Stereoselective synthesis of 19-hydroxytaxoid using intramolecular pinacol coupling reaction

Article abstract of DOI:10.1246/cl.2004.1412

The ABC-ring system of 19-hydroxytaxol is stereoselectively constructed by intramolecular pinacol coupling of diketone 12 with low valent titanium species prepared from TiCl₂ and LiAlH₄. After manipulations of hydroxy protecting grou

Full text of DOI:10.1246/cl.2004.1412

1412
Chemistry Letters Vol.33, No.11 (2004)
Stereoselective Synthesis of 19-Hydroxytaxoid
Using Intramolecular Pinacol Coupling Reaction
Teruaki Mukaiyama,ꢀy;yy Yasuyuki Ogawa,y;yy Kiichi Kuroda,y;yy and Jun-ichi Matsuoy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received August 5, 2004; CL-040926)
The ABC-ring system of 19-hydroxytaxol is stereoselective-
ly constructed by intramolecular pinacol coupling of diketone 12
with low valent titanium species prepared from TiCl2 and
LiAlH4. After manipulations of hydroxy protecting groups, a
new 19-hydroxytaxoid 18 was afforded by olefination of vicinal
diol part of 17.
OMOM
OH
O
O
BnO
TBSO
O
BnO
TBSO
OMOM
9
a
9
7
7
H
H
5
7
PMBO OBn
PMBO OBn
b
In the course of our synthetic research on preparing a new
anticancer agent by chemical modification of a potent anticancer
drug, taxolÒ (1), 19-hydroxytaxol (2) was chosen so as to im-
prove its pharmacological profile, especially its water-solubility,
by putting hydrophilic molecules on its newly-introduced C-19
hydroxy group of 2 (Scheme 1). Although 19-hydroxybaccatin
III (3) can be isolated from natural resources,1 quantities of 3
are not sufficient for synthesizing its derivatives 2. It was then
considered to synthesize 2 from D-pantolactone, adapting our
strategy for the total synthesis of 1: that is, to construct B-ring
first, and to attach C-ring and A-ring successively to the B-ring.2
O
O
BnO
HO
O
O
BnO
TBSO
OMOM
OMOM
c
1
1
H
H
9
O
8
HO OBn
OBn
d
O
O
BnO
O
O
O
BnO
OMOM
e
OMOM
HO
11
O
12
R2
1
c-Hex Si
AcO
O
H
OBn
H
OH
O
O
BnO
HO
19
Me
10
c-HexMe2SiO OBn
11
OMOM
HO
B
C
2
f
A
R1O
O
H
H
HO BzO
O
O
BnO
OAc
O
O
BnO
HO
4
c-HexMe2SiO OBn
OMOM
OMOM
O
Taxol(1): R1 = BzNHCH(Ph)CH(OH)CO, R2 = H
19-Hydroxytaxol (2): R1 = BzNHCH(Ph)CH(OH)CO,
R2 = OH
HO
11
12
g
O
H
H
19-Hydroxybaccatin III (3): R1 = H, R2 = OH
c-HexMe2SiO OBn
12
c-HexMe2SiO OBn
4
OMOM
OH
BnO
O
Scheme 2. Reagents and conditions a) AlH3, THF ꢁ23 ꢂC (81%);
2,2-dimetoxypropane, CSA, CH2Cl2 rt (92%). b) DDQ, phosphate buf-
fer, CH2Cl2 0 ꢂC (quant.); Dess–Martin periodinane, NaHCO3,
CH2Cl2 rt (95%). c) homoallyl lithium, benzene ꢁ23 ꢂC to 0 ꢂC
(97%); TBAF, THF 50 ꢂC (80%). d) cyclohexylmethyldichlorosilane,
imidazole, DMF rt (99%). e) MeLi, THF-HMPA ꢁ78 ꢂC (99%). f)
Dess–Martin periodinane, NaHCO3, CH2Cl2 0 ꢂC (97%); PdCl2,
DMF–H2O rt (83%). g) TiCl2, LiAlH4, THF (64%) 40 ꢂC.
O
BnO
TBSO
TBSO
OH
OH
H
5
PMBO OBn
PMBO OBn
6
Scheme 1.
