Stereocontrolled total synthesis of (±)-pisiferol and (±)-pisiferal

Article abstract of DOI:10.1016/j.tetlet.2004.10.089

The stereoselective total synthesis of (±)-pisiferol (1) and (±)-pisiferal (2) has been successfully accomplished using the trans-octahydrophenanthrene derivative 20 as a key intermediate. Intramolecular cyclisation of the diazoketone 15 followed by catalytic hydrogenation provided, stereoselectively, the keto-ester 17 which was converted into the acetate 20 through the intermediates 18 and 19.

Full text of DOI:10.1016/j.tetlet.2004.10.089

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9451–9453
Stereocontrolled total synthesis of ( )-pisiferol and ( )-pisiferal
Lokesh Chandra Pati and Debabrata Mukherjee*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Calcutta 700 032, India
Received 13 September 2004;revised 8 October 2004;accepted 14 October 2004
Available online 5 November 2004
Abstract—The stereoselective total synthesis of ( )-pisiferol (1) and ( )-pisiferal (2) has been successfully accomplished using the
trans-octahydrophenanthrene derivative 20 as a key intermediate. Intramolecular cyclisation of the diazoketone 15 followed by cata-
lytic hydrogenation provided, stereoselectively, the keto-ester 17 which was converted into the acetate 20 through the intermediates
18 and 19.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The tricyclic diterpenes (+)-pisiferol (1) and (+)-pisiferal
(2) were isolated1,2 from the leaves of Chamaecyparis
pisifera along with several closely related diterpenes
and incorporate a trans-fused octahydrophenanthrene
ring system as the basic carbocyclic framework. Strong
antifungal activity of the diterpenes 1 and 2 against
the rice blast fungus Pyricularia oryzae was reported
by Tomita and co-workers.3 Also, the diterpenes have
been reported4,5 to possess antimite, antioxidative, anti-
bacterial and antitumour activities and have been used
in pharmaceuticals and cosmetics for controlling acne
and dandruff, for treatment of skin disorders and as
deodorants. Widespread interest in pisiferol is reflected
in the number of diverse synthetic approaches repor-
ted6–11 in the literature over the last two decades. The
total synthesis of the diterpenes 1 and 2 is associated with
the difficulty in the generation of an oxygenated methyl
group as an angular substituent and an appropriately
substituted aromatic C ring in the trans-octahydrophen-
anthrene nucleus. Earlier methodologies for the synthe-
sis of these diterpenes most commonly employed
transannular oxidation of the angular methyl group6,7
or Robinson annulation8,9 of an appropriate Wieland-
Miescher ketone as key reactions. Kametani et al.
accomplished10 the synthesis of pisiferol methyl ether 3
involving thermolysis of the olefinic benzocyclobutene
4 as the key step. Thermolysis of 4 proceeded through
intramolecular Diels–Alder reaction of an o-quinodi-
methane to generate the angularly cyano substituted
octahydrophenanthrenes 6 and 8 (Fig. 1) in the ratio
of 1:4. Recently, Bush and Jones achieved11 an im-
proved synthesis of 6 using thermolysis of the benzocy-
clobutene 5 which provided 7 and 9 in the ratio of 1.5:1.
The transformation of 7 into 6 was carried out in a
straightforward manner. The transformation of pisiferol
methyl ether 3 into the diterpene pisiferin (10) (Fig. 1)
through skeletal rearrangement was reported by Kame-
tani et al.10
Starting from the easily accessible tetrahydrophenanth-
rene 11,12 we report herein a stereoselective synthesis of
the diterpenes 1 and 2 in racemic form employing an aryl
participating diazoketone cyclisation13 strategy to gener-
ate intermediate hydrophenanthrene derivatives suitable
for the synthesis. 1,1-Dimethyl-6,9-dimethoxy-1,2,3,4-
tetrahydrophenanthrene (11), easily prepared12 from
commercially available 1,6-dihydroxynaphthalene, was
used as the starting material for the synthesis of the di-
terpenes 1 and 2 as shown in Scheme 1. Oxidation of
11 with pyridinium chlorochromate furnished the ketone
12 in 85% yield. The ketone was condensed with ethyl
formate in the presence of sodium hydride and the result-
ing crude hydroxymethylene derivative was treated14
with alkaline hydrogen peroxide followed by CH2N2 to
afford the diester 1315 in 82% overall yield. Partial
hydrolysis of the diester under controlled conditions
yielded the acid–ester 14 (87%). Reaction of 14 with ethyl
chloroformate in the presence of Et3N followed by treat-
ment of the resulting mixed anhydride with CH2N2 pro-
vided the diazomethyl ketone 15 in 90% yield. On
treatment with trifluoroacetic acid in CH2Cl2 at À20ꢁC
for a brief period, the diazoketone underwent intramole-
cular cyclisation to provide the enedione 1616 in 64%
yield which on catalytic hydrogenation yielded the
Keywords: Terpenes;Phenols;Diazoketone;Cyclisation;Hydrogen-
ation;Demethylation.
