Chemoenzymatic synthesis of (+)-α-polypodatetraene and methyl (5R,10R,13R)-labda-8-en-15-oate

Article abstract of DOI:10.1248/cpb.56.118

The reported enzymatic resolution products {acetate of (1S,4aS,8aS)-1,2,3, 4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2- ethylene acetal} (8aS)-5 (>99% ee)] and [(1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a- decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-4 (98% ee) were converted to (+)-α-polypodatetraene (1) and methyl (5R,10R,13R)-labda-8-en-15-oate (2), respectively. For the synthesis of (5R,10R,13R)-2, chiral isoprene congener (3S)-26 corresponding to the right part of 2 was synthesized based on the lipase-assisted resolution of (±)-2-methyl-3- (p-methoxyphenyl)propanol (17).

Full text of DOI:10.1248/cpb.56.118

118
Notes
Chem. Pharm. Bull. 56(1) 118—123 (2008)
Vol. 56, No. 1
a
Chemoenzymatic Synthesis of (ꢀ)- -Polypodatetraene and Methyl
(5R,10R,13R)-Labda-8-en-15-oate
Masako KINOSHITA,a Takahiro MIYAKE,a,b Yuusuke ARIMA,a Minako OGUMA,a and Hiroyuki AKITA*,a
a School of Pharmaceutical Sciences, Toho University; 2–2–1, Miyama, Funabashi, Chiba 274–8510, Japan: and
b Tsukuba Research Institute, Novartis Pharma K.K.; 8 Ohkubo, Tsukuba, Ibaraki 300–2611, Japan.
Received September 13, 2007; accepted October 15, 2007; published online October 15, 2007
The reported enzymatic resolution products {acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-
trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal} (8aS)-5 (ꢂ99% ee)] and [(1R,4aR,8aR)-
1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-4
(98% ee) were converted to (ꢀ)-a-polypodatetraene (1) and methyl (5R,10R,13R)-labda-8-en-15-oate (2), respec-
tively. For the synthesis of (5R,10R,13R)-2, chiral isoprene congener (3S)-26 corresponding to the right part of 2
was synthesized based on the lipase-assisted resolution of (ꢁ)-2-methyl-3- (p-methoxyphenyl)propanol (17).
Key words (ꢀ)-a-polypodatetraene; methyl (5R,10R,13R)-labda-8-en-15-oate; total synthesis
The chiral structural unit A possessing decaline ring sys- rence in nature is important for the mechanistic study of the
tem attached with three methyl group is the important nuclei biosynthesis of polycyclic triterpenoids. (ꢀ)-a-Polypodate-
found in a variety of natural products such as drimane traene (1) is the first compound of this class and was isolated
sesquiterpenes and other terpenes. Among them, (ꢀ)-a- from the fresh leaves of Polypodium fauriei and Lemmaphyl-
polypodatetraene (1)1) and methyl (5R,10R,13R)-labda-8-en- lum microphyllum.1) Total synthesis of (ꢁ)-1 was reported
15-oate (2)2) are typical compounds (Chart 1). For the syn- based on mercury(II)trifluoromethanesulphonate-amine com-
thesis of these compounds, (8aS)- and (8aR)-b-keto esters (3) plex-induced olefin cyclization,5) while stepwise synthesis of
are the desirable compound as starting material. We already (ꢀ)-a-polypodatetraene (1) from (ꢀ)-(8sS)-albicanol (10)
reported that lipase-assisted resolution of racemic primary was reported by us.6) Straightforward synthesis of (ꢀ)-a-
alcohol (ꢁ)-4 derived from (ꢁ)-3 gave (8aS)-acetate 5 (49%, polypodatetraene (1) from (8aS)-6 was shown in Chart 2.
ꢂ99% ee) and (8aR)-primary alcohol 4 (49%, 98% ee).3)
Silylation of (8aS)-6 followed by Wittig olefination gave a
This enzymatic resolution was found to be effective and the silyl ether (8aS)-9 which was treated with tetrabutylammo-
E-value of this resolution was estimated to be 921. Conver- nium fluoride (TBAF) provided (ꢀ)-(8aS)-albicanol (10)
sion of (8aS)-5 to a hydroxyl-ketone (8aS)-6 was achieved,3) in 75% overall yield from (8aS)-6. The physical data (mp
while the synthesis of (8aR)-bicyclofarnesol (7) from (8aR)-4 70 °C, [a]D24 ꢀ12.8° (cꢃ1.14, CHCl3) and 1H-NMR) of
via (8aR)-b-keto ester (3) was also reported by us.4) Herein the synthetic (8aS)-10 were identical with those (mp 68—
1
we report the concise synthesis of (ꢀ)-a-polypodatetraene 69 °C,7) [a]D ꢀ13.0° (cꢃ0.6, CHCl3)7) and H-NMR8)) of
(1) from (8aS)-acetate 5 and (5R,10R,13R)-labda-8-en-15- the reported (8aS)-10. Mesylation of (8aS)-10 followed
oate (2) from (8aR)-bicyclofarnesol (7).
by the treatment with benzenethiolate ion (PhSꢄNaꢀ) gave
Synthesis of (ꢀ)-a-Polypodatetraene (1) Polypodanes sulfide (8aS)-12 in 74% overall yield from (8aS)-10. Oxi-
constitute a new class of bicyclic terpenoids and their occur- dation of (8aS)-12 with 30% H2O2 in the presence of
Chart 1
∗ To whom correspondence should be addressed. e-mail: akita@phar.toho-u.ac.jp
© 2008 Pharmaceutical Society of Japan

January 2008
119
Chart 2
Chart 3
Mo7O24(NH4)6·4H2O afforded sulfone (8aS)-13 in 90% isomers was achieved by the dehydration of natural methyl
yield. By applying the reported procedure,5) (8aS)-13 was labdanolate.10) We first tried to synthesize (5R,10R,13R)-
lithiated with LDA followed by treatment with (E,E)-farnesyl labda-8-en-15-oate (2) corresponding to the left carboxylic
bromide to give a diastereomeric mixture of (8aS)-14 in 83% acid part of 16. Retrosynthesis of (5R,10R,13R)-2 was shown
yield. Treatment of (8aS)-14 with 5% Na–Hg gave (ꢀ)-a- in Chart 3.