In our preceding papers, a new and efficient method for the
construction of BC-ring unit 5 by samarium(II) iodide-mediated
intramolecular cyclization of the epoxyketo aldehyde derived
from 8-memberd ring 6, was reported.3,4 In this communication,
we would like to describe the stereoselective construction of
ABC-ring system of 19-hydroxytaxol by successive reactions
of intramolecular pinacol coupling to form A-ring and of olefina-
tion of its diol unit.
The conversion of 5, which was prepared by the previously
described samarium(II) iodide-mediated double aldol reaction,
to the key intermediate diol 4 is shown in Scheme 2. First,
MOM-protected double aldol 5 was diastereoselectively reduced
with AlH3 to afford the corresponding C-7,C-9-cis-diol preferen-
tially,5 and protection of thus formed cis-diol with isopropyli-
dene acetal provided tricyclic compound 7. Then it was convert-
ed to 8-membered ring ketone 8 by oxidative deprotection of
PMB group and by successive oxidation of C-1 hydroxy group
with Dess–Martin periodinane. Alkylation of 8 at C-1 position
with homoallyllithium2 in benzene produced the desired ꢀ-alco-
hol in high yield with perfect diastereoselectivity. Deprotection
of TBS group resulted in the formation of cis-diol 9 and succes-
sive treatment of 9 with dichlorocyclohexylmethylsilane yielded
silylene 10 in high yield. Alkylaton of 10 with methyllithium
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.11 (2004)
1413
furnished 11, which had the desired C-1 siloxy group. Oxidation
of thus formed secondary hydroxy group at C-11 with Dess–
Martin periodinane gave the corresponding ketone in good yield.
The terminal olefin of 11 was then oxidized by using PdCl2 in
DMF-H2O to afford the desired diketone 12 in good yield. By
the above sequence of manipulations, compound 12, a precursor
for the construction of ABC-ring system, was efficiently synthe-
sized from BC-ring units. Intramolecular pinacol coupling of
diketone 12 using low-valent titanium reagent,6 prepared form
TiCl2 and LiAlH4, gave ABC-ring system of 4 as a main prod-
uct. Under the pinacol coupling conditions, MOM group of
C-19 hydroxy group was not cleaved. On the other hand, the
same pinacol coupling reaction using samarium(II) iodide did
not give the coupling product.
Deprotection of both MOM group and isopropylidene acetal un-
der acidic conditions was tried at this point. Acid hydrolysis with
6 N HCl followed by protection with i-Pr2Si(OTf)2 unexpectedly
gave cyclic ether 14 in moderate yield. Through careful observa-
tion, it was revealed that the deprotection of MOM group and the
intramolecular ether formation took place spontaneously while
isopropylidene acetal was not completely deprotected. Since it
was difficult to suppress the formation of cyclic ether, C-19 hy-
droxy group, which was formed by selective deprotection of
MOM group, was protected by the intramolecular bromo ether
formation procedure using N-bromosuccinimide (NBS).7 Isopro-
pylidene acetal of cyclic bromo ether 15 was easily deprotected
with HCl, and regioselective protection of hydroxy group at C-7
with TESOTf afforded tetraol 16. Deprotection of cyclic bromo
ether 16 with zinc–silver couple in EtOH,8 protection of the
formed primary hydroxy group with TBSOTf, and the following
selective acetylation of hydroxy group at C-10 gave acetate 17.
A novel 19-hydroxytaxoid 18 was synthesized from acetate 17
by two-step procedures. Namely, conversion of the vicinal diol
moiety to the corresponding thiocarbonate using thiophosgene,
and 19-hydroxytaxoid 18 was afforded by heating the thiocar-
bonate with trimethylphosphite.9
The conversion of 4 to 19-hydroxytaxoid 18 is shown in
Scheme 3. After deprotecting benzyl groups of 4 with Na/
NH3 and of cyclohexyldimethylsilyl group with TBAF, regiose-
lective protection of thus formed pentanol with bis(trichlorome-
thyl)carbonate afforded C-1, C-2 carbonate 13 in high yield.
O
O
O 19 O
BnO
HO
HO
HO
OMOM
OMOM
Thus, asymmetric synthesis of the ABC-ring system of
19-hydroxytaxol was completed via two key reactions; namely,
intramolecular pinacol coupling and olefination of diol. This is
the first report on the synthesis of 19-hydroxytaxoid,10 and this
taxoid is expected to be employed as not only a precursor of
19-hydroxytaxol but also as a starting material for new
chemotherapeutic agents.
