A direct and efficient stereocontrolled synthetic route to the pseudopterosins, potent marine antiinflammatory agents

Article abstract of DOI:10.1021/ja983041s

Described herein is a new synthetic route to pseudopterosin aglycone (3), a key intermediate for the synthesis of a group of antiinflammatory natural products including pseudopterosin A (1) and E (2). The pathway of synthesis starts with the abundant and inexpensive (S)-(-)-limonene and its long-known cyclic hydroboration product (4) and leads to the chiral hydroxy ketone 6. Conversion of 6 to 10 followed by a novel aromatic annulation produced 15 which underwent a highly diastereoselective cyclization to afford the protected pseudopterosin aglycone 16. The naturally occurring pseudopterosins such as 1 and 2 are readily available from this key intermediate.

Full text of DOI:10.1021/ja983041s

J. Am. Chem. Soc. 1998, 120, 12777-12782
12777
A Direct and Efficient Stereocontrolled Synthetic Route to the
Pseudopterosins, Potent Marine Antiinflammatory Agents
E. J. Corey* and Scott E. Lazerwith
Contribution from the Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts, 02138
ReceiVed August 24, 1998
Abstract: Described herein is a new synthetic route to pseudopterosin aglycone (3), a key intermediate for the
synthesis of a group of antiinflammatory natural products including pseudopterosin A (1) and E (2). The
pathway of synthesis starts with the abundant and inexpensive (S)-(-)-limonene and its long-known cyclic
hydroboration product (4) and leads to the chiral hydroxy ketone 6. Conversion of 6 to 10 followed by a novel
aromatic annulation produced 15 which underwent a highly diastereoselective cyclization to afford the protected
pseudopterosin aglycone 16. The naturally occurring pseudopterosins such as 1 and 2 are readily available
from this key intermediate.
The pseudopterosins, produced by the Caribbean sea whip
Pseudopteragorgia elisabethae and exemplified by pseudoptero-
sins A (1) and E (2),1 are remarkably active antiinflammatory
of laboratories have described studies on the total synthesis of
pseudopterosins. The earliest syntheses were developed by C.
A. Broka and co-workers5 and in these laboratories,6 including
the first stereocontrolled enantioselective syntheses of 1 and 2
from either (+)-menthol6a or (S)-citronellal.6b Subsequently, a
variety of additional synthetic approaches have been developed
by other groups.7-10 Although the more recent syntheses involve
fascinating and elegant design, they appear to fall short of
practicality. Described herein is a new process for the synthesis
of pseudopterosins which has a number of advantages including
(1) an inexpensive chiral starting material (limonene), (2) the
use of common or readily available reagents, (3) stereocontrol,
(4) simplicity of execution, (5) good yields, and (6) directness.
In addition, this synthesis illustrates a number of new and
potentially widely useful synthetic methods and noteworthy
aspects of stereocontrol and site selectivity.
The starting material for the present synthesis of pseudoptero-
sins was diol mixture 4 which can be obtained in nearly
quantitative yield from (S)-(-)-limonene by cyclic hydroboration
and alkaline peroxide oxidation.11 Although this mixture of diols
(nearly 1:1) is readily available in quantity, it has neither been
separated nor been used as starting material in a stereocontrolled
synthesis, to the best of our knowledge. Neither chromatographic
nor distillation methods allow separation. Nonetheless, we found
agents2 which were discovered by W. Fenical and collaborators.
The analgesic activity of 1 (administered subcutaneously) is
severalfold greater than that of indomethacin,2 and that of 2 is
some 50 times greater.3 This potency and the fact that the
biological mode of action of 1 and 2 appears to be novel2 have
made these substances (and their analogues) attractive targets
for synthetic and for biological/biochemical research. Further
interest in the pseudopterosins derives from their commercial
use as topical antiinflammatory agents in the cosmetic field and
the limited supply available from natural sources.4 A number
(4) Rouhi, A. M. Chem. Eng. News 1995, November 20, 42-44.
(5) Broka, C. A.; Chan, S.; Peterson, B. J. Org. Chem. 1988, 53, 1584-
1586.
(6) (a) Corey, E. J.; Carpino, P. J. Am. Chem. Soc. 1989, 111, 5472-
5474. (b) Corey, E. J.; Carpino, P. Tetrahedron Lett. 1990, 31, 3857-
3858.
(7) (a) McCombie, S. W.; Cox, B.; Lin, S.-I.; Ganguly, A. K.; McPhail,
A. T. Tetrahedron Lett. 1991, 32, 2083-2086. (b) McCombie, S. W.; Ortiz,
C.; Cox, B.; Ganguly, A. K. Synlett 1993, 541-547.
(8) (a) Buszek, K. R. Tetrahedron Lett. 1995, 36, 9125-9128. (b) Buszek,
K. R.; Bixby, D. L. Tetrahedron Lett. 1995, 36, 9129-9132.
(9) Gill, S.; Kocienski, P.; Kohler, A.; Pontiroli, A.; Qun, L. J. Chem.
Soc., Chem. Commun. 1996, 1743-1744.
(10) (a) Majdalani, A.; Schmalz, H.-G. Tetrahedron Lett. 1997, 38,
4545-4548. (b) Majdalani, A.; Schmalz, H.-G. Synlett. 1997, 1303-1305.
(c) Kato, N.; Zhang, C.-S.; Matsui, T.; Iwabachi, H.; Mori, A.; Ballio, A.;
Sassa, T. J. Chem. Soc., Perkin Trans. 1 1998, 2475.
(11) (a) Brown, H. C.; Pfaffenberger, C. D. J. Am. Chem. Soc. 1967,
89, 5475-5477. (b) Brown, H. C.; Negishi, E.-i. Tetrahedron 1977, 33,
2331-2357.
(1) (a) Look, S. A.; Fenical, W.; Matsumoto, G.; Clardy, J. J. Org. Chem.
1986, 51, 5140-5145. (b) Fenical, W. J. Nat. Prod. 1987, 50, 1001-1008.
(c) Look, S. A.; Fenical, W. Tetrahedron 1987, 43, 3363-3370.
(2) Look, S. A.; Fenical, W.; Jacobs, R. S.; Clardy, J. Proc. Natl. Acad.
Sci. U.S.A. 1986, 83, 6238-6240.
(3) Personal communication from Professor William Fenical whom we
thank for this information and for generously providing samples of naturally
derived pseudopterosins A and E.
