A highly efficient synthesis of the C-13 side-chain of taxol using Shibasaki's asymmetric Henry reaction

Article abstract of DOI:10.1016/j.tetlet.2004.02.150

The synthesis of the C-13 side-chain of taxol has been achieved using Shibasaki's asymmetric Henry reaction catalyzed by an optically active rare earth lanthanum-(R)-binaphthol complex.

Full text of DOI:10.1016/j.tetlet.2004.02.150

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3689–3691
A highly efficient synthesis of the C-13 side-chain of taxol using
Shibasaki’s asymmetric Henry reaction
Jagat C. Borah, Siddhartha Gogoi, Joshodeep Boruwa, Biswajit Kalita and
Nabin C. Barua*
Natural Products Chemistry Division, Regional Research Laboratory (CSIR), Jorhat 785006, Assam, India
Received 6 January2004; revised 16 February2004; accepted 27 February2004
Abstract—The synthesis of the C-13 side-chain of taxol has been achieved using Shibasaki’s asymmetric Henry reaction catalyzed by
an opticallyactive rare earth lanthanum-( R)-binaphthol complex.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Taxol,1 an antimicrotubule agent isolated from Taxus
brevifolia2 has attracted much attention in recent years
because of its efficacyin the treatment of various types
of cancer. However, the major drawbacks in using taxol
in cancer chemotherapyare its extremelylimited avail-
abilityfrom the natural source as well as the complexity
involved in its total synthesis. The most attractive way
of obtaining taxol at present is its partial synthesis from
10-DAB III, a diterpene analogous to taxol but devoid
of the C-13 side-chain, which co-occurs with taxol in
fairlyhigh yield (1 g/kg) in the leaves of the European
yew (Taxus baccata). Thus, bysnythesizing the C-13
side-chain and linking it to 10-DAB III, taxol could be
synthesized. Several syntheses of this moiety have been
reported in recent years.3
complex, the reaction can be performed in an enantio-
selective manner giving 2-nitroalcohols with the desired
stereochemistry. In continuation of our interest on the
chemistryof aliphatic nitro compounds and their
application in the synthesis of bioactive natural prod-
ucts,9 we report here a significantlyimproved prepara-
tion of the taxol side-chain that is not onlyconsiderably
shorter and higher in yield, but also experimentally
much simpler involving Shibasaki’s asymmetric Henry
reaction as the keystep.
The requisite aldehyde 2 was first prepared from epi-
chlorohydrin in three steps (Scheme 1). Treatment of
benzyl alcohol with epichlorohydrin and 50% aq NaOH
solution in the presence of tetrabutylammonium bro-
mide (TBAB) at <25 ꢁC gave compound 1 in 80% yield.
Transformation to its diol using 30% HClO4 in Et2O at
room temperature and subsequent treatment of this diol
with Pb(OAc)4 in CH2Cl2 at 0 ꢁC for 30 min10 gave the
aldehyde 2 in 52% overall yield.
4
The Henryreaction (nitro-aldol) is one of the most
powerful C–C bond-forming reactions in organic syn-
thesis. The resulting nitro-aldol products can be easily
transformed into various useful derivatives such as
b-amino alcohols and a-hydroxy carbonyl compounds.
b-Amino alcohols are found as important partial
structures of manybioactive compounds such as a/b-
adrenergic agonists or antagonists,5 HIV protease
inhibitors6 and antifungal or antibacterial peptides.7
The classical Henryreaction has been given a new
Treatment of aldehyde 2 with phenylnitromethane as
per the procedure described byShibasaki and co-
workers11 at ꢀ50 ꢁC in the presence of the asymmetric
La-(R)-BINOL catalyst12 (10 mol %) prepared from
8
dimension byShibasaki and co-workers who demon-
strated that byusing an appropriate opticallyactive La
O
ii,iii
i
OH
O
O
CHO
2
1
Keywords: Taxol; C-13 side chain of taxol; Asymmetric Henry reac-
tion; La-(R)-binaphthol.
Scheme 1. Reagents and conditions: (i) epichlorohydrin, 50% aq
NaOH, TBAB, <25 ꢁC (80%); (ii) 30% HClO4, Et2O, rt (77%); (iii)
Pb(OAc)4, CH2Cl2, 0 ꢁC (84%).
* Corresponding author. Tel.: +91-376-2370121; fax: +91-376-23700-
11; e-mail: ncbarua@csir.res.in
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.150

