An efficacious synthetic strategy for cis-clerodane diterpenoids. Application to the total synthesis of (±)-6β-acetoxy-2-oxokolavenool

Article abstract of DOI:10.1055/s-2001-18105

An efficient synthetic strategy for cis-clerodane diterpenoids has been developed. The key ingredient is the face selective Diels-Alder reaction of dienophile 8. The successful application of this strategy has culminated in the total synthesis of the naturally occurring compound 6β-acetoxy-2-oxokolavenool in racemic form.

Full text of DOI:10.1055/s-2001-18105

LETTER
1805
An Efficacious Synthetic Strategy for cis-Clerodane Diterpenoids. Application
to the Total Synthesis of ( )-6 -Acetoxy-2-oxokolavenool
oids Jang Liu,*a,b Yun-Lung Ho, Jen-Dar Wu, Kak-Shan Shia
a
a
c
A
H
n
Efficacious Sy
s
nthetic Str
i
ategyf
n
or cis-Clerod
g
a
ne
D
iterpen
-
a
b
c
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 30013, R.O.C.
Institute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan 11529, R.O.C.
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Nankang, Taipei, Taiwan 11529, R.O.C.
Fax +886(3)5720711; E-mail: hjliu@mx.nthu.edu.tw
Received 7 August 2001
have been successfully addressed. In this communication
we wish to illustrate this newly developed synthetic strat-
egy for cis-clerodanes using compound 1 as a specific ex-
ample.
Abstract: An efficient synthetic strategy for cis-clerodane diterpe-
noids has been developed. The key ingredient is the face selective
Diels–Alder reaction of dienophile 8. The successful application of
this strategy has culminated in the total synthesis of the naturally oc-
curring compound 6 -acetoxy-2-oxokolavenool in racemic form.
Key words: reductive alkylation -cyano ketones, total synthesis,
cis-clerodanes
COOMe
O
O
HO
COOMe
a
b,c,d
OH
H
H
Clerodane diterpenoids form a very large family of sec-
ondary metabolites; over one thousand members have so
BnO
e
2
3
BnO
BnO
1
far been identified. From a biological point of view, cle-
O
rodanoids are rather interesting. A broad spectrum of sig-
f
g
nificant biological activities has been found for the major
2
portion of the relative few compounds screened. Accord-
H
H
ing to the stereochemistry around the ring junction of the
decalin nucleus, clerodanes are subdivided into the trans-
and cis-series in roughly 2:1 ratio. During the past twenty
years, extensive efforts have been devoted towards the to-
4
5
BnO
BnO
OH
OH
OH
h
i, j
3
tal synthesis of this family of the diterpenoids. Most of
H
H
the synthetic approaches, however, are designed to tackle
a specific target molecule. The natural abundance of a se-
ries of structurally closely related clerodanes dictates the
development of a common strategy for their synthesis.
Recently, a general approach to the cis-series of com-
H
CHO
HO
k
O
6
OH
AcO
l
4
+
C-13 epimer
pounds has been developed in our laboratories. As dem-
O
onstrated in Scheme 1 with (+/–)-6 -acetoxy-2-
H
H
4
c
HO
HO
oxokolavenool (1) as a specific example, the key opera-
tion involves the face selective Diels–Alder addition of di-
enone ester 2 to trans-piperylene allowing the rapid
7
1
construction, in a highly stereoselective manner, of the re- Scheme 1 Reagents and conditions: (a) trans-piperylene, ZnCl ; (b)
2
quired decalin core with concomitant placement of sever- (CH
)
CuLi, then LiAlH
; (c) MsCl, Et N; (d) NaI, Zn; (e) p-TsOH;
3
2
4
3
(
f) LiAlH ; (g) Lithium naphthalenide; (h) (Ph P) RuCl ; (i) -me-
al functional groups into the strategic positions. This
approach proved to be highly versatile. Its application has
resulted in the successful synthesis of several other cis-
4
3
3
2
thoxyethyltriphenyl phosphonium chloride, n-butyllithium; (j) 20%
HClO (k) vinylmagnesium bromide; (l) Ac O, DMAP, O , pyridine,
TPP, h , CCl4.
4
;
2
2
4
b,c,5
clerodanes.
However, there are a couple of drawbacks
which reduce the overall efficiency of the synthetic ap-
proach. Both the installation of the angular methyl group
The key to the success of the new synthetic strategy is the
selection of compound 8 as the starting dienophile in
which the cyano group could be readily transformed to a
(
3 4) and the modification of the benzyl side chain to the
butanone moiety (5 6) require lengthy operations (four
steps each). We have since developed a considerably
more efficient general strategy in which these problems
6
methyl group by a reductive alkylation process and the 3-
butenyl side chain to a 3-butanone moiety via the Wacker
7
reaction; each requires only a single operation. Com-
8
pound 8 was readily prepared (Scheme 2) by Stork–Dan-
Synlett 2001, No. 11, 26 10 2001. Article Identifier:
4c,9
heiser alkylation
of 6-methyl-3-ethoxy-2-cyclo-
1
©
437-2096,E;2001,0,11,1805,1807,ftx,en;Y16701ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
hexenone with 4-bromo-1-butene followed by LiAlH re-
4
duction and treatment with hydrochloric acid. The cyano

