv). We were delighted that employing 11 and 10 solving it in deuterium oxide (99.9% D2O, 100 equiv), this
mol% potassium carbonate in a homogenous mixture of solution was added to 14 dissolved in acetonitrile.26 After
deuterium oxide–acetonitrile-d3 (1:1) gave, after only two two hours at ambient temperature and only one cycle of
hours, 13 in 45% yield, and, most importantly, with ≥95% deuterium oxide, 14 was transformed into 15 with ≥95%
D-incorporation. Reducing the catalyst to 1 mol% or 0.1 D-incorporation (Scheme 3). As previously reported, we
mol% afforded 13 in two and four hours in 72% and 53% observed the α-diazoester H/D exchange of the terminal
yields and with impressive levels of D-incorporation, i.e. proton on the alkyne of 14 underwent H/D exchange with
≥95% and 86%, respectively. The lower isolated yield of ≥95% D-incorporation.27
13 using 0.1 mol% potassium carbonate for the longer
four-hour reaction time was attributed to 12 reacting with
MeCN, D2O
r.t., 2 h
H
D
D
the deuterium oxide affording tert-butyl glycolate which,
being more water soluble, was not extracted into dichloro-
methane.
O
O
N2
N2
K2CO3
(1 mol%)
62% yield
O
O
2 x 95%
D-incorporation
Table 1 Solvent Study on H/D Exchange and Synthesis of 13 Using
14
a Mixture of Deuterium Oxide and Solventa
15
Scheme 3 Synthesis of double isotope labelled 15
Solvent
D2O miscibility (%)
D-Incorporation (%)c
t-BuOMe
Et2O
5
42
51
46
55
80
80
59
47
46
76
79
59
Employing deuterium oxide (99.9 atom% D, 100 equiva-
lents) and 1 mol% potassium carbonate a variety of struc-
turally diverse α-diazoacetates28 were screened for their
transformation into the corresponding deuterated forms.
The results from this study are outlined in Table 2.
7
EtOAc
MEK
9
24
Badet et al. reported the synthesis of undeuterated 2,5-di-
oxopyrrolidin-1-yl diazoacetate and its ability to diazo-
acetylate efficiently amines, phenols, thiophenols, or
peptides.29 Reacting base-sensitive undeuterated 2,5-di-
oxopyrrolidin-1-yl diazoacetate under our deuteration
conditions generated α-D-24 in 72% yield and ≥95% D-
incorporation. Although the isolated yields were on the
whole acceptable, i.e. 19 (89%) and 20 (90%), the isolated
yields of, for example 21 (67%) and 24 (72%) were slight-
ly lower, this was attributed to the formation of the corre-
sponding glycolate or hydrolysis of the sensitive ester
group in 24. The synthesis of cholesteryl α-D-diazoace-
tate (not shown) was complicated and problematic. Its li-
pophilic nature made its dissolution in the deuterium
oxide–acetonitrile mixture incomplete, a waxy solid
b
acetone-d6
CD3ODb
i-PrOH
dioxane
THF
100
100
100
100
100
100
100
100
b
DMSO-d6
DMF
CD3CNb
a Reaction conditions: 11 (1 mmol), solvent (0.5 mL), D2O (0.5 mL),
23 °C, 2.5 h.
b Deuterated solvents were employed in these examples for direct 1H
NMR analysis used to establish the levels of deuterium incorporation. formed that was recalcitrant to H/D exchange. Warming
c Levels of deuterium were established by removing the solvent, re-
dissolving in CDCl3 and integrating the singlet at 4.80 ppm.
to 35 °C negated the solubility issue, however for reasons
that are not yet clear the level of D-incorporation re-
mained low at 49%.
We investigated the levels of D-incorporation and yield of
13 when reduced amounts of deuterium oxide were em-
ployed i.e. 10, 20, and 33 equivalents in the presence of
11, 1 mol% potassium carbonate, and undeuterated
HPLC-grade acetonitrile over a two-hour reaction period.
Utilising 10 equivalents of deuterium oxide gave 13 in
63% yield with 79% D-incorporation, increasing to 20
equivalents of deuterium oxide afforded 13 in 59% yield
and an increased 90% D-incorporation. When 33 equiva-
lents of deuterium oxide were employed, 13 was obtained
in 65% yield with a further increased D-incorporation of
95%. With the solvent study complete and confident that
Finally testing an α-D-diazoketone was considered impor-
tant. Diazoacetophenone was transformed into α-D-25
with ≥95% D-incorporation and in 85% yield (Table 2).
Expanding the substrate scope more complex functional
groups were considered important. Reacting succinimidyl
diazoacetate with rac-phenylalanine methyl ester, (S)-leu-
cine methyl ester, (S)-proline methyl ester, and tert-butyl
(S)-3-amino-3-phenylpropanoate afforded the corre-
sponding N-diazoacetamides in good yields (58–65%).
When subjected to our standard deuteration conditions the
desired, previously unreported, α-D-diazoacetamide de-
© Georg Thieme Verlag Stuttgart · New York
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906
S. P. Bew et al.
PAPER
Table 2 H/D Exchange and D–Incorporation To Give 16–25a,b
rived amino acids 26–29 (Figure 2) were afforded in 71–
84% yields and superb levels of D-incorporation, i.e. all
≥95%. Furthermore comparing the optical rotation ([α]D)
values of the undeuterated precursors methyl N-diazoace-
tyl-L-leucinate (–6.3) and methyl N-diazoacetyl-L-pro-
linate (–114.9) with the corresponding deuterated forms,
i.e. (S)-27 (–6.0) and (S)-28 (–124.7) indicated that during
the H → D exchange process no racemisation of the ste-
reogenic centre within the α-amino acids had taken place.
