An efficient synthesis of (-)-chloramphenicol via asymmetric catalytic aziridination: a comparison of catalysts prepared from triphenylborate and various linear and vaulted biaryls.

Article abstract of DOI:10.1021/ol010180x

[reaction--see text] The antibiotic (-)-choramphenicol has been synthesized in only four steps from p-nitro-benzaldehyde in optically pure form from an asymmetric catalytic aziridination reaction with a chiral catalyst prepared from triphenylborate and the (R)-VAPOL ligand. Catalysts generated from the VAPOL and VANOL ligands give much higher asymmetric induction than do catalysts prepared from 6,6'-diphenylVAPOL, BINOL, and BANOL ligands.

Full text of DOI:10.1021/ol010180x

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3675-3678
An Efficient Synthesis of
(−)-Chloramphenicol via Asymmetric
Catalytic Aziridination: A Comparison
of Catalysts Prepared from
Triphenylborate and Various Linear and
Vaulted Biaryls
Catherine Loncaric and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
wulff@cem.msu.edu
Received August 15, 2001
ABSTRACT
The antibiotic (−)-choramphenicol has been synthesized in only four steps from p-nitro-benzaldehyde in optically pure form from an asymmetric
catalytic aziridination reaction with a chiral catalyst prepared from triphenylborate and the (R)-VAPOL ligand. Catalysts generated from the
VAPOL and VANOL ligands give much higher asymmetric induction than do catalysts prepared from 6,6′-diphenylVAPOL, BINOL, and BANOL
ligands.
One of the oldest antibacterial agents is chloroamphenicol,
which was first isolated from Streptomyces Venezuelae in
1947.1 This antibiotic is obtained commercially by chemical
synthesis and is biological active only as its 2R,3R enanti-
omer. It is used clinically as a broad spectrum antibiotic and
is particularly useful for the treatment of salmonella, typhi,
rickettsia, and meningeal infections.2 As a result of its link
to bone marrow depression, it use is reserved for serious
infections with organisms that have been demonstrated to
be resistant to all other appropriate anti-microbial agents. A
number of chemical syntheses of racemic chloramphenicol
have been reported,3 as well as a few in the past decade that
are selective for the formation of (-)-chloramphenicol.4 We
report here an asymmetric synthesis of optically pure (-)-
chloramphenicol that is the shortest of all syntheses reported
to date.
The strategy for the synthesis of (-)-chlormaphenicol is
outlined in Scheme 1 and features an asymmetric catalytic
aziridination reaction that has recently been developed in
Scheme 1. Catalytic Asymmetric Aziridination en Route to
(-)-Chloramphenicol
(1) Ehrlich, J.; Bartz, Q. R.; Smith, R. M.; Josylyn, D. A.; Burkholder,
P. R. Science 1947, 106, 417.
(2) Physicians’ Desk Reference, 46th ed.; Medical Economics Data, 1992
10.1021/ol010180x CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/17/2001

Table 1. Asymmetric Catalytic Aziridinations with Linear and Vaulted Biarylsa
a Unless otherwise specified, all reactions were run in methylene chloride (0.5 M in imine) with 10 mol % catalyst at 22 °C and with 1.1 equiv of ethyl
diazoacetate. b Isolated yield after silica gel column chromatography. c Determined by 1H NMR spectrum of crude reaction mixture by the average integration
of aziridine methine protons. d Determined by HPLC on a Chiralcel OD column. e Determined from 1H NMR spectrum of crude reaction mixture by integration
against aziridine. f See ref 5a. g BANOL ligand used was 98 % ee. h Reaction performed with 2 mol % catalyst. i In toulene at 0 °C for 5 h and then warmed
to 22 °C. j Products is enantiomer of aziridine shown. k In toulene at 0 °C for 10 h and then warmed to 22 °C. l 50% conversion.
our laboratories.5 Specifically, it is anticipated that the
reaction of the benzhydryl imine of 4-nitrobenzaldehyde (1,
R ) 4-NO2C6H4) with ethyl diazoacetate mediated by a
catalyst generated from triphenylborate and the VAPOL
ligand would give the aziridine 4, from which a synthesis
of (-)-chloroamphenicol could be fashioned. Since it has
been recently found that the VAPOL and VANOL ligands
give essentially the same asymmetric inductions and yields
over a wide range substrates,5a it was decided that the
asymmetric aziridination reaction should be screened with
an expanded set of biaryl ligands, which are shown in Table
1. In addition to VAPOL and VANOL, these include BINOL,
BANOL,6 and 6,6′-diphenylVAPOL.7 Catalysts prepared
from this set of five ligands were used to screen the
aziridination of three different imines, which were derived
from benzaldehyde, cyclohexane carboxaldehyde, and 4-
nitrobenzaldehyde, the latter of which is the requisite
substrate for the synthesis of (-)-chloroamphenicol.
The results from the screening of five different catalysts
for the aziridination of imines 1a, 1b, and 1c are presented
in Table 1 and reveal that the VANOL and VAPOL ligands
make the most effective asymmetric catalysts. Unless
otherwise specified, these reactions were performed with 10
mol % catalyst in methylene chloride at room temperature.
The reaction times were not optimized and should not be
taken to be indicative of the relative rates of catalysts
generated from different ligands. The reaction time in entry
4 is longer since this reaction was performed with only 2
mol % catalyst. Performing the reaction in toluene at 0 °C
(3) (a) Controulis, J.; Rebstock, M. C.; Crooks, H. M., Jr. J. Am. Chem.
Soc. 1949, 71, 2463. (b) Long, L. M.; Troutman, H. D. J. Am. Chem. Soc.
1949, 71, 2469. (c) Long, L. M.; Troutman, H. D. J. Am. Chem. Soc. 1949,
71, 2473. (d) Ehrhart, G.; Siedel, W.; Nahm, H. Chem. Ber. 1957, 90, 2088.
E. Hazra, B. G.; Pore, V. S.; Maybhate, S. P. Synth. Commun. 1997, 27,
1857.
3676
Org. Lett., Vol. 3, No. 23, 2001

