Chiral synthesis of the CD ring unit of paclitaxel from D-glucal

Article abstract of DOI:10.1039/b006170k

The chiral synthesis of the fully functionalized CD ring unit of paclitaxel 3 is described; the three component coupling reaction of a cyclohexenone derived from D-glucal by way of Ferrier's carbocyclization with vinyl cuprate and formal-dehyde effectivel

Full text of DOI:10.1039/b006170k

Chiral synthesis of the CD ring unit of paclitaxel from -glucal
D
Takayuki Momose, Masaki Setoguchi, Toshiki Fujita, Hitoshi Tamura and Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan. E-mail: chida@applc.keio.ac.jp
Received (in Cambridge, UK) 31st July 2000, Accepted 5th October 2000
First published as an Advance Article on the web 31st October 2000
The chiral synthesis of the fully functionalized CD ring unit
CuCNLi2] in Et2O at 278 °C caused the stereoselective
of paclitaxel 3 is described; the three component coupling
conjugated addition of the vinyl group to give an enolate
reaction of a cyclohexenone derived from
D-glucal by way of
intermediate,§ which was then reacted with a THF solution of
23
Ferrier’s carbocyclization with vinyl cuprate and formal-
dehyde effectively constructed the carbon framework of 3.
formaldehyde at 260 °C to provide 11 {mp 50–52 °C; [a]D +
23
12 (c 1.0, CHCl3)} and its C-3 isomer 12 {[a]D + 93 (c 1.0,
CHCl3)} in 62 and 33% isolated yields, respectively. The
observed coupling constants and NOE unambiguously sup-
ported the structure of 11 (Scheme 2). Base-induced epimeriza-
tion of 12 gave an additional amount of 11 (44% yield, 12 was
recovered in 51% yield); thus 11 was obtained in 76% overall
yield from 10 after one-cycle epimerization of 12. Protection of
the hydroxy group in 11 as a THP ether afforded 14 in 90%
yield. To introduce an hydroxy function at C-5, ketone 14 was
treated with LiHMDS at 278 °C, and the resulting kinetic
enolate was trapped with TMSCl to provide silylenol ether,
which was then reacted with MCPBA at 220 °C followed by
treatment with TMSCl and triethylamine to give 15 and 16 in 53
and 26% isolated yields, respectively. Reaction of 15 with
Tebbe’s reagent9 and subsequent removal of the silyl protecting
group under basic conditions afforded exo-alkene 17 in 64%
yield.¶ Vanadium catalyzed epoxidation10 of 17 gave 18 as a
single isomer in 81% yield. Reaction of 18 with potassium
acetate in DMF, followed by treatment with acetic anhydride
and pyridine at rt gave 19 in 95% yield. The secondary hydroxy
group in 19 was mesylated to afford 20 (96% yield). Removal of
the O-acetyl group, followed by reaction with DBU4c in toluene
at 100 °C cleanly generated oxetane 21 in 65% yield.
Acetylation of tertiary alcohol in 21 afforded 22 (100%).
Deprotection of the O-THP group in 22 with CAN11∑ gave 23,
which was oxidized with TPAP12 to furnish the desired
Paclitaxel (Taxol®) 1 is a well-documented natural diterpenoid
and is known to show highly promising antitumor activity.1 The
challenging structure as well as important biological activities
of 1 has attracted much attention of the synthetic community,
and six successful total syntheses of 1 have been reported to
date.2 Our own synthetic endeavor to paclitaxel required the
fully functionalized CD ring unit 3 as the key intermediate; the
formyl function at C-3 (paclitaxel numbering) would be utilized
for the coupling reaction with a paclitaxel A-ring 2, and the
vinyl group at C-8 would serve as the key functionality for the
construction of a taxane skeleton. Successful precedents for
preparation of taxane tricarbocyclic structures by way of final
B-ring closure of connected AC ring systems revealed the
possibility of this approach.3 The highly oxygenated structure
of 3, which contains five contiguous chiral centers including a
quaternary carbon and a strained oxetane ring is synthetically
fascinating, and it is a significant aim to establish an effective
synthetic route to 3 from readily available material for the
development of a novel approach to the clinically important
compounds.4 In this communication, we report a synthesis of 3,
23
aldehyde 3 {[a]D 2137 (c 0.07, CHCl3)} in 80% yield from
22. The observed NOE between the methyl at C-8 and the
formyl hydrogen, H-20, and H-6b, and between H-7 and H-3
clearly supported the assigned structure.
