Asymmetric synthesis and stereochemical assignment of RS-97613, a potent immunosuppressive and antiinflammatory agent

Full text of DOI:10.1021/jo951883t

2236
J . Org. Chem. 1996, 61, 2236-2241
Asym m etr ic Syn th esis a n d Ster eoch em ica l
Assign m en t of RS-97613, a P oten t
Im m u n osu p p r essive a n d An tiin fla m m a tor y
Agen t†
David B. Smith,* Ann Marie Waltos,
David G. Loughhead, Robert J . Weikert,
David J . Morgans, J r., J ohn C. Rohloff,
J ohn O. Link, and Rong-rong Zhu‡
F igu r e 1. Mycophenolic acid (1) and RS-97613.
Sch em e 1
Institute of Organic Chemistry, Department of Medicinal
Chemistry, and Institute of Analytical Research,
Syntex Discovery Research, 3401 Hillview Avenue,
Palo Alto, California 94304
Received October 23, 1995
In tr od u ction
As part of a medicinal chemistry program directed
toward the design and synthesis of analogues of the
immunosuppressive agent mycophenolic acid (1), we
discovered RS-97613 as an entity worthy of further study
(Figure 1).1 In order to advance this compound we
required a synthesis capable of providing multigram
quantities. The initial synthesis was tedious, involving
a separation of the compound from the less active
diastereomer and thus could provide only milligram
amounts at best. This paper describes an efficient
preparative scale synthesis of nonracemic RS-97613
along with information gathered to assign both absolute
and relative stereochemistry of the compound.2
Resu lts a n d Discu ssion
The synthesis began with a side-chain degradation of
mycophenolic acid 1 (Scheme 1). After Fischer esterifi-
cation to provide compound 2, the phenol was protected
as the tert-butyldimethylsilyl ether 3.3 Compound 3 was
then subjected to excess ozone in methylene chloride/
methanol to provide aldehyde 4 after thiourea reduction
of the intermediate methoxy hydroperoxide.4 At that
stage, oxidation using sodium periodate and catalytic
ruthenium trichloride in ethyl acetate/water afforded the
acid 5.5 Initial coupling of a cyclopentenylzinc reagent
with the acid chloride derived from 5 used an organo-
metallic prepared from cyclopentenyl bromide. Following
reports in the literature, preparation of this bromide is
capricious at best and hazardous at worst.6 We were
fortunate to discover that commercially available cyclo-
pentenyl chloride may readily be used for our purposes.7
Lithiation of this chloride was followed by transmetala-
tion with anhydrous zinc chloride to provide a reagent
that reacted smoothly with the acid chloride under
palladium catalysis to provide enone 6.8
† Contribution no. 927 from the Institute of Organic Chemistry.
Address correspondence to Roche Bioscience, 3401 Hillview Avenue,
Palo Alto, CA 94304.
At that stage, asymmetry was introduced using a
modification of the method of Corey (CBS reduction,
Scheme 2).9 The use of borane‚dimethyl sulfide
‡ Institute of Analytical Research.
(1) Previous work from these laboratories: Nelson, P. H.; Eugui,
E.; Wang, C. C.; Allison, A. C. J . Med. Chem. 1990, 33, 833. Original
isolation of mycophenolic acid: Gosio, B. Riv. Igiene Sanita Pub. Ann.
1896, 7, 825. Biological activities of mycophenolic acid: Antitumor;
J ones, D. F.; Mills, S. D. J . Med. Chem. 1971 14, 305. Antiviral; Hupe,
D. J .; Azzolina, B. A.; Behrens, N. D. J . Biol. Chem. 1986, 261, 8363.
Antipsoriatic; Epinette, W. W.; Parker, C. M.; J ones, E. L. Greist, M.
C. J . Am. Acad. Dermatol. 1987, 17, 962. Immunosuppressive; Ohsugi,
Y.; Suzuki, S; Takagaki, Y. Cancer Res. 1976, 36, 2923. Antiinflam-
matory; Nelson, P. H.; Allison, A. C.; Eugui, E. M. U.S. Patent 4686234,
1987.
(5) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936. We have also examined this and similar
procedures for utility in the oxidative cleavage of 3 and related esters
to 5. To date, we have not been able to achieve greater than about
50% yield for the direct transformation.
(6) The following two procedures proved useful for the preparation
of 1-bromocyclopentene: (a) Ndebeka, G.; Raynal, S.; Caubere, P. J .
Org. Chem. 1980, 45, 5394. (b) Maitte, P. Bull. Soc. Chim. Fr. 1959,
499. Several of us were unable to reproduce the procedures given in
(c) Bandodakar, B. S.; Nagendrappa, G. Synthesis, 1990, 843.
(7) Braude, E. A.; Forbes, W. F. J . Chem. Soc. 1951, 1755.
(8) (a) Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F.-T.; Miller, J .
A.; Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181. (b) Grey, R. A. J . Org.
Chem. 1984, 49, 2288.
(2) For the sake of clarity, the absolute and relative stereochemistry
as determined herein is depicted throughout this work.
(3) For leading references relating to the formation and removal of
the tert-butyldimethylsilyl ether, see: Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 2nd ed.; Wiley-Interscience:
New York, 1991; pp 77-83.
(4) Gupta, D.; Soman, R.; Dev, S. Tetrahedron 1982, 38, 3013.