did not enhance the asymmetric induction for the catalyst
prepared from the VAPOL ligand (entries 4 and 5), but a
slight increase was noted for the BANOL ligand (entries 8
and 9). The catalyst prepared from the BINOL ligand
consistently gave the lowest asymmetric induction for all
three of the imine substrates. Catalysts prepared from the
BANOL and the Ph-VAPOL ligand gave intermediate levels
of induction, whereas the VAPOL and VANOL ligands both
gave rise to catalysts that gave high inductions with all three
substrates. The levels of diastereoselection for the cis-isomer
of the aziridine were also the highest for the VAPOL and
VANOL derived catalysts. As was observed previously,5b
the VAPOL and VANOL ligands gave very similar induc-
tions for the substrates examined, which is surprising and at
this point not understood.
tuted imine 1b reacts faster than the unsubstituted phenyl
imine 1a, this substrate can be aziridinated in reasonable
times even at subambient temperatures and under reduced
catalyst loadings. The asymmetric induction and cis/trans
selection is higher at 0 °C than at 20 °C, and this is true for
both toluene (entries 3 and 4) and methylene chloride (entries
1 and 2) as solvent. However, no increase in induction was
observed when the temperature was lowered from 0 °C to
-20 °C (entries 4 vs 5) despite the fact that the diastereo-
selection did increase. The asymmetric induction is not
greatly effected by the stoichiometry of catalyst formation
(entries 4, 6, and 7). The catalyst is prepared from the
VAPOL ligand and triphenyl borate as indicated in Scheme
1, and the induction ranges from 93.4% to 96% ee as the
equivalents of borate to VAPOL is varied from 1.1 to 3.0.
There is a slight dependence in the asymmetric induction
on the catalyst loading for the p-nitro substrate 1b (entries
4, 8, 10, and 13), which is in contrast to the observation
made for the unsubstituted phenyl substrate 1a.5b The
induction drops from 96% to 88.7% ee as the loading is
reduced from 10 mol % to 1 mol %. However, this can be
recovered to some extent by increasing the scale of the
reaction. With 2.5 mol % catalyst, the induction is 89.6%
ee on a 1 mmol scale and 93% ee on a 5 mmol scale (entries
10 and 12). These experiments reveal that the cis/trans
selectivity can also be recovered with this same scale change
(entries 4 vs 12). In addition to the improvement noted with
the scale, it was found that the aziridine 4b could be
improved from 90% to 99% ee by a single crystallization
from hexane/methylene chloride (first crop, 65% recovery).
The aziridination of the p-nitrobenzaldimine 1b is the key
step in the synthetic route to chloramphenicol, and thus the
effect of the reaction conditions on this reaction was
examined in greater detail, with particular focus on lowering
the catalyst loading. The results are given in Table 2. Toluene
Table 2. Asymmetric Catalytic Aziridinations with Imine 1ba
cis-4b
trans-4bc 4bd
B(OPh)3
entry catalyst VAPOL
mol %
% yield
4bb
% ee % yield
5be
1f
2f
3
4
5
6
7
8
9
10
10
10
10
10
10
10
5
5
2.5
2.5
2.5
3
3
3
3
3
2
1.1
3
1.5
3
69
81
76
80
95
88
86
85
95
85
80
82i
19:1
22:1
28:1
30:1
41:1
28:1
23:1
40:1
33:1
15:1
14:1
33:1
80g
90.3
83g
96
96h
93.5
93.4
92.6
89.9
89.6
89
13
8
9
7
3
6
4
<2
<2
<2
5
The successful synthesis of (-)-chloramphenicol from the
azirdine 4b requires the nucleophilic ring opening of the
aziridine at the benzylic position with an oxygen nucleophile
with inversion of configuration. We were thus pleased to
find that treatment of aziridine 4b with 1 equiv of trifluo-
racetic acid in methylene chloride lead to a single diastere-
omer of the â-hydroxy amino ester 12 in 80% yield. The
treatment of this aziridine with excess trifluoroacetic acid
under more forcing conditions resulting in the heuristic
finding that the aziridine ring is opened with inversion of
configuration at the benzylic carbon and the benzhydryl
protecting group on the amine is cleaved and that the amine
is trifluoroacetylated. This transformation is accounted for
by the sequence of events that is outlined in Scheme 2. Upon
protonation, the aziridine is opened by attack of trifluoro-
acetate to give the intermediate 15. Protonation of the amine
function in 15 thus is envisioned to lead to the loss of the
benzhydryl cation and the formation of the amino ester 17.
Finally, a trifluoroacetyl transfer from oxygen to nitrogen
would lead to the observed product of this reaction. On the
basis of this observation, it was thus foreseen that it may be
possible to synthesize chloroamphenicol from the aziridine
4b with simultaneous opening of the aziridine and introduc-
tion of the dichloroacetamide function by simple treatment
with dichloroacetic acid.
10
11
12
1.5
3
93
a Unless otherwise specified, all reactions were run at 0 °C in toulene
(0.5 M in imine) with 1 mmol of imine and with 1.1 equiv of ethyl
diazoacetate. Reaction times were 1-5 h with 10 mol % catalyst and 5-10
h with 1-5 mol % catalyst. Reactions run below room temperature were
warmed to ambient for several hours after the indicated time. b Same as
Table 1. c Same as Table 1. d Same as Table 1. e Same as Table 1. f In
methylene chloride. g Reaction run at 20 °C. h Reaction run at -20 °C for
24 h. i Reaction run on 5 mmol scale.
is clearly superior to methylene chloride as solvent for this
reaction both in terms of asymmetric induction and in cis/
trans selection (entries 2 vs 4). Because the p-nitro substi-
(4) (a) Cherevert, R.; Thiboutot, S. Synthesis 1989, 444. (b) Rao, A. V.
R.; Rao, S. P.; Bhanu, M. N. J. Chem. Soc., Chem. Commun. 1992, 859.
(c) Lou, B.-L.; Zhang, Y.-Z.; Dai, L.-X. Chem. Ind. 1993, 7, 249. (d)
Veeresa, G.; Datta, A. Tetrahedron Lett. 1998, 39, 8503. (e) Corey, E. J.;
Choi, S. Tetrahedron Lett. 2000, 41, 2765. (f) Park, J. N.; Ko, S. Y.; Koh,
H. Y. Tetrahedron Lett. 2000, 41, 5553.
(5) (a) Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39,
4518. (b) Antilla, J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099.
(6) Yamanoto, K.; Fukushima, H.; Nakazaki, M. J. Chem. Soc., Chem.
Commun. 1984, 1490. (b) Toda, F.; Tanaka, K.; Nassimbeni, L.; Niven,
M. Chem. Lett. 1988, 8, 1371. (c) Noyori, R.; Suga, S.; Kawai, K.; Okada,
S.; Kitamura, M. Pure Appl. Chem. 1988, 60, 1597.
The optimized synthesis of (-)-chloroamphenicol based
on the catalytic asymmetric azirdination of imines is outlined
in Scheme 3. The synthesis begins with commercially
(7) Heller, D. P.; Wulff, W. D. Unpublished results.
Org. Lett., Vol. 3, No. 23, 2001
3677

