Stereoselective construction of BC-ring unit of 19-hydroxytaxol by samarium(II) iodide-mediated double aldol cyclization

Article abstract of DOI:10.1246/cl.2004.124

The C-ring of 19-hydroxytaxol is stereoselectively constructed by samarium(II) iodide-mediated intramolecular double aldol cyclization of epoxyketo aldehyde to form the BC-ring unit which has the desired stereochemistry.

Full text of DOI:10.1246/cl.2004.124

124
Chemistry Letters Vol.33, No.2 (2004)
Stereoselective Construction of BC-ring unit of 19-Hydroxytaxol
by Samarium(II) Iodide-mediated Double Aldol Cyclization
Jun-ichi Matsuo,y;yy Yasuyuki Ogawa,y;yy Khanitha Pudhom,y;yy and Teruaki Mukaiyamaꢀy;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 October 28, 2003; CL-031029)
The C-ring of 19-hydroxytaxol is stereoselectively con-
BnO
TBSO
O
BnO
TBSO
O
OH OTES
OTES
structed by samarium(II) iodide-mediated intramolecular double
aldol cyclization of epoxyketo aldehyde to form the BC-ring unit
which has the desired stereochemistry.
a
PMBO OBn
PMBO OBn
7
8
To develop a new antitumor agent by synthesizing ana-
logues of a potent anticancer drug, taxol1 (1), 19-hydroxytaxol
(2) was chosen as a target molecule on the expectation that its
increased solubility in water will improve pharmacokinetics of
1 by introducing a hydroxy group to the 19-position of 1 and fur-
ther by introducing a hydrophilic molecule to the above 19-hy-
droxy group (Scheme 1). As 19-hydroxybaccatin III (3) is isolat-
ed in very small quantities from natural resources, synthesis of 2
and its derivatives in quantities for biological testing is difficult
from isolated 3. It was considered then that our strategy for the
total synthesis of 1 from D-pantolactone may be quite practical in
synthesizing 2: that is, to construct B-ring first and then to attach
C-ring and A-ring to thus constructed B-ring unit.1
b
c
BnO
TBSO
O
OH
BnO
TBSO
O
O
O
O
PMBO OBn
PMBO OBn
9
10
Scheme 2. Reagent and conditions: a) Ac2O, DMAP, pyridine
(89%); DBU, CH2Cl2 (75%); b) 0.5N HCl, THF, ꢁ20 ꢂC
(88%); H2O2, NaOH, MeOH, 0 ꢂC (79%); c) PhSNHtBu,
NCS, K2CO3, MS4A, CH2Cl2 (95%).
In the preceding papers, new and efficient construction of
eight-membered B-ring 5 by samarium(II) iodide-mediated in-
tramolecular cyclization of a linear epoxyketo aldehyde 6,2
and the subsequent introduction of a side chain for the construc-
tion of C-ring by trimethylaluminum-assisted 1,4-addition of
higher order cyanocuprate3 were reported. In the above strategy
for the total synthesis of 2, construction of C-ring will be a key
step since a double aldol unit should be prepared stereoselective-
ly at this stage. The synthetic plan is to construct the C-ring by
samarium(II) iodide-mediated double aldol cyclization of
epoxyketoaldehyde (10) similar to B-ring construction. In this
communication, we would like to describe the stereoselective
C-ring construction of 2.
Preparation of the key intermediate, epoxyketo aldehyde 10,
is shown in Scheme 2: namely, hydroxymethyl ketone 7, pre-
pared by the above-mentioned 1,4-addition of higher order cya-
nocuprate, was acetylated first, and ꢀ,ꢁ-unsaturated ketone 8
was obtained by regioselective elimination of the formed ꢀ-acet-
oxymethyl ketone with DBU. After deprotection of triethylsilyl
group, epoxidation of enone using H2O2 and NaOH gave ꢀ-ep-
oxy ketone 9 as a 1:1 mixture of diastereomers. Swern oxidation
and tetrapropylammonium perruthenium (TPAP)-catalyzed oxi-
dation of the primary hydroxy group of a diastereomixture of 9
did not give the desired aldehyde 10 whereas sulfenamide-cata-
lyzed oxidation with N-chlorosuccinimide4 oxidized 9 success-
fully, and 10 was obtained in 95% yield.
R2
OH
O
O
AcO
BnO
TBSO
OH
19
OH
B
C
2
A
R1O
H
O
HO BzO
OAc
PMBO OBn
Then, samarium(II) iodide-mediated cyclization of 10 was