*
Corresponding author. Fax: +91 33 2473 2805;e-mail: ocdm@
mahendra.iacs.res.in
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.089

9452
L. C. Pati, D. Mukherjee / Tetrahedron Letters 45 (2004) 9451–9453
1
NC
R
NC
MeO
RO
Me
O
H
H
X
X
1, R = H, R1 = CH2OH
2, R= H, R1 = CHO
4, X = H
5, X = SO2Ph
6, X = H
7, X = SO2Ph
3, R = Me, R1 = CH2OH
NC
HO
MeO
H
H
X
8, X = H
10
9, X = SO2Ph
Figure 1.
O
R
R
MeO2C
MeO
MeO
ii - iv
MeO2C
MeO
vii
OMe
OMe
O
16
11, R = H2
12, R = O
13, R = CO2Me
14, R = CO2H
15, R = COCHN2
i
v
viii
vi
R
R
AcOH
2C
MeO2C
HO
MeO
R
MeO
xi,xii
xv
H
H
H
20, R = H
23, R = CH2OAc
1, R = CH2OH
2, R = CHO
xiii
xiv
17, R = O
18, R =
ix
x
xvi
S
S
21, R = COCH3
xvii
22, R = CHMe2
19, R = H2
Scheme 1. Reagents and conditions: (i) PCC, CH2Cl2, rt, 85%;(ii) NaH, HCO 2Et, C6H6, 0ꢁC to rt;(iii) aq NaOH, H 2O2, 0ꢁC to rt, H3O+, 85%;(iv)
CH2N2, Et2O, 0ꢁC, 97%;(v) KOH, H 2O, THF, rt, 24h, 60ꢁC, 1h, H3O+, 87%;(vi) ClCO 2Et, Et3N, Et2O, THF, À10ꢁC, 1h then CH2N2, Et2O, 0ꢁC
to rt, 16h, 90%;(vii) TFA, CH 2Cl2, À20ꢁC, 3min, 64%;(viii) H 2, 10% Pd–C, EtOAc, 93%;(ix) HSCH 2CH2SH, BF3ÆEt2O, MeOH, rt, 90%;(x) Raney
nickel, EtOH, reflux, 85%;(xi) LiAlH , THF, reflux, 95%;(xii) Ac O, C5H5N, 70ꢁC, 86%;(xiii) AcCl, AlCl , CH2Cl2, 0ꢁC to rt, H3O+, 84%;(xiv)
4
2
3
MeMgI, Et2O, reflux, aq NH4Cl then Ac2O, C5H5N, 70ꢁC;H 2, 10% Pd–C, AcOH, HClO4 (trace), 78%;(xv) AlCl 3, EtSH, rt, 75%;(xvi) LiAlH
,
4
THF, rt, 87%;(xvii) Jones’ reagent, Me CO, 0ꢁC, 1min, 48%.
2
trans-fused keto-ester 17 as the sole product (93%). The
assignment of trans stereochemistry to 17 was confirmed
by single crystal X-ray crystallography (Fig. 2) as well as
by subsequent transformation of 17 into the diterpenes 1
and 2 possessing trans-stereochemistry at the A/B ring
junction.
In order to remove the carbonyl group from the ring A,
17 was converted into the corresponding ethylene thio-
acetal 18 (90%) which on desulfurisation with Raney
16
nickel furnished the ester 19 in 85% yield. Reduction
of 19 with LiAlH4 followed by acetylation of the result-
ing primary alcohol provided the acetate 20 (82%) which
on treatment with CH3COCl in the presence of anhy-
drous AlCl3 afforded the methyl ketone 2116 in 84%
yield. Reaction of 21 with MeMgI followed by treat-
ment of the crude product with Ac2O and subsequent
Figure 2. Single crystal X-ray structure of the keto-ester 17 (an
ORTEP drawing).