polypodatetraene (1, [a]D21 ꢀ26.0° (cꢃ0.99, CHCl3), 44%
Target molecule 2 could be obtained by coupling reaction
yield) and a conjugated diene ((8aS)-15, [a]D21 ꢀ21.6° of chiral isoprene unit B and (8aR)-bicyclofarnesyl part C.
(cꢃ0.94, CHCl3), 27% yield). (11E)-Geometry of 15 was Synthesis of chiral isoprene unit B could be achieved by the
confirmed by NMR analysis due to J11,12 coupling constant oxidative cleavage of the p-methoxyphenyl moiety of chiral
(15 Hz). The physical data ([a]D24 and H-NMR) of the syn- alcohol (S)-17, which could be obtained by lipase-assisted
1
thetic (ꢀ)-1 were identical with those ([a]D ꢀ27.4° (cꢃ0.4, resolution of (ꢁ)-17. On the other hand, (8aR)-bicyclofarne-
CHCl3) and 1H-NMR) of the reported (ꢀ)-1.1)
syl part C could be obtained from the reported (8aR)-bicy-
Synthesis of Methyl (5R,10R,13R)-Labda-8-en-15-oate clofarnesol (7). The synthesis of substrate (ꢁ)-17 for enzy-
(2) Marine dorid nudibranchs are known to contain ter- matic resolution was shown in Chart 3. Wittig reaction of
penoid glyceryl esters in their mantle. Among them, a single p-anisole with (ethoxycarbonylethylidene)triphenylphospho-
specimen of the Antractic nudibranch Austrodoris kerguelen- rane gave a,b-unsaturated ester (18) in 99% yield, which was
sis contained two major glyceride ester, 2ꢅ-acetoxyglyceryl subjected to catalytic hydrogenation to afford (ꢁ)-19 in 97%
(5R,10R,13R)-labda-8-en-15-oate (16) and 3ꢅ-acetoxyglyc- yield. LiAlH4 reduction of (ꢁ)-19 gave the desired primary
eryl (5R,10R,13R)-labda-8-en-15-oate.2) These terpenoid alcohol (ꢁ)-17 in 93% yield. For the purpose of the deter-
glyceryl esters are potent activators of protein kinase C mination of enantiomeric excess (ee) of enzymatic reac-
and very active in a regenerative test with the fresh water tion product, the racemate (ꢁ)-17 was analyzed to provide
hydrozoan Hydra vulgaris.9) Synthesis of a mixture of well separated peaks (33.5, 40.4 min) corresponding
(5S,10S,13S)-labda-8-en-15-oate (2) and another two regio- to the enantiomers using Chiralcel AD (250 mmꢆ4.6 mm)

120
Vol. 56, No. 1
under the following analytical conditions (eluent, n- tained by treatment of the reported (8aR)-bicyclofarnesol
hexane/EtOHꢃ100 : 1; detection, UV at 254 nm; flow rate, (7)4) with PBr3. The anion of (3S)-26 generated by treatment
1 ml/1 min). Initially, (ꢁ)-17 was subjected to a screening ex- with lithium diisopropylamide (LDA) in the presence of
periment using several kinds of commercially available li- hexamethylphosphoramide (HMPA) was subjected to alkyla-
pases. Among them, lipase Amano P from Pseudomonas sp. tion with the above bromide (8aR)-27 to give a diastere-
was found to give an acetate (S)-20 (42% yield) and un- omeric mixture of coupling product 28 in 70% yield. Reduc-
changed (ꢀ)-17 (54% yield, [a]D27 ꢀ10.1° (cꢃ0.66, CHCl3) tion of 28 with Na/Hg in MeOH followed by deprotection of
corresponds to 78% ee) in the presence of vinyl acetate as an the THP group with pyridinium p-toluenesulfonate (PPTS)
acyl donor as shown in Table 1 (entry 1).
provided alcohol (5R,10R,13R)-30 ([a]D18 ꢄ63.0° (cꢃ0.84,
The ee of the (ꢀ)-17 was determined by HPLC analysis CHCl3)) in 20% overall yield. Jones oxidation of
on a Chiralcel AD. The absolute structure of (ꢀ)-17 was (5R,10R,13R)-30 followed by treatment with CH2N2–ether
confirmed to be R-configuration in comparison to a specific solution gave (5R,10R,13R)-2 ([a]D21 ꢄ63.6° (cꢃ0.80,
rotation ([a]D25 ꢄ11.9° (cꢃ1.02, CHCl3) corresponds to CHCl3)) in 49% overall yield. The specific rotation and H-
1
ꢂ99% ee) of the reported (S)-17.11) Deprotection of the ac- NMR of synthetic (5R,10R,13R)-2 were consistent with those
etate (20) with K2CO3 in MeOH gave the (ꢄ)-17 ([a]D25 ([a]D ꢄ49° (cꢃ0.21, CHCl3)) of the reported (5R,10R,13R)-
ꢄ12.5° (cꢃ0.67, CHCl3) corresponds to ꢂ99% ee by HPLC 2.2)
analysis), thence the absolute structure of the acetate (20)
was confirmed to be S-configuration. The 78% ee of (ꢀ)-17 Discussion
was again subjected to enzymatic acetylation to afford (S)-20
Although lipases are widely used as enantioselective hy-
(15% yield, 29% ee) and unchanged (R)-17 (84% yield, drolysis or transesterification catalysts, the structural basis
ꢂ99%) as shown in Table 1 (entry 2). Then the synthesis of for this enantioselectivity were unknown so far. The enantio-
(5R,10R,13R)-2 from (S)-20 was shown in Chart 4.
