Stereocontrolled synthesis of ent-grindelic acid. A useful example of diastereofacial guidance in an oxonium ion-initiated pinacolic ring expansion

Article abstract of DOI:10.1021/jo960547p

An enantioselective synthesis of (+)-grindelic acid is described, confirming that the dextrorotatory enantiomer is antipodal to the natural diterpenoid. The optically pure bicyclic ketone 5 representing the AB ring system is constructed from the levorotatory Wieland-Miescher ketone and must therefore possess the absolute configuration shown. Coupling of 5 with the 5-lithio derivative of optically active 2,3-dihydrofuran 3 derived from (R)-(-)-linalool was effected for the purpose of realizing acid-catalyzed rearrangement with generation of the appropriate spirocyclic framework. This key step is highly stereocontrolled, leading predominantly to 7. Once the advanced intermediate 15 is available in this fashion, its subsequent exposure to oxidation and dehydration steps led to the target molecule. The synthesis demonstrates unequivocally that natural (-)-grindelic acid is a true labdane diterpenoid.

Full text of DOI:10.1021/jo960547p

5352
J . Org. Chem. 1996, 61, 5352-5357
Ster eocon tr olled Syn th esis of en t-Gr in d elic Acid . A Usefu l
Exa m p le of Dia ster eofa cia l Gu id a n ce in a n Oxon iu m Ion -In itia ted
P in a colic Rin g Exp a n sion
Leo A. Paquette* and Hui-Ling Wang†
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received March 22, 1996X
An enantioselective synthesis of (+)-grindelic acid is described, confirming that the dextrorotatory
enantiomer is antipodal to the natural diterpenoid. The optically pure bicyclic ketone 5 representing
the AB ring system is constructed from the levorotatory Wieland-Miescher ketone and must
therefore possess the absolute configuration shown. Coupling of 5 with the 5-lithio derivative of
optically active 2,3-dihydrofuran 3 derived from (R)-(-)-linalool was effected for the purpose of
realizing acid-catalyzed rearrangement with generation of the appropriate spirocyclic framework.
This key step is highly stereocontrolled, leading predominantly to 7. Once the advanced
intermediate 15 is available in this fashion, its subsequent exposure to oxidation and dehydration
steps led to the target molecule. The synthesis demonstrates unequivocally that natural
(-)-grindelic acid is a true labdane diterpenoid.
The grindelane class of bicyclic diterpenoids, encom-
acid belongs to the ent-labdane series and is therefore
1b. Despite justifiable recorded claims to the contrary,4b,6,7
the acceptance of 1b as the correct absolute configuration
persists to the present time.8
passing many compounds at the present time, has been
the subject of continuous phytochemical investigation for
more than 20 years.1 Grindelic acid (1), the most
prominent member of this class,2 is widely considered to
be the biogenetic precursor to many structurally interest-
ing, more highly oxygenated metabolites. Despite the
central role played by 1, the assignment of its absolute
stereochemistry has been the subject of considerable
confusion. Initially, this spirocyclic tetrahydrofuran was
formulated to exist in the labdane series, viz. 1a , on the
basis of spectroscopic considerations3 and chemical cor-
relation with sclareol.4 In 1986, J akupovic et al. suc-
ceeded in transforming (-)-1 into methyl 6-oxo-7,8-
A need to clarify the stereochemical lineage of grindelic
acid consequently exists. An opportunity to develop a
new method for generating the structural array present
in 1 engaged our attention. The successful plan had
necessarily to include provision for the elaboration of a
spirocyclic carbon with full control over absolute config-
uration. Ideally, the margins of stereoselectivity would
be sufficiently elevated that introduction of the various
chirality elements would prove to be strikingly simple.
Experimentally evaluated herein is the adaptation of
oxonium ion activated pinacol ring expansion9,10 to the
total synthesis of 1b. These studies have established the
feasibility of incorporating all of the essential structural
features of this substance by means of a highly stereo-
controlled master reaction. Since 1b prepared in this
manner has proven to be dextrorotatory, it is abundantly
clear that natural (-)-grindelic acid is unequivocally the
labdane diterpenoid 1a .11
dihydrogrindelate, which exhibited a positive Cotton
effect.5 Application of the octant rule to this observation
led to the alternative conclusion that natural grindelic
Syn th etic Str a tegy
(R)-(-)-Linalool (2) had earlier been transformed into
dihydrofuran 3, an intermediate that is amenable to
deprotonation at the vinylic center R to the oxygen
† On leave from the Department of Chemistry, National Tsing Hua
University, Hsinchu 30043, Taiwan, Republic of China.
X Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) Recent reports of new isolations include: (a) Aphaijitt, S.;
Nimgiravath, K.; Suksamrarn, A.; Tooptakong, U. Aust. J . Chem. 1995,
48, 133. (b) Hayashi, T.; Okamura, K.; Tamada, Y.; Iida, A.; Fujita,
T.; Morita, N. Phytochemistry 1993, 32, 349. (c) Urones, J . G.; Marcos,
I. S.; Moro, R. F.; Rodilla, J . M. L.; Mendonca, A. G. Phytochemistry
1993, 32, 401. (d) Fang, J . M.; Sou, Y. C.; Chiu, Y. H.; Cheng, Y. S.