Yield
(%)
D-Incorporation
(%)
Product
D
O
N2
c
–
≥95
O
16
D
O
D
D
N2
H
N
H
H
N
H
74
74
≥95
≥95
O
N2
N2
O
O
17
O
O
O
O
D
Me
Me
O
78%
75%
N2
> 95% D-incorporation
> 95% D-incorporation
H
O
(S)-27
rac-26
18
D
H
O
H
N
H
N2
Me
N
O
O
O
O
N2
N2
O
89
82
≥95
≥95
O
O
D
D
84%
71%
19
> 95% D-incorporation
95% D-incorporation
(S)-28
(S)-29
D
O
Figure 2 α-D-Diazoacetamide-derived α- and β-amino acids 26–29
N
N2
O
Employing O-benzotriazol-1-yl-N,N,N′,N′-tetramethylu-
ronium tetrafluoroborate (TBTU), 30, and rac-N-Boc-
phenylalanine or (S)-N-Boc-leucine afforded rac-(E)-4-
(diazoacetoxy)but-2-enyl 2-[(tert-butoxycarbonyl)ami-
no]-3-phenylpropanoate or (S)-(E)-4-(diazoacetoxy)but-
2-enyl 2-[(tert-butoxycarbonyl)amino]-4-methylpentano-
ate, respectively, which when subjected to our standard
deuteration conditions afforded rac-31 and (S)-32
(Scheme 4) with superb levels of deuterium incorporation
(both ≥95%) and in excellent yields (78% and 88% yields,
respectively).
20
D
D
O
O
N2
67
90
76
≥95
≥95
≥95
O
21
O
S
N2
D
O
O
22
Azaserine is the most widely studied naturally occurring
diazo compound with over 1100 publications.30 Isolated
(Streptomyces fragilis) as a pale yellow-green crystalline
solid in 195431 it has antitumour as well as antibiotic prop-
erties and, as an analogue of (S)-glutamine, it functions as
a competitive inhibitor of enzymes that use (S)-glutamine.
The cytotoxic effects of azaserine have been attributed to
inhibition of purine synthesis, primarily via inhibiting
conversion of formylglycinamide ribotide into formylgly-
cinamidine ribotide through alkylation of a cysteine
residue in the active site of phosphoribosyl formylglycin-
amidine synthetase.32
HO
N2
O
23
O
O
N2
N
O
D
72
85
≥95
≥95
O
24
O
N2
However recent structural studies with the δ-glutamyl-
transpeptidase azaserine complex have indicated that glu-
tamine antagonists may act via an alternative
mechanism.33 A large number of studies on the antitu-
mour properties of azaserine have been conducted, these
have been reviewed.34 Although a number of clinical trials
D
25
a One Cycle of D2O was used throughout.
b Reaction conditions: K2CO3 (1 mol%) D2O–MeCN (1.17:1), r.t., 2 h.
c Not determined.
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Synthesis of α-D-Carbonyl Compounds
907
OH
N2
O
30
O
D
H
BocHN
O
O
O
N2
R
O
1. TBTU, Et3N
MeCN, r.t., 4 h
2. D2O, MeCN
rac-31 (R = Bn)
78% yield
88% yield
95% D-incorporation
K2CO3 (1 mol%)
(S)-32 (R = 2-methylpropyl)
95% D-incorporation
+
rac-N-Boc
phenylalanine
or (S)-N-Boc
leucine
O
O
O
1. bromoacetyl bromide, K2CO3
D
O
OEt
NHBoc
HO
OEt
2. N,N'-ditosylhydrazine, DBU, 0 °C
N2
NHBoc
3. D2O–MeCN, K2CO3, r.t., 2 h
34
33
>95% D-incorporation
85% yield
Scheme 4 Synthesis of rac-31, (S)-32, and (S)-N-Boc-α-D-azaserine ethyl ester 34
have been performed using azaserine with some showing rium incorporation into structurally diverse substrates will
useful levels of activity in leukaemia, azaserine was less allow this protocol to have widespread application in syn-
effective than other agents, and as a result, clinical studies thetic, biological, agrochemical, medicinal, and pharma-
on the compound have been abandoned.
ceutical chemistry laboratories alike.
The widespread use and application of isotope-labelled
pharmaceuticals and NCEs make the synthesis of an iso-
tope-labelled azaserine analogue highly desirable. React-
ing (S)-33 using Fukuyama reaction conditions allowed
the subsequent α-diazodeuteration to be investigated. Em-
ploying our standard isotope incorporating conditions the
synthesis of ethyl (S)-N-(Boc)-3-(α-D-diazoacetoxy)pro-
panoate 34 was achieved with ≥95% D-incorporation in
only two hours (Scheme 4). This represents the first syn-
thesis of a deuterium-labelled analogue of the important
antibiotic azaserine.
MeCN UpS ultra gradient and D2O (99.9 atom% D) were purchased
from ROMIL (Cambridge, UK) and Sigma-Aldrich, respectively,
and used as supplied. NMR solvents were purchased from Apollo
Scientific Limited and used as supplied. CDCl3 was filtered through
basic alumina into a bottle wrapped in Al foil and stored in a dry
box. All products were characterised by 1H and 13C NMR spectros-
1
copy, FT-IR and HRMS. H and 13C NMR data were recorded on
300 MHz and 400 MHz spectrometers and unless otherwise stated
with CD3CN or CDCl3 as solvent referenced to the residual solvent
signal [CD3CN: δ = 1.94 (1H), δ = 1.39 and 118.69 (13C); CDCl3:
δ = 7.26 (1H), δ = 77.16 (13C)]. Melting points were recorded using
open capillary tubes on melting point apparatus and are uncorrect-
ed.