preference toward secondary alcohols by lipase from Can-
Thus obtained (S)-20 was converted into the desired dida rugosa has established a simple empirical rule.12,13)
tetrahydropyranyl (THP) ether (3S)-26 by the reported proce- Most lipases indicate low enantioselectivity toward primary
dure11) in 52% overall yield (7 steps) as shown in Chart 4. On alcohols. Only lipase from Pseudomonas cepacia (PCL) and
the other hand, (8aR)-bicyclofarnesyl bromide (27) was ob- lipase from porcine pancreas (PPL) show moderate to high
enantioselectivity toward a wide range of primary alcohols,
but even for these the enantioselectivity is usually lower than
Table 1.
toward secondary alcohols. The empirical rule summarize
the enantioperference of PCL toward primary alcohol or its
acylated derivative as shown in Chart 5.14,15) When the hy-
droxy methyl (–CH2OH) or acyloxy methyl (–CH2OCOR)
groups exist back with the plane of the page, the favored
enantiomer bears a large substituent (L) on the right, and a
medium substituent (M) on the left. In the present case, pre-
diction of enantioperference toward primary alcohol (ꢁ)-17
was fairly explained by the empirical rule. It is worth noting
that the preparation of both (S)-20 and (R)-17 possessing
high enantiomeric excess was achieved based on lipase cat-
alyzed esterification.
Entry
Substrate
(ꢁ)-17
Products
1
2
(S)-20 (42%, ꢂ99% ee) (R)-17 (54%, 78% ee)
(R)-17 (78% ee) (S)-20 (15%, 29% ee)
(R)-17 (84%, ꢂ99% ee)
Chart 4

January 2008
121
DMSO (10.0 ml) was added a solution of the above mesylate (8aS)-11 in
DMSO (10.0 ml) and thiophenol (PhSH, 2.20 g, 20.0 mmol). The whole
mixture was stirred for 20 min at rt and for 12 h at 100 °C. The reaction mix-
ture was diluted with 2 M aqueous NaOH and extracted with Et2O. The or-
ganic layer was washed with brine and dried over MgSO4. Evaporation of
the organic solvent gave a residue, which was chromatographed on silica gel
(30.0 g, n-hexane) to afford (8aS)-12 (1.05 g, 74%) as a colorless oil. (8aS)-
12: [a]D27 ꢀ164.6° (cꢃ0.41, CHCl3). IR (KBr): 1647, 1452 cmꢄ1. H-NMR
1
Chart 5
(CDCl3) d: 0.76 (3H, s), 0.81 (3H, s), 0.87 (3H, s), 1.08—1.23 (3H, m),
1.28—1.43 (2H, m), 1.45—1.65 (2H, m), 1.69—1.81 (2H, m), 2.00—2.09
(2H, m), 2.43 (1H, ddd, Jꢃ2, 4, 15 Hz), 2.98 (1H, t, Jꢃ12 Hz), 3.17 (1H, dd,
Jꢃ2, 12 Hz), 4.67 (1H, s), 4.96 (1H, s), 7.15 (1H, t, Jꢃ8 Hz), 7.23—7.35
(4H, m). 13C-NMR: d 14.5 (q), 19.2 (t), 21.7 (q), 24.1 (t), 29.9 (t), 33.5 (q),
33.6 (s), 37.7 (t), 39.1 (t), 40.2 (s), 41.9 (t), 55.1 (d), 56.9 (d), 107.8 (t),
125.5 (d), 128.6 (2C, d), 128.8 (2C, d), 138.4 (s), 147.2 (s). Anal. Calcd for
C21H30S: C, 80.19; H, 9.61. Found: C, 80.09; H, 9.62.
Conclusion
The reported enzymatic resolution products {acetate of
(1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-
trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethyl-
ene acetal} (8aS)-5 (ꢂ99% ee)] and [(1R,4aR,8aR)-
1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-
trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-4
(98% ee) were converted to (ꢀ)-a-polypodatetraene (1) and
methyl (5R,10R,13R)-labda-8-en-15-oate (2), respectively.
For the synthesis of (5R,10R,13R)-2, chiral isoprene con-
gener (3S)-26 corresponding to the right part of 2 was syn-
thesized based on the lipase-assisted resolution of (ꢁ)-2-
methyl-3-(p-methoxyphenyl)propanol (17).
(8aS)-Albicanyl Phenyl Sulfone (13) To
a solution of (8aS)-12
(0.500 g, 1.60 mmol) in EtOH (5.00 ml) was added Mo7O24(NH4)6·4H2O
(0.187 g, 0.150 mmol) and 30% H2O2 (1.40 ml) at 0 °C and the whole mix-
ture was stirred for 3 h at rt. The reaction mixture was diluted with 10%
aqueous Na2S2O3 and extracted with Et2O. The organic layer was washed
with brine and dried over MgSO4. The organic layer was evaporated to give
a crude residue, which was chromatographed on silica gel (30.0 g, n-
hexane : AcOEtꢃ30 : 1) to afford (8aS)-13 (0.498 g, 90%). (8aS)-13: mp
111 °C (colorless needles from n-hexane), [a]D26 ꢀ28.1° (cꢃ0.99, CHCl3).