Phytochemistry 1993, 34, 1581. (e) San Feliciano, A.; Miguel del Corral,
J . M.; Lopez, J . L.; de Pascual-Teresa, B. Phytochemistry 1993, 33,
1165.
(6) Adinolfi, M.; Della Greca, M.; Mangoni, L. Phytochemistry 1988,
27, 1878.
(7) (a) Olivieri, A. C.; Gonza´lez-Sierra, M.; Ru´veda, E. A. J . Org.
Chem. 1986, 51, 2824. (b) Gonza´lez-Sierra, M.; Olivieri, A. C.; Colombo,
M.; Ru´veda, E. A. J . Chem. Soc., Perkin Trans. 1 1989, 1393.
(8) Shimizu, T.; Hiranuma, S.; Qian, Z.-h.; Yoshioka, H. Synlett
1991, 725.
(9) (a) Paquette, L. A.; Lawhorn, D. E.; Teleha, C. A. Heterocycles
1990, 30, 765. (b) Paquette, L. A.; Negri, J . T. J . Am. Chem. Soc. 1991,
113, 5073. (c) Paquette, L. A.; Negri, J . T.; Rogers, R. D. J . Org. Chem.
1992, 57, 3947. (d) Paquette, L. A.; Andrews, J . F. P.; Vanucci, C.;
Lawhorn, D. E.; Negri, J . T.; Rogers, R. D. J . Org. Chem. 1992, 57,
3956. (e) Paquette, L. A.; Dullweber, U.; Cowgill, L. D. Tetrahedron
Lett. 1993, 34, 8019. (f) Paquette, L. A.; Branan, B. M.; Friedrich, D.;
Edmondson, S. D.; Rogers, R. D. J . Am. Chem. Soc. 1994, 116, 506.
(10) (a) Paquette, L. A.; Lord, M. D.; Negri, J . T. Tetrahedron Lett.
1993, 34, 5693. (b) Lord, M. D.; Negri, J . T.; Paquette, L. A. J . Org.
Chem. 1995, 60, 191.
(2) Panizzi, L.; Mangoni, L.; Belardini, M. Tetrahedron Lett. 1961,
376. Gazz. Chim. Ital. 1962, 92, 522.
(3) (a) Mangoni, M.; Belardini, M. Gazz. Chim. Ital. 1962, 92, 983,
995. (b) Bohlmann, F.; Ahmed, M.; Borthakur, N.; Wallmeyer, M.;
J akupovic, J .; King, R. M.; Robinson, H. Phytochemistry 1982, 21, 167.
(4) (a) Mangoni, M.; Belardini, M. Gazz. Chim. Ital. 1962, 92, 1379;
1963, 93, 455. (b) Adinolfi, M.; Laonigro, G.; Parrilli, M.; Mangoni, M.
Gazz. Chim. Ital. 1976, 106, 625.
(5) J akupovic, J .; Baruah, R. N.; Zdero, C.; Eid, F.; Chau-Thi, T. V.;
Bohlmann, F.; King, R. M.; Robinson, H. Phytochemistry 1986, 25,
1873.
(11) Preliminary communication: Paquette, L. A.; Wang, H.-L.
Tetrahedron Lett. 1995, 36, 6005.
S0022-3263(96)00547-6 CCC: $12.00 © 1996 American Chemical Society

Stereocontrolled Synthesis of ent-Grindelic Acid
J . Org. Chem., Vol. 61, No. 16, 1996 5353
Sch em e 1
Sch em e 3
Sch em e 2
atom.10 Since the basicity of the resulting organolithium
species could be significantly reduced by conversion to
the organocerate 4,10 the possibility existed that 1,2-
addition to bicyclic ketone 5 could be carried out without
the serious incursion of competing enolization (Scheme
1). This condensation was expected to proceed from the
sterically less congested â face12 to deliver the tertiary
carbinol 6. It was further conjectured that the protona-
tion of 6 would result in generation of a reactive oxonium
ion whose fate it would be to experience a Wagner-
Meerwein shift. This migration should involve the more
electron-rich tertiary carbon, which should be quite
sensitive to prevailing steric factors due to its very
substantial space-filling requirements (note the added
neopentyl feature). The hope was that the reduced level
of nonbonded steric compression present in A as com-
pared to B (Scheme 2) would be met by kinetically
controlled diastereoselection in favor of the first trajec-
tory. The two π surfaces in the oxonium ion acceptor
should be equally receptive to bonding, such that differ-
ences in reaction exothermicity cannot be distinguished
on this basis. However, the migration syn to methyl as
encountered in A can be expected to be energetically less
costly than compression against the vinyl group. The
basis for this contention stems from an awareness that
the tertiary methyl substituted carbon in oxonium ions
C and D prefers to follow the first of these pathways by
a factor of 2:1.10 The situation in A and B should be even
more imbalanced.
