An improved general synthetic approach to cis-clerodane diterpenoids. A more efficient total synthesis of (±)-6β-acetoxy-2-oxokolavenool

Article abstract of DOI:10.1016/S0040-4039(01)00706-7

The previously developed general synthetic approach to cis-clerodane diterpenoids has been greatly improved using 4-(2-benzyloxy)ethyl-2-cyano-4-methyl-2,5-cyclohexadien-1-one (4) as the starting dienophile. This approach allows the direct incorporation of an angular methyl group via reductive alkylation of the α-cyano ketone system. The viability of this approach to cis-clerodanes has been demonstrated in the alternative total synthesis of (±)-6β-acetoxy-2-oxokolavenool (1).

Full text of DOI:10.1016/S0040-4039(01)00706-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4207–4209
An improved general synthetic approach to cis-clerodane
diterpenoids. A more efficient total synthesis of
( )-6b-acetoxy-2-oxokolavenool
Jen-Dar Wu, Kak-Shan Shia and Hsing-Jang Liu*
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 30043, ROC
Received 21 December 2000; accepted 27 April 2001
Abstract—The previously developed general synthetic approach to cis-clerodane diterpenoids has been greatly improved using
4-(2-benzyloxy)ethyl-2-cyano-4-methyl-2,5-cyclohexadien-1-one (4) as the starting dienophile. This approach allows the direct
incorporation of an angular methyl group via reductive alkylation of the a-cyano ketone system. The viability of this approach
to cis-clerodanes has been demonstrated in the alternative total synthesis of ( )-6b-acetoxy-2-oxokolavenool (1). © 2001 Elsevier
Science Ltd. All rights reserved.
Clerodane diterpenoids are distributed widely in nature.
More than eight hundred compounds have been iso-
lated to date and many possess interesting biological
activities.1,2 Clerodanes are further subdivided more or
less equally into the trans- and cis-series according to
the stereochemistry about the ring junction of the
decalin core. In view of the abundance of these struc-
turally closely related natural products, a general syn-
thetic scheme which allows easy access to many target
molecules is desirable.3 Such a scheme towards the
cis-series has been developed in our laboratories
recently, making use of a face-selective Diels–Alder
reaction as the key operation4–6 as illustrated in Scheme
1 with ( )-6b-acetoxy-2-oxokolavenool (1)6 as a specific
Scheme 1. Reagents and conditions: (a) trans-piperylene, ZnCl2, ether, 0°C, 68 h, 85%; (b) (CH3)2CuLi, ether, 0°C, 1 h; then
LiAlH4, 0°C, 0.5 h, 62%; (c) MsCl, Et3N, THF, rt, 21 h; (d) NaI, Zn, DMF, 130°C, 28 h, 54% over two steps; (e) p-TsOH,
CH2Cl2, rt, 40 min, 97%.
Keywords: reductive alkylation; a-cyano ketones; total synthesis.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00706-7

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J.-D. Wu et al. / Tetrahedron Letters 42 (2001) 4207–4209
example. The generality of the scheme is apparent as it
has been applied successfully to the total synthesis of
several cis-clerodane diterpenoids.5–7 However, the
efficiency of the synthetic approach suffers somewhat
from the lengthy operation (four steps, 30% overall
yield) required for the conversion of the ester group to
the angular methyl group (2“3). An improved syn-
thetic approach has now been developed using cyano
dienone 4 as the starting dienophile. This approach
allows the direct installation of the required angular
methyl group via a reductive alkylation process,8
whereby the efficiency of the general synthetic approach
to cis-clerodane diterpenoids is greatly enhanced.
benzyl ether group, giving rise, after aqueous work-up,
to cyclic ether 711 as the only product in 86% yield.
Treatment of Diels–Alder adduct 7 with 1,5-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) and t-butyldimethylsilyl
chloride (TBDMSCl) in refluxing tetrahydrofuran
effected the opening of the ether ring to regenerate the
conjugated enone moiety. The product 8 thus obtained
was then subjected to reductive removal of the cyano
group with lithium naphthalenide in tetrahydrofuran at
−25°C. Trapping of the ensuing enolate with methyl
iodide8 proceeded with complete stereoselectivity giving
directly the desired enone 912 in 76% yield. This method
of installing an angular methyl group represents a
considerable improvement over the multistep process
used in our original synthesis (vide supra) involving an
ester group. Enone 9 was subjected to conjugate addi-
tion with lithium dimethylcuprate in ether in the pres-
ence of trimethylsilyl bromide13 as an activating agent,
and the product thus obtained was treated with tetra-n-
butylammonium fluoride in tetrahydrofuran to give
keto alcohol 10. Lithium aluminum hydride reduction
of 10 gave rise to diol 11, an advanced intermediate in
our previous synthesis of ( )-6b-acetoxy-2-oxo-
kolavenool (1).6 The sequence outlined in Scheme 2
constitutes a more efficient total synthesis, in racemic
form, of the naturally occurring clerodane 1.
Cyano dienone 4 was readily prepared according to the
sequence outlined in Scheme 2. 4-(2-Benzyloxy)ethyl-4-
methyl-2-cyclohexenone4 was formylated and the
product converted to the corresponding isoxazole. Base
induced rearrangement of the isoxazole ring followed
by oxidation with 2,3-dichloro-5,6-dicyano-1,4-quinone
(DDQ)9 gave cyano dienone 4.10 Under Lewis acid
catalysis, compound 4 was shown to undergo face-
selective Diels–Alder reaction with trans-piperylene.
Several Lewis acids were effective including AlCl3,
CeCl3, MgBr2, ZnCl2 and SnCl4. In each case, the
preferential formation of the desired adduct 5 along
with its stereoisomer 6 (ca. 3–5:1 ratio, 85–95% yield)
was observed. More interestingly, when boron trichlo-
ride was applied as the Lewis acid, the cycloaddition
occurred extremely rapidly (ca. 5 min at −78°C in
methylene chloride) with concomitant cleavage of the
The combination of Diels–Alder chemistry of the 2-
cyano-2-cyclohexenone system and subsequent reduc-
tive methylation of the resulting cycloadduct provides a
Scheme 2. Reagents and conditions: (a) NaH, ethyl formate, EtOH (cat.), THF, rt, 4 h; (b) NH2OH·HCl, K2CO3, EtOH, reflux,
2 h, 73% over two steps; (c) NaOEt, EtOH, reflux, 2 h; (d) DDQ, THF, 1 h, 64% over two steps; (e) trans-piperylene, BCl3,
CH2Cl2, −78°C, 5 min, 86%; (f) DBU, TBDMSCl, THF, reflux, 8 h, 88%; (g) lithium naphthalenide, THF, −25°C; then CH3I, rt,
24 h, 76%; (h) (CH3)2CuLi, TMSBr, −10°C, Et2O, 24 h; (i) n-Bu4N+F−, THF, rt, 2 h, 86% over two steps; (j) LiAlH4, THF, 0°C,
30 min, 90%.