0022-3263/96/1961-2236$12.00/0 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 6, 1996 2237
Sch em e 2
ethyl orthoacetate directly from the supplier, or after
distillation and storage for more than a few hours, had
a detrimental effect on the yield of the reaction.
From 8, all that remained to complete the synthesis
was stereoselective introduction of the methyl group and
saponification of the ethyl ester. We were gratified to
discover that the dianion of 8, formed at -78 °C in THF
with sodium hexamethyldisilazide in the presence of 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),
reacted with methyl iodide to form compound 9 with
>20/1 selectivity.11 We believe that the diastereoselec-
tivity of this step can be explained by invoking a enolate
dianion in which the enolate double bond eclipses the
adjacent C-H allylic bond (minimizing allylic 1,3-
strain).12 In this conformation nucleophilic attack onto
methyl iodide from the less hindered pro-S face of the
enolate leads to the observed product. We speculate that
the role of DMPU in this process may be as a modifier of
enolate aggregation state.
Treatment of 9 with lithium hydroxide in aqueous
ethanol then afforded RS-97613 after acidic workup and
chromatography.13 Analysis (nonracemic HPLC, see
Experimental Section) of compound prepared in this
manner indicated >98% chemical, diastereomeric, and
enantiomeric purity. To date, over 100 g of RS-97613
has been prepared via this procedure, enabling a more
detailed investigation of the pharmacological profile of
the compound.14
Having established a route to multigram quantities of
RS-97613, we turned our attention to the question of the
relative stereochemistry of the compound.2 The absolute
stereochemistry at the cyclopentyl center had been as-
signed based on the diphenylprolinol enantiomer used
in the CBS reduction of 6, as well as from previous work
involving a Sharpless kinetic resolution of racemic 7.15,16
We were frustrated in our spectroscopic attempts to
determine the relative stereochemistry, so we turned to
a degradative approach (Scheme 3).
(BH3‚DMS) in a noncoordinating solvent as the stoichio-
metric reductant provided allylic alcohol 7 in 92-97%
enantiomeric excess (ee). The application of the previ-
ously reported conditions for the CBS9a reduction of
enones using either borane‚THF9b or catecholborane9c as
the reductant provided 7 in lower yield and lower
enantiomeric purity. Additionally, we found it critical
for the success of this step to remove from 6 all traces of
palladium-related materials. When such impurities were
present, we observed lower yields with concomitant
formation of the 1,4-reduction product. Following the
CBS reduction, the enantiomeric excess (ee) of the
carbinol formed (92-97% ee) could be upgraded beyond
detection limits (>99% ee, nonracemic HPLC, see Ex-
perimental Section) by recrystallization. It is of interest
to note that enantioenrichment occurred in the mother
liquor; the crystals of 7 that were recovered in this
manner were near racemic. When pure 7 was then
subjected to the conditions of the J ohnson Claisen re-
arrangement10 (using freshly distilled triethyl ortho-
acetate), followed by treatment of the rearrangement
product with tetra-n-butylammonium fluoride, compound
8 could be isolated in excellent yield (ee > 99%, non-
racemic HPLC, see Experimental Section). Use of tri-
(11) In the absence of DMPU, the stereoselectivity drops to ca. 8/1.
For a highly related dianion alkylation, see: Rohloff, J . C.; Gardner,
J . O.; Towne, R. W. Tetrahedron Lett. 1995, 36, 7803.
(12) For a review of allylic 1,3-strain containing several related
examples, see: Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(13) As part of our studies in this area, we prepared a 1:1 mixture
of esters 9 via reaction of 7 with triethyl orthopropionate. Under the
conditions of hydrolysis used here, we observed a selective reaction of
the diastereomer leading to RS-97613. Along with the selective
alkylation of ester 8, this kinetic resolution in the hydrolysis of 9
accounts for the very high diastereomeric excess observed in the final
product.
(9) (a) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh,
V. K. J . Am. Chem. Soc. 1987, 109, 7925. (b) Corey, E. J .; Da Silva
J ardine, P. Tetrahedron Lett. 1989, 30, 7297. (c) Corey, E. J .; Bakshi,
R. K. Tetrahedron Lett. 1990, 31, 611.
(10) J ohnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J .; Li, T.; Faulkner, D. J .; Petersen, M. R. J . Am. Chem. Soc. 1970,
92, 741.
(14) Manuscripts detailing the synthesis and biological profile of our
most potent analogues are in progress and will appear in due course.
(15) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765. Racemic 7
was readily obtained via the addition of cyclopentenylmagnesium
bromide to aldehyde 4.

2238 J . Org. Chem., Vol. 61, No. 6, 1996
Notes
Sch em e 3
F igu r e 2. 13C spectral data for lactone 11 shows a downfield
shift of the methyl group relative to the methyl group of 12,
similar to that observed in the 1,2-dimethylcyclopentanes.19
In addition, only in lactone isomer 11 is an NOE observed from
the methyl group to the proximal ring fusion proton (indicated
by an arrow above).
Sch em e 4
lytic plaque-forming assay, rat adjuvant-induced arthri-
tis), the compound has proven to be more than 5 times
as potent as mycophenolic acid (1) as an immuno-
suppressive and antiinflammatory agent.14
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, materials were obtained
from commercial suppliers and were used without further
purification. Tetrahydrofuran (THF) was distilled under nitro-
gen atmosphere from sodium/benzophenone directly before use.