A straightforward, durable, efficient deuteration protocol
amenable to the production of structurally diverse α-D-di-
azoacetates, α-D-diazoacetamides, and α-D-diazoketones
has been developed. Our method is quick, uses an off-the-
shelf catalyst; it requires neither specialist equipment nor
rigorously dried solvent; is conducted at ambient temper-
ature and proceeds via a one-cycle–one-pot reaction using
inexpensive, readily available deuterium oxide (≥95%
isotope inclusion). Generating the isotope-labelled com-
pounds via a single cycle rather than the conventional
‘multiple work up, analysis, resubmit regimes’ affords
significant cost and time savings.
The following compounds were prepared by published procedures
and in each case the spectral data matched those previously report-
ed: benzyl diazoacetate (0.75 g, 4.26 mmol, 46%);28 prop-2-ynyl di-
azoacetate (0.55 g, 4.43 mmol, 25%);28 (1R,2S,5R)-(–)-menthyl
diazoacetate (0.72 g, 3.21 mmol, 50%);34 diazoacetophenone (1.04
g, 7.12 mmol, 44%);34 allyl diazoacetate (1.04 g, 8.25 mmol,
48%);35 cholesteryl diazoacetate (0.3 g, 0.66 mmol, 25%).36
rac-3,7-Dimethyloct-6-enyl Diazoacetate28
Yellow liquid; yield: 0.45 g (2.01 mmol, 32%).
IR (ATR): 3190, 2914, 2106, 1690, 1455, 1358, 1237, 1180, 1054,
740 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.01 (t, J = 9 Hz, 1 H), 4.65 (s, 1
H), 4.18–4.06 (m, 2 H), 1.98–1.83 (m, 2 H), 1.69–1.03 (m, 11 H),
0.84 (d, J = 9.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 131.6, 124.7, 63.6, 46.3, 37.1,
35.8, 29.6, 25.9, 25.6, 19.6, 17.8.
We have exemplified the broad utility of this procedure
and its applicability to functionalised systems by synthe-
sising deuterated N-diazoacetamide-derived racemic and
optically active α- and β-amino acids. Furthermore the
utility of the protocol within isotope derived natural prod-
uct synthesis has been demonstrated via the efficient for-
mation of a N-Boc-protected analogue of biologically
active (S)-α-D-azaserine. The ease of conducting these re-
actions, their efficiency and the excellent levels of deute-
MS (MALDI-TOF): m/z = 242.2 [M + NH4].
HRMS (HCIP): m/z [M + NH4] calcd for C12H24N3O2: 242.1863;
found: 242.1862.
Furan-2-ylmethyl Diazoacetate28
Yellow liquid; yield: 0.86 g (5.18 mmol, 51%).
© Georg Thieme Verlag Stuttgart · New York
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908
S. P. Bew et al.
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IR (ATR): 3118, 2106, 1681, 1379, 1344, 1231, 1150, 999, 736
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.39 (dd, J = 2, 0.8 Hz, 1 H), 6.39
(d, J = 3.2 Hz, 1 H), 6.33 (dd, J = 3.2, 1.6 Hz, 1 H), 5.11 (s, 2 H),
4.75 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 149.6, 143.5, 111.0, 110.8, 58.4,
46.6.
MS (MALDI-TOF): m/z = 156.1 [M].
HRMS (HCIP): m/z [M + H] calcd for C6H9N2O3: 157.0608; found:
157.0609.
(E)-4-(Diazoacetoxy)but-2-enyl 2-[(tert-Butoxycarbonyl)ami-
no]-3-phenylpropanoate
Synthesised according to published procedures.38 Purification of the
product by chromatography (silica gel, EtOAc–petroleum ether,
3:7) afforded a yellow oil; yield: 0.04 g (0.10 mmol, 73%).
MS (MALDI-TOF): m/z = 166.9 [M].
IR (ATR): 2976, 2108, 1687, 1364, 1157, 1020 cm–1.
HRMS (HEIP): m/z [M] calcd for C7H6N2O3: 166.0373; found:
1H NMR (300 MHz, CD3CN): δ = 7.36–7.15 (m, 5 H), 5.86–5.61
(m, 2 H), 5.55 (s, 1 H, NH), 5.00 (s, 1 H), 4.75–4.65 (m, 4 H), 4.39–
4.32 (m, 1 H), 3.10 (dd, J = 14.0, 5.5 Hz, 1 H), 2.91 (dd, J = 13.7,
8.7 Hz, 1 H), 1.35 (s, 9 H).
166.0372.
Pyridin-2-ylmethyl Diazoacetate28
Yellow liquid; yield: 0.61 g (3.44 mmol, 38%).
IR (ATR): 3096, 2106, 1680, 1592, 1385, 1348, 1230, 1170, 995,
737 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.53 (d, J = 4.1 Hz, 1 H), 7.64 (td,
J = 7.7, 1.8 Hz, 1 H), 7.28 (d, J = 7.8 Hz, 1 H), 7.20–7.12 (m, 1 H),
5.25 (s, 2 H), 4.81 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 173.5, 155.9, 149.7, 137.0, 123.1,
121.9, 67.2, 46.7.