10.1021/ja983041s CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/17/1998

12778 J. Am. Chem. Soc., Vol. 120, No. 49, 1998
Corey and Lazerwith
Chart 1
that the diastereomeric mixture could be utilized for synthesis
using the novel separation process outlined in Chart 1. A 54:46
C(8) diastereomeric mixture of diols (4) underwent selective
oxidation at C(2) upon exposure to 1.5 equiv of sodium
hypochlorite12 in aqueous acetic acid to form the diastereomeric
mixture of hydroxy ketones 5 in excellent yield. Exposure of
this mixture to isopropenyl acetate in isopropyl ether at 23 °C
using Amano PS lipase as the catalyst resulted in selective
acetylation of the (8S)-hydroxy ketone after 17 h. Flash
chromatography of the resulting mixture on silica gel afforded
the desired (8R)-alcohol 6 (36% based on 5) as an oil (ratio
8R/8S ) 99:1 as determined by HPLC analysis of the corre-
sponding p-nitrobenzoate ester) and the acetate of the (8S)-
diastereomer of 6. Oxidation of 6 in a CH2Cl2-H2O system
with sodium hypochlorite and 2,2,6,6-tetramethyl-1-piperidi-
nyloxy radical (TEMPO) as catalyst13 at pH 8 gave keto
aldehyde 7 in 92% yield. Wittig-Vedejs E-selective olefination14a
of 7 using the ylide 814b as reagent in dimethoxyethane produced
the E-diene 9 in excellent yield, as shown in Chart 1, without
the loss of stereochemical integrity at the labile C(8) position.
With the successful establishment of three of the four
stereocenters of pseudopterosin aglycone (3), the next task called
for in our strategic plan was the attachment of the aromatic ring,
i.e., the conversion 9 f 14 in Chart 1. This was accomplished
using a new aromatic annulation protocol starting with Mu-
kaiyama-type Michael coupling of the enol silyl ether 10 and
the functionalized R,â-enone 11.15,16 This coupling product was
obtained in 74% yield (correcting for a small amount of
recovered 9) using 1.1 equiv of SnCl4 as the catalyst in CH2Cl2
at -78 °C for 40 min. Treatment of 12 with ethanolic KOH at
0 °C effected aldol cyclization to a â-hydroxy ketone which
was dehydrated by treatment with SOCl2-pyridine at 23 °C
for 1 h to form the R,â-enone 13. The enol tert-butyldimeth-
ylsilyl (TBS) ether of 13 was prepared by deprotonation (alpha
to methyl) and silylation with TBS-triflate, and then the
resulting ether was aromatized by stirring with activated MnO2
(Aldrich Co., Milwaukee) in methylcyclohexane at 70 °C for
36 h to provide the aromatic hydronaphthalene 14 in 90% overall
yield from 13. We discovered that the MnO2-induced aroma-
tization process proceeds more readily and in higher yield with
methylcyclohexane as solvent than in benzene or toluene as
solvent17 and that by using the dry MnO2-methylcyclohexane
system aromatization of a wide range of 1,4- and 1,3-
cyclohexadienes can be effected efficiently. A summary of these
studies is presented below. In contrast to the success achieved
using the MnO2-methylcyclohexane aromatization system, a
number of other oxidants that have previously been recom-
mended for aromatization failed, including (1) Pd-C, (2)
dichlorodicyanoquinone, (3) o-chloranil, (4) 2,6-dichloro-1,4-
benzoquinone, and (5) Cr(CO)3‚3CH3CN, norbornene.18
Desilylation of 14 (Bu4NF in THF) and reaction with CH3-
SO2Cl-Et3N in CH2Cl2 provided the mesylate 15 which upon
treatment with 5 equiv of CH3SO3H in CH2Cl2 at -50 °C
(16) For some examples of Mukaiyama-type Michael Reactions see: (a)
Narasaka, K.; Soai, K.; Aikawa, Y.; Mukaiyama, T. Bull. Chem. Soc. Jpn.
1976, 49, 779-783. (b) Heathcock, C. H.; Norman, M. H.; Uehling, D. E.
J. Am. Chem. Soc. 1985, 107, 2797-2799. (c) Ranu, B. C.; Saha, M.; Bhar,
S. J. Chem. Soc., Perkin Trans. 1 1994, 2197-2199 and references therein.
(17) See (a) Mashraqui, S.; Keehn, P. Synth. Commun. 1982, 12, 637-
645. (b) Sodeoka, M.; Satoh, S.; Shibasaki, M. J. Am. Chem. Soc. 1988,
110, 4823-4824.
(12) Stevens, R. V.; Chapman, K. T.; Stubbs, C. A.; Tam, W. W.;
Albizati, K. F. Tetrahedron Lett. 1982, 23, 4647-4650.
(13) Aneli, P. L.; Banfi, S.; Montanari, F.; Quici, S. J. Org. Chem. 1989,
54, 2970-2972.
(14) (a) Vedejs, E.; Fang, H. W. J. Org. Chem. 1984, 49, 210-212. (b)
Cristau, H.-J.; Ribeill, Y. Synthesis 1988, 911-912.
(15) The R,â-enone 11 was prepared by Swern oxidation of 1-benzyloxy-
3-methylbut-3-ene-2-ol, see: Terao, S.; Shiraishi, M.; Kato, K. Synthesis
1979, 467-468.
(18) Problems with these reagents included desilylation of the starting
material and interfering processes involving the diene appendage.

Synthetic Route to the Pseudopterosins
J. Am. Chem. Soc., Vol. 120, No. 49, 1998 12779
Table 1. Aromatization of Cyclohexadienes by MnO2 at 70 °C in
Methylcyclohexane
Chart 2
underwent highly diastereoselective cationic cyclization (25:1)
to form 16 in very high yield. Reaction of 16 with MeMgBr
produced cleanly the monophenol 17 which was debenzylated
to give pseudopterosin aglycone (3). The various pseudopterosins
may be accessed from 17 or 3 by procedures previously
developed in these laboratories.6 Comparison of synthetic 3
[R]23D -95 (c ) 1, CHCl3) with authentic 36 revealed identical
1
IR, H NMR, 13C NMR, and high-resolution mass spectra.
It is interesting that the methanesulfonic acid cyclization of
TBS ether 14 afforded primarily (8:1) the product 18, corre-
sponding to 16 with the (S)-configuration at C(1) (Chart 2).
This remarkable difference in the stereochemistry of cationic
cyclization of 14 and 15, clearly dependent on the electron-
donating properties of TBSO vs MsO, is most readily explained
as due to a difference in mechanistic pathway, as shown in Chart
2. The pathway from 15 to 16 probably involves direct
6-membered ring closure of allylic cation 19. However, as
shown in Chart 2, the pathway from 14 to 18 can most
reasonably be explained by cyclization of allylic cation 19 to
the 5-membered spiro cation 2019 followed by 1,2-rearrangement
with 5 f 6 ring expansion. Thus, the differences in stereopref-
erences for formation of 16 and 18 reflect stereoelectronic
preferences of the intermediate steps 19 f 16 and 19 f 20.
a Low yield due to volatility of product. b An ) 4-methoxyphenyl.