Resu lts a n d Discu ssion
Bond disconnection at the carbinol center in 6 leads
in turn to the need to prepare the specific enantiomer of
bicyclic ketone 5 shown. Our approach to this intermedi-
ate was based on ring contraction of the readily available
(-)-Wieland-Miescher ketone 8.13 Advantage was taken
of the known propensity of its monoethylene ketal for
incorporation of a (phenylthio)methylene group R to the
carbonyl when treated with aqueous formaldehyde,
thiophenol, and triethylamine in ethanol.14 Following
Birch reduction, in situ methylation of the resulting
desulfurized enolate anion with methyl iodide,15 Wolff-
Kishner reduction,16 and ketal hydrolysis afforded 9,
[R]24 +34.5 (c 0.055, CHCl3).17 To set the stage for the
D
cleavage of ring B (Scheme 3), 9 was brominated with
pyridinium bromide perbromide in acetic acid18 and
exposed to sodium hydroxide in aqueous DMF.19 As
expected from earlier precedent, the yield in both steps
was very good, affording the acyloin 10b in 84% overall
yield.20
Subsequent treatment of 10b with lead tetraacetate
in benzene containing methanol at rt21 afforded aldehydo
(13) (a) Buchschacher, P.; Fu¨rst, A.; Gutzwiller, J . Organic Synthe-
ses; Wiley: New York, 1990, Coll. Vol. VII, p 368. (b) Harada, N.;
Sugioka, T.; Uda, H.; Kuriki, T. Synthesis 1990, 53.
(14) Kirk, D. N.; Petrow, V. J . Chem. Soc. 1962, 1091.
(15) Smith, A. B., III; Mewshaw, R. J . Org. Chem. 1984, 49, 3685.
(16) Snitman, D. L.; Tsai, M.-Y.; Watt, D. S.; Edwards, C. L.; Stotter,
P. L. J . Org. Chem. 1979, 44, 2838.
The expected adoption of transition state A would lead
to 7 and constitute a rather interesting example of
diastereofacial guidance. In the end, the challenge of
establishing proper absolute configuration in a spirocyclic
carbon is met by controlling the ultimate course of a
pinacolic-like ring expansion.
(17) The reported optical rotation for 9 is [R]20 +30.8 (c 0.05,
D
CHCl3): Okamura, W. H.; Peter, R.; Reischl, W. J . Am. Chem. Soc.
1985, 107, 1034.
(18) Ihara, M.; Toyota, M.; Fukumoto, K.; Kametani, T. J . Chem.
Soc., Perkin Trans. 1 1986, 2151.
(19) Numazawa, M.; Nagaoka, M. J . Org. Chem. 1982, 47, 4024.
(20) The optical rotations recorded for 10a and 10b are [R]24D +17.3
(c 0.295, CHCl3) and [R]24 +32.7 (c 0.29, CHCl3), respectively. The
D
results of Ihara et al.18 who worked in the enantiomeric series are [R]17
D
(12) For example: Renoud-Grappin, M.; Vanucci, C.; Lhommet, G.
J . Org. Chem. 1994, 59, 3902.
-22.0 (c 0.30, CHCl3) and [R]17 -28.9 (c 0.28, CHCl3). Their sample
D
of ent-9 was reported to exhibit [R]17 -39.1 (c 0.44, CHCl3).
D

5354 J . Org. Chem., Vol. 61, No. 16, 1996
Paquette and Wang
Sch em e 4
ester 11, which was directly oxidized to the dicarboxylate
level. Two methods for accomplishing this conversion
were examined.
In the first, 11 was admixed with iodine and potassium
hydroxide in methanol.22 However, the yield of 12b
produced under these conditions (52% for the two steps)
was determined to be less efficient than sequential
treatment with sodium chlorite23 and acidic methanol
(87% overall).
Dieckmann cyclization of 12b was accomplished most
efficaciously by making recourse to sodium hexamethyl-
disilazide in THF at 20 °C.24 The ability to carry out this
ring closure in high yield made possible access to respect-
able amounts of ketone 5 following decarbomethoxylation
by an established protocol.25
Preliminary studies involving the condensation of the
lithio derivative of 3 with 5 showed the ketone to be easily
deprotonated. This is as expected in light of the sterically
hindered nature of the carbonyl group and its setting in
a five-membered ring. In order to achieve reduced
basicity, transmetalation with anhydrous cerium trichlo-
ride26 was implemented to generate 4 as the reactive
nucleophile. Under these circumstances, 1,2-addition
occurred smoothly to give 6 (Scheme 4). The projected
sensitivity of this alcohol prompted us to treat it directly
with a catalytic quantity of camphorsulfonic acid in CH2-
Cl2 at rt. Within 10 min, 6 had been completely con-
sumed and replaced by a 10.4:1 mixture (GC analysis)
of spirocyclic ketones 7 and 14 (76%). This result
occasioned no surprise.
The very similar Rf values of these ring-expanded
intermediates prompted introduction of the final requisite
carbon atom in advance of chromatographic separation.