13C NMR (100 MHz, CD3CN): δ = 172.1, 161.9, 155.7, 137.4,
129.6, 128.8, 128.7, 127.9, 127.1, 79.3, 60.6, 60.2, 55.3, 46.1, 37.3,
27.6.
MS (MALDI-TOF): m/z = 442.1 [M + K].
HRMS (NSI): m/z [M + Na] calcd for C20H25N3NaO6: 426.1636;
found: 426.1639.
(S,E)-4-(Diazoacetoxy)but-2-enyl 2-[(tert-Butoxycarbonyl)ami-
no]-4-methylpentanoate
MS (MALDI-TOF): m/z = 200.3 [M + Na].
Synthesised according to a published procedure.38 Purification of
the product by chromatography (silica gel, EtOAc–petroleum ether,
3:7) afforded a yellow oil; yield: 0.03 g (0.08 mmol, 47%).
HRMS (NSI): m/z [M + Na] calcd for C8H7N3NaO2: 200.0430;
found: 200.0425.
Thiophen-2-ylmethyl Diazoacetate28
Yellow liquid; yield: 0.71 g (3.90 mmol, 45%).
[α]D21 –11.9 (c 1.0, CHCl3).
IR (ATR): 3108, 2106, 1681, 1385, 1339, 1229, 1155, 1001, 834
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.30 (dd, J = 5.1, 1.2 Hz, 1 H),
7.10–7.05 (m, 1 H), 6.96 (dd, J = 5.0, 3.5 Hz, 1 H), 5.31 (s, 2 H),
4.75 (s, 1 H).
IR (ATR): 2958, 2111, 1694, 1366, 1160 cm–1.
1H NMR (300 MHz, CD3CN): δ = 5.81–5.66 (m, 2 H), 5.56 (s, 1 H,
NH), 4.99 (s, 1 H), 4.76–4.66 (m, 4 H), 4.12 (dd, J = 15.5, 7.9 Hz,
1 H), 1.73–1.59 (m, 1 H), 1.51 (t, J = 7.2 Hz, 2 H), 1.40 (s, 9 H),
0.91 (t, J = 6.6 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 166.7, 137.9, 128.6, 127.1, 126.7,
13C NMR (100 MHz, CD3CN): δ = 173.3, 162.0, 155.9, 128.6,
60.6, 46.6.
128.0, 79.1, 60.6, 60.3, 52.5, 46.3, 40.5, 27.8, 24.8, 22.4, 21.0.
MS (MALDI-TOF): m/z = 204.9 [M + Na].
MS (MALDI-TOF): m/z = 409.2 [M + K].
HRMS (HEIP): m/z [M] calcd for C7H6N2O2S: 182.0144; found:
182.0142.
HRMS (NSI): m/z [M + NH4] calcd for C17H31N4O6: 387.2238;
found: 387.2241.
Synthesis of (E)-4-Hydroxybut-2-enyl Diazoacetate (30)
Succinimidyl Diazoacetate
Synthesised according to a published procedure; yield: 0.416 g
(2.27 mmol, 46%); spectral data match those previously reported
for this compound.39
(E)-4-Hydroxybut-2-enyl Bromoacetate37
From but-2-ene-1,4-diol as a pale yellow liquid; yield: 1.08 g (5.17
mmol, 65%).
IR (ATR): 3370, 2968, 1730, 1407, 1278, 1160, 1109, 960 cm–1.
Methyl N-Diazoacetyl-D,L-phenylalaninate; Typical Procedure
To a soln of the amine (117 mg, 0.66 mmol) dissolved in dry
CH2Cl2 (1.5 mL) in a flame-dried round bottom flask was added an-
hyd Et3N (115 μL, 0.82 mmol) under an atmosphere of N2. The soln
was cooled to 0 °C. After stirring for 10 min, a soln of succinimidyl
diazoacetate (100 mg, 0.55 mmol) in CH2Cl2 (1 mL) was added
dropwise via syringe. The yellow soln was allowed to warm to r.t.
and stirred for 72 h. The solvent was evaporated in vacuo and puri-
fication of the product by chromatography (silica gel, Et2O–petro-
leum ether, 3:1) afforded a yellow solid; yield: 83 mg (0.34 mmol,
61%); mp 126–128 °C.
1H NMR (300 MHz, CDCl3): δ = 5.97–5.77 (m, 1 H), 5.62 (m, 1 H),
4.76 (d, J = 7.0 Hz, 2 H), 4.26 (d, J = 6.5 Hz, 2 H), 3.83 (s, 2 H),
2.13 (s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 167.4, 134.4, 124.5, 61.7, 58.4,
25.6.
MS (MALDI-TOF): m/z = 232.8 [M + Na].
HRMS (NSI): m/z [M + Na] calcd for C6H9BrNaO3: 232.9607;
found: 232.9607.
IR (ATR): 3101, 3063, 3028, 2945, 2107, 1740, 1603, 1509, 1443,
1382, 1200, 998 cm–1.
1H NMR (300 MHz, CD3CN): δ = 7.37–7.19 (m, 5 H), 6.34 (s, 1 H),
5.05 (s, 1 H), 4.71 (m, 1 H), 3.66 (s, 3 H), 3.13 (dd, J = 13.8, 5.7 Hz,
1 H), 2.96 (dd, J = 13.9, 8.1 Hz, 1 H).
13C NMR (100 MHz, CD3CN): δ = 172.4, 165.6, 137.1, 129.5,
128.7, 127.1, 54.3, 52.0, 46.8, 37.7.
(E)-4-Hydroxybut-2-enyl Diazoacetate (30)28
From (E)-4-hydroxybut-2-enyl bromoacetate as a yellow liquid;
yield: 0.08 g (0.10 mmol, 56%).