Concentration of organic extracts was performed under reduced
pressure (house vacuum) with the aid of a rotary evaporator.
Reactions and chromatography fractions were monitored by thin
layer chromatography (TLC) using Analtech 250-µm silica gel
plates. Chromatography was carried out using Merck 60 230-
400 mesh silica gel, except as otherwise noted. With the
exception of HPLC analyses, analytical data (microanalyses,
NMR spectra, mass spectra, IR spectra, optical rotations and
melting points) were collected by the Syntex Institute of Analyti-
cal Research. 1H NMR measurements were recorded at 300.13
MHz, and 13C NMR measurements were recorded at 75.40 MHz
using a Bruker AMX 300 instrument. Spectra are reported in
ppm downfield from tetramethylsilane as the internal standard.
Melting points are uncorrected. IR spectra were recorded as thin
films.
Treatment of intermediate 9 with excess ozone in the
usual manner afforded keto ester 10. Reduction of 10
under Luche17 conditions then provided lactone 11.
Compound 11 and the R-methyl epimeric lactone 12 could
be prepared in racemic form following a variation of a
literature procedure (Scheme 4).18 Reaction of cis-cyclo-
pent-4-ene-1,3-diol with triethyl orthopropionate at 145
°C in the presence of hydroquinone gave the unsaturated
lactones 13, which upon reduction afforded a fully
1
separable 1:1 mixture of 11 and 12. Based on H NOE
and 13C resonances19 obtained for these compounds
(Figure 2), it was possible to assign relative stereochem-
istry and thus derive the relative stereochemistry of RS-
97613.
Meth yl (E) 6-(1,3-Dih yd r o-4-h yd r oxy-6-m eth oxy-7-m eth -
yl-3-oxo-5-isoben zofu r a n yl)-4-m eth yl-4-h exen oa te (2). To
a mechanically stirred suspension of mycophenolic acid (1) (500
g, 1.56 mol) in methanol (4 L) under a nitrogen atmosphere was
added sulfuric acid (10 mL) dropwise, and the suspension was
stirred at room temperature. After 2 h the reaction became
homogeneous, and soon thereafter a precipitate began to come
out of solution. The reaction was allowed to stir at room
temperature for 20 h at which time TLC indicated complete
reaction (80/20/0.5 hex/EtOAc/HOAc). The reaction was cooled
in an ice bath to 10 °C and then filtered using a 2 L Buchner
funnel. The filter cake was washed with ice cold methanol (750
mL) followed by hexanes (750 mL) and then dried in a vacuum
oven at 45 °C to give 497 g (95%) of the desired product 2 as a
light beige solid (mp 96-97 °C). 1H (CDCl3): 7.17 (s, 1H), 5.23
(m, 1H), 5.20 (s, 2H), 3.76 (s, 3H), 3.62 (s, 3H), 3.38 (d, J ) 6.8
Hz, 2H), 2.3-2.5 (m, 4H), 2.15 (s, 3H), 1.8 (s, 3H). 13C (CDCl3):
173.8, 173.0, 163.7, 153.7, 144.0, 134.2, 122.8, 122.2, 116.74,
106.4, 77.5, 77.1, 76.7, 70.1, 61.0, 51.5, 34.6, 32.9, 22.6, 16.1,
11.6. IR (3426 cm-1, 1732 cm-1). MS (M+, 334). Anal. Calcd
for C18H22O6: C 64.66, H 6.63. Found: C 64.50, H 6.50.
Meth yl (E)-6-[4-[(ter t-Bu tyld im eth ylsilyl)oxy]-1,3-d ih y-
d r o-6-m eth oxy-7-m eth yl-3-oxo-5-isoben zofu r a n yl]-4-m eth -
yl-4-h exen oa te (3). Mycophenolic acid methyl ester (2) (208
g, 0.622 mol) was dissolved in DMF (1.5 L) under a nitrogen
atmosphere. To this was added imidazole (84.7 g, 1.24 mol) in
one portion followed by tert-butyldimethylsilyl chloride (122 g,
0.81 mol) in one portion. The solution was stirred at room
Con clu sion
In summary, a practical asymmetric synthesis of RS-
97613 has been achieved. The synthesis begins with
mycophenolic acid as the starting material and utilizes
as key steps the coupling of cyclopentenylzinc chloride
to an acid chloride, a CBS reduction of an achiral enone,
a J ohnson Claisen rearrangement, and a diastereoselec-
tive alkylation of an ester. The overall yield for the nine-
step sequence to RS-97613 is 25%. Both the absolute and
relative stereochemistry of the compound have been
unambiguously established. In vitro studies have shown
RS-97613 to be a potent inhibitor of inosine monophos-
phate dehydrogenase (IMPDH). In vivo (mouse hemo-
(16) The empirical models that predict the sense of asymmetric
induction to be expected in the Sharpless asymmetric epoxidation of
racemic allylic alcohol 7 and in the CBS reduction of enone 6 are in
agreement with the results described here. We have also assumed a
stereospecific reaction via a chair transition state for the Claisen
rearrangement of intermediate 7. See reference 12 for
a related
example.