Experimental Section
(1S, 4S, 8R,S)-Menth-2-one-9-ol (5). A solution of a 54:46 mixture
of C(8) diastereomeric diols 4 (7.225 g, 41.94 mmol) in acetic acid
(70 mL) was treated with aqueous sodium hypochlorite (33.1 mL, 63
mmol) dropwise over 15 min.12 The mixture was stirred at 23 °C for
3 h. Isopropyl alcohol (10 mL) was added, and the mixture was stirred
an additional 10 min. After the mixture was concentrated in vacuo to
remove most of the acetic acid, water was added, and the aqueous
solution was extracted three times with CH2Cl2. The organic layers
were carefully washed with NaHCO3 (saturated aqueous), and the
NaHCO3 was extracted twice with CH2Cl2. The combined organic layers
were dried over MgSO4 and concentrated in vacuo. Flash chromatog-
raphy (CH2Cl2-EtOAc 90:10 f 75:25) afforded 6.11 g (86%) of
hydroxy ketone 5 as a clear oil with a diastereomeric ratio of 54:46
(determined by HPLC analysis of the p-nitrobenzoate ester): Rf ) 0.26
We believe that the synthetic process described herein and
outlined in Chart 1 provides a very direct and practical route
for the synthesis of pseudopterosins in quantity. A number of
the key steps are also of broader interest from the viewpoint of
general synthetic methodology, including (1) the use of an
inexpensive, recoverable lipase to effect separation of the
diastereomers of 5, (2) the new procedure for the aromatic
annulation of 9 f 14, (3) the remarkably stereoselective
cyclizations of 15 f 16 and 14 f 18, and (4) the superiority
of MnO2 as a mild reagent for aromatization of cyclohexadienes.
1
(hexanes-EtOAc, 50:50); H NMR (400 MHz, CDCl3) δ 3.63-3.48
(m, 2H), 2.39-2.34 (m, 2H), 2.19-2.07 (m, 2H), 1.88-1.82 (m, 2H),
1.70-1.20 (m, 4H), 1.01 (d, J ) 6.5 Hz, 3H), 0.93 (m, 3H).
(1S, 4S, 8R)-(+)-Menth-2-one-9-ol (6). The above mixture of keto
alcohols 5 (3.89 g, 22.85 mmol) in isopropyl ether (175 mL) was treated
with Amano PS lipase (1.13 g) followed by isopropenyl acetate (5.0
mL, 45.70 mmol) and stirred at 23 °C. The progress of the reaction
was monitored by NMR analysis of small aliquots. After 17 h, the
reaction mixture was filtered and concentrated. Flash chromatography
(using as eluent hexanes-Et2O 70:30, followed by Et2O) afforded
acetylated product and 1.412 g (36%) of the desired keto alcohol 6 as
an oil of 98% de (determined by HPLC analysis of the p-nitrobenzoate
ester): Rf ) 0.26 (hexanes-EtOAc 50:50); [R]23D +4.0 (c 0.96, CHCl3);
With regard to the usefulness of dry MnO2 in methylcyclo-
hexane as a reagent for the aromatization of cyclohexadienes,
we present additional results that have been obtained with a
diverse collection of substrates, as summarized in Table 1. The
aromatization reactions, which were generally monitored by
thin-layer chromatography, proceed at varying rates as shown
in Table 1. The aromatization of dimethyl trans-1,2-dihydro-
phthalate was found to be considerably faster than that of various
alkyl- or oxy-substituted dihydrobenzenes, an indication that
the first step in the process may be a hydrogen atom rather than
a hydride abstraction.
1
FTIR (film) 3440, 1710 cm-1; H NMR (400 MHz, CDCl3) δ 3.55
(dd, J ) 10.7, 6.1 Hz, 1H), 3.47 (dd, J ) 10.7, 6.3 Hz, 1H), 2.35-
2.26 (m, 2H), 2.19-2.05 (m, 3H), 1.89-1.78 (m, 2H), 1.56 (sept, J )
6.2 Hz, 1H), 1.44 (dq, J ) 13.0, 3.3 Hz, 1H), 1.27 (dq, J ) 13.0, 3.3
Hz, 1H), 0.97 (d, J ) 6.5 Hz, 3H), 0.90 (d, J ) 6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 213.5, 65.6, 46.3, 45.0, 41.7, 40.3, 35.0, 27.6,
14.3, 13.2; CIMS (NH3) 188 [M + NH4]+, 170 [M]+, 153 [M - OH]+;
HRMS calcd for [C10H18O2 + H]+ 171.1385, found 171.1389; HPLC
(19) See Corey, E. J.; Sauers, C. K. J. Am. Chem. Soc. 1957, 79, 248.

12780 J. Am. Chem. Soc., Vol. 120, No. 49, 1998
Corey and Lazerwith
(chiral) Chiralpak at 23 °C, λ ) 254 nm, hexane-isopropyl alcohol
85:15, retention times: 25.1 min (major), 33.2 min (minor) at 1 mL/
min flow rate.
was treated with potassium carbonate (1 mL, 5% aqueous solution)
and warmed to 23 °C. The mixture was partitioned between water and
CH2Cl2. The organic layer was separated, and the aqueous layer was
extracted twice with CH2Cl2. The combined organic layers were washed
with water and brine, dried over Na2SO4 (anhydrous), and concentrated
in vacuo. Flash chromatography (hexanes-ether 90:10) afforded 0.0058
g (22%) of the starting keto diene 9 and (hexanes-ether 80:20) 0.0284
g (58%, 74% with respect to recovered 9) of the Michael adduct 12 as
a clear oil: Rf ) 0.52 and 0.58 (hexanes-EtOAc 70:30); FTIR (film)
1708 cm-1; 1H NMR (of the lower Rf spot) (400 MHz, CDCl3) δ 7.40-
7.29 (m, 5H), 6.20 (dd, J ) 15.2, 10.7 Hz, 1H), 5.78 (d, J ) 10.8 Hz,
1H), 5.48 (dd, J ) 15.2, 6.9 Hz, 1H), 4.62 (m, 2H), 4.41 (d, J ) 17.5
Hz, 1H), 4.20 (d, J ) 17.6 Hz, 1H), 2.67 (m, 1H), 2.53 (m, 1H), 2.36
(m, 2H), 2.07 (m, 1H), 1.91 (m, 1H), 1.74 (m, 6H), 1.60-1.07 (m,
5H), 0.95 (m, 9H); EIMS 410 [M]+, 392 [M - H2O]+; HRMS calcd
for [C27H38O3]+ 410.2811, found 410.2813.