1
806
H.-J. Liu et al.
LETTER
group was subsequently introduced via formylation, isox-
O
O
1
0
CN
azole formation and its rearrangement. This was fol-
2
5
1
0a
a
1
b
8
+
lowed by DDQ oxidation to install the dienophilic
double bond.
H
H
O
9
10
OEt
OEt
O
O
a
b
O
c
d
e
O
H
H
O
O
O
11
12
CN
CN
O
c, d, e
f
f
7
H
8
HO
15
Scheme 2 Reagents and conditions: (a) LDA, THF, –78 °C, 1 h,
then BrCH CH CH=CH , r.t., 60 h, 73%; (b) LiAlH THF, r.t., 6 h,
2
2
2
4
then 2 N HCl, r.t., 18 h, 95%; (c) NaH, HCOOEt, THF, r.t., 1 h, 73%;
Scheme 3 Reagents and conditions: (a) ZnI , Et O, r.t., 48 h, 73%;
2
2
(
d) NH OH HCl, K CO , EtOH, reflux, 2 h, 85%; (e) Na, EtOH, r.t.,
2 2 3
(b) Lithium naphthalenide, THF, –25 °C, 2 h, then CH I, r.t., 24 h,
3
2
h, 85%; (f) DDQ, K CO , THF, r.t., 3 h, 85%.
2 3
83%; (c) (CH ) CuLi, TMSBr, Et O, –10 °C, 3 h, 85%; (d) CuCl,
3
2
2
PdCl , O , DMF–H O, r.t., 1.5 h, 85%; (e) CH =CHMgBr, THF, 0 °C,
2
2
2
2
2
h, 90%; (f) LiAlH , THF, 0 °C, 98%.
4
Under zinc iodide catalysis (Scheme 3), the Diels–Alder
reaction of compound 8 and trans-piperylene occurred, as
expected, mainly from the sterically less hindered face
OH
(
9
(
methyl face) of the dienophile to give the desired adduct
as the major product (73% yield). A small amount
12% yield) of its C-5 epimer was also produced as a re-
b
1
1
a
11
O
H
H
sult of the addition from the sterically more hindered face
occupied by the butenyl side-chain. After serving as an ac-
tivating as well as a directing group for the Diels–Alder
reaction, the cyano group was readily replaced by a meth-
yl group. Reductive alkylation of 9 by sequential treat-
O
14
13
Scheme 4 Reagents and conditions: (a) LiAlH , THF, 0 °C, 1 h,
4
8
5%; (b) CuCl, PdCl , O , DMF–H O, r.t., 3 h, 67%.
2 2 2
ment with lithium naphthalenide and methyl iodide6
gave an 83% yield of ketone 10. This compound was then
subjected to conjugate addition with lithium dimethylcu-
prate in the presence of trimethylsilyl bromide as an acti-
12
The foregoing discussion shows that a rather complex cle-
rodane diterpenoid (i.e. 1) can be prepared from a readily
accessible dienophile (i.e. 8) in seven steps and 12% over-
all yield. This highly effective synthetic strategy, with ap-
propriate minor adjustments, should also facilitate the
total synthesis of many natural products of the cis-cle-
rodane family, which is currently under active investiga-
tion.
1
3
vating agent. Upon treatment under the standard Wacker
1
4
reaction conditions (PdCl , CuCl and O ), the addition
2
2
product 11, thus obtained in 85% yield, was readily oxi-
1
5
dized to give the desired diketone 12. Interestingly,
when alcohol 13 obtained from LiAlH reduction of 11
4
was subjected to Wacker oxidation (Scheme 4), keto ether
1
4 was produced in 67% yield, apparently as a result of Acknowledgement
1
6
PdCl catalyzed cyclization. Diketone 12 was readily
2
We are grateful to the National Science Council of the Republic of
China (NSC 89-2113-M-007-045) for financial support.
converted to (+/–)-6 -acetoxy-2-oxokolavenool (1) as