IR (ATR): 3374, 2921, 2107, 1671, 1377, 1236, 1176, 1016, 739
cm–1.
1H NMR (300 MHz, CD3CN): δ = 5.75 (dtt, J = 11.2, 6.2, 1.4 Hz, 1
H), 5.62–5.51 (m, 1 H), 4.98 (s, 1 H), 4.70 (ddt, J = 6.7, 1.4, 0.7 Hz,
2 H), 4.16–4.08 (m, 2 H), 2.86 (t, J = 5.6 Hz, 1 H, OH).
LRMS (ES): 270.0 [M + Na].
13C NMR (100 MHz, CD3CN): δ = 134.4, 124.8, 60.5, 57.8, 46.3.
HRMS (NSI): m/z [M + Na] calcd for C12H13N3NaO3: 270.0849;
found: 270.0850.
Synthesis 2013, 45, 903–912
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of α-D-Carbonyl Compounds
909
tert-Butyl (S)-3-(Diazoacetamido)-3-phenylpropanoate
Yellow oil; yield: 33 mg (0.11 mmol, 61%).
1H NMR (300 MHz, CD3CN): δ = 5.04 (residual 1 H), 4.73 (s, 2 H),
2.78 (residual 1 H).
[α]D23 –54.7 (c 1.5, CHCl3).
13C NMR (100 MHz, CD3CN): δ = 162.0, 77.9, 77.8, 77.7, 75.7,
75.3, 74.9, 52.0.
IR (ATR): 3277, 3095, 2983, 2938, 2099, 1727, 1619, 1561, 1375,
1251, 1146, 701 cm–1.
MS (MALDI-TOF): m/z = 151.0 [M + Na].
1H NMR (300 MHz, CD3CN): δ = 7.35–7.16 (m, 5 H), 6.59 (s, 1 H),
5.19 (m, 1 H), 4.96 (s, 1 H), 2.61 (m, 2 H), 1.32 (s, 9 H).
HRMS (HCIP): m/z [M + NH4] calcd for C5H6D2N4O2: 144.0737;
found: 144.0737.
13C NMR (100 MHz, CD3CN): δ = 169.9, 165.0, 142.2, 128.7,
127.6, 126.8, 80.7, 50.9, 46.8, 42.2, 27.4.
Benzyl α-D-Diazoacetate (17)
Yellow liquid; yield: 37.3 mg (0.21 mmol, 74%); ≥95% D-incorpo-
MS (MALDI-TOF): m/z = 327.9 [M + K].
ration.
HRMS (NSI): m/z [M + H] calcd for C15H20N3O3: 290.1499; found:
IR (ATR): 2104, 1679, 1299, 1166, 1003 cm–1.
290.1503.
1H NMR (300 MHz, CD3CN): δ = 7.40–7.33 (m, 5 H), 5.17 (s, 2 H),
5.03 (residual 1 H).
13C NMR (100 MHz, CD3CN): δ = 162.0, 136.8, 128.8, 128.4,
Methyl N-Diazoacetyl-L-leucinate
Yellow oil; yield: 101 mg (0.48 mmol, 58%).
[α]D19 –6.3 (c 1.0, CHCl3).
128.3, 66.3.
MS (MALDI-TOF): m/z = 197.0 [M + NH4].
IR (ATR): 3105, 2959, 2877, 2100, 1741, 1616, 1536, 1380, 1204,
1148 cm–1.
1H NMR (300 MHz, CD3CN): δ = 6.40 (s, 1 H), 5.06 (s, 1 H), 4.42
(dd, J = 14.8, 7.9 Hz, 1 H), 3.65 (s, 3 H), 1.68–1.48 (m, 3 H), 0.90
(m, 6 H).
13C NMR (100 MHz, CD3CN): δ = 173.6, 165.8, 52.0, 51.3, 46.8,
40.7, 24.8, 22.4, 21.1.
(±)-3,7-Dimethyloct-6-enyl α-D-Diazoacetate (18)
Yellow liquid; yield: 22.2 mg (0.10 mmol, 74%); ≥95% D-incorpo-
ration.
IR (ATR): 2912, 2105, 1686, 1307, 1176 cm–1.
1H NMR (300 MHz, CD3CN): δ = 5.15–5.07 (m, 1 H), 4.93 (resid-
ual 1 H), 4.22–4.09 (m, 2 H), 2.06–1.89 (m, 2 H), 1.67 (s, 3 H), 1.60
(s, 3 H), 1.54–1.10 (m, 5 H), 0.90 (d, J = 6.6 Hz, 3 H).
MS (MALDI-TOF): m/z = 252.0 [M + K].
HRMS (NSI): m/z [M + H] calcd for C9H16N3O3: 214.1186; found:
13C NMR (100 MHz, CD3CN): δ = 163.1, 132.4, 125.9, 64.2, 38.0,
214.1187.
36.7, 30.5, 26.4, 26.2, 20.1, 18.1.
MS (MALDI-TOF): m/z = 242.3 [M + NH4].
Methyl N-Diazoacetyl-L-prolinate
Yellow oil; yield: 70 mg (0.35 mmol, 65%).
(1R,2S,5R)-(–)-Menthyl α-D-Diazoacetate (19)
Yellow solid; yield: 44.6 mg (0.20 mmol, 89%); ≥95% D-incorpo-
ration; mp 36–38 °C.
[α]D21 –85.0 (c 1.0, CHCl3).
[α]D22 –114.9 (c 0.8, CHCl3).