(1S, 4S, 8R)-(-)-Menthane-2,9-dione (7). A solution of keto alcohol
6 (0.404 g, 2.37 mmol) in CH2Cl2 (8 mL) was treated with 2,2,6,6-
tetramethyl-1-piperidinyloxy, free radical (TEMPO) (0.008 g, 0.051
mmol) and potassium bromide (0.028 mL, 0.237 mmol).13 The solution
was cooled to 0 °C and treated with 6% aqueous sodium hypochlorite
which had been adjusted to pH ∼8 using NaHCO3 (4.0 mL, 3.8 mmol).
The reaction mixture was stirred at 0 °C for 1.5 h and poured into 0.1
M HCl (30 mL). The aqueous solution was extracted three times with
CH2Cl2, and the combined organic extracts were washed with Na2S2O3
(saturated aqueous). The organic layer was dried over Na2SO4
(anhydrous), filtered, and concentrated in vacuo. Flash chromatography
(hexanes-EtOAc 75:25) afforded 0.367 g (92%) of desired keto
aldehyde 7 as a clear oil: Rf ) 0.30 (hexanes-EtOAc 70:30); [R]23
D
-47.5 (c 1.20, CHCl3); FTIR (film) 1713 cm-1; H NMR (500 MHz,
1
r,â-Enone 13. A solution of diketone 12 (0.214 g, 0.521 mmol) in
ethanol (104 mL) was cooled to 0 °C and treated with potassium
hydroxide (0.78 mL, 2 M solution in ethanol, 1.56 mmol). After 1 h,
the reaction mixture was treated with pH 4 buffer (100 mL), resulting
in a white precipitate. The mixture was concentrated in vacuo to remove
most of the ethanol and extracted three times with ether. The combined
organic layers were washed with brine, dried over MgSO4 (anhydrous),
filtered, and concentrated. Flash chromatography (hexanes-ether 90:
10) afforded 0.150 g (70%) of aldol cyclization product (â-hydroxy
ketone) as a white solid: Rf ) 0.27 (hexanes-ether 80:20); [R]23D -47
CDCl3) δ 9.66 (d, J ) 1.8 Hz, 1H), 2.41-2.11 (m, 6H), 1.78 (m, 1H),
1.54 (m, 1H), 1.36 (m, 1H), 1.12 (d, J ) 7.3 Hz, 3H), 1.03 (d, J ) 6.3
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 211.5, 203.8, 50.9, 45.9, 44.8,
40.0, 34.5, 27.9, 14.3, 9.8; EIMS 168[M]+; HRMS calcd for [C10H16O2]+
168.1150, found 168.1151.
Keto Diene 9. Diphenyldiprenylphosphonium bromide (0.956 g, 2.37
mmol)14b was azeotropically dried with benzene (2 × 2 mL), dissolved
(mostly) in dimethoxyethane (20 mL), cooled to 0 °C, and treated with
potassium tert-butoxide (2.37 mL, 1 M solution in DME, 2.37 mmol).14
The mixture immediately turned red. This solution of ylide 8 was
transferred dropwise via cannula to a solution of keto aldehyde 7 (0.362
g, 2.15 mmol) in DME (20 mL) at -60 °C, over 3 min (the ylide
solution was washed in with an additional 3 mL DME). After 10 min
NH4Cl (saturated aqueous) was added, and the reaction mixture was
partitioned between water and ether. The organic layer was separated,
and the aqueous phase was extracted again with ether. The combined
organic layers were washed with brine, dried over MgSO4 (anhydrous),
filtered, and concentrated in vacuo. Flash chromatography (hexanes-
EtOAc 80:20) afforded 0.401 g (85%) of keto diene 7 as a clear oil:
Rf ) 0.66 (hexanes-EtOAc 70:30); [R]23D +7.21 (c 1.04, CHCl3); FTIR
1
(c 0.86, CHCl3); FTIR (film) 3500, 1726 cm-1; H NMR (400 MHz,
CDCl3) δ 7.52-7.28 (m, 5H), 6.17 (dd, J ) 15.2, 10.7 Hz, 1H), 5.79
(d, J ) 10.9 Hz, 1H), 5.55 (dd, J ) 15.2, 6.4 Hz, 1H), 4.78 (d, J )
10.5 Hz, 1H), 4.38 (d, J ) 10.5 Hz, 1H), 3.85 (s, 1H), 2.51 (m, 1H),
2.39 (m, 1H), 2.30 (s, 1H), 2.01 (m, 1H), 1.75 (s, 3H), 1.74 (s, 3H),
1.69-1.20 (m, 8H), 1.10 (d, J ) 6.4 Hz, 3H), 1.03 (d, J ) 6.6 Hz,
3H), 0.91 (d, J ) 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.1,
137.5, 137.0, 133.1, 128.6, 128.4, 127.9, 125.5, 125.2, 88.1, 80.8, 72.6,
45.8, 43.4, 42.3, 40.4, 35.7, 34.2, 32.3, 26.0, 25.3, 18.6, 18.3, 14.0,
11.7; CIMS (NH3) 428 [M + NH4]+; HRMS calcd for [C27H38O3 +
NH4]+ 428.3165, found 428.3157.
A solution of the above â-hydroxy ketone (0.150 g, 0.365 mmol) in
pyridine (20 mL) was treated with thionyl chloride (0.107 mL, 1.46
mmol) and stirred at 23 °C. After 1.5 h the solution was poured into
ice-water and extracted three times with EtOAc. The combined organic
layers were washed with brine, dried over Na2SO4 (anhydrous), filtered,
and concentrated. Flash chromatography (hexanes-ether 95:5) afforded
0.100 g (70%) of R,â-enone 13 as a colorless powder (one diastere-
omer): Rf ) 0.45 (hexanes-ether 80:20); [R]23D -45.3 (c 1.18, CHCl3);
FTIR (film) 1676 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.44-7.29 (m,
5H), 6.21 (dd, J ) 16.0, 10.8 Hz, 1H), 5.79 (d, J ) 10.6 Hz, 1H), 5.52
(dd, J ) 15.2, 7.0 Hz, 1H), 4.92 (d, J ) 11.0 Hz, 1H), 4.83 (d, J )
11.0 Hz, 1H), 2.79 (m, 1H), 2.60 (m, 1H), 2.50-2.30 (m, 2H), 2.13
(m, 1H), 1.77 (m, 6H), 1.68-1.27 (m, 6H), 1.19 (m, 6H), 0.95 (d, J )
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.3, 154.9, 146.8, 138.1,
135.9, 133.6, 128.3, 128.1, 127.7, 125.6, 125.1, 73.1, 41.5, 40.9, 36.8,
35.9, 35.5, 31.2, 26.5, 26.0, 19.4, 18.4, 18.3, 15.3, 11.7; EIMS 392
[M]+, 301 [M - Bn]+; HRMS calcd for [C27H36O2]+ 392.2715, found
392.2708.
