Conversion of (+)-confertifolin into 11,12-bisnordriman-9-one and (+)-8αH,9αH-11,12-diacetoxydrimane

Article abstract of DOI:10.1081/SCC-100104043

A short synthesis of naphthalenone (-)-1 and natural drimanic diacetate ((+)-3), from confertifolin ((+)-4), is reported. The proposed absolute configuration of (+)-3 was confirmed.

Full text of DOI:10.1081/SCC-100104043

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CONVERSION OF (+)-
CONFERTIFOLIN INTO 11,12-
BISNORDRIMAN-9-ONE
AND (+)-8αH,9αH-11,12-
DIACETOXYDRIMANE*
Julio Benites a , Marcelo D. Preite b & Manuel
Cortés c
a Pontificia Universidad Católica de Chile ,
Facultad de Química, Casilla 306, Correo 22,
Santiago, Chile
b Pontificia Universidad Católica de Chile ,
Facultad de Química, Casilla 306, Correo 22,
Santiago, Chile
c Pontificia Universidad Católica de Chile ,
Facultad de Química, Casilla 306, Correo 22,
Santiago, Chile
Published online: 09 Nov 2006.
To cite this article: Julio Benites , Marcelo D. Preite & Manuel Cortés (2001)
CONVERSION OF (+)-CONFERTIFOLIN INTO 11,12-BISNORDRIMAN-9-ONE AND
(+)-8αH,9αH-11,12-DIACETOXYDRIMANE* , Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
31:9, 1347-1354, DOI: 10.1081/SCC-100104043
To link to this article: http://dx.doi.org/10.1081/SCC-100104043

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SYNTHETIC COMMUNICATIONS, 31(9), 1347–1354 (2001)
CONVERSION OF (þ)-CONFERTIFOLIN
INTO 11,12-BISNORDRIMAN-9-ONE AND
(þ)-8aH,9aH-11,12-DIACETOXYDRIMANE*
Julio Benites, Marcelo D. Preite,{ and Manuel Cortes{
Facultad de Quımica, Pontificia Universidad Catolica de Chile,
Casilla 306, Correo 22, Santiago, Chile
ABSTRACT
Ashort synthesis of naphthalenone ( À)-1 and natural drima-
nic diacetate ((þ)-3), from confertifolin ((þ)-4), is reported.
The proposed absolute configuration of (þ)-3 was confirmed.
INTRODUCTION
Naphthalenone 1 has been widely used as a key intermediate in the
syntheses of a variely of biologically important terpenes, such as warburga-
nal,1 albicanol,2 atisirene,3 pallescensin A,4 and recently, racemic 1 was
converted into (Æ)-hispanolone.5 Optically pure (À)-1 was previously
prepared from (þ)-Wieland-Miescher ketone (2) in a six-step sequence.3
On the other hand, the drimanic diacetate 3 has been recently isolated
from the sponge, Dysidea fusca.6 Its absolute configuration (normal drimane
skeleton) was assigned only by biosynthetic reasons. Compound 3 was
*Dedicated to Prof. E. A. Ruveda on the occasion of his retirement.
{ Corresponding authors. Fax: þ56-2-686-4744; E-mail: mpreite@puc.cl
1347
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1348
BENITES, PREITE, AND CORTES
previously prepared from zamoranic acid methyl ester, but the sign of the
specific rotation was not reported.7
Continuing our interest in the synthesis of terpenoids and related
compounds from natural drimanic sesquiterpenes,8–10 we report here a
short alternative synthesis of (À)-1 and (þ)-3, to confirm the proposed
absolute stereochemistry of the latter, by using natural (þ)-confertifolin (4)
as starting material. Confertifolin ((þ)-4) has been prepared in a
three-step sequence from commercially available manool,11 and also from
abietic acid.12
RESULTS AND DISCUSSION
The syntheses of (À)-1 and (þ)-3 are shown in Scheme 1. Lactone (þ)-
4 was reduced with LiAlH4 in THF at reflux, to give enediol (þ)-5 (85%
yield)13. Epoxidation of (þ)-5 with mCPBAin CH 2Cl2 at room temperature
gave the a-epoxide (þ)-6 (85% yield). As the reagent should attack from the
less hindered a-face of the double bond, the stereochemistry of the epoxide
was consequently assigned as a-.
Reduction of (þ)-6 with LiAlH4 afforded triol (þ)-7 in 65% yield.
Oxidation of (þ)-7 with NaIO4 in THF/water gave the corresponding
ketone (À)-8 in 77% yield. Transformation of (À)-8 into (À)-1 was carried
out by treatment with Jones reagent. The carboxylic acid could not be
isolated because of spontaneous decarboxylation. Aretro-aldol process
was discarded, because when (À)-8 was treated with a mixture of sulfuric
acid, water, and acetone (same conditions as for a Jones reaction, without
oxidant), the starting material was recovered unchanged. The specific rota-
tion and spectral data of (À)-1 were concordant with those previously
reported3 (vide infra, Tab. 1 and 2, and Experimental).

