Synthesis and absolute configuration of (-)-subersic acid, a sponge-derived, terpenoidal inhibitor of human 15-lipoxygenase

Article abstract of DOI:10.1002/ejoc.200390128

(-)-Subersic acid (1), a new derivative of p-hydroxybenzoic acid in which the m-position is substituted with a bicyclic diterpenoid was synthesized from (S)-3-hydroxy-2,2-dimethylcyclohexanone and p-hydroxybenzoic acid. The stereochemistry of this sponge-

Full text of DOI:10.1002/ejoc.200390128

FULL PAPER
Synthesis and Absolute Configuration of (؊)-Subersic Acid, a Sponge-Derived,
Terpenoidal Inhibitor of Human 15-Lipoxygenase[‡]
Yoshihisa Tanada[a] and Kenji Mori*[b]
Keywords: Carbocycles / Inhibitors / Natural products / Terpenoids / Total synthesis
(−)-Subersic acid (1), a new derivative of p-hydroxybenzoic
acid in which the m-position is substituted with a bicyclic
diterpenoid, was synthesized from (S)-3-hydroxy-2,2-di-
methylcyclohexanone and p-hydroxybenzoic acid. The ste-
reochemistry of this sponge-derived inhibitor of human 15-
lipoxygenase was established as (5R,10R)-1.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
In 2001, Crews and co-workers isolated (Ϫ)-subersic acid
(1, Scheme 1) from the Papua New Guinean sponge Sub-
erea sp. as an inhibitor of human 15-lipoxygenase.[1] The
compound’s structure 1 was proposed on the basis of
extensive NMR analysis, and its (5R,10R) absolute stereo-
chemistry was suggested by the positive molar rotation of
1.[1] We became interested in synthesizing (Ϫ)-1 so as to
verify its proposed structure, including its stereochemistry.
Scheme 1 shows our synthetic plan for (Ϫ)-subersic acid:
the target molecule 1 was to be constructed by alkylation
of the sesquiterpene part A with the m-prenylated p-hydro-
xybenzoic acid part B. The sesquiterpene part A was to be
synthesized from the known β-oxo ester C,[2] which has
been prepared from (S)-3-hydroxy-2,2-dimethylcyclohexa-
none (D).[3] The p-hydroxybenzoic acid derivative B was to
be synthesized from p-hydroxybenzoic acid F via its m-pre-
nylated derivative E. This paper describes the successful
execution of the above plan to give (5R,10R)-(Ϫ)-subersic
acid (1).
Results and Discussion
The synthesis of the β-oxo ester (ϩ)-10 is summarized in
Scheme 2. The starting ketone 2 (ϭ D) was converted into
5 (ϭ C) by Mori and Koga’s method.[2] Namely, ring-clos-
ure of unsaturated β-oxo ester 3 by treatment with tin()
chloride in wet dichloromethane gave a mixture of 4 and 5,
which could be separated by silica gel chromatography to
Scheme 1. Structure and retrosynthetic analysis of (؊)-subersic
acid; the numbering system used for 1 is that by Crews[1]
[‡]
Diterpenoid Total Synthesis, XXXIII. Part XXXII: A. Yajima,
give 5 in 7% overall yield based on 2 (nine steps). Acetaliz-
ation of the oxo ester 5 under Noyori conditions[4] provided
ethylene acetal (ϩ)-6, the benzyl protective group of which
was removed by hydrogenolysis to furnish crystalline (Ϫ)-
K. Mori, Eur. J. Org. Chem. 2000, 4079Ϫ4091.
[a]
Tokushima Second Factory, Otsuka Pharmaceutical Co., Ltd.,
Kawauchi, Tokushima 771-0192, Japan
[b]
Insect Pheromone and Traps Division, Fuji Flavor Co., Ltd.,
Midorigaoka 3-5-8, Hamura-City, Tokyo 205-8503, Japan
848
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0305Ϫ0848 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 848Ϫ854

Synthesis and Absolute Configuration of (Ϫ)-Subersic Acid
FULL PAPER
7. Dehydration of 7 with trifluoromethanesulfonyl (triflyl ϭ
Tf) chloride and 4-(dimethylamino)pyridine (DMAP) in
dichloromethane[5] yielded olefin (Ϫ)-8. Hydrogenation of
(Ϫ)-8 in the presence of palladium/charcoal gave (Ϫ)-9,
which was treated with hydrochloric acid to give β-oxo ester
(ϩ)-10 in 50% overall yield based on 5 (five steps).
Scheme 3. Preparation of (ϩ)-10 from (Ϯ)-10; reagents: (a) (2S,3S)-
1,2,3,4-butanetetraol 1,4-dibenzyl ether; (b) H2, 10% Pd/C, EtOAc;
then SiO2 chromatography [33% of 11 and 30% of 12 from (Ϯ)-
10]; (c) 5% H2SO4, MeOH, heat (91%)
Scheme 2. Synthesis of (ϩ)-10 from 2; reagents: (a) SnCl4, wet
CH2Cl2 (7% of 5 from 2, nine steps); (b) (TMSOCH2)2, TMSOTf,
CH2Cl2 (76%); (c) H2, 10% Pd/C, EtOAc (80%); (d) TfCl, DMAP,
CH2Cl2 (90%); (e) H2, 10% Pd/C, EtOAc (quant.); (f) 6  HCl,
THF (91%)
Katsumura and co-workers, however, recently reported
an alternative procedure for the preparation of (ϩ)-10
(Scheme 3).[6] They converted (Ϯ)-10[7] into a diastereom-
eric mixture of acetals 11 and 12, which could be separated
by silica gel chromatography. Acid hydrolysis of 12 afforded
(ϩ)-10. This is indeed a short, six-step procedure to secure
(ϩ)-10 from geraniol, but chromatographic separation of 11
and 12 was found to be rather tedious in our hands. In spite
of the linear and multi-step nature of our route, our syn-
thesis readily provided a substantial amount of pure (ϩ)-
Scheme 4. Synthesis of (Ϫ)-17; reagents: (a) NaH, (EtO)2POCl,
THF (89%); (b) Me2CuLi, THF (87%); (c) (iBu)2AlH, CH2Cl2
(95%); (d) MsCl, LiCl, DMF; (e) PhSO2Na, DMF (70% based
on 15)
The prenylated p-hydroxybenzoic acid derivative 21 (ϭ
10, because the separation of 4 and 5 was easier than that B) was synthesized as summarized in Scheme 5. p-Hydro-
of 11 and 12. xybenzoic acid (18 ϭ F) was dissolved in aqueous sodium
Scheme 4 shows the conversion of (ϩ)-10 into (Ϫ)-17 (ϭ hydroxide, and prenyl bromide was added to the solution
A). By the known procedure recorded for conversion of to effect prenylation.[10] The crude product was treated in
(Ϯ)-10 to (Ϯ)-15,[8] (ϩ)-10 furnished crystalline alcohol DMF with benzyl bromide and potassium carbonate to give
(Ϫ)-15, [α]2D4 ϭ Ϫ115 (c ϭ 0.13, CHCl3), via (Ϫ)-13 and the benzyl-protected prenylation product 19 (ϭ E) in 9.5%
(Ϫ)-14. The known (ϩ)-15, previously prepared from natur- yield after chromatographic purification. Although the
ally occurring (Ϫ)-sclareol, was reported to have the specific yield of 19 was quite low, 19 could be obtained readily, be-
rotation value [α]D18 ϭ ϩ113 (c ϭ 0.14, CHCl3).[9] Treatment cause the crystalline by-product (benzyl p-benzyloxybenzo-
of (Ϫ)-15 with methanesulfonyl (mesyl ϭ Ms) chloride and ate) in this step could be removed simply by filtration. Ox-
lithium chloride in DMF gave the unstable chloride 16, idation of 19 with selenium dioxide and tert-butyl hydroper-
which was used immediately for the next step to give the oxide afforded a mixture of the starting material 19, alcohol
desired phenyl sulfone (Ϫ)-17 (ϭ sesquiterpene part A) as 20, and the corresponding aldehyde. This mixture was re-
crystals.