3690
J. C. Borah et al. / Tetrahedron Letters 45 (2004) 3689–3691
NO2
NO2
NO2
i
OBn
ii
OBn
OHC
O
+
OH
OAc
2
(2R,3S)-3
(2R,3S)-4
iii
PhCONH
NH2
O
NH2
O
iv
v,vi
OH
OH
OH
OAc
OAc
OH
(2R,3S)-5
(2R,3S)-6
(2R,3S)-7
Scheme 2. Reagents and conditions: (i) La-(R)-BINOL (10 mol %), THF, ꢀ50 ꢁC (80%); (ii) Ac2O/Py(93%); (iii) 10% Pd/C, Et 2OH, H2, rt (80%); (iv)
CrO3, glacial acetic acid, water, 5 ꢁC (82%); (v) benzoyl chloride, Et3N, 0 ꢁC (80%); (vi) Et2NMe–H2O (85%).
9289–9292; (e) Hamamoto, H.; Mamedov, V. A.; Kita-
LaCl3Æ7H2O,
dilithium
(R)-(þ)-binaphthoxide
moto, M.; Hayashi, N.; Tsuboi, S. Tetrahedron: Asymme-
try 2000, 11, 4485–4497; (f) Wang, Z.-M.; Kolb, H. C.;
Sharpless, K. B. J. Org. Chem. 1994, 59, 5104–5105.
4. (a) Henry, L. C. R. Acad. Sci. Ser. C 1895, 1265; (b)
Henry, L. C. R. Bull. Soc. Chim. Fr. 1895, 13, 999–1004;
(c) Luzzio, F. A. Tetrahedron 2001, 57, 915–945.
5. (a) Bloom, J. D.; Dutia, M. D.; Johnson, B. D.; Wissner,
A.; Burns, M. G.; Largis, E. E.; Dolan, J. A.; Claus, T. H.
J. Med. Chem. 1992, 35, 3081–3084; (b) Howe, R.; Rao, B.
S.; Holloway, B. R.; Stribling, D. J. Med. Chem. 1992, 35,
1751–1759.
6. Askin, D.; Wallace, M. A.; Vacca, J. P.; Reamer, R. A.;
Volante, R. P.; Shinkai, I. J. Org. Chem. 1992, 57, 2771–
2773.
7. Ohfune, Y. Acc. Chem. Res. 1992, 25, 360–366.
8. Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M.
J. Am. Chem. Soc. 1992, 114, 4418–4420.
9. (a) Sarma, B. K.; Barua, N. C. Tetrahedron 1993, 49,
2253–2260; (b) Sarma, B. K.; Barua, N. C. Ind. J. Chem.
1993, 32B, 615–617; (c) Saikia, A. K.; Hazarika, M. J.;
Barua, N. C.; Bezbarua, M. S.; Sharma, R. P.; Ghosh, A.
C. Synthesis 1996, 981–985; (d) Bezbarua, M. S.; Saikia,
A. K.; Barua, N. C.; Kalita, B. Synthesis 1996, 1289–1290;
(e) Bez, G.; Bezbarua, M. S.; Saikia, A. K.; Barua, N. C.
Synthesis 2000, 537–540; (f) Barua, A.; Kalita, B.; Barua,
N. C. Synlett 2000, 1064–1066.
(1 mol equiv), NaO-t-Bu (1 mol equiv) and H2O
(4 mol equiv) in THF gave the nitro-aldol product
(2R,3S)-3 in 90% ee13 and in 80% yield (Scheme 2).
The nitro-aldol product (2R,3S)-3 was transformed into
its acetate using acetic anhydride and pyridine in 93%
yield and the resulting nitro-acetate (2R,3S)-4 on
hydrogenation with 10% Pd/C gave (2R,3S)-5 in 80%
yield and 98% ee. Treatment of (2R,3S)-5 with CrO3 in
glacial acetic acid at 5 ꢁC gave (2R,3S)-6 in 82% yield
and in 96% ee. Reaction of (2R,3S)-6 with benzoyl
chloride in the presence of triethylamine in an aqueous
acetone mixture14 and subsequent hydrolysis of the
acetate group with Et2NMe–H2O15 gave the C-13 taxol
side chain16 (2R,3S)-7 in an overall yield of 33% from
(2R,3S)-3.
In summary, a novel approach to the C-13 side-chain of
taxol has been achieved with excellent optical purity
using Shibasaki’s asymmetric catalyst, La-BINOL
complex.
10. Pianetti, P.; Rollin, P.; Pougny, J. R. Tetrahedron Lett.
1986, 27, 5853–5856.
Acknowledgements
11. Sasai, H.; Itoh, N.; Suzuki, T.; Shibasaki, M. Tetrahedron
Lett. 1993, 34, 855–858.
12. Sasai, H.; Suzuki, T.; Itoh, N.; Shibasaki, M. Tetrahedron
Lett. 1993, 34, 851–854.
13. The enantiomeric excess (ee) was measured byHPLC anal-
ysis carried out using a Waters 510 HPLC system. Chiracel
OD packed in a SS column of 4.6 mm i.d. ·250 m was used.
Isocratic elution was applied with a mobile phase consist-
ing of n-hexane 90% and isopropanol 10% at a flow rate of
0.8 mL/min and a pressure of 125 psi. UV detection at 243 nm.
14. Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C.
J. Org. Chem. 1998, 63, 2351–2353.
The authors gratefullyacknowledge the Director,
Regional Research Laboratory(CSIR), Jorhat, India,
for providing facilities for this work. S.G. thanks CSIR,
New Delhi for the award of Junior Research Fellowship.
References and notes
1. Kingston, D. G. I.; Samaranayake, G.; Ivey, C. A. J. Nat.
Prod. 1990, 3, 1–12.
15. Kunz, H.; Maerz, J. Synlett 1992, 591–592.
20
D
(CHCl3): 3422, 2922, 2868, 1632, 1554, 1496, 1453, 1365,
2. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.;
McPhail, A. T. J. Am. Chem. Soc. 1971, 93, 2325–2327.
3. (a) Denis, J.-N.; Greene, A. E.; Serra, A. A.; Luche, M. J.
J. Org. Chem. 1986, 51, 46–50; (b) Cardillo, G.; Gentilucci,
L.; Tolomelli, A.; Tomasini, C. J. Org. Chem. 1998, 63,
2351–2353; (c) Koskinen, A. M. P.; Karvinen, K. E.;
Siirila, J. P. J. Chem. Soc., Chem. Commun. 1994, 21–22;
(d) Barco, A.; Benetti, S.; Risi, D. C.; Pollini, P. G.;
Romagnoli, R.; Zanirato, V. Tetrahedron Lett. 1994, 35,
16. (2R,3S)-3: gum; ½aŠ ꢀ40.3 (c 1, CHCl3); ee: 90%. IR
1114, 736 cmꢀ1
.
1H NMR (300 MHz, CDCl3) d ¼ 7:82
(10H, aromatic), 5.61 (d, J ¼ 9:4 Hz, 1H, CHNO2), 4.51
(m, 1H, CHOH), 4.25 (s, 2H, OCH2Ph), 3.45 (d, J ¼ 4 Hz,
1H, CHaO–), 3.17 (d, J ¼ 4 Hz, 1H, CHbO–), 2.80 (br, 1H,
OH). MS(ESI) m=z ¼ 310 (MþþNa). Anal. Calcd for
C16H17NO4: C, 66.89; H, 5.95; N, 4.88. Found: C, 66.94;
H, 5.89; N, 4.91.