(17) Luche, J .-L.; Gemal, A. L. J . Am. Chem. Soc. 1981, 103, 5454.
(18) Kondo, K.; Matsumoto, M.; Mori, F. Angew. Chem., Int. Ed.
Engl. 1975, 14, 103.
(19) Christl, M.; Reich, H. J .; Roberts, J . D. J . Amer. Chem. Soc.
1971, 93, 3463.

Notes
J . Org. Chem., Vol. 61, No. 6, 1996 2239
temperature for 20 h at which time TLC indicated complete
reaction (60/40 hex/EtOAc). The reaction was partitioned in a
5 L separatory funnel between ethyl acetate (2 L) and water (2
L). After the emulsion settled, the ethyl acetate layer was
removed and the aqueous layer was extracted twice with ethyl
acetate (1 L each). The ethyl acetate layers were combined and
washed with 5% HCl (1 L), saturated NaHCO3 (1 L), and brine
(1 L) and then dried over magnesium sulfate and filtered. The
solvent was removed on a rotary evaporator to afford an orange
oil which crystallized after being placed under high vacuum. The
solid was dissolved in hot hexanes (1 L) and transferred to a 2
L Erlenmeyer flask with stirring. The flask was placed in an
ice bath causing the product to precipitate. The solution was
filtered using a Buchner funnel, and after drying there was
obtained 3 as a colorless solid (235 g, 85%)(mp 48-49 °C). 1H
(CDCl3): 5.21 (m, 1H), 5.07 (s, 2H), 3.74 (s, 3H), 3.62 (s, 3H),
3.38 (d, J ) 6.4 Hz, 2H), 2.21-2.41 (m, 4H), 2.15 (s, 3H), 1.75
(s, 3H), 1.03 (s, 9H), 0.25 (s, 6H). 13C (CDCl3): 173.7, 169.2,
163.2, 151.7, 146.1, 133.7, 127.6, 123.7, 117.9, 111.6, 67.6, 60.7,
51.4, 34.5, 32.9, 25.9, 23.7, 18.8, 18.7, 16.3, 11.4, -3.6. IR (1761
cm-1, 1734 cm-1). MS (M+, 448). Anal. Calcd for C24H36SiO6:
C 64.25, H 8.08. Found: C 64.36, H 7.93.
[4-[(ter t-Bu tyld im eth ylsilyl)oxy]-1,3-d ih yd r o-6-m eth oxy-
7-m eth yl-3-oxoisoben zofu r a n -5-yl]a cetyl Ch lor id e. To an
ice/water bath cooled suspension of 36.66 g (0.100 mol) of
arylacetic acid 5 in 400 mL of ethyl acetate was added 11.3 mL
(0.13 mol) of oxalyl chloride and 4 drops of DMF. After 1 h, the
ice bath was removed and the mixture was allowed to warm to
room temperature. After 2 h, the now homogeneous solution
was concentrated on the rotary evaporator. The residue was
then dissolved in ethyl acetate and again concentrated to give a
yellow solid, which was kept on the vacuum pump overnight
before use.
1-Lith io-1-cyclop en ten e. Lithium with high (0.5%) sodium
content (13.2 g of a 30% dispersion in mineral oil) was suspended
in 175 mL of ether and stirred under argon. 1-Chloro-1-
cyclopentene (23.0 g, 224 mmol; freshly distilled (b.p. ∼60 °C/
∼100 torr)) was dissolved in 50 mL of ether and added to the
lithium suspension via addition funnel. After about half the
chlorocyclopentene solution had been added, the addition was
stopped until a gentle reflux was observed. The remainder of
the chlorocyclopentene solution was then added dropwise at a
rate sufficient to maintain gentle reflux. The mixture was
allowed to stir overnight, at which time it was filtered through
a Schlenk filter. Titration, using diphenylacetic acid in THF
(-30 °C), indicated the clear, yellow filtrate was 0.84 M in
cyclopentenyllithium.
2-[4-[(ter t-Bu tyld im eth ylsilyl)oxy]-1,3-d ih yd r o-6-m eth -
oxy-7-m et h yl-5-isob en zofu r a n yl]a cet a ld eh yd e (4). The
TBDMS-protected methyl ester 3 (100 g, 0.223 mol) was dis-
solved in methylene chloride (930 mL) and methanol (930 mL).
To this was added pyridine (7 mL), and the solution was cooled
6-[7-[(ter t-Bu tyld im eth ylsilyl)oxy]-2-cyclop en t-1-en yl-2-
oxoeth yl]-5-m eth oxy-4-m eth yl-3H-isoben zofu r a n -1-on e (6).