duced with sodium borohydride, and the product was puri-
Eur. J. Org. Chem. 2003, 848Ϫ854
849

Y. Tanada, K. Mori
FULL PAPER
fied by silica gel chromatography to furnish pure 20 in 45%
yield. The alcohol 20 gave the corresponding bromide 21
(ϭ B) as crystals upon treatment with methanesulfonic an-
hydride and lithium bromide in the presence of DMAP and
collidine in DMF.
Scheme 5. Synthesis of 21; reagents: (a) i) Me2CϭCHCH2Br,
NaOH, H2O; ii) BnBr, K2CO3, DMF (9.5%); (b) i) SeO2, tBuO2H,
CH2Cl2, ii) NaBH4, THF/H2O (45%); (c) Ms2O, LiBr, DMAP, s-
collidine, DMF (87%)
Scheme 6 shows the final stage of the synthesis to give
(Ϫ)-subersic acid (1). A carbanion was generated from the
phenyl sulfone 17 in THF by treatment with n-butyllithium
in the presence of HMPA. It was then alkylated with the
bromide 21 to give the coupling product 22 as a diastereom-
eric mixture.[11] Reductive removal of the phenylsulfonyl
group of 22 was achieved by use of 5% sodium amalgam
(126 equiv.) in the presence of disodium hydrogen phos-
phate (20 equiv.) in THF/MeOH (1:5) to give 23, in 35%
yield based on 17 and as fine needles after chromatographic
purification and recrystallization. Unfortunately, the crys-
tals of 23 were not suitable for X-ray analysis. NMR ana-
lysis of the mother liquor after collection of 23 revealed the
Scheme 6. Synthesis of (Ϫ)-subersic acid (1); reagents: (a) nBuLi,
THF/HMPA; (b) 5% Na/Hg, Na2HPO4, MeOH/THF (35% based
on 17); (c) Li, naphthalene, THF (75%); the numbering system used
for 23 follows that for 1 by Crews;[1] the IUPAC names of 1 and
23 are given in the Exp. Sect.
Crews.[1] The overall yield of (Ϫ)-1 was 6.7% based on 5
(13 steps).
presence of a by-product, which seemed to be a ∆9(11)
double bond isomer of 23 generated by the migration of the
8(9)-double bond in the course of the reductive removal of
the phenylsulfonyl group.
-
∆
Experimental Section
The concluding step of the synthesis was the removal of General: Boiling and melting points: Uncorrected values. Melting
points: Yanaco MP-S3, Büchi B-540. nD: Atago DNT-1. [α]D: Jasco
DIP-370, Jasco DIP-1000, Jasco DIP-1010. IR: Jasco IRA-102, Ja-
sco FT/IR-460 plus, PerkinϪElmer FT-IR 1640. 1H NMR: Jeol
JNM-EX 90A (90 MHz), Jeol JNM-LA 400, Bruker DPX 300,
Bruker DPX 500 (TMS at δH ϭ 0.00 or CHCl3 at δH ϭ 7.26 as an
internal standard). 13C NMR: Jeol JNM-LA 400 (100 MHz),
Bruker DPX 300(75 MHz), Bruker DPX 500(125 MHz) (CDCl3 at
the benzyl protective group of 23. Treatment of 23 with a
freshly prepared 1.0  solution of lithium naphthalenide (4
equiv.) in THF furnished (Ϫ)-subersic acid (1) as a slightly
unstable, amorphous solid. Its chromatographic purifica-
tion, TLC separation, dissolution in CDCl3 for NMR
measurement, irradiation with UV or visible light, and even
concentration of its solution in vacuo all increased the
amount of impurities in the synthetic sample. The 1H NMR
and 13C NMR spectra of our synthetic 1 were identical with
those of the natural (Ϫ)-subersic acid.[1]
δ
C ϭ 77.0 as an internal standard). MS: Jeol JMS-AX 505HA, Jeol
SX-102A. CC: Merck Kieselgel 60 Art 1.07734 or Kanto Chemical
silica gel 60N (spherical neutral). TLC: 0.25 mm Merck silica gel
plates (60F-254).
Our synthetic (5R,10R)-subersic acid (1) was levorota-
tory: [α]2D4 ϭ Ϫ52.2 (c ϭ 0.52, CHCl3). Since the natural 1
was also levorotatory {[α]D ϭ Ϫ46 (c ϭ 0.5, CHCl3)}, our
synthetic 1 must possess the same absolute configuration as
that of the natural product. It was therefore concluded that
Methyl (1S,4aS,6S,8aR)-6-Benzyloxy-2,2-ethylenedioxy-5,5,8a-tri-
methyldecahydronaphthalene-1-carboxylate (6): TMSOTf (0.73 mL,
4 mmol) was added at Ϫ78 °C under argon to a stirred solution of
5 (14.2 g, 39.6 mmol) and 1,2-bis(trimethylsilyloxy)ethane (12.4 g,
59.8 mmol) in CH2Cl2 (60 mL). The resulting mixture was stirred
(Ϫ)-subersic acid was indeed (5R,10R)-1, as proposed by at Ϫ78 °C for 4 h and at 0 °C for 16 h, and was then poured into
850 Eur. J. Org. Chem. 2003, 848Ϫ854

Synthesis and Absolute Configuration of (Ϫ)-Subersic Acid
FULL PAPER
water (150 mL), and extracted with Et2O (2 ϫ 500 mL). The com-
bined organic phases were washed with a saturated aqueous so-
dium hydrogen carbonate solution and brine (each 1 ϫ 150 mL),
dried with magnesium sulfate, and concentrated in vacuo to give
20 g of a crude red oil. This was purified by silica gel chromato-
graphy (600 g, EtOAc/n-hexane, 1:6, then 1:4) to give 6 (12.1 g,
76%) as a pale yellow oil: n2D2 ϭ 1.5171. [α]2D3 ϭ ϩ2.44 (c ϭ 1.16,
from n-hexane to give an analytical sample as colorless needles.