Phenolic Ether 14. Diisopropylamine (0.045 mL, 0.321 mmol) in
THF (2 mL) was cooled to 0 °C and treated dropwise with n-BuLi
(0.124 mL, 2.59 M solution in hexanes, 0.321 mmol). The solution
was stirred for 15 min and cooled to - 78 °C. In a separate flask,
R,â-enone 13 (0.0420 g, 0.107 mmol) was azeotropically dried with
benzene (1 mL), dissolved in THF (1 mL), and added dropwise via
cannula to the reaction mixture (residual 13 was washed in with an
additional 0.5 mL of THF). The solution was stirred for 15 min and
treated with tert-butyldimethylsilyl trifluoromethanesulfonate (0.098
mL, 0.428 mmol). The reaction mixture was stirred for 15 min at -78
°C and then warmed to 0 °C for 15 min. After the mixture was recooled
to -78 °C, triethylamine (1 mL) was added, followed by NaHCO3
(saturated aqueous, 1 mL), and the mixture was allowed to warm to
23 °C. Water was added, and the aqueous layer was extracted three
times with petroleum ether. The combined organic layers were dried
over K2CO3 (anhydrous), filtered, and concentrated in vacuo. The
1
(film) 1712 cm-1; H NMR (500 MHz, CDCl3) δ 6.18 (dd, J ) 15.1,
10.8 Hz, 1H), 5.78 (d, J ) 10.9 Hz, 1H), 5.39 (dd, J ) 15.1, 8.5 Hz,
1H), 2.41 (ddd, J ) 13.2, 3.6, 2.3 Hz, 1H), 2.31 (sept, J ) 6.3 Hz,
1H), 2.16, (m, 1H), 2.08 (m, 1H), 2.01 (dt, J ) 13.2, 0.9 Hz, 1H), 1.86
(m, 1H), 1.76 (s, 3H), 1.74 (s, 3H), 1.66 (m, 1H), (dq, J ) 12.8, 3.6
Hz, 1H), 1.30 (dq, J ) 13.1, 3.4 Hz, 1H), 1.02 (d, J ) 6.8 Hz, 3H),
1.00 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 213.5, 134.2,
133.7, 126.9, 124.9, 45.8, 45.5, 44.9, 42.3, 35.0, 29.5, 25.9, 18.3, 17.8,
14.4; CIMS (NH3) 238 [M + NH4]+, 221 [M + H]+; HRMS calcd for
[C15H24O + NH4]+ 238.2171, found 238.2171.
Diketone 12. A solution of diisopropylamine (0.084 mL, 0.6 mmol)
in DME (1 mL) was cooled to 0 °C and treated dropwise with n-BuLi
(0.232 mL, 2.59 M in hexanes, 0.6 mmol). The solution was stirred
for 15 min, cooled to -78 °C, and treated with chlorotrimethylsilane
(0.152 mL, 1.20 mmol). In a separate flask, keto diene 9 (0.0265 mg,
0.120 mmol) was azeotropically dried with benzene (1 mL), dissolved
in DME (1 mL), and transferred dropwise via cannula to the reaction
mixture (remaining 9 was washed in with an additional 0.5 mL of
DME). After 5 min the reaction mixture was treated with dry
triethylamine (1 mL) and NaHCO3 (saturated aqueous) and warmed to
23 °C. The mixture was diluted with water and extracted three times
with petroleum ether. The combined organic layers were dried over
K2CO3 (anhydrous), filtered, and concentrated in vacuo. This afforded
0.0359 g (100%) of the enol ether 10 as an 8:1 mixture of regioisomers
1
(as determined by H NMR analysis): Rf ) 0.68 (hexanes-EtOAc-
Et3N, 89:10:1); 1H NMR (400 MHz, C6D6) δ 6.35 (dd, J ) 15.0, 10.8
Hz, 1H), 5.94 (d, J ) 10.1 Hz, 1H), 5.53 (dd, J ) 15.1, 8.4 Hz, 1H),
5.00 (s, 1H), 2.2-1.9 (m, 3H), 1.80 (m, 1H), 1.66 (s, 3H), 1.65 (s,
3H), 1.63 (m, 1H), 1.3-1.1 (m, 2H), 1.16 (d, J ) 6.8 Hz, 3H), 1.04
(d, J ) 6.7 Hz, 3H), 0.21 (s, 9H).
Enol ether 10 and enone 11 (0.025 g, 0.132 mmol) were combined,
azeotropically dried with benzene (2 × 0.5 mL), and dissolved in CH2-
Cl2 (1.2 mL). The solution was cooled to -78 °C and treated with tin
tetrachloride (0.015 mL, 0.132 mmol). After 40 min the reaction mixture

Synthetic Route to the Pseudopterosins
J. Am. Chem. Soc., Vol. 120, No. 49, 1998 12781
residue was purified by flash chromatography (hexanes-ether-triethyl-
amine 89:10:1) to afford 0.0565 g (100%) of the enol TBS ether of 13
as a clear oil: Rf ) 0.47 (MeOH, reverse phase C18 plate); H NMR
(500 MHz, C6D6) δ 7.43 (d, J ) 7.8 Hz, 2H), 7.19 (t, J ) 7.6 Hz, 2H),
7.09 (t, J ) 7.5 Hz, 1H), 6.38 (dd, J ) 15.0, 10.7 Hz, 1H), 5.95 (d, J
) 10.8 Hz, 1H), 5.63 (dd, J ) 15.1, 7.0 Hz, 1H), 4.98 (d, J ) 11.8,
Hz), 4.70 (d, J ) 11.8 Hz, 1H), 2.78 (m, 1H), 2.55 (m, 1H), 2.19 (m,
2H), 1.97 (m, 1H), 1.85 (s, 3H), 1.75 (m, 1H), 1.68 (s, 3H), 1.67 (s,
3H), 1.61 (m, 2H), 1.33 (m, 2H), 1.21 (d, J ) 7.1 Hz, 3H), 1.02 (s,
9H), 0.89 (d, J ) 6.9 Hz, 3H), 0.22 (s, 3H), 0.19 (s, 3H).