Although vinyl triflate 20 was easily accessible,27 cou-
pling with lithium dimethyl cuprate28 could not be
effected under a wide variety of conditions. The steric
blockade associated with the neopentyl nature of the
reaction center is held responsible for this lack of reactiv-
ity. These developments prompted investigation of me-
thyllithium addition. In both instances, the methyl group
was introduced from the â-face to provide 15 (87%) and
21 (10%) as easily purified diastereomers. The stereo-
chemical assignments to 7, 15, and 21 are reliably
founded on extensive 1H-1H COSY and NOE studies
performed at 300 MHz. Some of these data are compiled
in Table 1.
subunit. To this end, 15 was subjected to standard
hydroboration conditions and diol 16 was smoothly
oxidized to hydroxy aldehyde 17a with PCC. Of the
methods examined to transform 17a into 17b, that
involving iodine and potassium hydroxide in methanol22
proved most serviceable and direct (72%).
Not unexpectedly, the dehydration of 17b with thionyl
chloride in pyridine containing DMAP28 resulted in
preponderant formation of exocyclic olefin 19 relative to
the desired endocyclic isomer 18 (ratio 2:1). To our
dismay, however, all efforts to achieve internal migration
of the double bond in 19 either with iodine in refluxing
benzene29 or with rhodium trichloride in hot ethanol30
Following arrival at 15, attention was given to conver-
sion of the vinyl substituent into the requisite acetic ester
(21) Hazen, J . R. J . Org. Chem. 1970, 35, 973.
(22) Inch, T. D.; Ley, R. V.; Rich, R. J . Chem. Soc. C 1968, 1693.
(23) (a) Balkrishna, S. B.; Childers, W. E., J r.; Pinnick, H. H.
Tetrahedron 1981, 37, 2091. (b) Schwab, J . M.; Klassen, J . B. J . Am.
Chem. Soc. 1984, 106, 7217.
(24) Welch, S. C.; Rao, A. S. C. P.; Gibbs, C. G.; Wong, R. Y. J . Org.
Chem. 1980, 45, 4077.
(25) (a) Krapcho, A. P. Synthesis 1982, 893. (b) Trost, B. M.;
J ungheim, L. N. J . Am. Chem. Soc. 1980, 102, 7910.
(26) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392.
(27) Review: Ritter, K. Synthesis 1993, 735.
(28) Posner, G. H.; Schulman-Roskes, E. M. Tetrahedron 1992, 48,
4677.
(29) Kircher, H. W.; Rosenstein, F. U. J . Org. Chem. 1987, 52, 2587.

Stereocontrolled Synthesis of ent-Grindelic Acid
J . Org. Chem., Vol. 61, No. 16, 1996 5355
Ta ble 1. Su m m a r y of NOE Differ en ce Exp er im en ts
absolute configuration of grindelic acid can now be
considered as closed.
Exp er im en ta l Section
Gen er a l P r oced u r e. All manipulations were performed
under a nitrogen atmosphere. Solvents were dried over 4 Å
molecular sieves before distillation. Benzene, ether, tetrahy-
drofuran, and toluene were distilled from sodium or sodium/
benzophenone ketyl. Dichloromethane, diisopropylamine, dim-
ethyl sulfoxide, dimethylformamide, and triethylamine were
each distilled from calcium hydride. Melting points are
uncorrected. Exact mass measurements were recorded on
Kratos MS-30 or VG-70-2505 mass spectrometers at The Ohio
State University Chemical Instrumentation Center. Elemen-
tal analyses were performed at the Scandinavian Microana-
lytical Laboratory, Herlev, Denmark. The chromatographic
separations were carried out either under flash conditions on
Fluka silica gel H or gravimetrically on Woelm silica gel 63-
200. The organic extracts were dried over anhydrous sodium
sulfate. All reagents were reagent grade and purified where
necessary.
(1R,2R)-2-Ca r b oxy-2,6,6-t r im et h ylcycloh exa n ep r op i-
on ic Acid Dim eth yl Ester (12b). To a magnetically stirred
solution of 10b, [R]24D +32.7 (c 0.29, CHCl3) (4.0 g, 19.05 mmol),
in a mixture of methanol (32 mL) and benzene (96 mL) cooled
to 0 °C was added lead tetraacetate (8.91 g, 19.10 mmol). After
30 min at rt, saturated NaHCO3 solution was introduced, the
mixture was filtered through a pad of Celite, and the filtrate
was extracted with ether. The combined extracts were dried
and evaporated to leave the aldehydo ester 11.
This product was dissolved in tert-butyl alcohol (190 mL)
containing 2-methyl-2-butene (32 mL), cooled to 0 °C, and
treated with a solution of NaClO2 (12.03 g, 133 mmol) and
NaH2PO4‚H2O (13.11 g, 95 mmol) in water (91 mL). During
12 h of stirring at rt, the yellow solution became colorless. Most
of the tert-butyl alcohol was removed on a rotary evaporator,
at which point the residue was diluted with water, acidified
with 5% HCl to pH 2, and extracted with ethyl acetate. The
combined organic phases were washed with brine, dried, and
concentrated to leave the crude carboxylic acid 12a , which was
taken up in methanol (380 mL) containing concentrated H2-
SO4 (2.1 mL) and stirred at 0 °C for 1 h. The reaction mixture
was concentrated in vacuo, diluted with water, and extracted
with ethyl acetate. The combined organic layers were dried
and concentrated, and the residue was purified by chroma-
tography on silica gel (elution with 20:1 hexanes/ethyl acetate)
to give 12b as a colorless oil (4.47 g, 87% overall); IR (neat,
were unsuccessful. The neighboring spirocyclic tetrahy-
drofuran was not accommodating of more strongly acidic
conditions.