M.p. 105.0Ϫ106.5 °C. [α]2D4 ϭ Ϫ27.4 (c ϭ 1.00, CHCl3). IR (KBr):
ν˜max ϭ 1735 cmϪ1(s, CϭO), 1195 (m, CϪOϪC), 1155 (m,
1
CϪOϪC), 1125 (m, CϪOϪC). H NMR (300 MHz, CDCl3): δ ϭ
0.91 (s, 3 H, 5-CH3), 0.98 (s, 3 H, 5-CH3), 1.21 (s, 3 H, 8a-CH3),
1.26 (dd, J ϭ 9.0 Hz, 6.0 Hz, 1 H, 4a-H), 1.37Ϫ1.52 (m, 1 H, 4ax-
H), 1.57Ϫ1.74 (m, 3 H, 4eq-H, 3ax-H, 8ax-H), 1.86 (dt, J ϭ 12.6 Hz,
CHCl3). IR (film): ν˜max ϭ 1740 (s, CϭO), 1195 (m, CϪOϪC), 1155 3.0 Hz, 1 H, 3eq-H), 1.96 (d, J ϭ 17 Hz, 1 H, 8eq-H), 2.55 (s, 1 H,
(m, CϪOϪC), 1125 (m, CϪOϪC) cmϪ1 1H NMR (400 MHz,
CHCO2CH3), 3.65 (s, 3 H, CO2CH3), 3.78 (dd, J ϭ 12.6 Hz,
CDCl3): δ ϭ 0.87 (s, 3 H, CH3), 0.99 (s, 3 H, CH3), 1.05Ϫ1.25 (m, 6.3 Hz, 1 H, OCH2CH2O), 3.87 (dd, J ϭ 12.6 Hz, 6.3 Hz, 1 H,
2 H, CH2), 1.25 (s, 3 H, CH3), 1.35Ϫ1.87 (m, 7 H), 2.60 (s, 1 H, OCH2CH2O), 3.95 (dd, J ϭ 12.6 Hz, 6.3 Hz, 1 H, OCH2CH2O),
.
CHCO2CH3), 3.06 (s, 1 H, CHOCH2Ph), 3.63 (s, 3 H, CO2CH3), 4.11 (dd, J ϭ 12.6 Hz, 6.3 Hz, 1 H, OCH2CH2O), 5.37 (dd, J ϭ
3.73 (dd, J ϭ 13.4 Hz, 6.0 Hz, 1 H, OCH2CH2O), 3.84 (dd, J ϭ 9.9 Hz, 2.4 Hz, 1 H, 6-H), 5.41 (ddd, J ϭ 9.9 Hz, 5.4 Hz, 0.9 Hz,
13.4 Hz, 6.0 Hz, 1 H, OCH2CH2O), 3.92 (dd, J ϭ 13.4 Hz, 6.0 Hz,
1 H, OCH2CH2O), 4.07 (dd, J ϭ 13.4 Hz, 6.0 Hz, 1 H, OCH2-
1 H, 7-H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 15.2, 20.9, 22.8,
31.8, 34.6, 37.0, 38.0, 39.6, 50.5, 51.1, 61.4, 64.1, 65.6, 76.6, 109.0,
CH2O), 4.34 (d, J ϭ 8.4 Hz, 1 H, OCH2Ph), 4.62 (d, J ϭ 8.4 Hz,1 120.6, 137.9, 171.1 ppm. C17H26O4 (294.4): calcd. C 69.36, H 8.90;
H, OCH2Ph), 7.26Ϫ7.37 (m, 5 H, Ph-H) ppm. 13C NMR (75 MHz, found C 69.32, H 8.99.
CDCl3): δ ϭ 14.7, 19.4, 20.3, 22.2, 28.8, 32.8, 37.5, 37.9, 38.8, 48.2,
Methyl (1S,4aR,8aR)-2,2-Ethylenedioxy-5,5,8a-trimethyldecahyd-
51.0, 62.2, 64.0, 65.5, 70.8, 83.0, 109.3, 127.2, 127.4, 128.2, 139.3,
171.4 ppm. C24H34O5 (402.5): calcd. C 71.61, H 8.51; found C
71.63, H 8.79.
ronaphthalene-1-carboxylate (9): A suspension of Pd on carbon
(10%, 0.6 g) in a solution of 8 (5.9 g, 20 mmol) in EtOAc (120 mL)
was stirred under H2 at room temperature for 19 h. The mixture
was filtered, and the filtrate was concentrated in vacuo to give
Methyl (1S,4aS,6S,8aR)-2,2-Ethylenedioxy-6-hydroxy-5,5,8a-trime-
5.98 g of crude 9 as a colorless solid. It was purified by silica gel
thyldecahydronaphthalene-1-carboxylate (7): A suspension of Pd on
chromatography (200 g, EtOAc/n-hexane, 1:4) to give 9 as a color-
carbon (10%, 1.2 g) in a solution of 6 (12 g, 30 mmol) in EtOAc
less solid (5.95 g, quant.), which was recrystallized from EtOAc/
(100 mL) was stirred under H2 at room temperature for 11 h. The
n-hexane to give an analytical sample as colorless needles. M.p.
mixture was filtered and the filtrate was concentrated in vacuo to
151.0Ϫ152.0 °C. [α]2D4 ϭ Ϫ30.4 (c ϭ 0.99, CHCl3). IR (KBr):
give 11.4 g of crude 7 as a colorless solid. It was recrystallized to
ν˜max ϭ 1735 cmϪ1 (s, CϭO), 1195 (m, CϪOϪC), 1145 (s,
give a first crop of 7 (4.9 g) as colorless needles. The mother liquor
1
CϪOϪC), 1120 (m, CϪOϪC). H NMR (300 MHz, CDCl3): δ ϭ
was concentrated and was purified by silica gel chromatography
0.85 (s, 3 H, CH3), 0.88 (s, 3 H, CH3), 0.92 (dd, J ϭ 11.4 Hz,
(300 g, EtOAc/n-hexane, 1:2) to give further 7 (2.5 g) as a colorless
2.4 Hz, 1 H), 1.10Ϫ1.25 (m, 2 H), 1.23 (s, 3 H, CH3), 1.30Ϫ1.72
solid. The total amount of 7 was 7.4 g (80%). M.p. 162.0Ϫ163.0
(m, 7 H), 1.86 (dt, J ϭ 12 Hz, 2.4 Hz, 1 H), 2.51 (s, 1 H,
°C (EtOAc/n-hexane). [α]2D4 ϭ Ϫ14.0 (c ϭ 1.00, CHCl3). IR (KBr):
CHCO2CH3), 3.634, 3.637 [each (s), total 3 H, CO2CH3], 3.74 (dd,
ν˜max ϭ 3430 cmϪ1 (s, OH), 1735 (s, CϭO), 1195 (m, CϪOϪC),
J ϭ 12.6 Hz, 6.3 Hz, 1 H, OCH2CH2O), 3.85 (dd, J ϭ 12.6 Hz,
1155 (m, CϪOϪC), 1125 (m, CϪOϪC). 1H NMR (400 MHz,
6.3 Hz, 1 H, OCH2CH2O), 3.94 (dd, J ϭ 12.6 Hz, 6.3 Hz, 1 H,
CDCl3): δ ϭ 0.87 (s, 3 H, 5-CH3), 0.97 (s, 3 H, 5-CH3), 1.11 (dt,
OCH2CH2O), 4.08 (dd, J ϭ 12.6 Hz, 6.3 Hz, 1 H, OCH2CH2O)
J ϭ 13.2 Hz, 3.1 Hz, 1 H), 1.24 (s, 3 H, 8a-CH3), 1.40Ϫ1.50 (m, 2
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 14.7, 18.4, 20.0, 21.5, 33.2,
H), 1.52Ϫ1.65 (m, 3 H), 1.71 (dt, J ϭ 13.4 Hz, 3.4 Hz, 1 H), 1.86
33.6, 37.6, 39.1, 39.7, 41.9, 51.0, 54.7, 62.7, 63.9, 65.5, 109.2, 171.3
(dt, J ϭ 12.9 Hz, 2.9 Hz,1 H), 1.98 (dddd, 14.4 Hz, 14.4 Hz, 3.4 Hz,
ppm. C17H28O4 (296.4): calcd. C 68.89, H 9.52; found C 68.93,
3.4 Hz, 1 H, 7eqϪH), 2.60 (s, 1 H, CHCO2CH3), 3.44 (seemingly
H 9.71.