(þ)-CONFERTIFOLIN CONVERSION
1349
Scheme 1. i) LiAlH4, THF, reflux, 2.5 h; ii) mCPBA, CH2Cl2, r.t., 2 h; iii) NalO4,
THF/H2O, r.t., 20 m; iv) Jones reagent, acetone; v) H2, PtO2, EtOAc, 40ꢀ, 2 h; vi)
Ac2O, Pyr, r.t., overnight.
Hydrogenation of (þ)-5 to give (þ)-9 was accomplished in 80% yield,
by using PtO2 in EtOAc. Finally, acetylation of (þ)-9 with Ac2O and pyr-
24
idine gave (þ)-3 (86% yield). The specific rotation of this synthetic product
was: ½aŠ ¼ þ46.8 (c ¼ 2.5, CHCl3), while the value reported in the literature
D
20
D
for the natural (þ)-3 was ½aŠ ¼ þ37 (c ¼ 1.4, CHCl3)6. Consequently, the
absolute configuration of (þ)-8aH,9aH,11,12-diacetoxydrimane is estab-
lished as shown in the formula.
EXPERIMENTAL
Melting points were measured on a Stuart-Scientific SMP3 apparatus
and are uncorrected. Optical rotations were obtained for CHCl3 solutions
on a Perkin-Elmer 241 polarimeter, and their concentrations are expressed
in g/100 mL. NMR spectra were recorded on a Bruker AM-200 spectro-
meter. Chemical shifts are expressed in ppm downfield relative to TMS
(ꢀ scale) in CDCl3 solutions. Carbon multiplicity was established by a
DEPT pulse sequence. IR spectra were recorded as KBr disks in a Bruker
FT-IR Vector-22 and frequencies are in cmÀ1. Elemental analyses were
obtained on a Fisons-Carlo-Erba FA-1108 Automost microanalyzer.