1
IR (KBr): 1647, 1308, 1151 cmꢄ1. H-NMR (CDCl3) d: 0.58 (3H, s), 0.74
(3H, s), 0.84 (3H, s), 1.09—1.30 (3H, m), 1.32—1.39 (2H, m), 1.42—1.57
(3H, m), 1.66—1.74 (1H, m), 1.91—1.97 (1H, m), 2.29—2.38 (2H, m), 3.20
(1H, dd, Jꢃ1, 15 Hz), 3.33 (1H, dd, Jꢃ9, 15 Hz), 4.43 (1H, s), 4.72 (1H, s),
Experimental
All melting points were measured on a Yanaco MP-3S micro melting 7.47—7.54 (2H, m), 7.56—7.61 (1H, m), 7.83—7.86 (2H, m). 13C-NMR: d
point apparatus and are uncorrected. 1H-NMR spectra were recorded on a 14.9 (q), 19.0 (t), 21.5 (q), 23.8 (t), 33.3 (q), 33.6 (s), 37.4 (t), 38.4 (t), 39.8
JEOL EX 400 spectrometer. Spectra were taken with 5—10% (w/v) solution (s), 41.6 (t), 50.6 (d), 52.2 (t), 55.1 (d), 107.7 (t), 128.1 (d), 129.0 (2C, d),
in CDCl3 with Me4Si as an internal reference. The mass spectra, FAB and 133.4 (2C, d), 140.0 (s), 145.6 (s). Anal. Calcd for C21H30O2S: C, 72.79; H,
EI, were obtained with a JEOL JMS-600 H (matrix; glycerol, m-nitrobenzyl 8.73. Found: C, 72.72; H, 8.68.
alcohol) or a JEOL JMS-AM II 50 spectrometer, respectively. IR spectra
(ꢀ)-a-Polypodatetraene (1) 1) 2.6 M n-butyllithium (n-BuLi) in
were recorded on a JASCO FT/IR-300 spectrometer. Optical rotations were hexame solution (1.90 ml, 4.90 mmol) was added to a stirred solution of di-
measured with a JASCO DIP-370 digital polarimeter. All evaporations were isopropylamine (0.490 g, 4.80 mmol) in THF (1.50 ml) at ꢄ78 °C under an
performed under reduced pressure. For column chromatography, silica gel argon atmosphere and the mixture was stirred for 15 min at the same temper-
(Kieselgel 60) was employed.
ature. A solution of (8aS)-13 (0.570 g, 1.60 mmol) in THF (1.50 ml) was
(8aS)-Albicanol (10) 1) To a solution of the reported (8aS)-6 (9.42 g,
added to the above LDA-THF solution and the whole mixture was stirred for
42.0 mmol) in DMF (100 ml) was added tert-butyldimethylsilyl chloride 15 min at the same temperature. To the above reaction mixture was added a
(TBDMSCl, 7.60 g, 50.4 mmol) and imidazole (5.70 g, 83.7 mmol) at 0 °C
and whole mixture was stirred for 1 h at rt. The reaction mixture was diluted
with brine and extracted with Et2O. The organic layer was dried over MgSO4
solution of (E,E)-farnesyl bromide (0.254 g, 0.890 mmol) in THF (1.00 ml)
and the whole mixture was stirred for 2 h at 0 °C. The reaction mixture was
diluted with brine and extracted with Et2O. The organic layer was dried over
and evaporated to give a crude silyl ether (8aS)-8 (14.4 g), which was used MgSO4. Evaporation of the organic solvent gave a crude oil, which was
for the next reaction without further purification. 2) A mixture of methyl- chromatographed on silica gel (45.0 g, n-hexane : AcOEtꢃ100 : 1) to afford
triphenylphosphonium bromide (Ph3Pꢀ-Me Brꢄ, 75.0 g, 210 mmol) and a diastereomeric mixture of (8aS)-14 (0.752 g, 83%) as a colorless oil. 2) A
sodium amide (NaNH2, 8.03 g, 206 mmol) in toluene (500 ml) was refluxed mixture of (8aS)-14 (0.746 g, 1.40 mmol) and 5% Na–Hg (6.04 g) in MeOH
with stirring for 3 h under argon atmosphere. To a solution of crude (8aS)-8
(14.4 g) in toluene (50.0 ml) was added the above yellow solution orated to give a residue, which was diluted with brine and extracted with
(Ph3PꢃCH2, ca. 500 ml) and the whole mixture was stirred for 9 h at rt. The
Et2O. The organic layer was dried over MgSO4. Evaporation of the organic
(10.0 ml) was refluxed for 24 h with stirring. The reaction mixture was evap-
reaction mixture was diluted with H2O and extracted with Et2O. The organic solvent gave a crude oil, which was chromatographed on silica gel (45.0 g,
layer was washed with brine and dried over MgSO4. Evaporation of the or- n-hexane) to afford (ꢀ)-1 (0.245 g, 44%) as a colorless oil and (8aS)-15
ganic solvent gave a crude oil (8aS)-9, which was used for the next reaction (0.150 g, 27%) as a colorless oil in elution order. (ꢀ)-1: [a]D21 ꢀ26.0°
without further purification. 3) To a solution of crude (8aS)-9 in THF
(200 ml) was added 1 M tetrabutylammonium fluoride (Bu4NꢀFꢄ, TBAF) in
THF solution (84.0 ml, 84.0 mmol) and the whole mixture was stirred for
(cꢃ0.99, CHCl3). FAB-MS m/z: 411 (Mꢀꢀ1). 1H- and 13C-NMR data of
(ꢀ)-1 were identical with those of the previously reported data of (ꢀ)-1.1)
(8aS)-15: [a]D21 ꢀ21.6° (cꢃ0.94, CHCl3). 1H-NMR (CDCl3) d: 0.78 (3H, s),
12 h at rt. The reaction mixture was diluted with H2O and extracted with 0.82 (3H, s), 0.87 (3H, s), 0.90—1.04 (1H, m), 1.07 (1H, dd, Jꢃ2, 12 Hz),
Et2O. The organic layer was washed with brine and dried over MgSO4.