0.41 (hexanes-EtOAc 80:20); [R]23 -109 (c 0.92, CHCl3); FTIR
D
(film) 1367, 1177 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.40 (m, 5H),
5.11 (dt, J ) 9.2, 1.2 Hz, 1H), 4.95 (d, J ) 11.0 Hz, 1H), 4.84 (d, J
) 11.0 Hz, 1H), 3.63 (br d, J ) 9.1 Hz, 1H), 3.36 (m, 1H), 3.06 (s,
3H), 2.21 (m, 1H), 2.19 (s, 3H), 2.10 (td, J ) 10.4, 4.3 Hz, 1H), 1.95
(m, 1H), 1.75 (s, 3H), 1.70 (s, 3H), 1.69-1.50 (m, 4H), 1.24 (d, J )
7.1 Hz, 3H), 1.11 (tt, J ) 9.8, 1.9 Hz, 1H), 1.05 (d, J ) 5.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 146.0, 140.6, 137.6, 137.1, 135.5, 135.1,
130.9, 129.9, 129.0, 128.7, 128.3, 127.9, 75.8, 42.4, 39.3, 39.1, 35.8,
30.1, 29.5, 27.6, 27.5, 25.8, 23.3, 21.0, 17.7, 12.8; EIMS 468 [M]+;
HRMS calcd for [C28H36O4S]+ 468.2334, found 468.2333.
1
A solution of the above enol ether of 13 (0.0148 g, 0.0292 mmol)
in methylcyclohexane (0.9 mL) was treated with activated manganese
dioxide (Aldrich Co., dried by azeotroping with toluene, 0.025 g, 0.292
mmol) and heated to 70 °C with stirring for 16 h. The mixture was
filtered through Celite, washed extensively with methylene chloride,
and the solvent was removed in vacuo, affording crude phenolic ether
14 as a clear oil: Rf ) 0.48 (hexanes-Et2O 95:5); 1H NMR (500 MHz,
CDCl3) δ 7.34 (m, 5H), 6.73 (s, 1H), 6.15 (dd, J ) 15.2, 10.8 Hz,
1H), 5.82 (d, J ) 10.7 Hz, 1H), 5.60 (dd, J ) 15.2, 6.9 Hz, 1H), 5.07
(d, J ) 12.1 Hz, 1H), 4.77 (d, J ) 12.1 Hz, 1H), 2.94 (m, 1H), 2.65
(m, 1H), 2.61 (m, 1H), 2.21 (s, 3H), 1.81-1.72 (m, 2H), 1.77 (s, 3H),
1.74 (s, 3H), 1.66 (m, 1H), 1.37 (m, 1H), 1.17 (d, J ) 6.9 Hz, 3H),
1.00 (s, 9H), 0.88 (d, J ) 6.8 Hz, 3H), 0.14 (s, 3H), 0.08 (s, 3H).
Mesylate 15. Phenolic ether 14 was dissolved in THF (1.5 mL) and
treated dropwise with tetrabutylammonium fluoride (0.060 mL, 1.0 M
solution in THF, 0.060 mmol). After the mixture stirred for 5 min,
silica gel (0.5 mL) was added, and the mixture was concentrated in
vacuo. The product absorbed on silica gel was purified by flash
chromatography (hexanes-ether 95:5) to afford 0.0098 g (86% from
13) of free phenol as a colorless powder: Rf ) 0.41 (hexanes-ether
80:20); [R]23D -47 (c 0.80, CHCl3); FTIR (film) 3510 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.42 (m, 5H), 6.74 (s, 1H), 6.17 (dd, J ) 15.0,
10.8 Hz, 1H), 5.83 (d, J ) 10.8 Hz, 1H), 5.62 (dd, J ) 15.2, 6.7 Hz,
1H), 5.39 (s, 1H), 4.99 (d, J ) 11.4 Hz, 1H), 4.80 (d, J ) 11.4 Hz,
1H), 3.09 (m, 1H), 2.67 (m, 2H), 2.20 (s, 3H), 1.93-1.81 (m, 2H),
1.77 (s, 3H), 1.75 (s, 3H), 1.68 (m, 1H), 1.45 (m, 1H), 1.24 (d, J ) 6.9
Hz, 3H), 0.92 (d, J ) 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
145.2, 143.4, 137.3, 133.7, 133.0, 130.5, 128.8, 128.4, 127.9, 127.2,
125.6, 125.3, 121.7, 75.6, 42.6, 41.5, 28.0, 27.8, 26.0, 22.3, 19.9, 18.3,
16.3, 15.6; CIMS (NH3) 408 [M + NH4]+; HRMS calcd for [C27H34O2
+ NH4]+ 408.2903, found 408.2910.
Phenol 17. Tricycle 16 (0.0124 g, 0.0265 mmol) was azeotropically
dried with benzene (0.5 mL), dissolved in THF (0.25 mL), and cooled
to 0 °C. This solution was treated dropwise with MeMgBr (0.018 mL,
3.0 M solution in ether, 0.053 mmol) and stirred for 18 h. NH4Cl
(saturated aqueous) was added, and the aqueous layer was extracted
three times with ether. The combined organic layers were dried over
MgSO4 (anhydrous), filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (hexanes-ether 95:5) to afford
0.0100 g (97%) of tricyclic phenol 17 (25:1 mixture of diastereomers)
as a clear oil: Rf ) 0.55 (hexanes-EtOAc 80:20); [R]22D -104 (c 1.00,
CHCl3); FTIR (film) 3529, 1451 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.43 (m, 5H), 5.49, (s, 1H), 5.14 (dt, J ) 9.2, 1.2 Hz, 1H), 4.89 (d, J
) 11.2 Hz, 1H), 4.83 (d, J ) 11.2 Hz, 1H), 3.63 (dt, J ) 9.0, 3.4 Hz,
1H), 3.38 (m, 1H), 2.21 (m 1H), 2.12 (dt, J ) 10.5, 4.8 Hz, 1H), 2.05
(s, 3H), 2.00 (m, 1H), 1.76 (d, J ) 0.9 Hz, 3H), 1.69 (s, 3H), 1.68-
1.50 (m, 4H), 1.30 (d, J ) 7.1 Hz, 3H), 1.13 (m, 1H), 1.05 (d, J ) 6.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 145.0, 141.9, 137.4, 134.8,
132.9, 130.0, 129.8, 129.3, 128.8, 128.4, 127.9, 120.5, 75.9, 42.0, 39.5,
35.6, 30.6, 29.9, 27.8, 27.6, 25.8, 23.1, 21.0, 17.8, 10.8; EIMS 390
[M]+, 299 [M - Bn]+; HRMS calcd for [C27H34O2]+ 390.2559, found
390.2563.
