Enantioselective synthesis of (+)-decarestrictine L from (2E,5E)- dibenzyloxy-2,5-heptadien-4-ol

Article abstract of DOI:10.3987/com-99-s60

(+)-Decarestrictine L has been synthesized in enantiomerically pure form from (3R,4S)-1-benzyloxy-6-heptene-3,4-diol, prepared from (2E,5E)-1,7- dibenzyloxy-2,5-heptadien-4-ol, employing either Me₂AlCl promoted methylative cleavage of (1R,5R,6S

Full text of DOI:10.3987/com-99-s60

ꢀꢀꢀ
HETEROCYCLES, Vol. 52, No. 2, 2000, pp.525 – 528, Received, 28th April, 1999
ENANTIOSELECTIVE SYNTHESIS OF (+)-DECARESTRICTINE L
FROM (2E,5E)-DIBENZYLOXY-2,5-HEPTADIEN-4-OL
Tomoyuki Esumi, Rieko Kimura, Masako Mori, Yoshiharu Iwabuchi,
*
Hiroshi Irie, and Susumi Hatakeyama
Faculty of Pharmaceutical Sciences, Nagasaki University, Nagasaki 852-8521, Japan
Abstract - (+)-Decarestrictine L has been synthesized in enantiomerically pure form from
(3R,4S)-1-benzyloxy-6-heptene-3,4-diol, prepared from (2E,5E)-1,7-dibenzyloxy-2,5-heptadien-
4-ol, employing either M e2AlCl promoted methylative cleavage of (1R,5R,6S)-6-benzyloxy-2,9-
dioxabicyclo[3.3.1]nonane or DIBAH promoted reductive cleavage of (1R,5R,6S)-6-benzyloxy1-
methyl-2,9-dioxabicyclo[3.3.1]nonane for the construction of the substituted pyran ring system.
Recently we have developed an efficient method for the preparation of all stereoisomers of (1a~d) in
enantiomerically pure form starting from ꢀ-symmetrical (2E,5E)-1,7-dibenzyloxy-2,5-heptadien-4-ol (2)
based on Red-Al® promoted reaction as depicted in 3.1 In order to demonstrate the synthetic utility of our
methodology, we envisaged its application towards a synthesis2 of (+)-decarestrictine L (4),3 a member of
the decarestrictine family3,4 which is a novel class of inhibitors of cholesterol biosynthesis. We now report
an enantioselective synthesis of (+)-decarestrictine L (4) employing a strategy based on stereoselective
methylative or reductive cleavage of dioxabicyclo[3.3.1]nonane intermediate (5) (R = H or Me) which is
accessible from a 1b-type chiral building block.
OH
RO OR
–
Al
OH
Y
1a: X = H, Y = OH
b: X = OH, Y = H
c: X = Y = OH
H
O
OBn
*
X
*
*
d: X = Me, Y = OH
X
BnO
OBn
Y
2
BnO
OR'
OBn
3
OH
R = H
"methylative cleavage"
O
R
1b
O
R = Me
O
O
"reductive cleavage"
(+)-decarestrictine L (4)
5
Scheme 1
According to our established procedure,1a the required 1b-type chiral building block (6) was prepared from
2 in optically pure form in 64% yield by combination of catalytic Katsuki-Sharpless asymmetric

epoxidation, regioselective DIBAH reduction, and Red-Al® promoted reductive cleavage of the benzyloxy
group. Upon sequential Birch reduction, benzylidene acetalization, and benzylation, 6 afforded benzylidene
acetal (7),5 [ꢀ]20 +9.8° (c 1.03, CHCl3), in 65 % overall yield.
Hydroboration of 7 with
D
dicyclohexylborane followed by oxidation afforded primary alcohol (8), [ꢀ]27D –1.4° (c 1.08, CHCl3), and
secondary alcohol (9) in a ratio of 78:22 almost quantitatively. Alcohol (8) was successively subjected to
Swern oxidation, methanolytic removal of the benzylidene acetal group, and intramolecular acetalization to
20
give (1R,5R,6S)-6-benzyloxy-2,9-dioxabicyclo[3.3.1]nonane (10), [ꢀ]D +139.6° (c 0.90, CHCl3), in 61%
overall yield.
Alternatively, alcohol (8) was converted to (1R,5R,6S)-6-benzyloxy-1-methyl-2,9-
24
dioxabicyclo[3.3.1]nonane (12), [ꢀ]D26 –7.9° (c 1.16, CHCl3), via methyl ketone 11, [ꢀ]D –14.7° (c 1.30,
CHCl3), in 71% overall yield through a five-step sequence involving Swern oxidation, Grignard reaction,
Swern oxidation, methanolytic removal of the benzylidene acetal group, and intramolecular ketalization.
1) Li, NH -THF, –33 °C
3
OBn
2) PhCH(OMe) , PPTS
1) Katsuki-Sharpless
L-DIPT
2
OH
O
Ph
CH Cl
2
2
OBn
2
O
2) DIBAH, toluene, 0 °C
®
3) PhCH Br, NaH,
2
OH
3) Red-Al , toluene
n-Bu NI, THF
4
6
7
reflux
64%
65%
OBn
OBn
OH
1) Swern oxidation
2) p-TsOH, MeOH
(c-Hex) BH
2
OBn
O
O
Ph
O
Ph
THF, –10 °C
+
8
O
O
then
3) p-TsOH, benzene
O
H O , NaOH
2
2
HO
reflux
66%
9 (21%)
10
8 (76%)
1) Swern oxidation
2) MeMgBr, THF
–15 °C
OBn
OBn
O
Ph
1) p-TsOH, MeOH
8
O
O
3) Swern oxidation
91%
2) p-TsOH, benzene
O
O
reflux
78%
11
12
Scheme 2
With the required bicyclic compounds (10) and (12) in hand, we then investigated their transformations into
the key intermediate (13). Although methylative cleavage6 of dioxabicyclo[3.3.1]nonane derivatives are
unprecedented, we found that Me2AlCl caused the cleavage of 10 with moderate diastereoselectivity, whereas
7
Me3Al itself resulted in no reaction. Thus, treatment of 10 with 3.5 equivalents of Me2AlCl inCH2Cl2at 0
23
26
°C produced the desired pyran (13), [ꢀ]D +55.6° (c 1.19, CHCl3), and its epimer (14), [ꢀ]D +60.1° (c
1.35, CHCl3), in a ratio of 80:20 in 65% yield. On the other hand, reductive cleavage8 of 12 with DIBAH
took place with excellent diastereoselectivity to give 13 and 14 in a ratio of 95:5 in 85% yield. When 12 was