s, 1 H, CHOH), 3.63 (s, 3 H, CO2CH3), 3.74 (dd, J ϭ 13.4 Hz,
Methyl (1S,4aR,8aR)-5,5,8a-Trimethyl-2-oxodecahydronaphthalene-
1-carboxylate (10): A solution of 9 (3.0 g, 10 mmol) in THF
(30 mL) and HCl (6 , 10 mL) was stirred at room temperature
for 24 h. The mixture was poured into saturated aqueous sodium
hydrogen carbonate solution (100 mL) and extracted with EtOAc
(3 ϫ 100 mL). The combined organic phases were washed with
brine (100 mL), dried with sodium sulfate, and concentrated in va-
cuo to give 2.62 g of the crude product as colorless granules. It was
recrystallized from Et2O/n-hexane to give a first crop of 10 (1.13 g).
6.3 Hz, 1 H, OCH2CH2O), 3.87 (dd, J ϭ 13.4 Hz, 6.3 Hz, 1 H,
OCH2CH2O), 3.93 (dd, J ϭ 13.4 Hz, 6.3 Hz, 1 H, OCH2CH2O),
4.08 (dd, J ϭ 13.4 Hz, 6.3 Hz, 1 H, OCH2CH2O) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 14.5, 19.6, 22.0, 25.1, 28.4, 32.4, 37.4, 37.6,
38.8, 47.5, 51.0, 62.3, 64.0, 65.6, 75.7, 109.2, 171.3 ppm. C17H28O5
(312.4): calcd. C 65.36, H 9.03; found C 65.43, H 9.17.
Methyl (1S,4aS,8aR)-2,2-Ethylenedioxy-5,5,8a-trimethyl-1,2,3,4,4a,
5,8,8a-octahydronaphthalene-1-carboxylate (8): Trifluoromethane-
sulfonyl chloride (0.23 mL, 2.15 mmol) was added at 0 °C under The mother liquor was concentrated and was purified by silica gel
argon to a stirred solution of 7 (268 mg, 0.86 mmol) and DMAP chromatography (200 g, EtOAc/n-hexane, 1:50 to 1:30 to 1:6) to
(630 mg, 5.15 mmol) in CH2Cl2 (15 mL). The resulting mixture was
stirred at room temperature for 2 h, and diluted with Et2O
(100 mL). The diethyl ether solution was washed with water
(150 mL), 10% aqueous citric acid solution, saturated aqueous so-
dium hydrogen carbonate solution, and brine (each 1 ϫ 20 mL),
give further 10 (1.17 g) as a colorless solid. The total amount of 10
was 2.30 g (91%). M.p. 104.6Ϫ105.1 °C (Et2O/n-hexane). [α]2D4
ϭ
ϩ57.3 (c ϭ 1.01, CHCl3). IR (KBr): ν˜max ϭ 1745 cmϪ1 (s, CϭO),
1700 (s, CϭO). 1H NMR (300 MHz, CDCl3): δ ϭ 0.89 (s, 3 H,
CH3), 0.97 (s, 3 H, CH3), 1.15 (s, 3 H, CH3), 1.20Ϫ1.32 (m, 2 H),
and dried with magnesium sulfate. The combined aqueous phase 1.40Ϫ1.75 (m, 5 H), 1.79 (dd, J ϭ 12.9 Hz, 5.4 Hz, 1 H), 1.98Ϫ2.09
was reextracted with EtOAc (2 ϫ 50 mL). The organic phase was
dried with magnesium sulfate. All of the organic phase was com-
bined, filtered and concentrated in vacuo to give 330 mg of a crude
solid. This was purified by silica gel chromatography (twice: 40 g,
EtOAc/n-hexane, 1:4; 40 g, Et2O/n-hexane, 1:20 to 1:12 to 1:8) to
give 8 (227 mg, 90%) as a colorless solid, which was recrystallized
(m, 1 H), 2.33 (dt, J ϭ 14.5 Hz, 7.6 Hz, 1 H), 2.51 (ddd, J ϭ
14.6 Hz, 5.4 Hz, 1.8 Hz, 1 H), 3.21 (s, 1 H, CHCO2CH3), 3.67 (s,
3 H, CO2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 14.7, 18.5,
21.6, 22.9, 33.4, 33.5, 39.1, 41.2, 41.8, 41.9, 51.3, 53.1, 69.9, 168.6,
205.4 ppm. C15H24O3 (252.3): calcd. C 71.39, H 9.59; found C
71.02, H 9.39.
Eur. J. Org. Chem. 2003, 848Ϫ854
851

Y. Tanada, K. Mori
FULL PAPER
Methyl
(4aR,8aR)-2-Diethoxyphosphoryloxy-5,5,8a-trimethyl-
concentrated in vacuo. The residue was purified by silica gel chro-
3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylate (13): A sus-
matography (200 g, EtOAc/n-hexane, 1:10, then 1:1 as eluents) to
pension of sodium hydride in mineral oil (60%, 340 mg, 8.5 mmol) give 15 as colorless rods (0.97 g, 95%). This was recrystallized from
was rinsed twice with 2-mL portions of dry n-hexane to remove the
mineral oil. Dry THF (10 mL) was added, and a solution of 10 in
dry THF (25 mL) was added dropwise, at 0 °C under argon, to the
resulting suspension. The resulting mixture was heated at reflux for
1 h, and diethyl chlorophosphate (1.35 g, 7.8 mmol) was added at
0 °C. After the mixture had been stirred at room temperature for
1 h, additional sodium hydride (90 mg, 2.3 mmol) and diethyl chlo-
n-pentane to give an analytical sample as colorless needles. M.p.