L. C. Pati, D. Mukherjee / Tetrahedron Letters 45 (2004) 9451–9453
9453
7. Matsumoto, T.;Endo, Y.;Okimoto, M. Bull. Chem. Soc.
Jpn. 1983, 56, 2018–2022.
8. Tamai, Y.;Hagiwara, H.;Uda, H. J. Chem. Soc., Perkin
Trans. 1 1986, 1311–1315.
9. Banerjee, A. K.;Hurtado, S. H.;Laya, M. M.;Acevedo, J.
C.;Alvarej, G. J. J. Chem. Soc., Perkin Trans. 1 1988,
931–938.
10. Kametani, T.;Kondoh, H.;Tsubuki, M.;Honda, T.
Chem. Soc., Perkin Trans. 1 1990, 5–10.
J.
11. Bush, E. J.;Jones, D. W. J. Chem. Soc., Perkin Trans. 1
1997, 3531–3536.
12. Bhattacharyya, S.;Ghosal, M.;Mukherjee, D. Tetrahe-
dron Lett. 1987, 28, 2431–2432.
13. Ye, T.;McKervey, M. A. Chem. Rev. 1994, 94, 1091–1160,
and references cited therein.
Figure 3. Single crystal X-ray structure of synthetic pisiferal 2 (an
ORTEP drawing).
14. Huffman, J. W.;Arapakos, P. G. J. Org. Chem. 1965, 30,
1604–1607.
15. Satisfactory spectroscopic and microanalytical data were
obtained for all new compounds.
hydrogenation in the presence of a catalytic amount of
HClO4 furnished the acetate 2216 (78%). Fujita and
co-workers reported17 that a combination of aluminium
halide and ethanethiol is very effective for demethylation
of methyl ethers of phenols whilst acetoxy groups are
stable to this reagent system. Demethylation of 22 with
anhydrous AlCl3 and EtSH afforded the phenol 23
(75%) which on reduction with LiAlH4 furnished ( )-
pisiferol (1)16 in 87% yield. The phenol 23 exhibits signi-
ficant antitumour activity and inhibits5 the growth of
human cervix uteri HeLa cells. Treatment of 1 with
Jones’ reagent at 0ꢁC for a brief period provided
( )-pisiferal (2)16 (48%). The identity of synthetic 2
was secured through single crystal X-ray crystallogra-
phy (Fig. 3). Also, the spectral data of 1 and 2 agreed
very well with those reported in the literature.
16. Selected spectral data for the enedione 16: 1H NMR
(CDCl3, 300MHz): d 1.29 (s, 3H), 1.37 (s, 3H), 2.34, 2.54
(ABq, 2H, J = 15.7Hz), 2.34, 3.80 (ABq, 2H, J = 18Hz),
3.63 (s, 3H), 3.88 (s, 3H), 6.71 (s, 1H), 6.94 (d, 1H,
J = 2.4Hz), 7.02 (dd, 1H, J = 8.7, 2.4Hz), 8.17 (d, 1H,
J = 8.7Hz); 13C NMR (CDCl3, 75MHz): d 30.5, 32.2,
38.1, 46.5, 51.7, 51.8, 53.6, 55.6, 110.3, 114.9, 123.7, 127.7,
129.1, 143.1, 162.4, 163.5, 171.8, 183.5, 206.2. For the ester
1
19: H NMR (CDCl3, 300MHz): d 0.77 (s, 3H), 0.96 (s,
3H), 1.18–1.31 (m, 2H), 1.43–1.52 (m, 2H), 1.58–1.66 (m,
1H), 1.87–2.05 (m, 2H), 2.37–2.55 (m, 1H), 2.80–2.96 (m,
3H), 3.54 (s, 3H), 3.73 (s, 3H), 6.69 (dd, 1H, J = 8.4,
2.6Hz), 6.84 (d, 1H, J = 2.6Hz), 7.00 (d, 1H, J = 8.4Hz);
13C NMR (CDCl3, 75MHz): d 18.6, 20.0, 20.3, 29.2, 32.0,
33.9, 37.0, 41.7, 48.0, 51.5, 52.2, 55.1, 110.9, 112.4, 129.0,
1
130.3, 141.5, 157.4, 175.7. For the methyl ketone 21: H
In conclusion, a stereocontrolled synthesis of the abi-
etane-type tricyclic diterpenes ( )-pisiferol and ( )-pisi-
feral has been accomplished involving aryl participated
intramolecular cyclisation of an appropriately substi-
tuted diazomethyl ketone as a key reaction.