Under a dry nitrogen atmosphere, zinc chloride in ether (130
mL of a 1.0 M solution) was chilled to <0 °C using an ice/brine
bath. Then 130 mL (109 mmol) of a 0.84 M solution of 1-lithio-
1-cyclopentene in ether was added at a rate such that the
temperature did not exceed 0 °C. Tetrakis(triphenylphosphine)-
palladium(0) (2.87 g, 2.5 mmol) was then added, followed by a
solution of 100 mmol of [4-[(tert-butyldimethylsilyl)oxy]-1,3-
dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)acetyl chlo-
ride in 100 mL of dichloromethane, which was added via addition
funnel while keeping the temperature of the reaction below 0
°C. The reaction mixture was stirred at -5 to 0 °C. After 3 h,
TLC (30/70 EtOAc/hexane) indicated the acid chloride was
consumed, and the mixture was poured into a separatory funnel
containing 500 mL of ice cold 1 M HCl and 1 L of EtOAc. The
EtOAc phase was washed with saturated NaHCO3 and brine,
dried (MgSO4), and concentrated onto 300 g of flash (230-400
mesh) silica gel. This material was placed at the top of a 1.5 kg
flash column which was eluted with 15/85 and then 20/80 EtOAc/
hexane. This gave 37.6 g of product, contaminated with a less
polar impurity. The material was then suspended in 200 mL of
10/90 ether/hexane, triturated at room temperature for 1 h, and
then filtered to give 31.88 g (77%) of 6 as an off-white powder
(mp 122.4-125.7 °C). 1H NMR (CDCl3): 6.81 (m, 1H), 5.08 (s,
2H), 4.06, (s, 2H), 3.69 (s, 3H), 2.59 (m, 4H), 2.16 (s, 3H), 1.94
(m, 2H), 1.00 (s, 9H), 0.21 (s, 6H). 13C NMR (CDCl3): 195.4,
169.3, 163.6, 152.0, 147.6, 145.5, 143.4, 122.3, 117.8, 111.6, 67.9,
to -70 °C with
a dry ice/acetone bath under a nitrogen
atmosphere. A stream of ozone (Fischer Ozonizer, O2 pressure
of 15 psi, flow ) 150, power ) 200, 2.8 A) was bubbled through
the reaction via a gas dispersion tube until the reaction became
blue in color (1.5 h). The ozone line was replaced with a stream
of nitrogen and bubbling continued until the blue color was
discharged (30 min). To this clear solution at -70 °C was added
thiourea (11.9 g, 0.16 mol, 0.7 equiv) in one portion, and the
cooling bath was removed. The reaction was allowed to stir at
room temperature for 20 h (no ozonides/peroxides present after
3 h by starch/aqueous KI). The cloudy solution was filtered to
remove solid thiourea S-dioxide and then partitioned in a
separatory funnel between methylene chloride (1 L) and water
(2 L). The organic layer was removed, and the aqueous layer
was extracted with methylene chloride (1 L). The combined
organic layers were washed with 5% HCl (1 L), saturated
NaHCO3 (1 L), and brine (1 L) and then dried over magnesium
sulfate and filtered. The filtrate was stripped on a rotary
evaporator to afford a yellow solid. Hexanes (200 mL) were
added and after trituration the solution was filtered and dried
in a Buchner funnel to afford 4 (64 g, 82%) as a light yellow
solid (mp 86-87 °C). 1H (CDCl3): 9.63 (m, 1H), 5.12 (s, 2H),
3.73 (s, 5H), 2.19 (s, 3H), 1.03 (s, 9H), 0.22 (s, 6H). 13C (CDCl3):
199.0, 189.1, 168.8, 163.2, 152.1, 148.0, 119.7, 118.0, 112.0, 67.75,
60.4, 39.7, 25.7, 18.6, 11.5, -3.6, -4.0. IR (1757 cm-1, 1716
cm-1). MS (M+, 350). Anal. Calcd for C18H26SiO5: C 61.68, H
7.48. Found: C 61.64, H 7.39.
60.9, 35.9, 34.2, 31.1, 26.2, 23.0, 18.8, 11.8, -3.4. IR (1759 cm-1
,
1676 cm-1). MS (M+ - 15, 401). Anal. Calcd for C23H32O5Si:
C 66.31, H 7.74. Found: C 66.51, H 7.68.
2-[4-[(ter t-Bu tyld im eth ylsilyl)oxy]-1,3-d ih yd r o-6-m eth -
oxy-7-m eth yl-5-isoben zofu r a n yl]a cetic Acid (5). The alde-
hyde 4 (67 g, 0.191 mol) was dissolved in ethyl acetate (950 mL),
to this was added water (950 mL), and the mixture was stirred
1-[2-[4-[(ter t-Bu tyldim eth ylsilyl)oxy]-1,3-dih ydr o-6-m eth -
oxy-7-m eth yl-3-oxo-5-isoben zofu r a n yl]-1(S)-h yd r oxyeth -1-
yl]cyclop en t-1-en e (7). To the ketone 6 (32.26 g, 77 mmol)
under
a nitrogen atmosphere. To this was added sodium
under
a nitrogen atmosphere was added (R)-tetrahydro-1-
periodate (81.8 g, 0.38 mol) in one portion followed by ruthe-
nium(III) trichloride hydrate (48 mg, 0.23 mmol). The mixture
was stirred at room temperature for 5 h at which time TLC
indicated complete reaction (75/25/0.5 hex/EtOAc/HOAc). The
ethyl acetate layer was removed in a separatory funnel, and the
aqueous layer was extracted with ethyl acetate (2 × 500 mL).