We thank Professor Takashi Takahashi and Dr Takayuki Doi
(Tokyo Institute of Technology, Japan) for valuable discussions
and information. Financial support of the Grant-in Aid for
Scientific Research on Priority Area from the Ministry of
which utilized commercially available tri-O-acetyl- -glucal 4
D
as a chiral starting material.
The known methyl glycoside 5,5† derived from 4 in a two
step reaction (90% overall yield) (Scheme 1) was converted into
primary iodide 6† in 87% yield, which was then treated with
NaH and benzyl bromide to afford enopyranoside 7† in 80%
yield. Ferrier’s carbocyclization6 of 7 using a catalytic amount
of Hg(OCOCF3)2,7 followed by b-elimination cleanly gen-
erated cyclohexenone 8 (80% yield). Reaction of 8 with MeLi
gave 1,2-adduct 9, whose oxidation with PCC afforded 10 in
83% yield from 8.
With a chiral cyclohexenone 10 in hand, generation of the
quaternary carbon at C-8 and the C–C bond at C-3 by a three
component coupling reaction8‡ of 10, a vinyl metal species, and
formaldehyde in a one-pot reaction was investigated. Treatment
of 10 with higher order vinylcuprate [(vinyl)2-
Scheme 1 Bn = 2CH2Ph. Reagents and conditions: i, MeOH, BF3·OEt2,
PhH, 0 °C, then H2, 10% Pd-C, EtOAc, rt; ii, MeONa, MeOH, 0 °C, then I2,
Ph3P, imidazole, THF, rt; iii, NaH, DMF, 0 °C, then BnBr, n-Bu4NI, DMF,
0 °C; iv, Hg(OCOCF3)2 (5 mol%), acetone–H2O (2+1), 0 °C, then MsCl,
Et3N, CH2Cl2, 0 °C; v, MeLi, Et2O, 278 °C; vi, PCC, molecular sieves 4
Å (powder), CH2Cl2, rt.
DOI: 10.1039/b006170k
Chem. Commun., 2000, 2237–2238
This journal is © The Royal Society of Chemistry 2000
2237

∑ Under the conditions of deprotection of the O-THP group with PPTS in
EtOH, the primary hydroxy group in the resulting 23 further attacked the
oxetane ring to generate a significant amount of a THF derivative.
1 Isolation of paclitaxel, see (a) M. C. Wani, H. L. Taylor, M. E. Wall, P.
Coggon and A. T. McPhail, J. Am. Chem. Soc., 1971, 93, 2325.
Biological activity, see (b) Taxane Anticancer Agents: Basic Science
and Current Status’ ed. I. Georg, T. T. Chen, I. Ojima and D. M. Vyas,
ACS Symposium Series 583, American Chemical Society, Washington
DC, 1995.
2 (a) R. A. Holton, H.-B. Kim, C. Somoza, F. Liang, R. J. Biediger, P. D.
Boatman, M. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. Suzuki, C.
Tao, P. Vu, S. Tang, P. Zhang, K. K. Murthi, L. N. Gentile and J. H. Liu,
J. Am. Chem. Soc., 1994, 116, 1599 and references therein; (b) K. C.
Nicolaou, Z. Yang, J.-J. Liu, H. Ueno, P. G. Nantermet, R. K. Guy, C.
F. Claiborne, J. Renaud, E. A. Couladouros, K. Paulvannan and E. J.
Sorensen, Nature, 1994, 367, 630; K. C. Nicolaou, H. Ueno, J.-J. Liu, P.
G. Nantermet, Z. Yang, J. Renaud, K. Paulvannan and R. Chadha, J. Am.
Chem. Soc., 1995, 117, 653 and references therein; (c) J. J. Masters, J.
