An efficient synthesis of taxotere side chain

Article abstract of DOI:10.2174/157017809790442871

An efficient synthesis of taxotere side chain has been achieved using Shibasaki's asymmetric Henry reaction as the key step.

Full text of DOI:10.2174/157017809790442871

616
Letters in Organic Chemistry, 2009, 6, 616-618
An Efficient Synthesis of Taxotere Side Chain
Th. Joymati Devi, Partha Pratim Saikia and Nabin C. Barua*
Natural Products Chemistry Division, North East Institute of Science and Technology, Jorhat-785006, India
Received June 02, 2009: Revised October 19, 2009: Accepted October 19, 2009
Abstract: An efficient synthesis of taxotere side chain has been achieved using Shibasaki’s asymmetric Henry reaction as
the key step.
Keywords: Taxol, Taxotere side chain, Anticancer agents, Asymmetric synthesis, Asymmetric Henry reaction, La-(R)-BINOL.
The celebrity molecule Taxol 1 (Fig. 1) was isolated [1]
in limited quantity from the bark of Pacific yew tree Taxus
bravifolia and was the most significant discovery ever made
in the field of naturally occurring anticancer agents. It has
severe water solubility problem for effective drug delivery
and therefore requires elaborate secondary treatment.
Moreover, the production of taxol from the slow growing
yew trees leads to problems of environmental consideration
as well as debatibility on the abundance of yew trees. To
overcome these problems associated with taxol to be used as
a drug; intensive search for suitable taxol analogue has
already been initiated. In recent years, more emphasis is
being given on the production of 10-DAB III, from which a
wide range of semisynthetic taxol analogues such as taxotere
2 can be made. A viable approach for the production of
taxotere from simpler 10-DAB III, 3, by fixing a synthetic 3-
phenylisoserine derived side chain has been reported [2].
A number of synthetic approaches for the synthesis of the
taxotere side chain are reported in the literature [3].
However, these syntheses involved several steps and also
low overall yield. We have long been engaged in the
synthesis of bioactive natural products involving nitro
aliphatics [4]. In this context and also with our previous
experience in the synthesis of taxol side chain [5], we report
herein a very short synthesis of the Taxotere side chain
starting from phenyl nitromethane in high enantiomeric
purity.
Our approach toward the synthesis of taxotere side chain
4 is depicted in Scheme 1. It is based on the reduction of the
nitro alcohol 5, the synthesis of which is anticipated by
Shibasaki’s asymmetric Henry reaction of phenyl
nitromethane and ethyl glyoxalate.
Accordingly, the synthesis of taxotere side chain
commenced with the Shibasaki’s asymmetric Henry reaction
HO
O
H
OH
O
AcO
O
H
OH
O
O
NH
O
Ph
NH
O
Ph
O
O
H
AcO
OBz
Ph
O
O
OH
H
AcO
OBz
OH
OH
OH
Taxol 1
Taxotere 2
HO
O
H
OH
HO
O
H
OH
AcO
OBz
10-DAB III, 3
Fig. (1). Structure of Taxol, Taxotere and 10-DAB III.
[6] of Phenyl nitromethane [7] with ethyl glyoxalate in the
presence of La-(R)-BINOL catalyst at -50 oC in THF to
*Address correspondence to the author at the Natural Products Chemistry
Division, North East Institute of Science and Technology, Jorhat-785006,
India; Email: ncbarua12@rediffmail.com
furnish the key intermediate
5
with satisfactory
diastereoselectivity (dr = 13:1; syn: anti) in 72% yield and
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