The combined ethyl acetate layers were washed with 5% sodium
metabisulfite (2 × 300 mL) and brine (1 L), dried over magne-
sium sulfate, and filtered. The filtrate was stripped on a rotary
evaporator to afford a beige solid. The solid was triturated using
hexanes (500 mL) for 30 min and then filtered and dried in a
Buchner funnel to afford 5 (67 g, 96%) as a colorless solid (mp
181-184 °C). 1H (CDCl3): 4.83 (s, 2H), 3.56 (s, 3H), 3.44 (s,
2H), 1.93 (s, 3H), 0.79 (s, 9H), 0.22 (s, 6H). 13C (CDCl3): 173.8,
169.0, 163.2, 151.9, 147.5, 121.7, 117.6, 111.5, 67.7, 60.7, 30.3,
26.0, 18.6, 11.5, -3.7. IR (1765 cm-1, 1714 cm-1). MS (M+, 366).
Anal. Calcd for C18H26SiO6: C 58.99, H 7.15. Found: C 58.97,
H 6.97.
methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c][1,3,2] oxazaborole (7.7
mL of a 1 M solution in toluene, 7.7 mmol, 10 mol %) via syringe.
The mixture was placed under high vacuum for 2 h to remove
most of the toluene. The mixture was then purged with
nitrogen, dry methylene chloride (65 mL) was added, and the
reaction was cooled to -30 °C with a Kryocooler. To this solution
at -30 °C was added borane dimethyl sulfide complex (8.1 mL
of a 10 M solution, 81.3 mmol) dropwise via a syringe pump over
a period of 7 h. After complete addition, the reaction was
allowed to stir at -30 °C for 16 h at which time TLC indicated
complete reaction (75/25 hex/EtOAc). To this mixture at -30
°C was added 1 M HCl in methanol (11.9 mL) dropwise over 10
min (hydrogen evolution). The reaction was then allowed to
come to room temperature and stirred for 30 min, which resulted
in a grey precipitate. To this solution was then added toluene
(75 mL), and the methylene chloride was removed on a rotary
evaporator. The resulting solution was filtered and the filter
cake washed with ethyl acetate (25 mL) to afford diphenylpro-

2240 J . Org. Chem., Vol. 61, No. 6, 1996
Notes
linol hydrochloride. The filtrate was diluted with ethyl acetate
(750 mL), washed with 5% HCl (500 mL), saturated NaHCO3
(500 mL), and brine (500 mL), and then dried over magnesium
sulfate and filtered. To the filtrate was added silica gel (250 g,
Whatman 230-400 mesh). The solvent was removed, and the
silica gel was placed at the top of a flash column (10 cm × 40
cm) and eluted with a gradient of ethyl acetate (15% to 25%)
and hexanes. The product-containing fractions were combined
and evaporated to afford 28.94 g (89%) of a white solid. Analysis
of this material by HPLC (Chiralcel OD-H, 94% hexanes/6%
isopropyl alcohol, flow ) 0.8 mL/min, 210 nm) indicated 92.0%
ee. This material was suspended in hexanes (932 mL) and to
this was added warm ethyl acetate (279 mL). The solution was
warmed on a hot plate until complete dissolution and then
allowed to stand at room temperature. After 30 h, HPLC (same
conditions as above) of the supernatant indicated >99.0% ee.
The supernatant was decanted from the crystals and evaporated
to afford the product 7 as a white solid, 24.5 g (76%) (mp 104-
105 °C). 1H (CDCl3): 5.62 (m, 1H), 5.07 (s, 2H), 4.45 (m, 1H),
3.82 (s, 3H), 2.97 (m, 2H), 2.33 (m, 4H), 2.18 (s, 3H), 1.91 (m,
2H), 1.04 (s, 9H), 0.22 (s, 6H). 13C (CDCl3): 169.0, 163.4, 152.2,
147.0, 125.3, 125.1, 118.2, 112.0, 71.0, 67.7, 60.9, 32.2, 31.5,
methyl iodide (11.2 mL, 179.9 mmol) was added via syringe over
5 min. Over approximately 15 min the reaction mixture went
from deep orange to yellow-orange. The mixture was allowed
to stir for 2 h and was then quenched by addition of saturated
aqueous ammonium chloride (400 mL). After warming to about
0 °C (the point at which the solid mass that results from addition
of the ammonium chloride solution has become liquid) the
solution was extracted with ethyl acetate (700 mL). The ethyl
acetate layer was washed with ammonium chloride (400 mL).
The combined aqueous layers were extracted with ethyl acetate
(700 mL). The combined organic layers were dried over mag-
nesium sulfate, filtered, and concentrated to afford 36 g of an
orange brown oil (theoretical yield 21.5 g). The orange brown
oil 9 was carried on.
The ethyl ester 9 from above was dissolved in EtOH (700 mL),
and then water (350 mL) and LiOH‚H2O (14 g, 334.8 mmol) were
added. The mixture was allowed to stir at room temperature
under nitrogen for 65.5 h. The reaction mixture was then
acidified with 5% aqueous HCl (1 L) and extracted with ethyl
acetate (1 L). The ethyl acetate layer was washed with 5%
aqueous HCl (400 mL), and the combined aqueous layers were
extracted with ethyl acetate (400 mL). The combined organic
layers were dried over magnesium sulfate, filtered, and concen-
trated in vacuo. The resultant orange oil was chromatographed
using 800 g of 230-400 mesh silica eluting with 80/20 hexanes/
ethyl acetate containing 1% acetic acid, to afford 13.5 g of a
colorless solid RS-97613 (68% yield) (mp 113-115 °C). Analysis
of this material by HPLC (Chiralpak AD, 90% (0.1% trifluoro-
acetic acid in hexanes)/10% isopropyl alcohol, flow ) 1.0 mL/
min, 210 nm) indicated >99% ee. 1H (CDCl3): 7.7 (br s, 1H),
5.25 (m, 1H), 5.2 (s, 2H), 3.76 (s, 3H), 3.4 (br d, J ) 7.1, 2H),
2.65 (dq, J ) 6.93, 6.85, 1H), 2.2-2.35 (m, 1H), 2.5 (m, 1H), 2.14
(s, 3H), 1.7-1.85 (m, 2H), 1.4-1.6 (m, 2H), 1.0 (d, J ) 7.0, 3H).