Nonetheless, saponification of 18 delivered dextroro-
tary grindelic acid, [R]24D +134.3 (c 0.035, CHCl3), whose
absolute configuration must be expressed as 1b. Com-
parable hydrolysis of natural methyl grindelate provided
by Dr. Shimizu gave (-)-1a , [R]24 -132.3 (c 0.034,
D
CHCl3). The fully synthetic sample exhibited spectral
properties showing it decisively to be identical to natural
grindelic acid except for the sign of optical rotation. On
this basis, it can be confidently asserted that 1 is a
member of the labdane family and that the many
grindelane diterpenoids derived from 1 are of the same
absolute configurational parentage.
1
cm-1) 1782, 1462, 1435, 1244, 1151, 1107, 1062, 980, 874; H
NMR (300 MHz, CDCl3) δ 3.65 (s, 6 H), 2.24 (m, 2 H), 1.72 (m,
3 H), 1.55-1.25 (series of m, 6 H), 1.20 (s, 3 H), 0.93 (s, 3 H),
0.90 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 179.4, 174.0,
51.8, 51.4, 48.8, 47.1, 40.8, 37.1, 34.9, 34.2, 32.8, 23.1, 22.6,
18.2, 17.6; MS m/ z (M+) calcd 270.1831, obsd 270.1834; [R]24
D
Su m m a r y
+4.0 (c 0.20, CHCl3). Anal. Calcd for C15H26O4: C, 66.62; H,
9.70. Found: C, 66.68; H, 9.69.
The total synthesis described above demonstrates the
capability of oxonium ion-initiated pinacolic ring expan-
sions for constructing oxygen-containing spirocyclic sys-
tems in a stereocontrolled manner. Much as in an earlier
described application involving preparation of the dac-
tyloxenes,10 substituent effects operate in the desired
direction to set appropriate absolute configuration. A
more detailed analysis of migratory aptitudes is under
investigation and will be reported shortly.
A number of other concepts were successfully utilized,
including the enhancement of effective levels of 1,2-
addition to 5 by prior formation of the organocerate. The
implementation of other chemoselective reactions was
met without setback, such that the saga surrounding the
(3a R,7a R)-Hexa h yd r o-4,4,7a -tr im eth yl-1-in d a n on e (5).
To a cold (0 °C), magnetically stirred solution of sodium
hexamethyldisilazide (3.1 mL of 1 M) in dry THF (4.7 mL) was
slowly added a solution of 12b (277 mg, 1.03 mmol) in the same
solvent (26 mL). After being stirred at rt for 2 h, the reaction
mixture was returned to 0 °C, quenched with cold 1 M HCl (6
mL), and extracted with ethyl acetate. The combined organic
phases were dried and evaporated to leave a residue that was
chromatographed on silica gel (elution with 20:1 hexanes/ethyl
acetate). There was isolated 242 mg (99%) of 13 as a colorless
oil.
The above material (258 mg, 1.08 mmol) was dissolved in
DMSO (5.0 mL) containing water (23 µL) and lithium chloride
(138 mg, 3.24 mmol), and the mixture was heated at 120-
140 °C for 2 h, cooled to rt, diluted with water (3 mL), and
extracted with ether. The combined ether phases were washed
with brine, dried, and concentrated to leave a yellow oil,
chromatography of which on silica gel (elution with 20:1
hexanes/ethyl acetate) afforded 176 mg (91%) of 5 as a colorless
(30) (a) Grieco, P. A.; Nishizawa, M.; Marinovic, N.; Ehmann, W. J .
J . Am. Chem. Soc. 1976, 98, 7102. (b) Andrieaux, J .; Barton, D. H. R.;
Patin, H. J . Chem. Soc., Perkin Trans. 1 1977, 359.

5356 J . Org. Chem., Vol. 61, No. 16, 1996
Paquette and Wang
oil: IR (neat, cm-1) 1739, 1474, 1459, 1369, 1120, 1020; 1H
NMR (300 MHz, CDCl3) δ 2.40 (dd, J ) 19.1, 8.8 Hz, 1 H),
2.04 (dt, J ) 19.1, 8.8 Hz, 1 H), 1.92-1.83 (m, 1 H), 1.75-1.55
(m, 4 H), 1.51-1.41 (m, 1 H), 1.27 (dd, J ) 13.2, 5.6 Hz, 1 H),
1.19-0.97 (m, 2 H), 0.95 (s, 3 H) 0.92 (s, 6 H); 13C NMR (75
MHz, CDCl3) ppm 221.3, 54.1, 47.9, 41.3, 35.3, 33.9, 32.2, 32.0,
21.4, 19.1, 19.0, 15.6; MS m/ z (M+) calcd 180.1514, obsd
180.1500; [R]24D -116.7 (c 0.18, CHCl3). The 2,4-dinitrophen-
ylhydrazone of 5 melted at 169-170 °C. Anal. Calcd for
C18H24N4O4: C, 59.97; H, 6.72. Found: C, 59.64; H, 6.72.
