A new and convenient method for the preparation of cyclooctanone containing bis-aldol skeleton by samarium(II) iodide-mediated intramolecular aldol cyclization of ω-oxiranyl keto octanal

Article abstract of DOI:10.1246/cl.2002.82

A polyoxy eight-membered ring compound containing a bisaldol skeleton, 2,6-dibenzyloxy-3-(t-butyldimethylsiloxy)-7-hydroxy-8-hydroxymethyl-5- (p-methoxybenzyloxy)-4,4-dimethyl-cyclooctanone 1, a key synthetic intermediate of 19-hydroxypaclitaxel, was prep

Full text of DOI:10.1246/cl.2002.82

82
Chemistry Letters 2002
A New and Convenient Method for the Preparation of Cyclooctanone Containing
Bis-Aldol Skeleton by Samarium(II) Iodide-mediated Intramolecular Aldol Cyclization
of !-Oxiranyl Keto Octanal
Khanitha Pudhom, Hidehiro Arai, Keiko Yamane, and Teruaki Mukaiyamaꢀ
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(Received October 10, 2001; CL-010996)
Base or
Low-valent Metal
A polyoxy eight-membered ring compound containing a bis-
aldol skeleton, 2,6-dibenzyloxy-3-(t-butyldimethylsiloxy)-7-hy-
droxy-8-hydroxymethyl-5-(p-methoxybenzyloxy)-4,4-dimethyl-
O
OP
R
RCHO
O
OP
Species
O
O
OP
OP
cyclooctanone 1,
a
key synthetic intermediate of 19-
X
HO
hydroxypaclitaxel, was prepared in high yield from 2,6-dibenzy-
loxy-5-(t-buthyldimethylsiloxy)-3-(p-methoxybenzyloxy)-4,4-di-
methyl-8,9-oxiranyl-7-oxononanal 6 by the samarium(II) iodide-
mediated intramolecular aldol cyclization.
Bis-aldol
O
2
X = H or Halogen
P = H or Protective group
X
3
Base or
Low-valent metal species
Taxane diterpenes, including antineoplastic agent Taxol, have
a highly oxidized tricyclic carbon framework consists of a central
eight-membered ring and two peripheral six-membered rings.1 In
the course of our synthetic studies on Taxol and its derivatives, fully
substituted cyclooctanone which corresponds to the eight-mem-
bered ring structure of Taxol was first prepared in good yield by
samarium(II) iodide-mediated aldol-type cyclization of a linear
optically active acyclic !-(ꢀ-bromoketo)octanal.2{6 Further, asym-
metric total synthesis of Taxol has been completed according to the
synthetic strategy that started from the above eight-membered ring
ketone.3
Scheme 2.
BnO
OBn
CHO
OPMB
X BnO
OBn
CHO
O
1
OH O
TBS
O
OPMB
O
O
TBS
4: X = H
5: X = Cl, Br, I
6
Scheme 3.
eight-membered ring that contains bis-aldol skeleton, from !-
oxiranyloxononanal. The SmI2-mediated aldol reaction of model
compound 8 was investigated first and was further applied to the
synthesis of an optically active fully oxidized cyclooctanone, a
precursor for the synthesis of 19-hydroxypaclitaxel.
The !-oxiranyl keto aldehyde 8 was prepared simply by four
steps: namely, alkylation of 5-phenyl-2-pentenal with lithium
reagent generated from !-bromo-1-tetrahydropyranyl ether 7 and t-
butyllithium, and deprotection of THP group, successive epoxida-
tion with m-CPBA, and Swern oxidation (Scheme 4).
In order to improve pharmacological profile of Taxol,
particularly to improve its solubility in water, synthesis of 19-
hydroxypaclitaxel, a new Taxol derivative, was planned.
OH
BnO
TBSO
O
O
OH
AcO
OH
19
Bz
Ph
NH O
OH
OH
1
O
O
H
OBn
PMBO
OAc
HO OBz
19-Hydroxypaclitaxel
1
OHC
tBuLi
Scheme 1.