1.11—1.54 (8H, m), 1.59 (6H, s), 1.66 (3H, s), 1.72 (3H, s), 1.91—2.19
Evaporation of the organic solvent gave a crude oil (8aS)-9, which was chro- (8H, m), 2.30—2.36 (1H, m), 2.38—2.46 (1H, m), 4.50 (1H, d, Jꢃ2 Hz),
matographed on silica gel (100 g, n-hexane : AcOEtꢃ10 : 1) to give (8aS)-10
(7.05 g, 75%). (8aS)-10: mp 70 °C (colorless needles from n-hexane), [a]D24
ꢀ12.8° (cꢃ1.14, CHCl3), 1H-NMR data of (8aS)-10 were identical with
4.71 (1H, d, Jꢃ2 Hz), 5.03—5.17 (2H, m), 5.59 (1H, dd, Jꢃ10, 15 Hz), 5.85
(1H, d, Jꢃ11 Hz), 6.18 (1H, dd, Jꢃ11, 15 Hz). EI-MS m/z: 408 (Mꢀ).
(ꢁ)-2-Methyl-3-(p-methoxyphenyl)propanol (17) 1) A mixture of p-
those of the reported (8aS)-10.8) Anal. Calcd for C15H22O: C, 81.02; H, anisole (1.00 g, 7.40 mmol) and (ethoxycarbonylethylidene)triphenyl phos-
11.79. Found: C, 81.19; H, 11.97.
(8aS)-Albicanyl Phenyl Sulfide (12) 1) To a solution of (8aS)-10
phorane (5.31 g, 14.7 mmol) in benzene (20.0 ml) was refluxed for 12 h with
stirring. The reaction mixture was diluted with brine and extracted with
(1.00 g, 4.50 mmol) in pyridine (15.0 ml) was added methanesulfonyl chlo- Et2O. The organic layer was dried over MgSO4. Evaporation of organic sol-
ride (MsCl, 0.620 g, 5.40 mmol) and 4-dimethylaminopyridine (DMAP, vent gave a crude oil which was chromatographed on silica gel (40.0 g, n-
0.060 g, 0.500 mmol) at 0 °C, and the whole mixture was stirred for 2 h at rt.
The reaction mixture was diluted with brine and extracted with Et2O. The
organic layer was washed with 7% aqueous NaHCO3 and dried over MgSO4.
hexane : AcOEtꢃ10 : 1) to afford 18 (1.61 g, 99% yield) as a homogeneous
1
oil. IR (neat) 1703 cmꢄ1. H-NMR (CDCl3) d: 1.33 (3H, d, Jꢃ7.1 Hz), 2.11
(3H, s), 3.81 (3H, s), 4.25 (2H, q, Jꢃ7.1 Hz), 6.90 (2H, d, Jꢃ8.8 Hz), 7.36
Evaporation of the organic solvent gave a crude mesylate (8aS)-11, which (2H, d, Jꢃ8.8 Hz), 7.62 (1H, s). 13C-NMR: d 14.0 (q), 14.1 (q), 55.3 (q),
was used for the next reaction without further purification. 2) 55% NaH in
60.7 (t), 113.8 (2C, d), 126.4 (s), 128.5 (s), 131.4 (2C, d), 138.3 (d), 159.6
oil (0.870 g, 19.9 mmol) was washed with n-hexane. To a mixture of NaH in (s), 168.9 (s). 2) A solution of 18 (0.500 g, 2.30 mmol) in EtOH (10.0 ml)

122
Vol. 56, No. 1
was subjected to hydrogenation at ordinary temperature and pressure in the
presence of 20% Pd(OH)2–C (0.05 g). After hydrogen absoprption had
passed through a solution of (S)-23 (1.52 g, 4.98 mmol) in AcOEt (20.0 ml)
at ꢄ78 °C for 2.5 h, then 30% aqueous H2O2 (10.0 ml) was added to the
ceased, the catalyst was filtered with the aid of celite and the filtrate was ozonolyzed product. The reaction mixture was stirred for 10 min at room
evaporated. The residue was chromatographyed on silicagel (20.0 g, n- temperature, then diluted with H2O and extracted with Et2O. The organic
hexane : AcOEtꢃ10 : 1) to afford (ꢁ)-19 (0.493 g, 97% yield) as a homoge- layer was washed with saturated brine, dried over MgSO4 and evaporated to
1
neous oil. IR (neat) 1730 cmꢄ1. H-NMR (CDCl3) d: 1.12 (3H, d, Jꢃ7 Hz),
afford a crude product (23) which was treated with CH2N2 in Et2O to pro-
vide an oily product. This was subjected to chromatographic separation on
1.17 (3H, d, Jꢃ7 Hz), 2.56—2.70 (2H, m), 2.92 (1H, dd, Jꢃ13, 7 Hz), 3.76
(3H, s), 4.07 (2H, q, Jꢃ7 Hz), 6.80 (2H, d, Jꢃ8.5 Hz), 7.06 (2H, d, silica gel (50.0 g, n-hexane : AcOEtꢃ5 : 1) to give (S)-24 as a homogeneous
1
Jꢃ8.5 Hz). 13C-NMR: d 14.2 (q), 16.7 (q), 38.9 (t), 41.7 (d), 55.2 (q), 60.2 oil (1.06 g, 83% overall yield). Spectral data (IR, H-NMR) were identical
(t), 113.7 (2C, d), 129.9 (2C, d), 131.5 (s), 158.1 (s), 176.1 (s). HR-MS (EI)
Calcd for C13H18O3: 222.1307. Found: 222.1256. 3) A solution of (ꢁ)-19
(0.493 g, 2.20 mmol) in Et2O (10.0 ml) was added to a suspension of LiAlH4
(0.133 g) in Et2O (10 ml) at 0 °C. The whole mixture was stirred for 1 h at
room temperature. The reaction mixture was diluted with 2 M aqueous HCl
with those of reported (S)-24.6)
(S)-3-Methyl-4-phenylsulfonylbutanol (25) LiBH4 (0.157 g, 7.21 mmol)
was added to a solution of (S)-24 (1.06 g, 4.15 mmol) in THF (20.0 ml)
at 0 °C and the whole was stirred for 12 h at 60 °C. The reaction mixture was
diluted with H2O and extracted with Et2O. The organic layer was
and extracted with Et2O. The organic layer was washed with saturated brine, washed with saturated brine, dried over MgSO4 and evaporated to afford
dried over MgSO4. Evaporation of the organic solvent gave a crude oil acrude product which was chromatographed on silica gel (30.0 g, n-
which was chromatographed on silica gel (20.0 g, n-hexane : AcOEtꢃ5 : 1) hexane : AcOEtꢃ1 : 2) to give (S)-25 as a homogeneous oil (0.812 g, 86%
to afford (ꢁ)-17 (0.373 g, 93% yield) as a colorless oil. IR (neat) 3379 cmꢄ1
.