J. C. Borah et al. / Tetrahedron Letters 45 (2004) 3689–3691
3691
20
(2R,3S)-5: ½aŠ þ36.7 (c 0.4, CHCl3); ee: 98%. IR (CHCl3):
(2R,3S)-6 (0.5 g, 2.2 mmol) and Et3N (0.54 g, 5.4 mmol)
in water (5 mL) and acetone (3 mL) at 0 ꢁC. The mixture
was stirred for 2 h at 0 ꢁC and then for 3 h at rt. After
precipitation, the acetone was removed under reduced
pressure and the residue was extracted with ethyl acetate,
dried over Na2SO4 and concentrated. The crude product
was purified bypreparative TLC using ethyl acetate/hexane
(1:10) to give the benzoylated product (0.76 g, 2.3 mmol)
which was hydrolyzed using a pH 9.0 solution of Et2NMe
(0.21 g, 2.3 mmol) in water. The progress of the reaction
was monitored byTLC. After completion, the reaction
mixture was extracted with ethyl acetate, dried over anhy-
drous Na2SO4 and concentrated under reduced pressure.
The crude product was purified bypreparative TLC using
ethyl acetate/hexane (1:7), to give the final product (2R,
3S)-7 in 85% yield (0.56 g, 1.9 mmol). Spectral data of
(2R,3S)-7 were identical with those of an authentic sample.3f
D
3400, 2926, 1722, 1602, 1454, 1237, 1037, 1072, 751,
699 cmꢀ1
.
1H NMR (300 MHz, CDCl3) d ¼ 7:42 (5H,
aromatic), 4.8 (m, 1H, CHOAc), 3.52 (d, J ¼ 4 Hz, 1H,
CHNH2), 3.5 (br, 2H, NH2), 2.80 (d, J ¼ 6 Hz, 2H,
CH2OH), 2.01 (s, 3H, OAc). MS(ESI) m=z ¼ 232
(MþþNa). Anal. Calcd for C11H15NO3: C, 63.14; H,
7.23; N, 6.69. Found: C, 63.26; H, 7.28; N, 6.72.
(2R,3S)-6: Yield: 82%, ee: 96%. IR (CHCl3): 3026, 1740,
1690, 1520, 1445, 1364, 1237, 1037 cmꢀ1
.
1H NMR
(300 MHz, CDCl3) d ¼ 7:44 (5H, aromatic), 5.3 (d,
J ¼ 4 Hz, 1H, CHOAc), 4. 0 (d, J ¼ 4 Hz, H, CHNH2),
3.5 (br, 2H, NH2), 1.98 (s, 3H, OAc). MS(ESI) m=z ¼ 246
(MþþNa). Anal. Calcd for C11H13NO4: C, 59.19; H, 5.87;
N, 6.27. Found: C, 59.22; H, 5.93; N, 6.35.
(2R,3S)-7: Benzoyl chloride (0.41 g, 2.9 mmol) in acetone
(3 mL) was added dropwise to a stirred solution of