T. Link, L. B. Snyder, W. B. Young and S. J. Danishefsky, Angew.
Chem., Int. Ed. Engl., 1995, 34, 1723; S. J. Danishefsky, J. J. Masters,
W. B. Young, J. T. Link, L. B. Snyder, T. V. Magee, D. K. Jung, R. C.
A. Isaacs, W. G. Bornmann, C. A. Alaimo, C. A. Coburn and M. J. Di
Grandi, J. Am. Chem. Soc., 1996, 118, 2843; (d) P. A. Wender, N. F.
Badham, S. P. Comway, P. E. Floreancig, T. E. Glass, J. B. Houze, N.
E. Krauss, D. Lee, D. G. Marquess, P. L. McGrane, W. Meng, M. G.
Natchus, A. J. Shuker, J. C. Sutton and R. E. Taylor, J. Am. Chem. Soc.,
1997, 119, 2757 and references therein; (e) I. Shiina, H. Iwadare, H.
Sakoh, M. Hasegawa, Y. Tani and T. Mukaiyama, Chem. Lett., 1998, 1;
I. Shiina, K. Saitoh, I. Fréchard-Ortuno and T. Mukaiyama, Chem. Lett.,
1998, 3; T. Mukaiyama, I. Shiina, H. Iwadare, M. Saitoh, T. Nishimura,
N. Ohkawa, H. Sakoh, K. Nishimura, Y. Tani, M. Hasegawa, K.
Yamada and K. Saitoh, Chem. Eur. J., 1999, 5, 121; (f) K. Morihira, R.
Hara, S. Kawahara, T. Nishimori, N. Nakamura, H. Kusama and I.
Kuwajima, J. Am. Chem. Soc., 1998, 120, 12980; H. Kusama, R. Hara,
S. Kawahara, T. Nishimori, H. Kashima, N. Nakamura, K. Morihara and
I. Kuwajima, J. Am. Chem. Soc., 2000, 122, 3811.
3 Examples of construction of taxane skeleton involving B-ring closure of
AC ring systems by McMurry reaction, see ref. 2b. Heck reaction, see
ref. 2c. Aldol reaction, see ref. 2f; R. Hara, T. Furukawa, Y. Horiguchi
and I. Kuwajima, J. Am. Chem. Soc., 1996, 118, 9186; M. R. R. Ferreira,
J. I. M. Hernando, J. I. C. Lena, N. Birlirakis and S. Areniyadis, Synlett,
2000, 113. Alkylation of cyanohydrin derivatives, see T. Takahashi, H.
Iwamoto, K. Nagashima, T. Okabe and T. Doi, Angew. Chem., Int. Ed.
Engl., 1997, 36, 1319. Pinacol coupling with SmI2, see C. S. Swindell
and W. Fan, Tetrahedron Lett., 1996, 37, 2321; J. Org. Chem., 1996, 61,
1109.
4 Reports on the synthesis of the fully functionalized paclitaxel CD ring
unit, see (a) T. V. Magee, W. G. Bornmann, R. C. A. Isaacs and S. J.
Danishefsky, J. Org. Chem., 1992, 57, 3274; (b) K. C. Nicolaou, C.-K.
Hwang, E. J. Sorensen and C. F. Clairborne, J. Chem. Soc., Chem.
Commun., 1992, 1117; (c) T. Takahashi, Y. Hirose, H. Iwamoto and T.
Doi, J. Org. Chem., 1998, 63, 5742; representative synthetic ap-
proaches, see (d) M. S. Ermolenko, T. Shekharam, G. Lukacs and P.
Potier, Tetrahedron Lett., 1995, 36, 2461; M. S. Ermolenko, G. Lukacs
and P. Potier, Tetrahedron Lett., 1995, 36, 2465; (e) A. N. Boa, J. Clark,
P. R. Jenkins and N. J. Lawrence, J. Chem. Soc., Chem. Commun., 1993,
151; (f) M. Nakada, E. Kojima and Y. Iwata, Tetrahedron Lett., 1998,
39, 313; (g) C.-K. Sha, S-J. Lee and W.-H. Tseng, Tetrahedron Lett.,
1997, 38, 2725, and references therein.