Ph
Br
THPO
OH
THF
THF
r.t., 6 h
It was then thought that the construction of polyoxy eight-
membered ring intermediate 1 containing bis-aldol skeleton should
be the first thing to be done; however, it was previously noted that
the bis-aldol was hardly obtained by base-promoted aldol reaction
between ꢁ-hydroxyketone and aldehyde or by Reformatsky type
aldol reaction between ꢀ-halo-ꢁ-hydroxyketone and aldehyde: that
is, when ꢁ-alkoxyketone 2 was treated with strong bases such as
LDA or reductants such as low-valent metal species, a dehydrated
product, ꢀ, ꢁ-unsaturated ketone 3, wasformed as shown inScheme
2.7
It thus seemed difficult to prepare eight-membered ring
compound 1 from 4 (mono-aldol) or 5 (ꢀ-halo-ꢁ-hydroxyketone)
on treatment with bases or reductants. On the other hand, it was
recently reported from our laboratory that a new and useful method
for the synthesis of unsymmetrical bis-aldols was established by
SmI2-mediated aldol reaction of aldehydes with aryl or alkyl
oxiranyl ketones.8 Therefore, it was considered that the synthesis of
intermediate 1 would be performed according to this method using
!-oxiranyl keto aldehyde 6 as sketched in Scheme 3.
7
0
, 6 h, 68
OH
m-CPBA
CSA
MeOH
, 2 h
quant.
Ph
Ph
CH2Cl2
, 2 h
quant.
0
OTHP
OH
0
O
OH
1) (COCl)2, DMSO
2) Et3N
O
O
Ph
Ph
CHO
CH2Cl2
to 0 , 2 h
93
OH
-78
8
Scheme 4.
In the first place, formation of the eight-membered ring
compound was tried by treating 8 with SmI2 and the desired product
10 was obtained in 30% yield. The reducing ability of low-valent
samarium species was generally known to be increased by the
coordination of electron rich ligands such as H2O to the metal ions.
Kamochi and Kudo reported their interesting observations on the
reduction of carboxylic acids, esters, amides and nitriles using
SmI2-H2O to support the above.9 Based on the above results, the
In this communication, we would like to describe an effective
method for the preparation of the above key intermediate 1, polyoxy
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
83
cyclization reaction was carried out by adding water and a mixture
of the cyclized product was obtained in 78% yield. Of possible four
stereoisomers, cis-syn and cis-anti, determined by their conversion
to the corresponding dimethyl acetonides, were isolated (Table 1,
Entry 2).
O
BnO
TBSO
O
BnO
TBSO
+
O
OH
OH
OH
OH
OH
TBSO
+
SmI2
6
OH
THF, -78
PMBO OBn
PMBO OBn
PMBO OBn
12 (by-product)
1a
1b
DDQ, H2O
CH2Cl2, r.t.
DDQ, H2O
CH2Cl2, r.t.
I2Sm
SmI2
O
O
OH
OH
O
O
H
H
SmI2
OBn
OH
OBn
OH
8
R
R
R
CHO
+
OH
OH
OH
OH
TBSO
TBSO
additive
OH
OH
cis-anti (10b)
O
O
cis-syn (10a)
9: R = (CH2)2Ph
Table 1. Yields of cyclooctaneones 10
OBn
OBn
13a
13b
a
Entry
1
2
Additive / eq
cis-syn / cis-anti)
Table 2. Yields of cyclooctaneone 1
b
none
30 (nd)
Entry
Additive / eq
None
1a/1b)
Water / 3
78 (50 / 50)
1
2
3
83a (50/50)
76 (39/61)
91 (49/51)
Water / 3
a
The ratio of the possible four isomers was determined by integration of the
iPrOH / 2
1
H NMR spectrum of a mixture of the corresponding dimethyl acetonide
b
a
The deoxygenated product 12 was also detected in ab
derivatives.
Not determined.
hydroxypaclitaxel, was efficiently performed by using an excess
amount of SmI2 via intramolecular aldol cyclization of the
disamarium alkoxy enolate.