tried (Table 1). First, the reaction was carried out at various tem-
peratures between ꢁ100 and ꢁ23 ꢂC in the absence of additives
(Entries 1–4). The desired isomer 4 was obtained in 71% yield
along with diastereomers 12 (10%) and 13 (15%)5,6 at
ꢁ100 ꢂC. On the other hand, the yields of both diastereomers
4 and 12 decreased as the reaction temperature rose. In these ex-
periments, a 1:1 diastereomixture of 10 was employed since the
results were the same even when a mixture or the single isomer
was used. Therefore, it is assumed that the desired facial selec-
tivity of the formed samarium enolate and an aldehyde moiety
would be controlled by lowering the reaction temperature. Next,
effects of additives were examined.2b,2c Contrary to our expecta-
4
Taxol®(1): R1 = BzNHC(Ph)C(OH)CO, R2 = H
19-Hydroxytaxol (2): R1 = BzNHC(Ph)C(OH)CO,
R2 = OH
19-Hydroxybaccatin III (3): R1 = H, R2 = OH
BnO
TBSO
O
BnO
O
OBn
O
OH
OH
CHO
OPMB
OTBS
PMBO OBn
6
5
Scheme 1.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.2 (2004)
125
Table 1. SmI2-mediated intramolecular cyclization of 10
OH
O
BnO
TBSO
O
BnO
TBSO
O
OH
O
SmI2
additive
THF
PMBO OBn
PMBO OBn
10
4
Figure 1. ORTEP drawing of compound 14.
the BC-ring compound 4, prepared as above.
OH
OH
OH
OH
OH
OH
O
O
O
BnO
TBSO
BnO
TBSO
BnO
TBSO
The present work was partially supported by Grant-in-Aids
for Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. The authors wish to
thank Dr. Youji Furukawa (Sankyo) for his support in X-ray
crystal structure analysis.
PMBO OBn
11
PMBO OBn
PMBO OBn
12
13
Entry Sml2
Additive
/equiv.
Temp.
/ꢂC
Yield/%
/equiv.
4
11 12 13
1
2
3
4
5
6
7
8
3.0
3.0
3.0
5.0
4.0
4.0
3.0
3.0
-
-
-
-
ꢁ100 71 NDa 10 15
References and Notes
ꢁ78 59 ND
ꢁ45 42 ND
ꢁ23 24 ND
9
3
2
16
20
16
6
1
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).
H2O (3.0)
ꢁ78 45 ND 44
MeOH (3.0) ꢁ78 27 ND 38
7
iPrOH (3.0)
ꢁ78 41 ND 35
9
2
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). c) K. Pudhom, H.
Arai, K. Yamane, and T. Mukaiyama, Chem. Lett., 2002, 82.
K. Pudhom, J. Matsuo, and T. Mukaiyama, Heterocycles, 59,
445 (2003).
a) J. Matsuo, D. Iida, H. Yamanaka, and T. Mukaiyama,
Tetrahedron, 59, 6739 (2003). b) T. Mukaiyama, J. Matsuo,
D. Iida, and H. Kitagawa, Chem. Lett., 2001, 846.
In order to make the structures of 12 and 13 clear, the PMB
groups of these bicyclic compounds were deprotected with
DDQ to lead to bridged tricyclic compounds, and their struc-
tures were determined by NOE.
HMPA (3.0) ꢁ78 45 ND 24 17
a
The product was not detected.
OH
OH
O
O
BnO
TBSO
BnO
TBSO
3
4
OH
OMOM
a
PMBO OBn
PMBO OBn
4
14
5
6
7
Scheme 3. Reagent and conditions; a) MOMCl, nBu4NI,
iPr2NEt, CH2Cl2 (76%).
tions, the addition of additives such as H2O, MeOH, i-PrOH, and
HMPA showed no improvement in the yield of the desired prod-
uct 4 while the yield of a diastereomer 12 increased. Formation
of diastereomer 11 was not observed through the above men-
tioned trials.
After protection of 19-hydroxy group of 12 and 13 with TBS
group, isomerization experiment by using NaOMe in
MeOH–THF did not give an isomerized product which have
the desired stereochemistry suited for synthesize 2.
Crystal data: C46H64O9Si (FW = 789.09), monoclinic, P21,
ꢀ
The stereochemistry of compound 4 was unambiguously
identified by X-ray crystal structure analysis of a MOM ether
14 which was obtained by the protection of 19-hydroxy group
of 4 with MOM group (Scheme 3, Figure 1).7
a ¼ 16:051ð3Þ, b ¼ 12:914ð4Þ, c ¼ 10:915ð3Þ A, ꢁ ¼
ꢂ
ꢁ3
,
ꢀ 3
93:73ð2Þ , V ¼ 2257 (1) A , Z ¼ 2, Dx ¼ 1:161 g cm
T ¼ 298 K. X-ray intensities were measured on Rigaku
AFC7R diffractometer with Cu Kꢀ radiation (ꢂ ¼
ꢀ
Currently, the total synthesis of 2 is in progress by utilizing
1:54178 A), and R ¼ 0:052 for 4209 observed reflections.
Published on the web (Advance View) January 8, 2004; DOI 10.1246/cl.2004.124