follows. Selective Grignard addition of vinylmagnesium
bromide to the sterically less hindered carbonyl group
gave an inseparable mixture of epimeric ketols 15 (90%
References and Notes
yield; 1:1) which was reduced with LiAlH to give, in vir-
4
(1) Bruno, M.; Bondi, M. L.; Rosselli, S.; Piozzi, F.; Al-Hillo,
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4
c
tually quantitative yield, the known diols 7. These
epimeric diols were converted previously to the naturally
occurring clerodane 1 and its C-13 epimer using a photo-
(b) Tokoroyama, T. Synth. Org. Chem. Jpn. 1993, 51, 1164.
4
c,17
(3) Tokoroyama, T. Synthesis 2000, 5, 611.
oxygenation reaction.
(
4) (a) Liu, H. J.; Shia, K. S.; Han, Y.; Wang, Y. Synlett 1995,
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(
5) Ly, T. W. Ph. D. Thesis; The University of Alberta: , 2000.
Synlett 2001, No. 11, 1805–1807 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
An Efficacious Synthetic Strategy for cis-Clerodane Diterpenoids
1807
+
(
(
(
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experiments.
(CH), 24.04 (CH ), 16.85 (CH ); HRMS: M = 255.1617
3
3
4
(calcd for C H ON: 255.1623).
17 21
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(15) Compound 12: IR (neat, cm ): 1712 (C=O), 1694 (C=O); H
NMR (300 MHz, CDCl3): = 5.78–5.84 (m, 1 H, CH=CH),
5.66–5.71 (m, 1 H, CH=CH), 2.35–2.41 (m, 2 H), 2.01–2.34
–
1
1
(
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(
(
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(m, 6 H), 2.15 (s, 3 H, COCH ), 1.84 (td, J = 7, 1 Hz, 1 H,
3
CHCH ), 1.48–1.55 (m, 2 H), 1.19 (s, 3 H, CH ), 0.95 (d,
3
3
–
1
11) Compound 9: IR (neat, cm ): 2230 (CN), 1702 (C=O),
J = 6 Hz, 3 H, CH ), 0.86 (s, 3 H, CH ), 0.85 (d, J = 6 Hz, 3
3
3
1
13
1
640, 1616 (C=C); H NMR (300 MHz, CDCl ): = 6.47
H, CH ); C NMR (100 MHz, CDCl ): = 216.68 (C=O),
3 3
3
(
dd, J = 10, 1.5 Hz, 1 H, CH=CHCO), 5.92 (d, J = 10 Hz, 1
208.48 (C=O), 132.49 (CH), 126.41 (CH), 50.83 (C), 46.89
H, CH=CHCO), 5.76–5.85 (m, 1 H, CH =CH), 5.56 (br. s, 2
(CH), 44.99 (C), 39.27 (CH), 38.42 (CH ), 37.55 (C), 35.79
2
2
H, CH=CH), 5.05 (dd, J = 17, 1.5 Hz, 1 H, trans CH=CHH),
(CH), 30.05 (CH ), 29.33 (CH ), 29.25 (CH ), 23.46 (CH ),
3
3
2
2
+
4
1
2
.98 (dd, J = 10, 1.5 Hz, 1 H, cis CH=CHH), 2.69–2.73 (m,
H), 2.56–2.61 (m, 1 H), 2.12–2.24 (m, 4 H), 1.82–2.00 (m,
H), 1.38 (d, J = 7.5 Hz, 3 H, CHCH ), 1.09 (s, 3 H, CH );
22.73 (CH ), 17.10 (CH ), 15.88 (CH ); HRMS: M calcd
3 3 3
for C H O : 276.2089; found, 276.2089
1
8
28
2
(16) (a) Korte, D. E.; Hegedus, L. S.; Wirth, R. K. J. Org. Chem.
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3
3
1
3
C NMR (75 MHz, CDCl3): = 190.84 (C=O), 155.20
(
(
CH), 137.60 (CH), 128.79 (CH), 125.28 (CH), 123.73
CH), 120.91 (C), 115.27 (CH ), 48.40 (C), 42.06 (CH),
2
4
0.11 (C), 38.98 (CH ), 37.71 (CH), 28.64 (CH ), 25.02
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2
2
4135.
Synlett 2001, No. 11, 1805–1807 ISSN 0936-5214 © Thieme Stuttgart · New York