NMR (CDCl3, 300MHz): d 0.98 (s, 6H), 1.25–1.84 (m,
8H), 1.93 (s, 3H), 2.54–2.60 (m, 1H), 2.59 (s, 3H), 2.81–
3.00 (m, 2H), 3.88 (s, 3H), 4.16, 4.54 (ABq, 2H, J = 11Hz),
6.88 (s, 1H), 7.46 (s, 1H); 13C NMR (CDCl3, 75MHz): d
18.2, 18.7, 20.9, 22.2, 28.1, 31.7, 33.1, 33.4, 33.5, 41.1, 41.2,
50.0, 55.4, 65.5, 109.9, 126.0, 128.1, 130.7, 150.1, 156.0,
170.5, 199.4. For the acetate 22: 1H NMR (CDCl3,
300MHz): d 0.96 (s, 6H), 1.18 and 1.19 (2 d, 2 · 3H,
J = 7.0Hz each), 1.24–1.93 (m, 8H), 1.92 (s, 3H), 2.53–2.57
(m, 1H), 2.83–2.94 (m, 2H), 3.22 (sept, 1H, J = 7.0Hz),
3.79 (s, 3H), 4.14, 4.55 (ABq, 2H, J = 10.8Hz), 6.76 (s,
1H), 6.86 (s, 1H); 13C NMR (CDCl3, 75MHz): d 18.6,
18.9, 21.0, 22.3, 22.6, 22.8, 26.4, 28.8, 33.3, 33.4, 33.6, 40.5,
41.5, 50.5, 55.5, 66.1, 109.2, 126.4, 127.5, 134.9, 142.0,
154.0, 170.8. For pisiferol 1: 1H NMR (CDCl3, 300MHz):
d 0.90 (s, 3H), 0.94 (s, 3H), 1.22 (d, 6H, J = 6.9Hz), 1.14–
1.90 (m, 8H), 2.46–2.50 (m, 1H), 2.80–2.96 (m, 2H), 3.19
(sept, 1H, J = 6.9Hz), 3.62, 3.99 (ABq, 2H, J = 11Hz),
6.65 (s, 1H), 6.90 (s, 1H); 13C NMR (CDCl3, 75MHz): d
18.4, 18.8, 22.3, 22.5, 22.7, 26.7, 28.7, 32.7, 33.2, 33.4, 41.6,
42.3, 50.1, 63.8, 112.8, 127.4, 127.7, 133.0, 141.3, 150.8.
For pisiferal 2: 1H NMR (CDCl3, 300MHz): d 0.82 (s,
3H), 1.00 (s, 3H), 1.22 (d, 6H, J = 6.9Hz), 1.13–1.72 (m,
6H),2.00–2.14 (m, 2H), 2.83–2.99 (m, 3H), 3.14 (sept, 1H,
J = 6.9Hz), 4.83 (br s, 1H), 6.56 (s, 1H), 6.92 (s, 1H), 9.89
(d, 1H, J = 1.2Hz); 13C NMR (CDCl3, 75MHz): d 18.3,
19.6, 20.6, 22.4, 22.5, 26.9, 30.1, 31.5, 32.6, 33.9, 41.3, 51.7,
53.1, 113.8, 127.2, 130.4, 133.4, 134.2, 151.6, 200.9.
17. Node, M.;Nishide, K.;Fuji, K.;Fujita, E. J. Org. Chem.
1980, 45, 4275–4277.
Acknowledgements
We are grateful to the CSIR, New Delhi, for financial
support (Grant No 01(1742)/02/EMR-II). One of us
(L.C.P.) thanks the CSIR for a fellowship.
References and notes
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3. Kobayashi, K.;Nishino, C.;Tomita, H.;Fukushima, M.
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1355–1362, Chem. Abstr. 1995, 122, 154117t.
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Patent No JP 61271216 A2 19861201 Showa; Chem. Abstr.
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