1350
BENITES, PREITE, AND CORTES
Table 1. IR and H NMR Chemical Shifts (CDCl3, 200.13 MHz)
1
Compound IR (cmÀ1
)
1H NMR (ꢀ, ppm)
1
1707
2.67–2.50 (m, 1H, H-8a), 2.24–2.16 (m, 1H, H-8b),
2.15–1.98 (m, 1H, H-7a), 1.79–1.06 (m, 10H), 1.14
(s, 3H, 10-Me), 0.92 (s, 3H, 4-Me-(), 0.88 (s, 3H, 4-Me-)
3
1741, 1237 4.26 (dd, J¼5.2, 11.3 Hz, 1H, H-11a), 4.12 (t, J=10.8 Hz,
1H, H-12a), 4.07–4.00 (m, 2H, H-11b(H-12b), 2.19–2.13
(m, 1H, H-8), 2.02 (s, 3H, AcO), 2.01 (s, 3H, AcO), 1.91–
1.75 (m, 1H) 1.72–0.90 (m, 11H), 0.83 (s, 3H, 4-Me-b),
0.81 (s, 3H, 10-Me), 0.78 (s, 3H, 4-Me-b).
5
6
3356, 2993, 4.24–3.97 (m, 4H, H11(H12), 2.71 (bs, 2H, 2ꢁOH), 2.26–
1452, 978
2.20 (m, 2H, H-7), 1.89–l.09 (m, 9H), 0.98 (s, 3H, 10-Me),
0.90 (s, 3H, 4-Me-b), 0.84 (s, 3H, 4-Me-b)
3320, 1036, 4.05 (dd, J¼4.6, 11.7, 1H, H-11), 3.70–3.35 (m, 5H, H-
914, 903
11bþH12 þ 2 ꢁOH), 2.16–1.10 (m, 11H), 1.09 (s, 3H,
10-Me), 0.81
(s, 3H, 4-Me-(), 0.78 (s, 3H, 4-Me-b)
7
8
3440, 1063 4.06 (bs, 1H, OH) 3 73–3.43 (m, 4H, H-11(H-12). 3.23
(bs, 1H, OH), 3.00 (bs, 1H, OH), 1.93–1.11 (m, 12H), 0.88
(s, 3H, 10-Me), 0.87 (s, 3H, 4-Me-a), 0.82 (s, 3H, 4-Me-b)
3443, 1699, (CDCl3þD2O) 3.65 (dd, J¼7.1, 11.5 Hz, 1H,H-12), 3.52
1461, 1058 (dd, J¼3.9, 11.5 Hz, 1H, H-12), 2.87–272 (m, 11H, H-8),
2.06–1.08 (m, 11H), 1.13 (s, 3H, 10-Me), 0.90
(s, 3H, 4-Me-b), 0.86 (s, 3H,4-Me-a)
3331, 1016 3.97–3.54 (m, 4H, H-11(H-12), 2.18–0.92 (m, 15H),
9
0.86 (s, 3H, 4-Me-a), 0.85 (s, 3H, 10-Me), 0.80
(s, 3H, 4-Me-b)
For analytical TLC, Merck silica gel 60 in 0.25 mm layer was used.
Chromatographic separations were carried out by conventional column
on Merck silica gel 60 (230–400 Mesh) using hexane-EtOAc gradients of
increasing polarity.
All reactions were routinely run under a N2 atmosphere. All organic
extracts were dried over anhydrous magnesium sulfate and evaporated
under reduced pressure, at a temperature below 65ꢀC.
(þ)-Confertifolin (4) was obtained from an hexane extract of the bark
13
of D. winteri
.
8,9-Drimen-11,12-diol (5)
To a suspension of LiAlH4 (0.4 g, 10.5 mmol) in dry THF (20 mL) was
added dropwise a solution of confertifolin (1.0 g, 4.2 mmol) solution in THF