treated with triethylsilane in the presence of TiCl4 in CH2Cl2 at –78 °C,8 the reductive cleavage occurred with
perfect but opposite diastereoselectivity to give 14 exclusively in 78% yield. These stereochemical outcomes
are well consistent with the results reported by Yamamoto and co-workers8a and can be explained on the
basis of their interpretation8c which suggests participation of the tight ion paired intermediates. Thus, in the
case of the DIBAH promoted reaction, the highly stereoselective reductive cleavage would occur via
intramolecular hydride transfer from the coordinated aluminum reagent of ion paired intermediate (15) (M =
i-Bu2AlH, R = Me). In the cases of the triethylsilane reduction and the Me2AlCl promoted reaction, the
observed stereoselectivities would arise from preferential bottom-face attack of the reagent to ion paired
intermediate (15) (M = TiCl4 or Me2AlCl, R = H or Me).
OBn
OBn
OBn
Me AlCl (3.5 equiv.)
2
O
+
O
O
O
CH Cl , 0 °C
2
2
OH
OH
10
13
14
65%
(80:20)
DIBAH (4.5 equiv.)
13
14
+
14
CH Cl , –45 °C
OBn
2
2
(95:5)
85%
O
Et SiH (4.0 equiv.)
3
O
TiCl (1.2 equiv.)
4
12
CH Cl , –78 °C
2
2
78%
–
O
M
+
O
BnO
R
15
Scheme 3
28
Compound (13) thus obtained was converted to methyl ketone (16), [ꢀ]D +54.0° (c 0.66, CHCl3), by
Swern oxidation, Grignard reaction, and Jones oxidation in 82% overall yield. Finally, hydrogenolytic
debenzylation of 16 furnished (+)-decarestrictine L (4), [ꢀ]26 +34.4° (c 0.59, MeOH) [lit.,1d [ꢀ]20
D
D
1
+26.0° (c 0.7, MeOH)], in 95% yield. The H and 13C NMR spectra were identical with those of (+)-
decarestrictine L synthesized by Kibayashi and co-workers.1a Similarly, (+)-6-epidecarestrictine L (17),
[ꢀ]21D +31.5° (c 0.36, MeOH), was also synthesized from 14 in 73% overall yield. The stereochemistries
of 4 and 17 were confirmed further by NOE experiments (500 MHz 1H NMR), making those of 13 and 14
unambiguous at this stage. Since all stereoisomers of 1b-type chiral building block are available from 2, the
present method enables us to synthesize all stereoisomers of (+)- decarestrictine L as well.

1) Swern oxidation
2) MeMgBr, THF
–15 ˚C
OBn
OBn
OH
H , 20% Pd-C
2
O
O
O
3) Jones oxidation
–10 ˚C
MeOH-CHCl
(100 : 1)
3
O
O
O
OH
13
82%
16
4
95%
OH
OBn
O
O
73%
OH
14
17
Scheme 4
ACKNOWLEDGMENT
We gratefully thank Professor Chihiro Kibayashi (Tokyo University of Pharmacy and Life Science) for
providing us with spectral data of (+)-decarestrictine L.
REFERENCES
1.
(a) S. Hatakeyama, K. Satoh, and S. Takano, Tetrahedron Lett., 1993, 34, 7425. (b) S. Hatakeyama,
K. Kojima, H. Fukuyama, and H. Irie, Chem. Lett., 1995, 763. (c) T. Esumi, H. Fukuyama, R. Oribe,
K. Kawazoe, Y. Iwabuchi, H. Irie, and S. Hatakeyama, Tetrahedron Lett., 1997, 38, 4823. (d) T.
Nishioka, Y. Iwabuchi, H. Irie, and S. Hatakeyama, Tetrahedron Lett., 1998, 39, 5597.
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5.
6.
All new compounds exhibited satisfactory spectral data (1H and 13C NMR, IR, HRMS).
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7.
8.
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