Scheme 2 THP = tetrahydropyran-2-yl, TBS = 2SiMe2(t-Bu), Ms =
2SO2Me. Reagents and conditions: i, CuCN (2 eq.), vinyllithium (4 eq.),
Et2O, 278 °C, 10 min, then formaldyhyde in THF (1 mol l21, excess
amount), 260 °C, 15 min; ii, K2CO3, MeOH, rt; iii, 3,4-dihydro-2H-pyran,
PPTS, CH2Cl2, rt; iv, LiHDMS, THF, 278 °C, then TMSCl–Et3N (1+1,
v/v), 278 °C; v, MCPBA , 220 °C, CH2Cl2, then TMSCl, Et3N, CH2Cl2;
vi, Tebbe reagent, THF, rt, then K2CO3, MeOH, rt.; vii, t-BuOOH,
VO(acac)2, rt; viii, AcOK, 18-crown-6, DMF, 100 °C, then acetic
anhydride, pyridine, rt; ix, MsCl, DMAP, CH2Cl2, rt; x, K2CO3, MeOH, rt;
then DBU, toluene, 100 °C; xi, acetic anhydride, DMAP, pyridine, 40 °C;
xii, CAN (3 mol%), CH3CN–borate buffer (pH 8, 1+1), 50 °C; xiii, TPAP,
NMO, rt.
Education, Science, Sports and Culture, Japanese Government
is gratefully acknowledged.
Notes and references
† This compound was an anomeric mixture (a+b = ca. 4+1), and used in the
next reaction without separation.
5 R. J. Ferrier and N. Presad, J. Chem. Soc. (C), 1969, 570.
6 R. J. Ferrier, J. Chem. Soc., Perkin Trans., 1, 1979, 1455; R. J. Ferrier
and S. Middleton, Chem. Rev., 1993, 93, 2779.
‡ A similar approach (starting from
Ermolenko, see ref 4d.
D-glucose) has been reported by
§ Conjugated addition of the vinyl group to enone 10 was found to proceed
highly stereoselectively. When the intermediate enolate was treated with
aqueous NH4Cl, a 1,4-adduct was obtained as a single isomer in 95% yield.
Reduction of the 1,4-adduct with NaBH4 afforded a cyclohexanol derivative
13, which was acylated with (R)- and (S)-acetylmandelic acid (DCC,
7 N. Chida, M. Ohtsuka, K. Ogura and S. Ogawa, Bull. Chem. Soc. Jpn.,
1991, 64, 2118; S. Amano, N. Takemura, M. Ohtsuka, S. Ogawa and N.
Chida, Tetrahedron, 1999, 55, 3855.
8 For a review, see R. J. K. Taylor, Synthesis, 1985, 364.
9 F. N. Tebbe, G. W. Parshall and G. S. Reddy, J. Am. Chem. Soc., 1978,
100, 3611; S. H. Pine, R. J. Pettit, G. D. Geib, S. G. Cruz, C. H. Gallego,
T. Tijerina and R. D. Pine, J. Org. Chem., 1985, 50, 1212.
10 K. B. Sharpless and R. C. Michaelson, J. Am. Chem. Soc., 1973, 95,
6136.
1
DMAP) to give (R)- and (S)-acetylmandelate derivatives, respectively. H
NMR analyses of the acetylmandelates revealed that they showed quite
different spectra, and no signal due to the (R)-isomer was observed in the
spectrum of the (S)-isomer, indicating the cyclohexanol 13 possessed high
optical purity ( ~ 100% ee), and no racemization had occurred during the
preparation of 8 and 10 and the 1,4-addition process.
11 I. E. Markó, A. Ates, B. Augustyns, A. Gautier, Y. Quesnel, L. Turet and
M. Wiaux, Tetrahedron Lett., 1999, 40, 5613.
¶ When compound 16 was subjected to the same reaction conditions, no
reaction took place resulting in the recovery of 16.
12 S. V. Ley, J. Norman, W. P. Griffith and S. P. Marsden, Synthesis, 1994,
639.
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Chem. Commun., 2000, 2237–2238