IR (ATR): 3075, 2961, 2927, 2855, 2107, 1736, 1607, 1413, 1163,
730 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.88 (s, 1 H), 4.53 (br s, 1 H), 3.72
IR (ATR): 2954, 2103, 1682, 1302, 1179 cm–1.
(s, 3 H), 3.43 (br s, 1 H), 3.28 (br s, 1 H), 2.25–1.90 (m, 4 H).
1H NMR (300 MHz, CD3CN): δ = 5.20 (s, 1 H), 4.39 (br s, 1 H),
3.66 (s, 3 H), 3.44–3.24 (m, 2 H), 2.20 (br s, 1 H), 1.93 (m, 3 H).
1H NMR (300 MHz, CD3CN): δ = 4.92 (residual 1 H), 4.72 (td,
J = 10.9, 4.4 Hz, 1 H), 1.90–1.78 (m, 1 H), 1.71–1.63 (m, 2 H),
1.57–1.32 (m, 2 H), 1.17–0.81 (m, 10 H), 0.77 (d, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CD3CN): δ = 173.3, 164.4, 59.1, 51.9, 46.5,
13C NMR (100 MHz, CD3CN): δ = 162.0, 74.5, 47.4, 41.3, 34.2,
29.3, 24.5.
31.5, 26.5, 23.6, 21.6, 20.2, 16.1.
MS (MALDI-TOF): m/z = 220.9 [M + Na].
MS (MALDI-TOF): m/z = 242.3 [M + NH4].
HRMS (NSI): m/z [M + H] calcd for C8H12N3O3: 198.0873; found:
198.0873.
Pyridin-2-ylmethyl α-D-Diazoacetate (20)
Yellow liquid; yield: 41.1 mg (0.23 mmol, 82%); ≥95% D-incorpo-
ration.
IR (ATR): 2105, 1679, 1302, 1167 cm–1.
1H NMR (300 MHz, CD3CN): δ = 8.55 (d, J = 4.7 Hz, 1 H), 7.77
(td, J = 7.7, 1.8 Hz, 1 H), 7.37 (d, J = 7.8 Hz, 1 H), 7.32–7.24 (m, 1
H), 5.23 (s, 2 H), 5.09 (residual 1 H).
tert-Butyl α-D-Diazoacetate (13); Typical Procedure for α-D-Di-
azoacetates, α-D-Diazoacetamides and α-D-Diazoketones
To a soln of tert-butyl α-diazoacetate (50 mg, 0.35 mmol) and
K2CO3 (0.49 mg, 0.0035 mmol) in MeCN (0.75 mL) was added
D2O (0.64 mL). The resulting mixture was stirred vigorously under
N2 for 2 h at r.t. The soln was then extracted with CH2Cl2 (3 × 3 mL)
and the combined organic layers were dried (MgSO4), filtered, and
concentrated to afford a yellow liquid; yield: 36 mg (0.25 mmol,
72%); ≥95% D-incorporation.
13C NMR (100 MHz, CD3CN): δ = 156.4, 149.6, 137.1, 123.2,
121.7, 66.8.
MS (MALDI-TOF): m/z = 196.9 [M + NH4].
IR (ATR): 2979, 2104, 1684, 1316, 1148 cm–1.
HRMS (NSI): m/z [M + H] calcd for C8H7DN3O2: 179.0674; found:
179.0672.
1H NMR (300 MHz, CD3CN): δ = 4.80 (residual 1 H), 1.45 (s, 9 H).
13C NMR (100 MHz, CD3CN): δ = 163.1, 82.2, 28.8.
MS (MALDI-TOF): m/z = 167.0 [M + Na].
Furan-2-ylmethyl α-D-Diazoacetate (21)
Yellow liquid; yield: 43.9 mg (0.26 mmol, 67%); ≥95% D-incorpo-
ration.
3-D-Prop-2-ynyl α-D-Diazoacetate (15)
Yellow liquid; yield: 31.1 mg (0.25 mmol, 62%); ≥95% D-incorpo-
ration (CDN2, C≡CD).
IR (ATR): 2107, 1680, 1300, 1161, 1026 cm–1.
IR (ATR): 2106, 1681, 1301, 1161 cm–1.
1H NMR (300 MHz, CD3CN): δ = 7.52–7.49 (m, 1 H), 6.48–6.45
(m, 1 H), 6.43–6.40 (m, 1 H), 5.12 (s, 2 H), 4.99 (residual 1 H).
13C NMR (100 MHz, CD3CN): δ = 163.0, 151.1, 144.9, 112.0, 59.1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 903–912

910
S. P. Bew et al.
PAPER
MS (MALDI-TOF): m/z = 186.2 [M + NH4].
1H NMR (300 MHz, CD3CN): δ = 6.34 (s, 1 H, NH), 5.05 (residual
1 H), 4.48–4.36 (m, 1 H), 3.66 (s, 3 H), 1.73–1.49 (m, 3 H), 0.91
(dd, J = 7.6, 6.4 Hz, 6 H).
13C NMR (100 MHz, CD3CN): δ = 173.6, 165.8, 52.0, 51.3, 40.7,
24.8, 22.4, 21.1.
HRMS (HCIP): m/z [M + NH4] calcd for C7H9DN3O3: 185.0779;
found: 185.0780.
Thiophen-2-ylmethyl α-D-Diazoacetate (22)
Yellow liquid; yield: 45.3 mg (0.25 mmol, 90%); ≥95% D-incorpo-
ration.
MS (MALDI-TOF): m/z = 253.1 [M + K].