119.0Ϫ120.1 °C. [α]2D4 ϭ Ϫ115 (c ϭ 0.13, CHCl3). IR (KBr): ν˜max ϭ
3360 cmϪ1 (s, OH), 1660 (w, CϭC), 1000 (s, CϭC), 985 (s, CϭC).
1H NMR (300 MHz, CDCl3): δ ϭ 0.84 (s, 3 H, 5-CH3), 0.89 (s, 3
H, 5-CH3), 0.96 (s, 3 H, 8a-CH3), 1.05Ϫ1.68 (m, 8 H), 1.72(s, 3 H,
2-CH3), 1.89 (br. d, J ϭ 12.4 Hz, 1 H, 4a-H), 1.97Ϫ2.15 (m, 2 H,
3-H), 4.04 (d, J ϭ 11.5 Hz, 1 H, CH2OH), 4.19 (d, J ϭ 11.5 Hz, 1
rophosphate (390 mg, 2.3 mmol) were added. The mixture was H, CH2OH) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 18.8, 18.9,
stirred for 1 h at room temperature, poured into water (100 mL),
and extracted with Et2O (2 ϫ150 mL). The combined organic ex-
tracts were washed with brine (1 ϫ 100 mL), dried with sodium
sulfate, and concentrated in vacuo to give 3.0 g of the crude prod-
uct as a pale yellow oil. The crude product was purified by silica
gel chromatography (150 g, EtOAc/n-hexane, 1:2 and then 1:1 as
eluents) to give 13 (2.47 g, 89%) as a pale yellow oil. n2D8 ϭ1.4821.
[α]2D4 ϭ Ϫ62.7 (c ϭ 1.09, CHCl3). IR (film): ν˜max ϭ 1730 cmϪ1 (s,
19.3, 20.7, 21.6, 33.2, 33.7, 36.8, 38.0, 41.6, 51.7, 58.3, 132.4, 141.0
ppm. C15H26O (222.4): calcd. C 81.02, H 11.79; found C 80.92,
H 11.64.
(4aR,8aR)-8-Benzenesulfonylmethyl-4,4,7,8a-tetramethyl-
1,2,3,4,4a,7,8,8a-octahydronaphthalene
(17):
Methanesulfonyl
chloride (1.46 mL, 18.9 mmol) was added dropwise under argon at
0 °C to a stirred solution of 15 (2.10 g, 9.44 mmol), collidine
(2.5 mL, 18.9 mmol), and LiCl (800 mg, 18.9 mmol) in DMF
(21 mL). After stirring at 5 °C for 46 h, the mixture was diluted
with Et2O (100 mL), and washed with water (100 mL). The aque-
ous phase was reextracted with additional Et2O (100 mL). The
combined organic extracts were washed with saturated aqueous so-
dium carbonate solution and brine (each 1ϫ 100 mL), dried with
magnesium sulfate, filtered, and concentrated to give 2.56 g of
crude 16 as an orange oil, which was used in the next step without
further purification. Sodium phenylsulfinate (5.66 g, 28 mmol) was
added under argon at room temperature to a stirred solution of
crude 16 (2.56 g) in DMF (20 mL). The mixture was stirred at room
temperature for 48 h, poured into water (100 mL), and extracted
1
CϭO), 1680 (w, CϭC), 1275 (s, PϭO), 1030 (s, CϪO). H NMR
(300 MHz, CDCl3): δ ϭ 0.84 (s, 3 H, 5-CH3), 0.90 (s, 3 H, 5-CH3),
1.17Ϫ1.27 (m, 2 H), 1.29 (s, 3 H, 8-CH3), 1.29Ϫ1.38 (m, 7 H,
CH3CH2O, CH2), 1.38Ϫ1.87 (m, 6 H), 2.36Ϫ2.61 (m, 2 H, 3-H),
3.72 (s, 3 H, CO2CH3), 4.04Ϫ4.21 (m, 4 H, CH3CH2O) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ15.9, 16.0, 18.3, 18.5, 20.60, 20.63,
21.3, 28.2, 33.0, 36.4, 37.0, 41.4, 50.0, 51.3, 64.20, 64.25, 64.29,
64.3, 128.7, 128.8, 146.2, 146.3, 167.6 ppm. C19H33O6P (388.4):
calcd. C 58.75, H 8.56; found C 58.36, H 8.58.
Methyl (4aR,8aR)-2,5,5,8a-Tetramethyl-3,4,4a,5,6,7,8,8a-octahyd-
ronaphthalene-1-carboxylate (14): A solution of methyllithium (1.10
 in Et2O, 67 mL, 74 mmol) was added dropwise at Ϫ65 °C under with Et2O (3 ϫ 100 mL). The combined organic extracts were
argon to a stirred suspension of dry CuI (7.0 g, 37 mmol) in dry
Et2O (150 mL), and the mixture was stirred at Ϫ20 °C for 1 h. A
solution of 13 (2.27 g, 6.10 mmol) in dry Et2O (50 mL) was then
added dropwise at Ϫ65 °C to the cooled mixture. The mixture was
stirred at Ϫ10 °C for 6 h and then poured into a saturated ammo-
nium chloride solution (100 mL), insoluble material was filtered
off, and the filtrate was extracted with Et2O (2 ϫ 200 mL). The
combined organic extracts were washed with a saturated aqueous
sodium hydrogen carbonate solution and brine (each 1 ϫ 200 mL),
dried with magnesium sulfate, and concentrated in vacuo to give
1.54 g of a crude yellow oil. This was purified by silica gel chroma-
washed with saturated aqueous sodium carbonate solution and
brine (each 1ϫ 100 mL), dried with sodium sulfate, filtered, and
concentrated in vacuo to give 5.88 g of an yellow oil. This was
purified by silica gel chromatography (300 g, EtOAc/n-hexane, 1:15
as an eluent) to give 17 (2.3 g, 70% in two steps from 15) as color-
less rods. M.p. 97.5Ϫ98.1 °C (Et2O/n-hexane). [α]2D4 ϭ Ϫ75.0 (c ϭ
1.03, CHCl3). IR (KBr): ν˜max ϭ 1585 cmϪ1 (w), 1305 (s), 1145 (s),
1
1085 (m), 725 (s). H NMR (300 MHz, CDCl3): δ ϭ 0.84 (s, 3 H,
4-CH3), 0.89 (s, 3 H, 4-CH3), 1.02 (s, 3 H, 8a-CH3), 1.05Ϫ1.25 (m,
2 H), 1.25Ϫ1.60 (m, 5 H), 1.64 (s, 3 H, 7-CH3), 1.65Ϫ1.75 (m, 2
H), 2.05Ϫ2.20 (m, 2 H), 3.85 (d, J ϭ 14.4 Hz, 1 H, PhSO2CH2),
tography (150 g, EtOAc/n-hexane, 1:10) to give 14 (1.32 g, 87%) as 4.00 (d, J ϭ 14.4 Hz, 1 H, PhSO2CH2), 7.70Ϫ7.60 (m, 3 H, Ph-H),
colorless oil. n2D8 ϭ1.4985. [α]2D4 ϭ Ϫ94.8 (c ϭ 1.07, CHCl3). IR
7.93 (dd, J ϭ 7.4 Hz, 1.4 Hz, 2 H, Ph-H) ppm. 13C NMR (75 MHz,
(film): ν˜max ϭ 1715 cmϪ1 (s, CϭO), 1660 (w, CϭC), 1265 (s, CϪO), CDCl3): δ ϭ18.2, 18.7, 19.0, 20.5, 20.7, 21.5, 21.7, 33.2, 33.4, 33.7,
1
1200 (s, CϪO), 1070 (s, CϪO). H NMR (300 MHz, CDCl3): δ ϭ 37.5, 37.9, 41.5, 50.8, 56.9, 127.8, 129.2, 129.5, 133.2, 138.1, 141.7
0.86 (s, 3 H, 5-CH3), 0.90 (s, 3 H, 5-CH3), 1.15Ϫ1.35 (m, 3 H), ppm. C21H30O2S (346.5): calcd. C 72.79, H 8.73; found C 72.50,
1.21 (s, 3 H, 8a-CH3), 1.40Ϫ1.65 (m, 5 H), 1.63 (s, 3 H, 2-CH3), H 8.48.