(þ)-CONFERTIFOLIN CONVERSION
Table 2. 13CNMR Chemical Shifts (CDCl3, 50.13 MHz)
1351
Carbon
1
3
5
6
7
8
9
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
33.06
18.11
41.62
34.18
53.51
20.97
26.35
37.64
216.03
49.11
—
39.14
18.40
41.79
33.17
56.17
17.56
29.11
34.89
51.43
37.14
62.64
63.94
16.44
33.43
21.47
21.03
21.03
171.17
171.17
36.19
18.85
41.52
33.28
51.33
18.71
31.26
136.01
146.16
38.19
57.89
63.98
20.40
33.19
21.56
—
34.45
18.34
41.26
32.85
43.32
17.16
25.85
65.55
72.12
37.29
61.42
66.02
16.41
33.63
21.50
—
31.51
18.69
41.49
33.38
46.13
21.22
26.07
42.88
75.35
41.53
63.56
64.91
15.36
33.56
22.10
—
32.81
18.03
41.51
34.29
53.87
20.65
29.26
47.18
218.41
49.09
—
63.01
18.61
33.06
22.06
—
39.38
18.47
41.87
33.18
56.41
18.34
30.02
37.87
54.53
37.33
60.40
16.44
16.44
33.52
21.61
—
C-9
C-10
C-11
C-12
10-Me
4-Me-
4-Me-b
AcO
AcO
AcO
AcO
—
18.61
33.16
22.09
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
(10 mL). The reaction mixture was refluxed for 2 h, then AcOEt (10 mL) and
1 N HCl (10 mL) were successively added to decompose the excess LiAlH4.
After extraction with AcOEt (3 ꢁ 25 mL), the combined organic extracts
were washed with saturated NaHCO3 solution, water, dried, and concen-
trated. The crude product was purified by column chromatography to afford
diol 5 (0.86 g, 85%) as a colorless solid: m.p. 123ꢀ–124ꢀC (AcOEt);
24
[aŠD þ120.0ꢀ (c ¼ 1.1); analysis: found C, 75.38%, H, 10.80%, C15H26O2
requires C, 75.58%, H, 11.00%.
8a,9a-Epoxidriman-11,12-diol
To a solution of diol 5 (1.00 g, 4.20 mmol) in CH2Cl2 (30 mL), mCPBA
(0.94 g, 5.4 mmol) was added. The resulting solution was stirred for 1 h at
room temperature, diluted with CH2Cl2 (20 mL), washed with saturated
solution of NaHCO3 (3 ꢁ 25 mL), water (50 mL), dried, and evaporated.
The residue was chromatographed, providing epoxide 6 (0.91 g, 85%) as

1352
BENITES, PREITE, AND CORTES
white crystals: m.p. 81ꢀ–82ꢀC (AcOEt), [a]2D4þ45.29 (c, 1.9); analysis found
C, 70.53%, H, 10.07%, C15H26O3 requires C, 70.83%, H, 10.30%.
(8bH)-9a,11,12-Drimantriol (7)
To a stirred suspension of LiAlH4 (200 mg, 5.25 mmol) in dry THF
(20 mL), a solution of epoxide 6 (200 mg, 0.8 mmol) in dry THF (10 mL) was
added, and the reaction mixture was heated at reflux temperature under
nitrogen for 4 h. The excess of reagent was decomposed by addition of
AcOEt and aqueous 10% HCl solution. The mixture was then extracted
with AcOEt (3ꢁ25 mL), and the organic phase was washed with saturated
NaHCO3 (25 mL), water (25 mL), dried, and evaporated. The residue was
chromatographed, affording triol 7 (202 mg, 64%), as a white solid: m.p.
24
54ꢀ–55ꢀC (AcOEt); ½aŠD þ24.1 (c, 1.9); analysis found C, 69.90%, H,
11.30%, C15H28O3 requires C, 70.27%, H, 11.01%.
12-Hydroxy-(8bH)-11-nordriman-9-one (8)
To a stirred solution of NaIO4 (107 mg, 0.5 mmol) in a mixture of
THF (0.2 mL) and water (0.6 mL), triol 7 (90 mg, 0.35 mmol) was added
and the solution stirred at room temperature. The reaction was completed
after 15 min. The reaction mixture was extracted with hexane (4 ꢁ 5 mL) and
the combined extracts were washed with saturated NaHCO3 solution, water,
dried and concentrated to give a yellowish oil. The crude product was
purified by column chromatography to provide ketol 8 (60 mg, 77%) as a
24
colorless oil: ½aŠD À25.54 (c, 1.1).
11,12-Bisnordriman-9-one (1)
To a stirred solution of compound 8 (160 mg, 0.71 mmol) in acetone
(15 mL), Jones reagent (5 mL) was added dropwise at 10ꢀC. The reaction
was monitored by TLC until disappearance of the starting material. The
excess reagent was destroyed by addition of MeOH. The resulting solution
was extracted with AcOEt (3 ꢁ 25 mL), and the organic phase was washed
with saturated NaHCO3 solution (25 mL), water (25 mL), dried, and evapo-
rated. The residue was chromatographed, affording 1 (100 mg, 72%) as an
17
oil: ½aŠD À39.1 (c, 0.44).

