Novel biocatalytic reduction of aryl azides: Chemoenzymatic synthesis of pyrrolo[2,1-c][1,4]benzodiazepine antibiotics

Article abstract of DOI:10.1039/a701249g

The chemoselective reduction of aryl azides to aryl amines, and the synthesis of the imine-containing pyrrolo[2,1-c][1-4]benzodiazepine DNA-binding antitumour antibiotics by selective biocatalytic reductive cyclization of azido aldehydes, has been achieved by employing baker's yeast.

Full text of DOI:10.1039/a701249g

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Novel biocatalytic reduction of aryl azides: chemoenzymatic synthesis of
pyrrolo[2,1-c][1,4]benzodiazepine antibiotics1
Ahmed Kamal,* Y. Damayanthi, B. S. Narayan Reddy, B. Lakminarayana and B. S. Praveen Reddy
Indian Institute of Chemical Technology, Hyderabad 500 007, India
The chemoselective reduction of aryl azides to aryl amines,
and the synthesis of the imine-containing pyrrolo[2,1-c]-
[1,4]benzodiazepine DNA-binding antitumour antibiotics by
selective biocatalytic reductive cyclization of azido alde-
hydes, has been achieved by employing baker’s yeast.
tion of the seven-membered ring via an enzymatic azido
reductive cyclization process. This enables cyclization of the
diazepine ring to take place under extremely mild and ambient
conditions, and involves a simple and rapid work-up proce-
dure.
The initial studies were carried out on the preparation of PBD
dilactams by the azido bioreductive cyclization process to
assess the scope of this reaction. The starting materials, methyl
(2S)-N-(2-nitrobenzoyl)pyrrolidine-2-carboxylate esters 3,
were prepared8 from 2-nitrobenzoic acids via their acid
chlorides, which were coupled with (S)-proline methyl ester
hydrochloride. The reaction of 3 with NaN3 in HMPA‡ gave the
azido derivatives 4 which, upon reduction with baker’s yeast,
gave the PBD dilactams 5a–d in quantitative yield (Scheme
2).
The precursor for PBD imine 8 was prepared by the reduction
of 3 with DIBAL-H to give the corresponding (2S)-N-
(2-nitrobenzoyl)pyrrolidine-2-carboxaldehydes 6. These, upon
subsequent reaction with NaN3 in HMPA followed by reduction
with baker’s yeast and chromatography of the crude product
(silica, chloroform–methanol, 9.8:0.2), gave the PBD imines
8a–d.§ This novel biocatalytic methodology has also been
extended to the synthesis of the natural product DC-81 8c.
The results contained in this report demonstrate that it is not
only possible to convert aryl azides to the amino arenes by
employing baker’s yeast, but also the usefuleness of baker’s
In the recent years there has been a growing interest in
biocatalysis and, in particular, transformations2 mediated by
baker’s yeast (Saccharomyces cerevisiae). Reduction of car-
bonyl compounds by baker’s yeast has become a valuable
strategy in organic synthesis.3 A variety of new and novel
abilities of baker’s yeast have been reported by us,4,5 for
example regeneration of carbonyl compounds and biooxidative
conversion of thio to oxo functionality. In continuation of these
efforts, we herein report a novel reduction of aryl azides to aryl
amines in quantitative yield. This is an exceptionally mild,
convenient and facile reduction employing baker’s yeast.
However, in the literature6 alkyl keto azides have been reduced
by baker’s yeast to afford the corresponding alkyl azido
alcohols. This is consistent with our finding that various alkyl
azides, e.g. 1-azido-3-aryloxypropan-2-ols, are resistant to
baker’s yeast reduction. Further, this biocatalytic reductive
methodology has been applied to the chemoenzymatic synthesis
of the DNA-binding pyrrolo[2,1-c][1,4]benzodiazepine (PBD)
system7 via the reductive cyclization of aryl azido aldehydes.
Interestingly, this investigation has revealed the unusual
chemoselective reduction of the aryl azido group in the presence
of an aldehyde group by baker’s yeast.
R1
R2
NO2
R1
R2
NO2
Some representative aryl azides 1a–g have been reduced by
baker’s yeast to afford the corresponding aryl amines 2a–g
(yields 83–92%), as illustrated in Scheme 1.†
CO2Me
CHO
iii
N
N
This biocatalytic reduction employing baker’s yeast has been
extended to the chemoenzymatic synthesis of the PBD class of
antitumour antibiotics. Although PBDs with either a secondary
amine or amide functionalty at N(10)–C(11) are readily
synthesised, the introduction of an imine or amino alcohol at
this position is problematic due to the reactivity of these
functional groups.8 In the literature, various approaches to the
synthesis of these antibiotics have been investigated.9 Our
interest in the design and synthesis of PBD analogues10 has led
us to develop a new chemoenzymatic methodology for the
DNA-interactive PBDs. This approach is based on the forma-
O
3a–d
O
6a–d
i
i
R1
R2
N3
R1
R2
N3
CO2Me
CHO
N
N
O
4a–d
O
7a–d
ii
ii
R1
R2
N3
R3
R1
R2
NH2
R3
H
N
O
H
i
R1
R2
R1
R2
N
H
10
11
A
B
11a
C
5
1a–g
2a–g
N
N
4
a R1 = R2 = R3 = H
O
5a–d
O
8a–d
b R1 = R3 = H, R2 = Cl
c R1 = R3 = H, R2 = F
d R1 = R3 = H, R2 = Me
e R1 = R3 = H, R2 = OMe
R1 = R2 = H, R3 = CO2H
g R1 = Me, R2 = H, R3 = OH
a R1 = R2 = H
b R1 = H, R2 = Me
c R1 = OH, R2 = OMe
d R1 = OBn, R2 = OMe
f
Scheme 2 Reagents and conditions: i, NaN3, HMPA, 6–8 h; ii, baker’s yeast
(phosphate buffer, pH 7.2), aq. EtOH, 1–2 d; iii, DIBAL-H, CH2Cl2,
278 °C, 45 min
Scheme 1 Reagents and conditions: i, baker’s yeast (phosphate buffer, pH
7.2), aq. EtOH, 6–8 h
Chem. Commun., 1997
1015