yield). Spectral data (IR, 1H-NMR) were identical with those of reported
1H-NMR (CDCl3) d: 0.89 (3H, d, Jꢃ6.8 Hz), 1.90—1.97 (2H, m), 2.35 (1H, (S)-25.6)
dd, Jꢃ8.3, 13.7 Hz), 2.68 (1H, dd, Jꢃ6.4, 13.7 Hz), 3.43 (1H, dd, Jꢃ6.4, (3S)-3-Methyl-4-phenylsulfonylbutyltetrahydropyranyl Ether (26)
A
10.7 Hz), 3.50 (1H, dd, Jꢃ6.4, 10.7 Hz), 3.77 (3H, s), 6.82 (2H, d, mixture of (S)-25 (0.109 g, 0.470 mmol), 3,4-dihydropyran (DHP) (0.108 g,
Jꢃ8.3 Hz), 7.07 (2H, d, Jꢃ8.3 Hz). Anal. Calcd for C11H16O2: C, 73.30; H, 1.28 mmol) and pyridinium p-toluenesulfonate (PPTS, 0.011 g, 0.043 mmol)
8.95. Found C, 73.30; H, 9.13. EI-MS m/z 180 (Mꢀ). The racemate (ꢁ)-17
in CH2Cl2 (2.00 ml) was stirred for 12 h at room temperature. The reaction
was analyzed to provide well separated peaks (33.5, 40.4 min) corresponding mixture was washed with aqueous NaHCO3 and saturated brine, and dried
to the enantiomers using Chiralcel AD (250 mmꢆ4.6 mm) under the follow- over MgSO4. The organic layer was evaporated to afford a crude product
ing analytical conditions (eluent, n-hexane/EtOHꢃ100 : 1; detection, UV at
which was chromatographed on silica gel (15.0 g, n-hexane : AcOEtꢃ4 : 1)
to give (3S)-26 as a homogeneous oil (0.142 g, 95% yield). Spectral data
254 nm; flow rate, 1 ml/1 min).
Enantioselective Acetylation of (ꢁ)-17 with Lipase Amano P 1) (IR, 1H-NMR) were identical with those of reported (3S)-26.6)
(Entry 1) A suspension of (ꢁ)-17 (3.88 g, 21.6 mmol), lipase Amano P
(8aR)-Cyclofarnesyl Bromide (27) To a solution of (8aR)-cyclofar-
(1.50 g) and vinyl acetate (4.00 g) in diisopropyl ether (150 ml) was incu- nesol (7) (0.590 g, 2.65 mmol) and pyridine (0.190 g, 2.40 mmol) in Et2O
bated at 33 °C for 1 h. After the reaction mixture was filtered, the precipitate (5.00 ml) was added phosphorus tribromide (PBr3; 0.300 ml, 312 mmol) at
was washed with AcOEt. The combined organic layer was dried over 0 °C and the reaction mixture was stirred for 10 min. The reaction mixture
MgSO4 and evaporated. The residue was chromatographed on silica gel was diluted with brine and extracted with Et2O. The organic layer was dried
(90 g) to give (S)-20 (2.04 g, 42% yield) as a colorless oil from n- over MgSO4 and evaporated to give a crude ((8aR)-27, 0.734 g), which was
hexane : AcOEtꢃ10 : 1 eluent, and (R)-17 (2.12 g, 54% yield) from n- used for the next reaction without further purification.