IR (ATR): 2108, 1679, 1304, 1157 cm–1.
1H NMR (300 MHz, CD3CN): δ = 7.43–7.41 (m, 1 H), 7.15–7.13
HRMS (NSI): m/z [M + Na] calcd for C9H14DN3NaO3: 237.1068;
found: 237.1068.
(m, 1 H), 7.02–7.00 (m, 1 H), 5.32 (s, 2 H), 5.00 (residual 1 H).
13C NMR (100 MHz, CD3CN): δ = 138.7, 128.7, 127.5, 127.2, 60.6.
Methyl (S)-1-(α-D-Diazoacetyl)pyrrolidine-2-carboxylate (28)
Yellow oil; yield: 21.9 mg (0.11 mmol, 84%); ≥95% D-incorpora-
tion.
[α]D21 –124.7 (c 1.0, CHCl3).
MS (MALDI-TOF): m/z = 206.1 [M + Na].
IR (ATR): 2106, 1737, 1699, 1601, 1405, 1174 cm–1.
(E)-4-Hydroxybut-2-enyl α-D-Diazoacetate (23)
Yellow liquid; yield: 38.1 mg (0.24 mmol, 76%); ≥95% D-incorpo-
ration.
IR (ATR): 3379, 2105, 1670, 1299, 1172, 1015 cm–1.
1H NMR (300 MHz, CD3CN): δ = 5.80–5.71 (m, 1 H), 5.61–5.51
(m, 1 H), 4.98 (residual 1 H), 4.72–4.69 (m, 2 H), 4.15–4.11 (m, 2
H), 2.87 (t, J = 5.6 Hz, 1 H, OH).
1H NMR (300 MHz, CD3CN): δ = 5.20 (residual 1 H), 4.38 (d,
J = 5.0 Hz, 1 H), 3.66 (s, 3 H), 3.40–3.25 (m, 2 H), 2.19 (br s, 1 H),
2.00–1.88 (m, 3 H).
13C NMR (100 MHz, CD3CN): δ = 173.3, 159.3, 59.1, 51.9, 46.5,
29.3, 24.5.
MS (MALDI-TOF): m/z = 221.1 [M + Na].
13C NMR (100 MHz, CD3CN): δ = 162.0, 134.4, 124.8, 60.5, 57.8.
HRMS (NSI): m/z [M + Na] calcd for C8H10DN3NaO3: 221.0755;
found: 221.0753.
MS (MALDI-TOF): m/z = 196.6 [M + K].
HRMS (NSI): m/z [M + Na] calcd for C6H7DN2NaO3: 180.0490;
found: 180.0485.
tert-Butyl (S)-3-(α-D-Diazoacetamido)-3-phenylpropanoate
(29)
Yellow oil; yield: 23.4 mg (0.081 mmol, 71%); ≥95% D-incorpora-
tion.
[α]D21 –35.4 (c 1.0, CHCl3).
IR (ATR): 2978, 2106, 1691, 1612, 1540, 1314, 1149 cm–1.
2,5-Dioxopyrrolidin-1-yl α-D-Diazoacetate (24)
Pale yellow solid; yield: 28.8 mg (0.16 mmol, 72%); ≥95% D-incor-
poration; mp 92–94 °C.
IR (ATR): 2121, 1719, 1303, 1198, 1097 cm–1.
1H NMR (300 MHz, CD3CN): δ = 5.45 (residual 1 H), 2.77 (s, 4 H).
13C NMR (100 MHz, CD3CN): δ = 170.7, 162.0, 25.6.
1H NMR (300 MHz, CD3CN): δ = 7.39–7.23 (m, 5 H), 6.61 (s, 1 H,
NH), 5.32–5.24 (m, 1 H), 5.01 (residual 1 H), 2.76–2.59 (m, 2 H),
1.34 (s, 9 H).
α-D-Diazoacetophenone (25)
Yellow solid; yield: 43 mg (0.29 mmol, 85%); ≥95% D-incorpora-
tion; mp 38–40 °C.
IR (ATR): 2108, 1599, 1571, 1323 cm–1.
1H NMR (300 MHz, CD3CN): δ = 7.82–7.77 (m, 2 H), 7.63–7.57
13C NMR (100 MHz, CD3CN): δ = 169.9, 162.0, 142.2, 128.7,
127.6, 126.8, 80.7, 50.9, 42.2, 27.4.
MS (MALDI-TOF): m/z = 313.1 [M + Na].
HRMS (NSI): m/z [M + Na] calcd for C15H18DN3NaO3: 313.1381;
found: 313.1381.
(m, 1 H), 7.52–7.46 (m, 2 H), 6.25 (residual 1 H).
13C NMR (100 MHz, CD3CN): δ = 187.4, 137.9, 134.0, 130.0,
127.9.
(E)-4-(α-D-Diazoacetoxy)but-2-enyl 2-[(tert-Butoxycarbon-
yl)amino]-3-phenylpropanoate (31)
Yellow oil; yield: 18 mg (0.045 mmol, 78%); ≥95% D-incorpora-
tion.
MS (MALDI-TOF): m/z = 186.2 [M + K].
IR (ATR): 2976, 2109, 1691, 1364, 1306, 1165, 1023 cm–1.
HRMS (HCIP): m/z [M + H] calcd for C8H6DN2O: 148.0616;
found: 148.0614.
1H NMR (300 MHz, CD3CN): δ = 7.34–7.20 (m, 5 H), 5.84–5.63
(m, 2 H), 5.55 (s, 1 H, NH), 5.00 (residual 1 H), 4.73–4.68 (m, 4 H),
4.39–4.31 (m, 1 H), 3.09 (dd, J = 14.0, 5.6 Hz, 1 H), 2.91 (dd,
J = 13.8, 8.9 Hz, 1 H), 1.35 (s, 9 H).