13C (CDCl3): 192.4, 180.9, 163.7, 153.8, 144.5, 144.0, 122.1, 118.6,
116.6, 106.4, 70.0, 61.0, 46.0, 41.7, 29.6, 28.2, 24.2, 24.1, 12.1,
11.5. IR (3650-3400 cm-1 broad, 1732 cm-1). MS (M+, 360).
Anal. Calcd for C19H22O6: C 66.65, H 6.71. Found: C 66.73, H
31.34, 26.0, 23.4, 18.7, 11.5, -3.3, -3.5, -3.6. IR (3541 cm-1
,
C
1768 cm-1). MS (M+, 418). Anal. Calcd for C23H34SiO5:
65.99, H 8.18. Found: C 65.97, H 7.99. [R]25 ) 33.1, c ) 0.46,
D
methanol.
{2-[2-(1,3-Dih yd r o-4-h yd r oxy-6-m e t h oxy-7-m e t h yl-3-
oxoisoben zofu r a n -5-yl)eth ylid en e]cyclop en tyl}a cetic Acid
Eth yl Ester (8). To a 1 L round bottom flask equipped with a
magnetic stirbar, short path distillation head, and nitrogen line
and containing alkenol 7 (24.5 g, 58.5 mmol) was added freshly
distilled triethyl orthoacetate (550 mL, still warm from the
distillation). After stirring for about 5 min, the alkenol had
completely dissolved. Pivalic acid (0.926 g, 9.08 mmol) was then
added and the mixture stirred another few minutes to allow
complete dissolution. The reaction was then placed in an oil
bath heated to 145 °C and stirred at that temperature for 4.5 h.
The reaction, initially colorless, became a bit yellow during the
course of the reaction. During the first hour or so of reaction, a
colorless liquid (presumably ethanol) distilled over from the
reaction. The heating bath was turned off and when the
temperature had reached about 80 °C the flask was placed on
the rotary evaporator and all solvents were removed under
reduced pressure. The crude light yellow oil thus obtained was
carried on without further purification.
6.72. [R]25 ) -14.3, c ) 0.55, chloroform.
D
Eth yl 2-(2-Oxocyclop en tyl)p r op ion a te (10). A solution of
ester 9 (0.26 g, 0.69 mmol) in 30 mL of 1/1 methylene chloride/
methanol containing 2 mL pyridine was cooled to -78 °C, and
ozone was bubbled through the solution until the blue color
persisted. After warming the reaction to ambient temperature,
thiourea (54 mg, 0.71 mmol) was added and the reaction was
stirred overnight. Filtration to remove the insoluble precipitate
was followed by solvent removal and flash chromatography (7/1
hexanes/ethyl acetate) to afford ketone 10 (77 mg, 62%) as an
oil. 1H (CDCl3): 4.17 (m, 2H), 2.81 (dq, J ) 6.1, 7.1, 1H), 2.61-
2.52 (m, 1H), 2.39-2.31 (m, 1H), 2.19-2.00 (m, 3H), 1.89-1.59
(m, 2H), 1.27 (t, J ) 7.1, 3H), 1.11 (d, J ) 7.1, 3H). 13C (CDCl3):
218.7, 175.4, 60.4, 51.3, 38.6, 37.9, 25.6, 20.3, 14.0, 13.5. IR
(1732 cm-1). MS (M+, 184).
3-Meth ylh exa h yd r ocyclop en ta [b]fu r a n -2-on e (11). A so-
lution of ketone 10 (63 mg, 0.342 mmol) in 5 mL of methanol
was treated with cerium chloride heptahydrate (0.129 g, 0.346
mmol) followed by sodium borohydride (13 mg, 0.34 mmol).
After 5 min, water was added and the product was extracted
into ether. The ethereal layer was washed with brine and dried
over magnesium sulfate. Filtration was followed by solvent
removal, and the residue was chromatographed on silica gel
using 4/1 hexanes/ether. A single diasteromeric lactone 11 (27.7
mg, 58%) was thus obtained. 1H (CDCl3): 5.00-4.95 (m, 1H),
2.55-2.48 (m, 1H), 2.37 (dq, J ) 7.4, 3.9, 1H), 2.05-2.00 (m,
1H), 1.89-1.59 (m, 5H), 1.32 (d, J ) 7.4, 3H). 13C (CDCl3):
180.7, 84.2, 46.7, 42.3, 33.3, 32.7, 23.4, 17.4. IR (1769 cm-1).
MS (M+, 140). HRMS Calcd for C8H12O2: 140.08373. Found:
140.08325.