J.-D. Wu et al. / Tetrahedron Letters 42 (2001) 4207–4209
4209
highly efficient access to the cis-decalin core found in
cis-clerodane diterpenoids. The improved synthetic
approach described above, in light of its efficiency and
flexibility, represents a general solution to meet the
synthetic challenge presented by the vast number of
structurally closely related diterpenoids of the clerodane
family.
7. Ly, T. W. Ph.D. Thesis, The University of Alberta, 2000.
8. Liu, H. J.; Zhu, J. L.; Shia, K. S. Tetrahedron Lett. 1998,
39, 4183.
9. Liu, H. J.; Sun, D.; Shia, K. S. J. Chin. Chem. Soc. 1999,
46, 453.
10. Satisfactory spectral and elemental or HRMS analytical
data were obtained for all new compounds. Where neces-
sary, the stereochemistry was further confirmed by NOE
experiments.
11. Compound 7: IR (cast, CHCl3): 1733 (ketone), 2224 cm−1
1
(CN); H NMR (300 MHz, CDCl3): l 5.55 (t, J=2 Hz,
2H), 4.16 (td, J=6, 3 Hz, 1H), 3.88 (m, 2H), 3.03 (m,
1H), 2.96 (dd, J=16, 6 Hz, 1H), 2.66 (m, 1H), 2.64 (dd,
J=16, 6 Hz, 1H), 2.57 (dd, J=10, 7 Hz, 1H), 2.48 (dm,
J=16 Hz, 1H), 1.87–1.81 (m, 2H), 1.41 (d, J=6 Hz, 3H),
1.18 (s, 3H); 13C NMR (75 MHz, CDCl3): l 199.2, 128.9,
123.6, 120.3, 83.4, 65.7, 49.7, 44.8, 42.5, 39.8, 38.5, 26.4,
25.4, 16.7; HRMS M+: 345.1415. (calcd. for C15H19NO2:
345.1415). Anal. calcd for C15H19NO2: C, 73.44; H, 7.81;
N, 5.71%. Found: C, 73.28; H, 7.70; N, 5.89%. The
structure of this compound was further confirmed by a
single crystal X-ray crystallographic analysis. The ether
ring formation most likely occurred during the work-up
and the chromatographic purification as the crude
product consisted mainly of the alcohol precursor.
12. Compound 9: IR (cast, CHCl3): 1672 (ketone), 1090
(SiO), 710 cm−1 (SiC); 1H NMR (400 MHz, CDCl3): l
6.56 (d, J=10 Hz, 1H), 5.95 (d, J=10 Hz, 1H), 5.64–5.71
(m, 1H), 5.49–5.52 (m, 1H), 3.56–3.60 (m, 2H), 2.18 (dm,
J=18 Hz, 1H), 2.08 (m, 2H), 2.03 (d, J=8 Hz, 1H),
1.71–1.77 (m, 1H), 1.55–1.61 (m, 1H), 1.30 (s, 3H), 1.04
(s, 3H), 0.94 (d, J=8 Hz, 3H), 0.85 (s, 9H), −0.006 (s,
6H). 13C NMR (100 MHz, CDCl3): l 204.4, 156.4, 130.5,
127.8, 123.9, 59.5, 45.7, 45.3, 40.5, 38.4, 36.8, 26.9, 25.8,
22.9, 22.4, 18.1, 17.6, −5.4; HRMS M+: 348.2483 (calcd.
for C21H36O2Si: 348.2484).
Acknowledgements
We are grateful to the National Science Council of the
Republic of China (NSC 88-2113-M-007-042) for finan-
cial support.
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