Pseudopterosin Aglycone 3. Phenol 17 (0.0148 g, 0.0379 mmol)
was azeotropically dried with benzene (0.5 mL), dissolved in CH2Cl2
(1.5 mL), and cooled to 0 °C. The solution was treated dropwise with
BBr3 (0.0036 mL, 0.0379 mmol) in CH2Cl2 (0.100 mL). After 5 min,
NaHCO3 (saturated aqueous, 1 mL) was added, and the mixture was
allowed to warm to room temperature. Water was added, and the
aqueous layer was extracted three times with CH2Cl2. The combined
organic extracts were dried over Na2SO4 (anhydrous), filtered, and
concentrated in vacuo. The residue was purified by flash chromatog-
raphy (hexanes-EtOAc 90:10) to afford 0.0094 g (83%) of pseudoptero-
This phenol (0.0292 g, 0.0748 mmol) was azeotropically dried with
benzene (1 mL), dissolved in CH2Cl2 (1.9 mL), and cooled to -30 °C.
This solution was treated dropwise with triethylamine (0.021 mL, 0.150
mmol), followed by methanesulfonyl chloride (0.009 mL, 0.112 mmol),
and stirred for 15 min. NaHCO3 (saturated aqueous, 1 mL) was added,
and the mixture was warmed to 23 °C. Water was added, and the
aqueous layer was extracted three times with ether. The combined
organic extracts were washed with brine, dried over MgSO4 (anhy-
drous), filtered, and concentrated in vacuo. The residue was purified
by flash chromatography (hexanes-ether 90:10) to afford 0.0337 g
(96%) of mesylate 15: Rf ) 0.41 (hexanes-EtOAc 80:20); [R]23D -109
sin aglycone (3) as an oil: Rf ) 0.28 (hexanes-EtOAc 80:20); [R]23
D
-95 (c 0.94, CHCl3); FTIR (film) 3449, 1448 cm-1; H NMR (500
1
MHz, CDCl3) δ 5.11 (dt, J ) 9.2, 1.4 Hz, 1H), 5.03 (br s, 1H), 4.82
(br s, 1H), 3.58 (m, 1H), 3.22 (m, 1H), 2.17 (m, 2H), 2.03 (s, 3H),
2.02 (m, 1H), 1.75 (d, J ) 1.1 Hz, 3H), 1.67 (s, 3H), 1.65-1.46 (m,
4H), 1.25 (d, J ) 7.0 Hz, 3H), 1.08 (m, 1H), 1.04 (d, J ) 6.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 139.9, 139.7, 130.3, 130.2, 129.9, 129.7,
125.9, 119.8, 43.2, 39.5, 35.4, 31.0, 30.0, 28.3, 27.4, 25.7, 23.1, 21.0,
17.7, 10.9; EIMS 300 [M]+; HRMS calcd for [C20H28O2]+ 300.2089,
found 300.2096.
1
(c 0.97, CHCl3); FTIR (film) 1368, 1170 cm-1; H NMR (500 MHz,
r,â-Enone 11. A solution of oxalyl chloride (0.523 mL, 6.00 mmol)
in CH2Cl2 (3 mL) was cooled to -78 °C and treated dropwise with
DMSO (0.929 mL, 13.1 mmol) in CH2Cl2 (4 mL). After 10 min, the
reaction mixture (at -78 °C) was treated dropwise with a solution of
1-benzyloxy-3-methylbut-3-ene-2-ol15 (azeotroped with 2 mL of ben-
zene, 1.049 g, 5.46 mmol) in CH2Cl2 (5 mL). The reaction mixture
was stirred for 15 min and treated dropwise with diisopropylethylamine
(4.76 mL, 27.3 mmol). After 15 min, the solution was warmed to 23
°C. Water was added, and the organic layer was separated. The aqueous
layer was extracted again with CH2Cl2, and the combined organic layers
were dried over Na2SO4 (anhydrous), filtered, and concentrated. Flash
chromatography (hexanes-EtOAc 90:10) afforded 0.941 g (91%) of
enone 11 as a clear oil: Rf ) 0.38 (hexanes-EtOAc 75:25); FTIR
(film) 1693 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 5H),
5.90 (s, 1H), 5.79 (q, J ) 1.5 Hz, 1H), 4.62 (s, 2H), 4.50 (s, 2H), 1.90
(dd, J ) 1.5, 1.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.6, 142.5,
137.4, 128.5, 128.0, 127.9, 124.9, 73.2, 71.7, 17.5; CIMS (NH3) 208
[M + NH4]+, 191 [M + H]+; HRMS calcd for [C12H14O2 + NH4]+
208.1338, found 208.1329.
CDCl3) δ 7.43-7.35 (m, 5H), 6.86 (s, 1H), 6.13 (dd, J ) 15.1, 10.8
Hz, 1H), 5.82 (d, J ) 10.7 Hz, 1H), 5.58 (dd, J ) 15.1, 7.0 Hz, 1H),
5.02 (d, J ) 11.1 Hz, 1H), 4.91 (d, J ) 11.1 Hz, 1H), 3.10 (s, 3H),
3.06 (m, 1H), 2.69 (m, 1H), 2.61 (sex, J ) 6.4 Hz, 1H), 2.36 (s, 3H),
1.80 (m, 2H), 1.77 (s, 3H), 1.73 (s, 3H), 1.71 (m, 1H), 1.46 (m, 1H),
1.20 (d, J ) 6.9 Hz, 3H), 0.91 (d, J ) 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 148.2, 140.6, 138.8, 136.9, 136.7, 135.9, 133.5, 130.3,
128.6, 128.3, 128.1, 127.9, 126.1, 125.1, 75.7, 42.6, 41.6, 39.3, 27.7,
27.0, 26.0, 22.3, 19.3, 18.3, 17.0, 16.5; FABMS (Na) 491 [M + Na]+,
359 [M - C8H13]+; HRMS calcd for [C28H36O4S + Na]+ 491.2232,
found 491.2222.