hexane : AcOEtꢃ5 : 1 eluent. (R)-17: [a]D27 ꢀ10.1° (cꢃ0.66, CHCl3) corre-
sponds to 78% ee. tRꢃ33.5 min (89%) and tRꢃ40.4 min (11%). 2) A suspen-
sion of (S)-20 (2.04 g, 9.2 mmol) and K2CO3 (1.92 g, 13.9 mmol) in MeOH
(5R,10R,13R)-Labda-8-en-15-ol (30) 1) n-Butyllithium (n-BuLi, 1 M in
hexane, 4.20 ml, 4.20 mmol) was added to a stirred solution of diisopropy-
lamine (4.00 ml) in THF (5.00 ml) at ꢄ78 °C under an argon atmosphere and
(20.0 ml) was stirred for 1 h at room temperature. The reaction mixture was the mixture was stirred for 30 min at the same temperature. To a solution of
evaporated, diluted with saturated brine and extracted with AcOEt. The or- (3S)-26 (0.403 g, 1.29 mmol) in THF (5.00 ml) at ꢄ78 °C was added the
ganic layer was dried over MgSO4 and evaporated to afford a crude product above LDA-THF solution (4.00 ml) and HMPA (4.00 ml). The whole was
which was chromatographed on silica gel (40.0 g) to give (S)-17 (1.63 g,
stirred for 1 h at ꢄ78 °C, then a solution of (R)-bromide (27, 0.734 g,
98% yield) from n-hexane : AcOEtꢃ5 : 1 eluent. (S)-17: [a]D25 ꢄ12.5° 2.57 mmol) in THF (5.00 ml) was added at the same temperature. The reac-
(cꢃ0.67, CHCl3) corresponds to ꢂ99% ee. tRꢃ33.5 min (ꢇ1%) and tion mixture was stirred for 12 h at room temperature. The reaction mixture
tRꢃ40.4 min (ꢂ99%). 3) (Entry 2) A suspension of 78% ee of (R)-17
was diluted with H2O and extracted with Et2O. The organic layer was
(2.12 g, 12 mmol), lipase (1.01 g) and vinyl acetate (2.50 g) in diisopropyl washed with saturated brine and dried over MgSO4. Removal of the organic
ether (4.0 ml) was incubated at 33 °C for 90 min. The reaction mixture was solvent gave an oily product, which was chromatographed on silica gel
worked up in the same way as entry 1 to afford (S)-20 (0.410 g, 15%) and
(R)-17 (84%, ꢂ99% ee). (R)-17: [a]D25 ꢀ12.9° (cꢃ0.96, CHCl3) corre- 28: FAB-MS: (m/z) 539 (MꢀNa)ꢀ. 2) To a solution of 28 (0.469 g,
sponds to ꢂ99% ee. tRꢃ33.5 min (ꢂ99%) and tRꢃ40.4 min (ꢇ1%). 4) A 0.9 mmol) in THF (3 ml) and MeOH (6.00 ml) were added Na2HPO4 (6.74 g,
suspension of (S)-20 (0.410 g, 1.0 mmol) and K2CO3 (0.384 g, 2.80 mmol) in 18.8 mmol) and 5% Na–Hg (26.9 g, 120 mmol) and whole mixture was
(50.0 g, n-hexane : AcOEtꢃ10 : 1) to afford 28 (0.469 g, 70%) as amorphous.
MeOH (10 ml) was stirred for 1 h at room temperature. The reaction mixture
was worked up in the same way as entry 2 to afford (S)-17 (0.310 g, 93%).
(S)-17: 29% ee. tRꢃ33.5 min (35.5%) and tRꢃ40.4 min (64.5%).
stirred for 2 d at 80 °C. The reaction mixture was filtered with the aid of
Celite and filtrate was condensed. The residue was treated with 2 M aqueous
NaOH and extracted with Et2O. The organic layer was washed with saturated
(S)-1-Bromo-2-methyl-3-p-methoxyphenylpropanol (21) Triphenyl- with brine and dried over MgSO4. Removal of the organic solvent gave an
phosphine (Ph3P, 0.295 g, 1.12 mmol) and CBr4 (0.372 g, 1.12 mmol) were oily product, which was chromatographed on silica gel (10.0 g, n-
added to a solution of (S)-17 (0.126 g, 0.7 mmol) in THF (2.00 ml)
and the resulting solution was stirred for 15 min at room temperature. The
hexane : AcOEtꢃ50 : 1) to afford 29 (0.283 g, 83%) as a homogeneous oil.
29: EI-MS: (m/z) 376 (Mꢀ). 3) A mixture of 29 (0.260 g, 0.69 mmol), PPTS
reaction mixture was diluted with saturated brine and extracted with (0.292 g, 1.16 mmol) in MeOH (5 ml) was stirred for 12 h at 40 °C. The reac-
Et2O. The organic layer was dried over MgSO4 and evaporated to afford a tion mixture was diluted with aqueous NaHCO3 and extracted with Et2O.
crude product which was chromatographed on silica gel (15.0 g, n- The organic layer was washed with brine and dried over MgSO4. The or-
hexane : AcOEtꢃ5 : 1) to give (S)-21 as a homogeneous oil (0.168 g, 98%
ganic layer was evaporated to afford a crude product which was chro-
yield). (S)-21: [a]D23 ꢀ28.3° (cꢃ1.21, CHCl3). Spectral data (IR and 1H- matographed on silica gel (10.0 g, n-hexane : AcOEtꢃ15 : 1) to give
NMR) were identical with those of reported (S)-21.6)
(5R,10R,13R)-30 (0.051 g, 25%) as a homogeneous oil. (5R,10R,13R)-30:
1
(S)-2-Methyl-3-(p-methoxyphenyl)-1-phenylsulfonylpropane (22)
A
[a]1D8 ꢄ63.0° (cꢃ0.84, CHCl3). IR (neat): 3328 cmꢄ1. H-NMR (CDCl3) d:
mixture of (S)-21 (1.54 g, 6.34 mmol) and sodium benzenesulfinate
0.81 (3H, s), 0.85 (3H, s), 0.91 (3H, d, Jꢃ6 Hz), 0.91 (3H, s), 1.04—1.25
(PhSO2Na·2H2O, 5.03 g, 25.1 mmol) in dimethylforamide (DMF, 30.0 ml) (5H, m), 1.28—1.47 (6H, m), 1.52 (3H, s), 1.55—1.66 (3H, m), 1.70—1.80
was heated at 100 °C for 1 h with stirring, then diluted with H2O and ex- (1H, m), 1.91—2.19 (4H, m), 3.61—3.72 (2H, m). 13C-NMR: d 19.1 (t),
tracted with Et2O. The organic layer was washed with saturated brine, dried 19.1 (t), 19.5 (q), 19.5 (q), 20.1 (q), 21.7 (q), 25.5 (t), 30.7 (d), 33.3 (q), 33.3
over MgSO4 and evaporated to afford a crude product which was chro- (s), 33.6 (t), 37.0 (t), 37.8 (t), 39.0 (s), 39.9 (t), 41.8 (t), 51.9 (d), 61.3 (t),
matographed on silica gel (30.0 g, n-hexane : AcOEtꢃ5 : 1) to give (S)-22 as
a homogeneous oil (1.55 g, 80% yield). Spectral data (IR, 1H-NMR) were 292.2778.