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yeast in the chemoenzymatic synthesis of natural and synthetic
analogues of PBDs. The present approach, which is performed
under extremely mild conditions, should maintain the stereo-
chemical integrity at C(11a) and may not effect the DNA
binding potential of the PBD imines, unlike other chemical
methods.10d
References
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Synthesis—Growing Interface with Adjacent Sciences’ Sept. 1996,
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Footnotes
* E-mail: root@csiict.ren.nic.in
† General procedure. To a solution of 2-azidobenzoic acid 1a (0.31 mmol)
in aq. EtOH (50%, 2 cm3) was added to a preincubated suspension of
baker’s yeast (2 g) in phosphate buffer solution of pH 7.2 (20 cm3) and
shaken in an orbital shaker for 6 h. The reaction was monitored by TLC
(EtOAc–hexane, 1:1). On completion of the reaction, EtOAc (20 cm3) was
added to the reaction mixture. The organic phase was separated, dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The residue
obtained was subjected to column chromatography (silica gel, EtOAc–
hexane, 1:1) to afford the reduced product, 2-aminobenzoic acid 2a in 85%
yield.
‡ General procedure. A solution of nitro esters 3 (514 mg, 1.85 mmol) or
nitro aldehydes 6 (459 mg, 1.85 mmol) and sodium azide (247 mg, 3.80
mmol) in HMPA (15 cm3) was stirred at room temperature for 6–8 h. The
reaction mixture was poured onto water and then extracted several times
with diethyl ether. Evaporation of the combined diethyl ether extract gave
the crude azides in 90–95%, which was further purified by column
chromatography on silica gel. Selected spectra data for 7a: 1H NMR (200
MHz, CDCl3): d 1.90–2.39 (m, 4 H), 3.32 (t, 2 H, J 7.0 Hz), 4.74 (t, 1 H, J
7.2 Hz), 7.50–7.98 (m, 3 H), 8.29 (d, 1 H, J 6.2 Hz); 9.87 (d, 1 H, J 4.2 Hz);
m/z 244 (M+, 8%).
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1
§ Selected spectra data for 8a: H NMR (200 MHz, CDCl3): d 1.56–2.48
(m, 4 H), 3.20–3.89 (m, 3 H), 7.10–7.59 (m, 3 H), 7.66 (d, 1 H J 4.2 Hz),
8.02 (d, 1 H, J 5.8 Hz); m/z 200 (M+ 100%).
Received in Cambridge, UK, 24th February 1997; Com.
7/01249G
1016
Chem. Commun., 1997