HO
HO
a
c
1
2
1
2
H
H
O
13
O
4
c-HexMe2SiO OBn
b
O
iPr iPr
Si
O 19
O
O
O
O
HO
HO
HO
The present work was partially supported by Grant of the
21st Century COE Program from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan.
HO
7
HO
HO
O
H
O
H
O
O
O
Br
References and Notes
J. L. McLaughlin, R. W. Miller, R. G. Powell, and C. R. Smith, Jr., J. Nat.
Prod., 44, 312 (1981).
14
1
d
O
O
15
2
a) T. Mukaiyama, I. Shiina, H. Iwadare, H. Sakoh, Y. Tani, M. Hasegawa,
and K. Saitoh, Proc. Jpn. Acad., 73B, 95 (1997). b) 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., 5, 121 (1999).
OTBS
OTES
OH
AcO
OH
HO
HO
OTES
HO
7
10
HO
HO
10
e
O
3
4
a) T. Mukaiyama, H. Arai, and I. Shiina, Chem. Lett., 2000, 580. b) T.
Mukaiyama, K. Pudhom, K. Yamane, and H. Arai, Bull. Chem. Soc.
Jpn., 76, 413 (2003).
a) K. Pudhom, H. Arai, K. Yamane, and T. Mukaiyama, Chem. Lett., 2002,
82. b) K. Pudhom, J. Matsuo, and T. Mukaiyama, Heterocycles, 59, 445
(2003). c) J. Matsuo, Y. Ogawa, K. Pudhom, and T. Mukaiyama, Chem.
Lett., 33, 124 (2004).
H
H
O
O
AcO
O
O
O
Br
17
O
O
16
f
OTBS
OTES
OH
5
6
The numbers on each carbon atom of all intermediates are according to
IUPAC taxane skeleton nomenclature.
TiCl2 was prepared from TiCl4 and Me3SiSiMe3 by a literature method: a)
R. C. Paul, A. Arneja, and S. P. Narula, Inorg. Nucl. Chem. Lett., 5, 1013
(1969). b) S. P. Narula and H. K. Sharma, Inorg. Synth., 24, 181 (1986). c)
T. Mukaiyama, A. Kagayama, and I. Shiina, Chem. Lett., 1998, 1107.
J. Ishihara, R. Nonaka, Y. Terasawa, R. Shiraki, K. Yabu, H. Kataoka,
Y. Ochiai, and K. Tadano, J. Org. Chem., 63, 2679 (1998).
a) J. M. Denis, C. Girard, and J. M. Conia, Synthesis, 1972, 549. b) T.
Tokoroyama, K. Matsuo, and R. Kanazawa, Bull. Chem. Soc. Jpn., 53,
3383 (1980).
H
O
7
8
O
18
Scheme 3. Reagents and conditions a) Na, liq. NH3, THF ꢁ78 ꢂC to
ꢁ45 ꢂC; TBAF, THF rt (94%); triphosgene, pyridine, CH2Cl2 ꢁ45 ꢂC
(95%). b) 6 N HCl, THF 60 ꢂC; i-Pr2Si(OTf)2, pyridine, CH2Cl2
ꢁ45 ꢂC (37%). c) 6 N HCl, THF rt (quant); NBS, CH2Cl2 rt (quant).
d) 3 N HCl, THF 60 ꢂC; TESOTf, pyridine ꢁ23 ꢂC (91%). e) Zn–
Ag, AcOH, EtOH 90 ꢂC (81%); TBSOTf, pyridine ꢁ23 ꢂC (83%);
Ac2O, DMAP, pyridine rt (77%). f) Thiophosgene, DMAP, CHCl3
60 ꢂC; P(OMe)3 110 ꢂC (43% based on 35% conversion).
9
a) E. Block, Org. React., 30, 457 (1984). b) E. J. Corey, F. A. Carey,
and R. A. E. Winter, J. Am. Chem. Soc., 87, 934 (1965). c) E. J. Corey
and P. B. Hopkins, Tetrahedron Lett., 23, 1979 (1982).
10 Kuwajima et al. already reported this taxoid as an intermediate
for synthesis of taxol; H. Kusama, R. Hara, S. Kawahara, T. Nishimori,
H. Kashima, N. Nakamura, K. Morihira, and I. Kuwajima, J. Am. Chem.
Soc., 122, 3811 (2000).
Published on the web (Advance View) September 29, 2004; DOI 10.1246/cl.2004.1412