identical with those of reported (S)-22.6)
Methyl (5R,10R,13R)-Labda-8-en-15-oate (2) To
Methyl (S)-3-Methyl-4-phenylsulfonylbutanoate (24) Ozone was (5R,10R,13R)-30 (0.052 g, 0.17 mmol) in acetone (3.00 ml) was added Jones
125.3 (s), 141.0 (s). HR-MS (EI) Calcd for C20H36O: 292.2766. Found:
a
solution of

January 2008
123
reagent (0.10 ml) at 0 °C and whole mixture was stirred for 10 min at the
same temperature. To the reaction mixture was added iso-PrOH (1.00 ml)
and whole mixture was stirred for 15 min. The reaction mixture was con-
densed, diluted with brine and extracted with Et2O. The organic layer was
dried over MgSO4. Removal of the organic solvent gave a crude carboxylic
acid (31, 0.052 g), which was treated with CH2N2–ether solution to afford a
crude residue. This was chromatographed on silica gel (5.00 g, n-
hexane : AcOEtꢃ100 : 1) to provide (5R,10R,13R)-2 (0.027 g, 49%) as a col-
orless oil. (5R,10R,13R)-2: [a]D21 ꢄ63.6° (cꢃ0.80, CHCl3). IR (neat):
based on the decaline structure.
4) Arima Y., Kinoshita M., Akita H., Tetrahedron: Asymmetry, 18,
1701—1711 (2007).
5) Nishizawa M., Nishide H., Hayashi Y., J. Chem. Soc., Chem.
Commun., 1984, 467—468.
6) Kinoshita M., Ohtsuka M., Nakamura D., Akita H., Chem. Pharm.
Bull., 50, 930—934 (2002).
7) Hellou J., Andersen R. J., Thompson J. E., Tetrahedron, 38, 1875—
1879 (1982).
8) Akita H., Nozawa M., Mitsuda A., Ohsawa H., Tetrahedron: Asymme-
try, 11, 1375—1388 (2000).
9) Gavagnin M., Napoli A. D., Cimino G., Iken K., Avila C., Garcia F. J.,
Tetrahedron: Asymmetry, 10, 2647—2650 (1999).
10) Vlad P. F., Ungur N. D., Aricu A. N., Andreeva I. Y., Russian Chem.
Bull., 46, 767—770 (1997).
11) Nozawa M., Takahashi K., Kato K., Akita H., Chem. Pharm. Bull., 48,
272—277 (2000).
1741 cmꢄ1
.
1H-NMR (CDCl3) d: 0.80 (3H, s), 0.85 (3H, s), 0.91 (3H, s),
0.94 (3H, d, Jꢃ6.6 Hz), 1.05—1.14 (3H, m), 1.23—1.59 (8H, m), 1.52 (3H,
s), 1.70—1.75 (1H, m), 1.88—2.14 (4H, m), 2.12 (1H, dd, Jꢃ15, 8 Hz), 2.31
(1H, dd, Jꢃ15, 6 Hz), 3.66 (3H, s). 13C-NMR: d 19.1 (t), 19.1 (t), 19.4 (q),
19.6 (q), 20.1 (q), 21.7 (q), 25.5 (t), 31.4 (d), 33.3 (q), 33.6 (t), 37.0 (t), 37.3
(t), 39.0 (s), 41.5 (t), 41.8 (t), 51.3 (q), 51.9 (d), 125.6 (s), 126.4 (s), 140.6
(s), 173.7 (s). HR-MS (EI) Calcd for C21H36O2: 320.2715. Found: 320.2725.
References and Notes
1) Shiojima K., Arai Y., Masuda K., Kamada T., Ageta H., Tetrahedron
Lett., 24, 5733—5736 (1983).
2) Davies-Coleman M. T., Faulkner D. J., Tetrahedron, 47, 9743—9750
(1991). Carbon number of compound (2) was employed based on
steroid skeleton.
12) Kazlauskas R. J., Weissfloch A. N. E., Rappaport A. T., Cuccia L. A.,
J. Org. Chem., 56, 2656—2665 (1991).
13) Cygler M., Grochulski P., Karlauskas R. J., Schrag J. D., Bouthillier F.,
Rubin B., Serreqi A. N., Gupta A. K., J. Am. Chem. Soc., 116, 3180—
3186 (1994).
14) Weissfloch A. N. E., Kazlauskas R. J., J. Org. Chem., 60, 6959—6969
(1995).
3) Amano Y., Kinoshita M., Akita H., J. Mol. Catalysis B: Enzymatic, 32,
141—148 (2005). Carbon number of (8aS)- and (8aR)-3 was employed 15) Tuomi W. V., Kazlauskas R. J., J. Org. Chem., 64, 2638—2647 (1999).