1.65Ϫ1.75 (m, 1 H), 2.10 (dd, J ϭ 8.8 Hz, 4.4 Hz, 2 H, 3-H), 3.72
(s, 3 H, CO2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ18.5,
18.7, 20.4, 20.8, 21.4, 32.1, 33.1, 36.7, 36.9, 41.7, 50.4, 51.0, 132.4,
138.6, 170.9 ppm. C16H26O2 (250.4) calcd. C 76.75, H 10.47; found
C 76.46, H 10.21.
Benzyl 3-(3Ј-Methyl-2Ј-butenyl)-4-benzyloxybenzoate (19): 3-
Methyl-2-butenyl bromide (32 g, 203 mmol) was added dropwise at
room temperature to a stirred solution of p-hydroxybenzoic acid
(28 g, 203 mmol) in aqueous NaOH solution (16 g in 364 mL
water). The mixture was stirred at room temperature for 24 h, co-
[(4aR,8aR)-2,5,5,8a-Tetramethyl-3,4,4a,5,6,7,8,8a-octahydro- oled to 0 °C, acidified with conc. HCl (35 mL), and extracted with
naphthalen-1-yl]methanol (15): A solution of DIBAL in n-hexane
(0.95 , 12.6 mL, 12 mmol) was added dropwise under argon at
EtOAc (3 ϫ 250 mL). The combined extracts were washed with
brine, dried with sodium sulfate, filtered, and concentrated in va-
Ϫ65 °C to a cooled and stirred solution of 14 (1.2 g, 4.6 mmol) in cuo. The residue was used for the next step without further puri-
CH2Cl2 (24 mL). After stirring at Ϫ65 °C for 2 h, the mixture was
quenched by addition of an aqueous solution (100 mL) of potas-
sium sodium tartrate (6.4 g). The mixture was extracted with
EtOAc (2 ϫ 150 mL). The combined organic extracts were washed
with brine (1 ϫ 150 mL), dried with sodium sulfate, filtered, and
fication. Benzyl bromide (72 g, 406 mmol) was added portionwise
to a suspension of the crude alkylation product and K2CO3 (56 g,
406 mmol) in DMF (200 mL). The resulting mixture was stirred at
room temperature for 15 h, poured into a mixture of water
(300 mL) and Et2O (300 mL), and filtered. The organic phase of
852
Eur. J. Org. Chem. 2003, 848Ϫ854

Synthesis and Absolute Configuration of (Ϫ)-Subersic Acid
the filtrate was separated, washed with 5% HCl and brine (each extracted with Et2O (2 ϫ 200 mL). The combined organic phases
FULL PAPER
50 mL), dried with magnesium sulfate, filtered, and concentrated
in vacuo to give a gummy solid. This was rinsed with Et2O/n-hex-
ane and filtered. The filtrate was concentrated to give purer reac-
tion product as a gummy solid. This was rinsed with Et2O/n-hexane
and filtered again. The filtrate was concentrated to give further,
purer product (30 g) as an yellow oil. This was purified by silica
gel chromatography (twice; 1.2 kg, EtOAc/n-hexane, 1:50 to 1:25
then 1.0 kg, EtOAc/n-hexane, 1:60 to 1:25) to give 7.5 g (9.5%) of
were washed with brine (3 ϫ 100 mL), dried with magnesium sulf-
ate, filtered, and concentrated in vacuo to give 2.22 g of a crude
product. This was purified by silica gel chromatography (150 g,
EtOAc/n-hexane, 1:2) to give 1.50 g (87% in two steps) of 21 as a
pale yellow gum. This solidified and was recrystallized from
EtOAc/n-hexane to give an analytical sample as colorless needles.
M.p. 60.0Ϫ61.0 °C. IR (KBr): ν˜max ϭ 1710 cmϪ1 (s, CϭO), 1605
(s, CϭC), 1500 (s, CϭC), 1260 (s, CϪOϪC), 1120 (s, CϪOϪC).
19 as a pale yellow oil. n2D4 ϭ1.5171. IR (film): ν˜max ϭ 1715 cmϪ1 1H NMR (300 MHz, CDCl3): δ ϭ 1.79 (s, 3 H, CH3), 3.42 (d, 2
(s, CϭO), 1605 (s, CϭC), 1500 (s, CϭC), 1455 (s, CϭC), 1260 (s, H, J ϭ 7.2 Hz, CHCH2Ar), 3.97 (s, 2 H, BrCH2), 5.13 (s, 2 H,
1
CϪOϪC), 1025 (m, CϪOϪC). H NMR (500 MHz, CDCl3): δ ϭ PhCH2), 5.33 (s, 2 H, PhCH2), 5.75 (t, J ϭ 7.2 Hz, 1 H,
1.65 (s, 3 H, CH3), 1.73 (s, 3 H, CH3), 3.38 (d, 2 H, J ϭ 7.4 Hz, CHCH2Ar), 6.91 (d, 1 H, J ϭ 8.4 Hz, Ph-H), 7.30Ϫ7.46 (m, 10 H,
CHCH2Ar), 5.14 (s, 2 H, PhCH2), 5.30 (t, J ϭ 7.4 Hz, 1 H,
CHCH2Ar), 5.33 (s, 2 H, ArCH2), 6.89 (d, 1 H, J ϭ 8.2 Hz, Ph-
Ph-H), 7.86(d, 1 H, J ϭ 1.8 Hz, Ph-H), 7.93 (dd, 1 H, J ϭ 8.4 Hz,
1.8 Hz, Ph-H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 14.8, 29.2,
H), 7.31Ϫ7.46 (m, 10 H, Ph-H), 7.89 (d, 1 H, J ϭ 2.3 Hz, Ph-H), 41.4, 66.4. 70.1, 110.9, 122.4, 127.3, 128.11, 128.13, 128.55, 128.60,
7.90 (dd, 1 H, J ϭ 8.2 Hz, 2.3 Hz, Ph-H) ppm. 13C NMR
128.64, 128.81, 130.0, 131.2, 133.2, 136.3, 160.3, 166.2 ppm.