Next, the present method was applied to the synthesis of key
intermediate 1, a polyoxy eight-membered ring compound
corresponding to the B ring of 19-hydroxypaclitaxel. The !-
oxiranyl keto aldehyde 6 was prepared from aldehyde 11 which
prepared from D-pantolactone according to the original procedure
of our laboratory (Scheme 5).3
A typical procedure for the SmI2-mediated cyclization
(Table 2, Entry 3) is as follows: to a solution of !-oxiranyl keto
aldehyde 6 (1.54 g, 2.38 mmol) in THF (100 mL) was added a
i
solution of SmI2 in THF (0.1 M, 71.4 mL, 7.14 mmol) and PrOH
(300 mg, 4.76 mmol) immediately in succession at ꢁ78 ꢂC under
argon. The reaction mixture was kept stirring for 30 min at the same
temperature and then saturated aqueous ammonium chloride was
added. The mixture was filtered through a short pad of Celite and the
filtrate was extracted with diethyl ether. The organic layer was
washed with water and brine, and dried over sodium sulfate. After
filtration of the mixture and evaporation of the solvent, the crude
product was purified by column chromatography (hexane/
AcOEt ¼ 3=1) to afford the cyclized products, 1a (0.72 g, 45%)
and 1b (0.75 g, 46%) as colorless oil.
OBn
OBn
OH
O
OTBS
a
OHC
O
OPMB
O
TBS
11
D-Pantlactone
OBn
OBn
OBn
OBn
O
b
c
OH
OTBS
6
OH O OPMB
TBS
OH O OPMB
TBS
Scheme 5. Reagent and conditions: a) vinylMgBr, THF, 0 ꢂC (98%); b)
1 M HCl, THF, r.t. (88%); m-CPBA, CH2Cl2, 50 ꢂC (96%); c) (COCl)2,
DMSO, Et3N, CH2Cl2, ꢁ78 ꢂC to 0 ꢂC (95%).
This work was partially supported by Grants-in-Aid for
Scientific Research from the Ministry of Education, Science,
Sports, and Culture, Japan.
The SmI2-mediated intramolecular aldol reaction of
6
proceeded to give the cyclized product 1 in 83% yield along with
2-debenzyloxygenation compound 12 in 10% yield in the absence
of H2O (Table 2, Entry 1). This debenzyloxygenation occurred by
further SmI2-reduction of 1 whose benzyloxy group was activated
with SmIII species generated by the reductive aldol reaction. Thus, it
was considered that the addition of water would reduce Lewis
acidity of the SmIII species to inhibit the reductive elimination of the
benzyloxy group with excess SmI2. When water was added to the
reaction mixture, the aldol reaction of 6 proceeded smoothly to give
the cyclized products, 1a and 1b, in 30% and 46% yields,
respectively, without forming 12 (Entry 2). A small amount of 4
wasformed by ring opening ofepoxide of 6 because hydrolysis of ꢁ-
metalloxyketo samarium enolate took place competitively with the
desired cyclization. It was furtherfound that theyield ofthe cyclized
product increased up to 91% when iPrOH was added (Entry 3). In
order to clarify the structure of these eight-membered ring
compounds, 1a and 1b were transformed into bicyclic derivatives
13a and 13b on treatment with DDQ and the structures of the formed
rigid bicyclic skeletons were confirmed by 1H NMR spectroscopy.
Thus, the synthesis of 8-membered ring compound containing
bis-aldol skeleton, the key intermediate of the synthesis of 19-
References and Notes
1
2
3
For a review see: D. G. I. Kingston, A. A. Molinero, and J. M. Rimoldi,
Prog. Chem. Org. Nat. Prod., 61, 1 (1993).
T. Mukaiyama, I. Shiina, H. Iwadare, H. Sakoh, Y. Tani, M. Hasegawa,
and K. Saitoh, Proc. Jpn. Acad., 73B, 95 (1997).
T. Mukaiyama, I. Shiina, H. Iwadare, M. Saitoh, T. Nishimura, N.
Ohkawa, K. Nishimura, Y. Tani, M. Hasegawa, K. Yamada, and K.
Saitoh, Chem. Eur. J., 1999, 5.
4
5
I. Shiina, K. Uoto, N. Mori, T. Kosugi, and T. Mukaiyama, Chem. Lett.,
1995, 181.
For reviews of the construction of cyclooctanoid systems, see a) G.
Mehta, and V. Singh, Chem. Rev., 1999, 881. b) N. A. Petasis and M. A.
Patane, Tetrahedoron, 48, 5757 (1992).
6
Formation of medium-sized ring carbocycles by SmI2-promoted
cyclization of ꢀ-bromo-!-oxoester: J. Inanaga, Y. Yokoyama, Y.
Handa, and M. Yamaguchi, Teterahedron Lett., 32, 6371 (1991).
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