(2R,4′a R,5R,8′a R)-Deca h yd r o-5,5′,5′,8′a -tetr a m eth yl-5-
vin ylspir o[fu r a n -2(3H),1′(2′H)-n a p h th a len ]-2′-on e (7) a n d
(2S,4′a R,5S,8′a R)-Deca h yd r o-5,5′,5′,8′a -tetr a m eth yl-5-vi-
n ylsp ir o[fu r a n -2(3H),1′(2′H)-n a p h th a len ]-2′-on e (14). Ce-
rium trichloride heptahydrate (3.94 g, 10.57 mmol) was ground
to a fine powder and then heated gradually to 100 °C during
12 h and to 135-140° during an additional 12 h while
evacuated to 0.5 Torr. While the flask was still hot, dry N2
was introduced and cooling to rt was allowed to proceed.
Freshly distilled anhydrous THF (26 mL) was introduced, and
the resulting suspension was well stirred overnight (14 h) at
rt.
In another flask, a solution of 3 (986 mg, 8.96 mmol) in dry
THF (13 mL) was cooled to -78 °C, treated with tert-
butyllithium (4.9 mL of 1.7 M in pentane, 8.33 mmol), and
stirred for 1 h. The CeCl3 slurry was also cooled to -78 °C,
and tert-butyllithium was added dropwise until a pink color
persisted (0.2 mL). The solution of lithiated dihydrofuran was
introduced via cannula to give a yellow-orange mixture and
stirring was maintained for 1 h. At this point, a solution of 5
(735 mg, 4.08 mmol) in THF (4.1 mL) cooled to -78 °C was
added via cannula. The reaction mixture was agitated at -78
°C for 3 h before being allowed to warm to rt overnight (15 h),
treated with saturated NaHCO3 solution (5 mL) at -78 °C,
and filtered through Celite. The filter cake was rinsed with
ether, and the combined filtrates were dried and concentrated
to leave impure 6 as a yellow oil.
For 15: colorless oil; IR (neat, cm-1) 3495, 1464, 1366, 1097,
1049, 1014, 913; H NMR (300 MHz, CDCl3) δ 6.08 (dd, J )
1
17.4, 10.8 Hz, 1 H), 5.08 (dd, J ) 17.4, 1.4 Hz, 1 H), 4.94 (dd,
J ) 10.8, 1.4 Hz, 1 H), 2.13-1.99 (m, 3 H), 1.89-1.73 (m, 2
H), 1.68-1.00 (series of m, 11 H), 1.31 (s, 3 H), 1.12 (s, 3 H),
1.07 (s, 3 H), 0.88 (s, 3 H), 0.83 (s, 3 H); 13C NMR (75 MHz,
CDCl3) ppm 146.2, 110.4, 93.7, 84.8, 75.8, 47.8, 42.3, 41.9, 38.3,
37.6 34.3, 33.6, 33.3, 30.1, 29.3, 26.8, 21.9, 18.5, 18.1, 17.8;
MS m/ z (M+) calcd 306.2559, obsd 306.2554; [R]25 +3.0 (c
D
0.23, CHCl3). Anal. Calcd for C20H34O2: C, 78.36; H, 11.19.
Found: C, 78.29; H, 11.22.
For 21: colorless oil; IR (neat, cm-1) 3480, 1464, 1367, 1101,
1081, 1048, 1016, 994, 913; 1H NMR (300 MHz, CDCl3) δ 6.08
(dd, J ) 17.5, 10.8 Hz, 1 H), 5.06 (dd, J ) 17.5, 1.2 Hz, 1 H),
4.94 (dd, J ) 10.8, 1.2 Hz, 1 H), 2.15-0.89 (series of m, 16 H),
1.33 (s, 3 H), 1.24 (s, 3 H), 1.08 (s, 3 H), 0.88 (s, 3 H), 0.81 (s,
3 H); 13C NMR (75 MHz, CDCl3) ppm 146.1, 109.9, 93.9, 85.0,
75.8, 46.9, 43.0, 41.7, 38.5, 36.9, 34.5, 33.38, 33.35, 29.6, 29.2,
27.2, 21.8, 18.3, 18.2, 17.9; MS m/ z (M+) calcd 306.2559, obsd
306.2556; [R]24 -4.0 (c 0.05, CHCl3).