(100 MHz, CDCl3): δ ϭ 17.8, 25.8, 28.7, 66.2, 69.9, 110.7, 121.7, C26H25BrO4 (465.4): calcd. C 67.10, H 5.41; found C 67.14, H 5.57.
122.2, 127.1, 127.9, 128.0, 128.4, 128.5, 129.4, 130.4, 131.1, 133.0,
136.4, 136.5, 160.2, 166.4 ppm. C26H26O3 (386.5): calcd. C 80.80,
H 6.78; found C 80.84, H 7.05.
4-Benzyloxy-3-{(2ЈE)-3Ј-methyl-5Ј-[(4a"R,8a"R)-2",5",5",8a"-
tetramethyl-3",4",4a",5",6",7",8",8a"-octahydronaphthyl]-2Ј-
pentenyl}benzoic Acid (23): nBuLi (1.59  in n-hexane, 2.5 mL,
3.95 mmol) was added dropwise at Ϫ65 °C to a stirred solution of
17 (920 mg, 2.65 mmol) and HMPA (4.5 mL, 26 mmol) in dry THF
(20 mL). After the mixture had been stirred for 0.5 h at Ϫ65 °C, a
solution of 21 (1.5 g, 3.2 mmol) in THF (20 mL) was added drop-
wise by cannula. The mixture was stirred for 2.5 h at Ϫ65 °C,
quenched with aqueous saturated NH4Cl solution (50 mL), allowed
to warm to room temperature, further stirred for 0.5 h, and ex-
tracted with EtOAc (2 ϫ 80 mL). The combined organic extracts
were washed with aqueous saturated NaHCO3 and brine (each 1
ϫ 80 mL), dried with sodium sulfate, filtered, and concentrated in
vacuo. The residue was purified by silica gel chromatography
(200 g, EtOAc/n-hexane, 1:8 as eluent) to give 1.71 g of 22 as a
colorless, amorphous solid, which was used in the next step without
further characterization.: HRMS (FABϩ): calcd. [M ϩ H]ϩ
(C47H55O5S) 731.3770, found 731.3787 (error ϩ2.3 ppm/ϩ1.7
mmu). 5% Na/Hg (62 g, 294 mmol) was added portionwise at 0 °C
to a stirred suspension of the solid 22 (1.71 g) and Na2HPO4 (6.7 g,
47 mmol) in THF/MeOH (17 mL/86 mL). The suspension was
stirred at 0 °C for 0.5 h and at room temperature for 16.5 h, and
was then filtered. The residue on the filter was washed with MeOH
(200 mL). All of the filtered organic solution was combined and
concentrated in vacuo. The residue on the filter was washed with
aqueous NaOH solution (25%, 350 mL) and water (350 mL). All
of the filtered aqueous phases was combined with the concentrated
organic phase, stirred for 0.5 h at room temperature, and acidified
with HCl (6 , 400 mL). The resulting solution was extracted with
EtOAc (3 ϫ 250 mL). The combined organic extracts were washed
with brine (2 ϫ 100 mL), dried with sodium sulfate, filtered, and
concentrated in vacuo to give 1.54 g of crude 23 as pale yellow
solid. This was purified by silica gel chromatography (250 g,
EtOAc/n-hexane, 1:4 as an eluent) to give purer 23 (0.86 g). The
obtained solid was recrystallized from EtOAc/n-hexane to give a
first (430 mg) and second crop (38 mg) of pure 23 as fine needles.
The total amount of 23 was 468 mg (35% in two steps). M.p.
136.6Ϫ142.7 °C. [α]2D4 ϭ Ϫ46.1 (c ϭ 1.00, CHCl3). IR (KBr):
ν˜max ϭ 3600Ϫ2700 cmϪ1(s, OH), 1682 (s, CϭO), 1604 (s, CϭC),
Benzyl 3-(3Ј-Hydroxymethyl-2Ј-butenyl)-4-benzyloxybenzoate (20):
A solution of 19 (7.1 g, 20 mmol) in CH2Cl2 (35 mL) was added
dropwise at room temperature over 0.5 h to a stirred suspension of
SeO2 (220 mg, 2.0 mmol) in a solution of tBuO2H (80%, 6.7 mL,
59 mmol) in CH2Cl2 (35 mL). The mixture was stirred at room tem-
perature for 71 h and concentrated in vacuo to a half volume.
Na2SO3 (8.0 g, 63 mmol) and water (100 mL) were added to the
concentrated mixture. The resulting mixture was extracted with
Et2O (2 ϫ150 mL). The combined organic extracts were washed
with aqueous saturated sodium hydrogen carbonate and brine
(each 1 ϫ 150 mL), dried with sodium sulfate, and concentrated in
vacuo to give 7.9 g of a crude yellow oil. This was used in the next
step without further purification. NaBH4 (757 mg, 20 mmol) was
added portionwise at 0 °C to a solution of the crude oil (7.9 g) in
THF/water (35 mL/35 mL), and the mixture was stirred at 0 °C
for an additional 1 h. The mixture was allowed to warm to room
temperature and stirred for an additional 1.5 h, and was then acidi-
fied with 2  HCl and extracted with Et2O (2 ϫ 150 mL). The
combined organic phases were washed with brine (1 ϫ 200 mL),
dried with sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by silica gel chromatography (150 g, EtOAc/n-
hexane, 1:2) to give 3.6 g (45% in two steps) of 20 as a colorless
solid, which was recrystallized from EtOAc/n-hexane to give an
analytical sample as colorless needles. M.p. 64.5Ϫ66.0 °C. IR
(KBr): ν˜max ϭ 3315 cmϪ1 (s, OH), 3230 (s, OH), 1715 (s, CϭO),
1605 (s, CϭC), 1505 (s, CϭC), 1270 (s, CϪOϪC). 1H NMR
(300 MHz, CDCl3): δ ϭ 1.70 (s, 3 H, CH3), 3.43 (d, 2 H, J ϭ
7.2 Hz, CHCH2Ar), 4.01 (s, 2 H, HOCH2), 5.13 (s, 2 H, PhCH2),
5.32 (s, 2 H, PhCH2), 5.57(t, J ϭ 7.2 Hz, 1 H, CHCH2Ar), 6.91 (d,
1 H, J ϭ 8.7 Hz, Ph-H), 7.30Ϫ7.46 (m, 10 H, Ph-H), 7.87 (d, 1 H,
J ϭ 2.1 Hz, Ph-H), 7.92 (dd, 1 H, J ϭ 8.7 Hz, 2.1 Hz, Ph-H) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 13.7, 28.4, 66.3, 68.7, 70.0, 110.8,
122.3, 123.3, 127.2, 128.0, 128.04, 128.07, 128.5, 128.6, 129.7,
131.2, 136.1, 136.3, 136.4, 160.3, 166.3 ppm. C26H26O4 (402.5):
calcd. C 77.59, H 6.51; found C 77.39, H 6.79.