Tricycle 16. A solution of mesylate 15 (0.0337 g, 0.0719 mmol) in
CH2Cl2 (7.2 mL) was cooled to -78 °C and treated dropwise with
methanesulfonic acid (0.023 mL, 0.360 mmol). The solution was
warmed to -50 °C and stirred for 10 h, and then triethylamine (0.150
mL) was added. The mixture was warmed to 23 °C, filtered through a
small plug of silica gel (hexanes-EtOAc 80:20), and concentrated in
vacuo to afford 0.0338 g (100%) of tricycle 16 as a clear oil: Rf )

12782 J. Am. Chem. Soc., Vol. 120, No. 49, 1998
Corey and Lazerwith
Enol Ether 21. Diisopropylamine (0.34 mL, 2.40 mmol) in THF
(10 mL) was cooled to 0 °C and treated dropwise with n-BuLi (0.92
mL, 2.61 M solution in hexanes, 2.40 mmol). The solution was stirred
for 15 min and cooled to - 78 °C. In a separate flask, dihydrocarvone20
(0.2434 g, 1.599 mmol) was azeotropically dried with benzene (1 mL),
dissolved in THF (1 mL), and added dropwise via cannula to the
reaction mixture (residual dihydrocarvone was washed in with an
additional 0.5 mL of THF). The solution was stirred for 15 min. and
treated with tert-butyldimethylsilyl trifluoromethanesulfonate (0.73 mL,
3.20 mmol). The reaction mixture was stirred for 15 min at -78 °C
and then warmed to 0 °C for 15 min. Triethylamine (2 mL) was added,
followed by NaHCO3 (saturated aqueous, 5 mL), and the mixture was
allowed to warm to 23 °C. Water was added, and the aqueous layer
was extracted three times with petroleum ether. The combined organic
layers were dried over K2CO3 (anhydrous), filtered, and concentrated
in vacuo. The residue was purified by flash chromatography (hexanes-
Et2O-triethylamine 89:10:1) to afford 0.423 g (99%) of enol ether 21
(400 MHz, CDCl3) δ 7.04 (d, J ) 7.6 Hz, 1 H), 6.73 (dd, J ) 7.7, 1.7
Hz, 1H), 6.63 (d, J ) 1.6 Hz, 1H), 2.81 (sept, J ) 6.9 Hz, 1H), 2.17
(s, 3H), 1.21 (d, J ) 6.9 Hz, 6 H), 1.02 (s, 9H), 0.22 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 153.8, 147.7, 130.7, 126.1, 119.0, 116.8, 33.7,
25.9, 24.1, 18.3, 16.4, -4.1; CIMS (NH3) 282 [M + NH4]+, 265 [M
+ H]+; HRMS calcd for [C16H28OSi + NH4]+ 282.2253, found
282.2251.
Anisoate 24. A solution of diene 2321 (0.0490 g, 0.190 mmol) in
methylcyclohexane (2 mL) was treated with manganese dioxide
(azeotroped from toluene, 0.207 g, 2.46 mmol), heated to 70 °C, and
stirred for 36 h. The reaction mixture was filtered through Celite and
washed extensively with CH2Cl2. The solvent was removed in vacuo
to afford 0.0403 g (83%) of anisoate 24 as a clear oil: Rf ) 0.30
(hexanes-Et2O, 80:20); FTIR (film) 1712, 1261 cm-1; 1H NMR (400
MHz, CDCl3) δ 8.02 (d, J ) 9.0 Hz, 2H), 7.34 (d, J ) 8.0 Hz, 2H),
7.19 (d, J ) 7.9 Hz, 2H), 6.91 (d, J ) 9.0 Hz, 2H), 5.30 (s, 3H), 3.85
(s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 163.5,
as a clear oil: Rf ) 0.73 (hexanes-ether 90:10); [R]23 +62 (c 0.95,
D
138.0, 133.4, 131.8, 129.3, 128.3, 122.7, 113.6, 66.4, 55.5, 21.3; CIMS
CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.56 (m, 1H), 4.76 (d, J ) 3.3
Hz, 1H), 2.16 (m, 1H), 2.00 (m, 2H), 1.72 (s, 3H), 1.60 (sept, J ) 6.6
Hz, 1H), 0.94 (s, 9H), 0.86 (m, 6H), 0.17 (s, 3H), 0.16 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 149.8, 132.2, 123.7, 105.5, 40.5, 31.7, 26.4,
25.9, 25.8, 20.0, 19.9, 18.3, 17.7, -2.5, -4.3, -4.5; CIMS (NH3) 284
[M + NH4]+, 267 [M + H]+; HRMS calcd for [C16H30OSi + H]+
267.2144, found 267.2149.
+
256 [M]+; HRMS calcd for [C16H16O3
]
+ 256.1100, found 256.1099.
4-Methoxyphenyl ether 26. A solution of diene 2521 (0.0509 g,
0.208 mmol) in methylcyclohexane (2 mL) was treated with manganese
dioxide (azeotroped from toluene, 0.228 g, 2.71 mmol), heated to 70
°C, and stirred for 36 h. The reaction mixture was filtered through
Celite and washed extensively with CH2Cl2. The solvent was removed
in vacuo, and the residue was purified by silica gel chromatography
(hexanes-Et2O 95:5) to afford 0.0412 g (82%) of ether 26 as a clear
TBS Ether 22. A solution of the enol TBS ether of dihydrocarvone
21 (0.0623 g, 0.234 mmol) in methylcyclohexane (5 mL) was treated
with activated manganese dioxide (azeotroped from toluene, 0.200 g,
2.38 mmol) and heated to 70 °C. After 36 h, the mixture was filtered
through Celite and washed extensively with CH2Cl2. The solvent was
removed in vacuo, and the residue was filtered through a short plug of
silica gel (hexanes-Et2O 90:10) affording 0.0521 g (84%) of ether 22
oil: Rf ) 0.45 (hexanes-Et2O 80:20); FTIR (film) 1509, 1232 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.19 (d, J ) 8.0 Hz, 2H), 7.14 (d, J )
8.0 Hz, 2H), 6.84 (m, 4H), 4.11 (t, J ) 7.2 Hz, 2H), 3.77 (s, 3H), 3.05
(t, J ) 7.2 Hz, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.9,
153.0, 136.0, 135.3, 129.2, 128.9, 115.6, 114.7, 69.6. 55.8, 35.8, 21.1;
EIMS 242 [M]+; HRMS calcd for [C16H18O2
242.1302.
]
242.1307, found
+
+
1
as a clear oil: Rf ) 0.38 (MeOH, reverse phase C18 plate); H NMR
(20) Prepared by Mr. Steven N. Goodman, of this group, according to
the procedure found in: Deslongchamps, P.; Be´langer, A.; Berney, D. J.
F.; Borschberg, H.-J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama,
H.; Lapalme, R.; Leturc, D. M.; Liao, C.-C.; MacLachlan, F. N.; Maffraud,
J.-P.; Marazza, F.; Martino, R.; Moreau, C.; Ruest, L.; Saint-Laurent, L.;
Saintonge, R.; Soucy, P. Can. J. Chem. 1990, 68, 127-152.
(21) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc.
1995, 117, 10805-10816.
Acknowledgment. This research was supported by a gradu-
ate fellowship from Boehringer Ingelheim Pharmaceutical, Inc.
(to S.E.L.) and by a grants from the National Institutes of Health
and the National Science Foundation.
JA983041S