(þ)-CONFERTIFOLIN CONVERSION
8aH,9aH-11,12-Drimantriol (9)
1353
To a hydrogenation vessel containing a solution of diol 5 (230 mg,
0.97 mmol) in AcOEt (10 mL), PtO2 (21 mg) was added. The vessel was
then pressurized to 30 psi with hydrogen, and shaken for 2 h at 40ꢀC. The
resulting suspension was filtered through a short silica gel plug, and the
filtrate was concentrated. The residue was chromatographed, affording
diol 9 (185 mg, 80%) as a white solid: m.p. l49ꢀ–150ꢀC (AcOEt);
24
½aŠD þ24.62 (c, 1.8); analysis: found C, 75.03%, H, 11.90%, C15H28O2
requires C, 74.95%, H, 11.74%.
8aH,9aH-11,12-Diacetoxydrimane (3)
Diol 9 (150 mg, 0.62 mmol) was acetylated with Ac2O (0.2 mL,
0.8 mmol) in pyridine (1 mL), using a standard procedure, to give diacetate
24
3 (350 mg, 86%), as an oil: ½aŠD þ46.8 (c, 2.5).
ACKNOWLEDGMENTS
The authors thank FONDECYT (Proyecto Nꢀ 2980047) for financial
support. J.B. thanks DIPUC (Direccion de Investigaciones de la Pontificia
Universidad Catolica de Chile) for a fellowship.
REFERENCES
1. Kende, A.S.; Blacklock, T.J. Tetrahedron Lett. 1980, 21, 3119.
2. Shishido, K.; Tokunaga, Y.; Omachi, N.; Hiroya, K.; Fukumoto, K.;
Kametani, T. J. Chem. Soc., Perkin Trans. 1 1990, 2481.
3. Ihara, M.; Toyota, M.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1
1986, 2151.
4. Smith, A.B., III; Mewshaw, R. J. Org. Chem. 1984, 49, 3685.
5. Cheung, W.S.; Wong, H.N.C. Tetrahedron Lett. 1998, 39, 6521.
6. Montagnac, A.; Martin, M.T.; Debitus, C.; Pais, M. J. of Nat. Prod.
1996, 59, 866.
7. Urones, J.G.; Marcos, I.S.; Gomez Perez, B.; Lithgow, A.M.; Dıez, D.;
Gomez, P.M.; Basabe, P.; Garrido, N.M. Tetrahedron 1995, 51, 1845.
8. Aranda, G.; Bertrane-Delahaye, M.; Lallemand, J.Y.; Azerad, R.;
Maurs, M.; Cortes, M.; Lopez, J. J. of Mol. Catal. B: Enzymatic
1998, 5, 203.

1354
BENITES, PREITE, AND CORTES
9. Reyes, M.E.; Armstrong, V.; Madariaga, E.; Cortes, M.; Lopez, J. Syn.
Commun. 1996, 26, 1995.
10. Armstrong, V.; Cortes, M.; Lopez, J. Nat. Prod. Lett. 1996, 8, 225.
11. Nakano, T.; Maillo, M. Syn. Commun. 1981, 11, 463.
12. Hiroyuki, A.; Oishi, T. Chem. & Pharm. Bull. 1981, 29, 1580.
13. Appel, H.H.; Connolly, J.D.; Overton, K.H.; Bond, R.P.M. J. Chem.
Soc. 1960, 4685.
Received in the USAJune 14, 2000