Methyl 2-(α-D-Diazoacetamido)-3-phenylpropanoate (26)
Yellow solid; yield: 27.1 mg (0.11 mmol, 75%); ≥95% D-incorpo-
ration; mp 80–82 °C.
IR (ATR): 2099, 1735, 1609, 1529, 1432, 1331, 1206 cm–1.
13C NMR (100 MHz, CD3CN): δ = 172.0, 162.0, 137.4, 129.5,
128.7, 128.7, 127.9, 127.0, 79.3, 60.7, 60.3, 55.4, 37.4, 27.7.
1H NMR (300 MHz, CD3CN): δ = 7.36–7.15 (m, 5 H), 6.34 (s, 1 H,
NH), 5.03 (residual 1 H), 4.73–4.66 (m, 1 H), 3.66 (s, 3 H), 3.11 (dd,
J = 13.9, 5.6 Hz, 1 H), 2.94 (dd, J = 13.9, 8.1 Hz, 1 H).
MS (MALDI-TOF): m/z = 443.0 [M + K].
HRMS (NSI): m/z [M + Na] calcd for C20H24DN3O6: 427.1698;
found: 427.1697.
13C NMR (100 MHz, CD3CN): δ = 172.4, 165.6, 137.1, 129.5,
128.7, 127.1, 54.3, 52.0, 37.7.
(S,E)-4-(α-D-Diazoacetoxy)but-2-enyl 2-[(tert-Butoxycarbon-
yl)amino]-4-methylpentanoate (32)
MS (MALDI-TOF): m/z = 271.1 [M + Na].
Yellow oil; yield: 23.7 mg (0.064 mmol, 88%); ≥95% D-incorpora-
tion.
[α]D21 –5.6 (c 1.0, CHCl3).
Methyl (S)-2-(α-D-Diazoacetamido)-4-methylpentanoate (27)
Yellow oil; yield: 31.2 mg (0.15 mmol, 78%); ≥95% D-incorpora-
tion.
IR (ATR): 2959, 2108, 1686, 1304, 1158 cm–1.
[α]D21 –6.0 (c 1.0, CHCl3).
1H NMR (300 MHz, CD3CN): δ = 5.82–5.65 (m, 2 H), 5.58 (s, 1 H,
NH), 4.99 (residual 1 H), 4.76–4.66 (m, 4 H), 4.11 (t, J = 6.5 Hz, 1
IR (ATR): 2956, 2099, 1739, 1612, 1535, 1337, 1202 cm–1.
Synthesis 2013, 45, 903–912
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Synthesis of α-D-Carbonyl Compounds
911
H), 1.73–1.59 (m, 1 H), 1.51 (t, J = 7.2 Hz, 2 H), 1.40 (s, 9 H), 0.91
(t, J = 6.6 Hz, 6 H).
13C NMR (100 MHz, CD3CN): δ = 173.3, 162.0, 156.0, 128.6,
IR (ATR): 2980, 2110, 1685, 1310, 1157 cm–1.
1H NMR (300 MHz, CD3CN): δ = 5.79 (s, 1 H, NH), 4.97 (residual
1 H), 4.46–4.31 (m, 3 H), 4.24–4.08 (m, 2 H), 1.41 (s, 9 H), 1.23 (t,
J = 7.1 Hz, 3 H).
128.0, 79.1, 60.6, 60.3, 52.5, 40.4, 27.8, 24.8, 22.4, 21.0.
MS (MALDI-TOF): m/z = 393.2 [M + Na].
13C NMR (100 MHz, CD3CN): δ = 169.9, 155.6, 79.5, 64.0, 61.7,
53.4, 27.7, 13.7.
HRMS (NSI): m/z [M + Na] calcd for C17H26DN3NaO6: 393.1855;
found: 393.1844.
MS (MALDI-TOF): m/z = 326.4 [M + Na].
HRMS (NSI): m/z [M + Na] calcd for C12H18DN3NaO6: 325.1229;
found: 325.1231.
Ethyl (S)-2-[(tert-Butoxycarbonyl)amino]-3-hydroxypropano-
ate (33)
Synthesised according to a modified procedure;40 spectral data
match those previously reported for this compound.41
Acknowledgment
To a soln of ethyl (S)-2-amino-3-hydroxypropanoate hydrochloride
(150 mg, 0.9 mmol) in a mixture of 1,4-dioxane (2.5 mL) and H2O
(2.5 mL), NaHCO3 (220 mg, 2.7 mmol) and Boc2O (0.23 mL, 0.97
mmol) were successively added at 0 °C. The reaction mixture was
allowed to warm to r.t. and stirred for 16 h. After that time, the so-
lution was extracted with EtOAc (3 × 5 mL), and the combined or-
ganic layers were dried over MgSO4, filtered and concentrated to
afford a white solid; yield: 130 mg (0.56 mmol, 62%).
The authors acknowledge the EPSRC and UEA for financial help.
The EPSRC Mass Spectrometry Service is gratefully acknow-
ledged.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
Ethyl (S)-2-[(tert-Butoxycarbonyl)amino]-3-(diazoacetoxy)pro-
panoate
References
Synthesised according to a published procedure.28 To a soln of ethyl
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Synthesis 2013, 45, 903–912

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Synthesis 2013, 45, 903–912
© Georg Thieme Verlag Stuttgart · New York