D
(2R,2′R,4′aR,5R,8′aR)-Decah ydr o-2′-h ydr oxy-2′,5,5′,5′,8′a-
p en t a m et h ylsp ir o[fu r a n -2(3H ),1′(2′H )-n a p h t h a len e]-5-
eth a n ol (16). A solution of 15 (34 mg, 0.11 mmol) in THF
(0.1 mL) was added to diborane in THF (0.16 mL of 1.0 M,
0.16 mmol) at -40 °C and stirred for 6 h at 0 °C before being
treated with 15% NaOH solution (0.16 mL) and 30% hydrogen
peroxide (0.16 mL) at 0 °C. The ice bath was removed, and
the mixture was stirred at rt for 30 min and diluted with water
and ether. The aqueous phase was extracted with ether and
with ethyl acetate. The combined organic layers were washed
with brine, dried, and concentrated. The residue was chro-
matographed on silica gel (elution with 1:1 hexanes/ethyl
acetate) to give 31 mg (87%) of 16 as colorless crystals, mp
134-135 °C (from CHCl3); IR (film, cm-1) 3384, 1455, 1388,
1372, 1197, 1171, 1108, 1059, 1003; 1H NMR (300 MHz, CDCl3)
δ 4.03 (ddd, J ) 11.2, 11.2, 2.6 Hz, 1 H), 3.75-3.65 (m, 1 H),
3.56 (s, 1 H), 3.53 (s, 1 H), 2.21-0.88 (series of m, 17 H), 1.33
(s, 3 H), 1.25 (s, 3 H), 1.06 (s, 3 H), 0.85 (s, 3 H), 0.81 (s, 3 H);
13C NMR (75 MHz, CDCl3) ppm 95.3, 86.3, 75.3, 60.2, 48.6,
43.1, 42.3, 41.8, 38.6, 34.5, 33.7, 33.4, 29.4, 27.6, 26.1, 21.9,
18.4, 17.9, 17.1; MS m/ z (M+) calcd 324.2664, obsd 324.2664;
This material was directly dissolved in CH2Cl2 (41 mL),
treated with camphorsulfonic acid (100 mg, 0.43 mmol), and
stirred at rt for 10 min. The resulting dark yellow reaction
mixture was quenched with saturated NaHCO3 solution (10
mL), and the separated organic layer was washed with brine,
dried, and concentrated to leave a yellow oil which was
chromatographed on silica gel (elution with 15:1 hexanes/
ether). There was isolated 897 mg (76%) of 7 and 14 as a
colorless oil. The isomeric ratio was determined to be 10.4:1
by GC analysis.
[R]24 -0.5 (c 0.20, CHCl3). Anal. Calcd for C20H36O3: C,
D
74.01; H, 11.19. Found: C, 74.01; H, 11.17.
(2R,2′R,4′aR,5R,8′aR)-Decah ydr o-2′-h ydr oxy-2′,5,5′,5′,8′a-
p en t a m et h ylsp ir o[fu r a n -2(3H ),1′(2′H )-n a p h t h a len e]-5-
a ceta ld eh yd e (17a ). Diol 16 (94.4 mg, 0.29 mmol) in CH2Cl2
(9 mL) was added to a magnetically stirred mixture of
pyridinium chlorochromate (128 mg, 0.59 mmol) and powdered
4 Å molecular sieves (50 mg) in CH2Cl2 (7 mL), stirred for 13
h at rt, diluted with ether (2 mL), and filtered through a pad
of Florisil. The pad was rinsed with ether and the combined
filtrates were evaporated. Flash chromatography of the
residue on silica gel (elution with 5:1 hexanes/ethyl acetate)
gave 17a (65.6 mg, 70%) as a white solid: mp 90-91 °C; IR
(film, cm-1) 3509 (br), 1721, 1464, 1388, 1108, 1048, 1001; 1H
NMR (300 MHz, CDCl3) δ 9.85 (t, J ) 2.8 Hz, 1 H), 2.81 (dd,
J ) 12.3, 2.8 Hz, 1 H), 2.53 (dd, J ) 12.3, 2.8 Hz, 1 H), 2.27-
1.01 (series of m, 16 H), 1.41 (s, 3 H), 1.19 (s, 3 H), 1.08 (s, 3
H), 0.87 (s, 3 H), 0.82 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
202.5, 94.7, 82.6, 75.5, 56.5, 47.8, 42.5, 41.9, 40.2, 38.4, 34.6,
33.6, 33.5, 29.7, 29.6, 26.7, 21.9, 18.4, 18.0, 17.8; MS m/ z (M+)
For 7: IR (neat, cm-1) 1717, 1464, 1368, 1097, 1060, 1021,
984, 918; 1H NMR (300 MHz, C6D6) δ 5.75 (dd, J ) 17.4, 10.7
Hz, 1 H), 5.02 (dd, J ) 17.4, 1.2 Hz, 1 H), 4.82 (dd, J ) 10.7,
1.2 Hz, 1 H), 3.05 (ddd, J ) 12.9, 12.9, 7.1 Hz, 1 H), 2.65-
2.58 (m, 1 H), 2.27 (ddd, J ) 12.9, 4.5, 2.1 Hz, 1 H), 2.07 (dd,
J ) 13.0, 3.2 Hz, 1 H), 1.89-1.81 (m, 1 H), 1.73-1.60 (m, 2
H), 1.43-0.85 (series of m, 8 H), 1.19 (s, 3 H), 0.81 (s, 3 H),
0.69 (s, 3 H), 0.62 (s, 3 H); 13C NMR (75 MHz, C6D6) ppm 210.3,
144.5, 111.7, 94.3, 84.2, 45.8, 43.9, 42.1, 38.4, 37.6, 33.6, 33.4,
32.2, 26.6, 24.1, 23.5, 22.0, 19.0, 15.9; MS m/ z (M+) calcd
290.2246, obsd 290.2244; [R]24 +26.6 (c 0.32, CHCl3). Anal.