Scheme 2
Scheme 3
chloroamphenicol in 74% yield and in greater than 99%
enantiomeric excess. The rotation measured on the synthetic
(-)-chloroamphenicol ([R]D ) -25.4°, c ) 1, EtOAc)
compares favorably with previously reported values ([R]D
) -25.5°, c ) 1, EtOAc).8 The synthesis of enantiomerically
pure (-)-chloroamphenicol is thus achieved in four steps
from commercially available starting materials in 38% overall
yield.
The results of this study serve to solidify the utility of
VANOL and VAPOL derived catalysts in asymmetric cata-
lytic aziridination reactions. Further studies on the scope and
mechanism of this reaction will be reported in due course,
as well as the applications of this process in organic synthesis.
available p-nitrobenzaldehyde and its conversion to its
corresponding benzhydryl imine 1b, which is obtained in
80% yield after crystallization from ethanol. The aziridination
is carried out with 10 mol % of the catalyst prepared from
the VAPOL ligand in toluene at 0 °C to give the aziridine
4b in 80% yield, 96% ee, and with a 30:1 cis/trans
selectivity. The enantiomeric purity of this aziridine could
be improved to 99% ee with a single crystallization from
hexane/methylene chloride (84% yield, first crop). As
anticipated by the above observations, treatment of the
optically pure aziridine with 10 equiv of dichloroacetic acid
in refluxing 1,2-dichloroethane for 1 h gave the hydroxy
acetamide 19 in 80% yield as a single diastereomer.
Completion of the synthesis was accomplished by reduction
of the ethyl ester with sodium borohydride, which gave (-)-
Acknowledgment. This work was supported by the
National Institutes of Health.
Supporting Information Available: Full experimental
details and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL010180X
(8) Bartz, Q. R. J. Biol. Chem. 1948, 172, 445.
3678
Org. Lett., Vol. 3, No. 23, 2001