1
Benzyl 3-(3Ј-Bromomethyl-2Ј-butenyl)-4-benzyloxybenzoate (21):
1502 (m), 1237 (s), 1019 (m, CϪO). H NMR (300 MHz, CDCl3):
Methanesulfonic anhydride (2.7 g, 15 mmol) was added in one por- δ ϭ 0.83 (s, 3 H, 5"-CH3), 0.88 (s, 3 H, 5"-CH3), 0.94 (s, 3 H, 8a"-
tion at 0 °C under argon to a suspension of LiBr (1.3 g, 15 mmol) CH3), 1.05Ϫ1.75 (m, 8 H), 1.58 (s, 3 H, 2"-CH3), 1.69 (s, 3 H, 3Ј-
in a solution of 20 (1.5 g, 3.7 mmol), collidine (2.0 mL, 15 mmol), CH3), 1.75Ϫ2.20 (m, 7 H), 3.40 (d, J ϭ 7.2 Hz, 2 H, CHCH2Ar),
and DMAP (50 mg) in DMF (15 mL). After stirring at 0 °C under
argon for 24 h, the mixture was diluted with water (100 mL), and
5.17 (s, 2 H, OCH2Bn), 5.34 (t, J ϭ 7.2 Hz, 1 H, CHCH2Ar), 6.93
(d, J ϭ 8.6 Hz, 1 H, 5-H), 7.33Ϫ7.44 (m, 5 H, Ph-H), 7.92 (br. s,
Eur. J. Org. Chem. 2003, 848Ϫ854
853

Y. Tanada, K. Mori
FULL PAPER
1 H, 2-H), 7.93 (dd, J ϭ 8.6 Hz, 2.2 Hz, 1 H, 6-H) ppm. 13C NMR H, 3Ј-H, 5"-H, 4"-H), 3.41 (d, J ϭ 7.0 Hz, 2 H, 1Ј-H), 5.34 (t, J ϭ
(75 MHz, CDCl3): δ ϭ16.2, 19.1, 19.5, 20.1, 21.7, 27.2, 28.7, 33.3, 7.0 Hz, 1 H, 2Ј-H), 6.85 (d, J ϭ 9.0 Hz, 1 H, 5-H), 7.89 (dd, J ϭ
33.7, 37.0, 39.1, 40.5, 41.9, 51.9, 70.0, 110.8, 120.9, 121.4, 125.8,
127.2, 128.0, 128.6, 130.2, 130.7, 131.7, 136.5, 137.8, 140.5, 160.9,
171.3 ppm. C34H44O3 (500.7): calcd. C 81.56, H 8.86; found C
81.28, H 8.87.
9.0 Hz, 2 Hz, 1 H, 6-H), 7.90 (s, 1 H, 2-H) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 16.4 (3Ј-CH3), 19.1 (C-4"), 19.1 (C-7"),
19.6 (2"-CH3), 20.1 (8a"-CH3), 21.7 (5"-CH3), 27.0 (C-5Ј), 29.6 (C-
1Ј), 33.33 (5"-CH3), 33.34 (C-5"), 33.6 (C-3"), 37.0 (C-8"), 39.0 (C-
8a"), 40.4 (C-4Ј), 41.8 (C-6"), 51.9 (C-4a"), 115.7 (C-5), 120.1 (C-
2Ј), 121.7 (C-1), 126.1 (C-2"), 126.8 (C-3), 130.5 (C-6), 132.6 (C-
2), 140.1 (C-1"), 140.6 (C-3Ј), 159.5 (C-4), 171.6 (1-CO2). HRMS
(FABϪ): calcd. [M Ϫ H]Ϫ (C27H37O3) 409.2743, found 409.2733
(error Ϫ2.5 ppm/Ϫ1.0 mmu). HRMS (FABϩ): calcd. [M ϩ Na]ϩ
(C27H38O3Na) 433.2719, found 433.2718 (error Ϫ0.1 ppm/ϩ0.0
mmu). The spectroscopic data of our synthetic 1 are identical with
those reported for natural 1.[1]
4-Hydroxy-3-{(2ЈE)-3Ј-methyl-5Ј-[(4a"R,8a"R)-2",5",5",8a"-tetra-
methyl-3",4",4a",5",6",7",8",8a"-octahydronaphthyl]-2Ј-pentenyl}-
benzoic Acid (1) [(5R,10R)-(؊)-Subersic Acid]: A freshly prepared
solution of lithium naphthalenide (1  in THF, 1.1 mL, 1.1 mmol)
was added dropwise under argon at Ϫ78 °C to a stirred solution
of 23 (135 mg, 0.27 mmol) in dry THF (2 mL). The mixture was
stirred at Ϫ78 °C for 0.5 h, quenched with saturated NH4Cl (5 mL),
allowed to warm to room temperature with stirring over 0.5 h, and
made alkaline with aqueous NaOH solution (25%, 7.5 mL), and the
aqueous layer was washed with Et2O. The separated aqueous phase
was acidified with HCl (6 ⁾ and extracted with Et2O (2 ϫ 50 mL).
The combined organic phase was washed with brine (2 ϫ 50 mL),
dried with sodium sulfate, filtered, and concentrated in vacuo to
give 145 mg of crude 1 as an yellow oil. This was purified by silica
gel chromatography (twice; 30 g, EtOAc/n-hexane, 1:2.5, then 30 g,
CH2Cl2/MeOH, 1:100 to 1:50 to 1:25 as eluents) to give 103 mg of
purer 1 as a colorless amorphous solid. It was purified again by
silica gel chromatography (70 g, EtOAc/n-hexane, 1:2.5 as an elu-
ent) to give 83 mg (75% from 23, 13% in 8 steps from 10, 6.7% in
13 steps from 5) of 1 as white amorphous foam. [α]2D4 ϭ Ϫ52.2 (c ϭ
0.52, CHCl3). IR (KBr): ν˜max ϭ 3600Ϫ2300 cmϪ1 (br, OH), 1688
(shoulder, CϭO), 1681 (s, CϭO), 1603 (s, CϭC), 1498 (s, CϭC),
1274 (s). 1H NMR (500 MHz, CDCl3): δ ϭ 0.83 (s, 3 H, 5a"-CH3),
0.88 (s, 3 H, 5a"-CH3), 0.94 (s, 3 H, 8a"-CH3), 1.14Ϫ1.20 (m, 3 H,
8"-H, 6"-H, 4a"-H), 1.35Ϫ1.52 (m, 3 H, 6"-H, 7" -H, 4"-H),
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Received October 8, 2002
[O02549]
1.53Ϫ1.67 (m,
2 H, 4"-H, 7"-H), 1.58 (s, 3 H, 2"-CH3),
1.75Ϫ1.84(m, 1 H, 8"-H), 1.83 (s, 3 H, 3Ј-CH3), 1.88Ϫ2.17 (m, 6
854
Eur. J. Org. Chem. 2003, 848Ϫ854