To the above oil in the original 1 L flask was added THF (400
mL) and a stirbar, and the whole was cooled to 0 °C under
nitrogen. Tetrabutylammonium fluoride (60 mL, 1 M in THF,
60 mmol) was added dropwise over about 10 min. After a total
of 0.5 h, 5% HCl was added (about 100 mL) and the product
extracted with ethyl acetate (two extractions). After drying over
MgSO4, the solution was filtered and solvent removed to leave
a solid residue. Chromatography using 125 g 230-400 mesh
silica (elution with 85/15 hexanes/ethyl acetate, then 80/20
hexanes/ethyl acetate) gave after solvent removal 20.73 g (95%)
of 8 as a colorless solid (mp 88.6-89.2 °C). Analysis of this
material by HPLC (Chiralpak AD, 97% hexanes/3% isopropyl
alcohol, flow ) 1.0 mL/min, 210 nm) indicated >99% ee. 1H
(CDCl3): 7.67 (br s, 1H), 5.22 (m, 1H), 5.20 (s, 1H), 4.08 (q, J )
7.1, 2H), 3.76 (s, 3H), 3.36 (d, J ) 6.9, 2H), 2.76 (m, 1H), 2.50
(dd, J ) 15.0, 5.3, 1H), 2.48 (br m, 2H), 2.17 (dd, J ) 15.0, 9.3,
1H), 2.15 (s, 3H), 2.0-1.89 (br m, 1H), 1.87-1.74 (br m, 1H),
1.70-1.56 (br m, 1H), 1.49-1.25 (br m, 1H), 1.21 (t, J ) 7.1,
3H). 13C (CDCl3): 173.1, 173.0, 163.7, 153.7, 146.0, 144.0, 122.2,
118.0, 116.7, 106.4, 70.1, 61.0, 60.1, 40.9, 39.4, 33.0, 29.1, 24.0,
23.9, 14.2, 11.6. IR (3700-3200 cm-1 broad, 1765 cm-1, 1736
cm-1, 1719 cm-1). MS (M+, 374). Anal. Calcd for C21H26O6: C
67.36 H 7.00. Found: C 67.54 H 6.95. [R]25 ) -30.0, c ) 1,
3-Met h ylh exa h yd r ocyclop en t a [b]fu r a n -2-on es 11 a n d
12. cis-Cyclopent-4-ene-1,3-diol (0.47 g, 4.69 mmol) was dis-
solved in 6 mL of triethyl orthopropionate, and hydroquinone
(75 mg, 0.68 mmol) was added. The mixture was heated in an
oil bath at 145 °C under nitrogen atmosphere for 16 h. After
cooling, the dark reaction was diluted with 1/1 hexanes/ethyl
acetate and washed successively with 5% HCl, water, and brine.
Drying was effected using magnesium sulfate, and then the
solution was filtered and solvent removed to leave a dark oil.
Chromatography using 8/1 hexanes/ether gave 0.35 g oil that
was used for the next reaction.
D
chloroform.
2-{2-[2-(1,3-Dih yd r o-4-h yd r oxy-6-m et h oxy-7-m et h yl-3-
o x o i s o b e n z o f u r a n -5 -y l ) e t h y l i d e n e ] c y c l o p e n t y l }-
p r op ion ic Acid (RS-97613). To a solution of sodium bis-
(trimethylsilyl)amide (165.9 mL, 1 M in THF, 165.9 mmol) cooled
to -78 °C under nitrogen was added DMPU (16.7 mL, 138.2
mmol). The yellow solution was allowed to stir for 15 min at
which time the ethyl ester 8 (20.7 g, 55.28 mmol) was added via
cannula over 45 min as a 0.5 M solution in THF. Upon addition,
the mixture turned a deep orange. After stirring for 0.5 h,

Notes
The oil from the above reaction was dissolved in ethyl acetate
J . Org. Chem., Vol. 61, No. 6, 1996 2241
(CDCl3): 179.4, 84.1, 43.9, 37.9, 32.4, 25.7, 24.1, 11.0. IR (1767
cm-1). MS (M+, 140). HRMS Calcd for C8H12O2: 140.08373.
Found: 140.08372.
(10 mL), and palladium (0.11 g, 10% on carbon) was added. The
solution was stirred under hydrogen atmosphere (balloon) for
18 h. Filtration through Celite removed the palladium, and
solvent was then removed to leave the products as an oil. Flash
chromatography using 10-40 µm silica gel (9/1 hexanes/ethyl
acetate) was carried out twice to achieve complete separation
of the diastereomeric products 11 and 12 (124 mg total, 18.8%).
Lactone 11 (68 mg, 10.3%): identical to above derived from RS-
97613. Lactone 12 (56 mg, 8.5%): 1H (CDCl3): 4.86 (dt, J )
1.7, 5.4, 1H), 2.85 (dq, J ) 8.8, 7.0, 1H), 2.85-2.74 (m, 1H), 2.05-
1.83 (m, 2H), 1.74-1.54 (m, 4H), 1.21 (d, J ) 7.0, 3H). 13C
Ack n ow led gm en t. We would like to thank Dr.
Peter H. Nelson for helpful discussions regarding the
synthetic portion of this work and Dr. Michael L.
Maddox for helpful discussions regarding the structural
assignment portion of this work.
J O951883T