An Efficient Synthesis of Taxotere Side Chain
Letters in Organic Chemistry, 2009, Vol. 6, No. 8
617
O
NO2
O
O
NH
O
Ph
NO2
Ph
OEt
Ph
OEt
OH
OH
4
5
Scheme 1. Retrosynthesis for the synthesis of taxotere side chain.
O
NO2
O
O
NH
O
ii, iii
i
Ph
NO2
Ph
OEt
Ph
OEt
72%
48%
over two steps
OH
OH
5
4
Scheme 2. Reagents and conditions (i) ethyl glyoxalate, La-(R)-BINOL (10 mol%), THF, -50 oC, 60 h; (ii) H2/Pd-C, MeOH, rt; (iii) (Boc)2O,
Et3N, CH2Cl2, rt.
81% ee [8] (Scheme 2). Catalytic hydrogenation of the nitro
group in 5 followed by protection of the amino group with
Et3N and (Boc)2O afforded the taxotere side chain in 48 %
yield over two steps (89% ee).
REFERENCES AND NOTES
[1]
Wani, M.C.; Taylor, H.L.; Wall, M.E.; Coggon, P.; McPhail, A.T.
Plant antitumor agents. VI: the isolation and structure of Taxol, a
novel antileukemic and antitumor agent from Taxus brevifolia. J.
Am. Chem. Soc., 1971, 93, 2325.
In conclusion, we have achieved a very short synthesis of
taxotere side chain in 34% overall yield starting from phenyl
nitromethane. We have performed this synthesis up to 1
gram level and hence this strategy is adaptable to gram scale
synthesis of taxotere side chain (34% yield, 89% ee). The
synthesis features an exception to the most other chiral
auxillary based approaches to taxotere side chain,
reaffirming the versatility of nitro aliphatics.
[2]
[3]
Borah, J.C.; Boruwa, J.; Barua, N.C. Synthesis of the C-13 side-
chain of taxol. Curr. Org. Synth., 2007, 4, 175.
Dziedzic, P.; Vesely, J.; Cordova, A. Catalytic asymmetric
synthesis of the docetaxel (taxotere) side chain: organocatalytic
highly enantioselective synthesis of esterification ready-ꢀ-hydroxy-
ꢂ-amino acids. Tetrahedron Lett., 2008, 49, 6631-6634 and
references cited therein.
(a). Kalita, D.; Khan, A.T.; Barua, N.C.; Bez, G. Total synthesis of
R-(+)-Patulolide A and R-(-)-Patulolide B: the macrolides isolated
from Penicillium urticae mutant. Tetrahedron, 1999, 55, 5177; (b)
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nitroalcohols by regioselective ring opening of epoxides with
[4]
SPECTRAL DATA OF SELECTED COMPOUNDS
Compound 4
MgSO4/MeOH/NaNO2
system:
a
short
synthesis
of
immunosuppressive agent FTY-720. Synlett, 2001, 1411; (c)
Gogoi, N.; Boruwa, J.; Barua, N.C. A total synthesis of (-)- bestatin
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Gogoi, N.; Boruwa, J.; Barua, N.C. A concise total synthesis of
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(f) Saikia, P.P.; Baishya, G.; Goswami, A.; Barua, N.C. An
efficient reduction protocol for the synthesis of ꢂ-hydroxy
carbamates from ꢂ-nitro alcohols in one pot: a facile synthesis of
(-)-ꢂ-conhydrine. Tetrahedron Lett., 2008, 49, 6508; (g) Saikia,
P.P.; Goswami A.; Baishya, G.; Barua, N.C. An efficient and
stereoselective route to 1-deoxy-5-hydroxy-sphingosine analogues.
Tetrahedron Lett., 2009, 50, 1328.
m.p 61-64 oC [ꢀ]D20 = +1.1 (c = 1.0, CHCl3). IR (CHCl3):
ꢁ = 3469, 1737, 1558 cm-1. 1H NMR (300 MHz, CDCl3): ꢀ =
7.53-7.36 (m, 5H), 5.75-5.73 (d, 1H, J = 5.7 Hz), 4.84 (t, 1H,
J = 6.3 Hz), 4.23-4.14 (nm 2H), 1.12 (t, 3H, J =6.9 Hz). 13C
NMR (75 MHz, CDCl3): ꢀ = 170.6, 131.0, 130.4, 129.5,
128.3, 92.0, 72.6, 63.1, 14.1. MS (ESI): m/z = 239.1 (M+).
Compound 5
m.p 118-120 oC. [ꢀ]D = +6.4 (c = 0.9, CHCl3). IR
20
1
(CHCl3): ꢁ = 3441, 2979, 1719 cm-1. H NMR (300 MHz,
CDCl3): ꢀ = 7.37-7.26 (m, 5H), 5.43-5.40 (d, 1H, J = 9.3),
[5]
[6]
Borah, J.C.; Gogoi, S.; Boruwa, J.; Kalita, B.; Barua, N.C. A highly
efficient synthesis of the C-13 side-chain of taxol using Shibasaki’s
asymmetric Henry reaction. Tetrahedron Lett., 2004, 45, 3689.
(a) Sasai, H.; Suzuki, T.; Arai, T.; Shibasaki, M. Basic character of
pure earth metal alkoxides: utilization in catalytic C-C bond
forming reactions and catalytic asymmetric nitroaldol reactions. J.
Am. Chem. Soc., 1992, 114, 4418.; (b) Sasai, H.; Suzuki, T.; Itoh,
N.; Shibasaki, M. Catalytic asymmetric nitroaldol reactions: a new
practical method for the preparation of the optically active
lanthanum complex. Tetrahedron Lett., 1993, 34, 851.
5.25-5.22 (d, 1H, J = 9.6), 4.46 (bs, 1H), 4.38-4.24 (m, 2H),
3.18 (bs, 1H), 1.41 (s, 9H), 1.35-1.3 (t, 3H, J = 16.2 Hz). 13
C
NMR (75 MHz, CDCl3): ꢀ = 172.9, 155.1, 139.2, 128.5,
127.6, 126.7, 79.8, 73.6, 62.5, 55.9, 28.2, 14.1. MS (ESI):
m/z = 332.1 (M++Na).
ACKNOWLEDGEMENTS
The authors thank the Director, NEIST, Jorhat for
providing facilities to carryout this work. TJD and PPS also
thank CSIR, New Delhi for the award of fellowships.
[7]
Kornblum, N.; Smiley, R.A.; Blackwood, R.K.; Iffland, D.C. The
mechanism of the reaction of silver nitrite with alkyl halides: the

618 Letters in Organic Chemistry, 2009, Vol. 6, No. 8
Devi et al.
contrasting reactions of silver and alkali metal salts with alkyl
halides: the alkylation of ambient anions. J. Am. Chem. Soc., 1955,
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conditions used for analysis were: Chiracel OD column, flow rate
0.8 mL/min, hexane/isopropanol 90 : 10, retention times (2R, 3S)
7.38 min (major isomer), (2S, 3S) 6.61 min (minor isomer).
[8]
The enantiomeric excess (ee) was measured by HPLC analysis
carried out using Waters 510 HPLC system. The HPLC
a