D
Calcd for C19H30O2: C, 78.56; H, 10.42. Found: C, 78.80; H,
10.40.
(2R,2′R,4′a R,5R,8′a R)-Deca h yd r o-2′,5,5′,5′,8′a -p en t a -
m eth yl-5-vin ylsp ir o[fu r a n -2(3H),1′(2′H)-n a p h th a len ]-2′-
ol (15) a n d (2S,2′R,4′a R, 5S,8′a R)-Deca h yd r o-2′,5,5′,5′,8′a -
pen tam eth yl-5-vin ylspir o[fu r an -2(3H),1′(2′H)-n aph th alen ]-
2′-ol (21). Dry THF (5.7 mL) was added to anhydrous CeCl3
calcd 322.2508, obsd 322.2520; [R]24 -38.5 (c 0.195, CHCl3).
D
Meth yl (2R,2′R,4′a R,5R,8′a R)-Deca h yd r o-2′-h yd r oxy-
2′,5,5′,5′,8′a -p en ta m eth ylsp ir o[fu r a n -2(3H),1′(2′H)-n a p h -
th a len e]-5-a ceta te (17b). A solution of 4% (w/v) potassium
hydroxide in methanol was added dropwise to a mixture of
17a (11.4 mg, 0.035 mmol) and iodine (17.8 mg, 0.07 mmol)
in methanol (0.5 mL) at 45-50 °C until no free iodine
remained. The reaction mixture was diluted with water (1
mL) and extracted with chloroform. The combined organic
phases were dried and concentrated to leave a residue that
was chromatographed on silica gel (elution with 6:1 hexanes/
ethyl acetate). There was isolated 9.0 mg (72%) of 17b as a
colorless oil; IR (neat, cm-1) 3542, 1738, 1463, 1364, 1201,
1094, 1048, 1022, 990; 1H NMR (300 MHz, CDCl3) δ 3.66 (s, 3
H), 2.70 (d, J ) 13.9 Hz, 1 H), 2.64 (d, J ) 13.9 Hz, 1 H), 2.12-
(1.7 mmol) and stirred overnight to produce a slurry.
A
solution of 1.4 M methyllithium in ether (1.2 mL) was added
to the cold (0 °C) slurry and stirred for 1.5 h at this temper-
ature. A mixture of 7 and 14 (51 mg, 0.17 mmol) was
introduced and, after 40 min, quenching was implemented
with saturated NH4Cl solution (1 mL) and brine (2 mL). The
aqueous layer was extracted with ether, and the combined
organic phases were washed with brine, dried, and concen-
trated. Purification of the residue by chromatography on silica
gel (elution with 20:1 hexanes/ethyl acetate) furnished 47 mg
(87%) of 15 and 5.2 mg (10%) of 21.

Stereocontrolled Synthesis of ent-Grindelic Acid
J . Org. Chem., Vol. 61, No. 16, 1996 5357
1.09 (series of m, 16 H), 1.38 (s, 3 H), 1.19 (s, 3 H), 1.07 (s, 3
H), 0.87 (s, 3 H), 0.81 (s, 3 H); 13C NMR (75 MHz, CDCl3) ppm
171.8, 94.1, 83.0, 75.6, 51.4, 47.7, 47.5, 42.5, 41.8, 39.0, 38.3,
34.5, 33.6, 33.4, 29.4, 28.3, 27.0, 21.9, 18.4, 18.0, 17.8; MS m/ z
51.2, 46.9, 46.7, 41.8 (2 C), 36.8, 33.6, 33.42, 33.36, 32.0, 27.2,
25.4, 23.7, 22.0, 19.2, 17.1; MS m/ z (M+) calcd 334.2508, obsd
334.2509; [R]24 -17.9 (c 0.28, CHCl3).
D
(+)-Gr in d elic Acid (1b). A solution of 18 (2.2 mg, 0.006
mmol) in methanol (1 mL) and water (0.1 mL) was treated
with potassium hydroxide (4.8 mg, 0.085 mmol), stirred at rt
for 48 h, quenched with 5% HCl (0.1 mL), and extracted with
ethyl acetate. The combined organic phases were dried and
concentrated to leave an oil, chromatography of which on silica
gel (elution with 10:1:0.2 hexanes/ethyl acetate/acetic acid)
afforded 1b as a colorless solid: mp 98-99 °C (from CHCl3);
IR (film, cm-1) 3500-3000, 1707, 1456, 1378, 1094, 1018, 993;
1H NMR (300 MHz, CDCl3) δ 5.61 (br s, 1 H), 2.68 (d, J ) 15.3
Hz, 1 H), 2.56 (d, J ) 15.3 Hz, 1 H), 2.17-1.12 (series of m, 13
H), 1.76 (s, 3 H), 1.38 (s, 3 H), 0.90 (s, 3 H), 0.87 (s, 3 H), 0.82
(s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 172.0, 133.1, 128.9,
92.6, 81.1, 47.4, 42.6, 41.8, 40.8, 39.5, 33.2, 32.9, 32.7, 27.5,
26.8, 24.2, 22.0, 21.2, 18.6, 16.7; MS m/ z (M+) calcd 320.2351,
(M+) calcd 352.2613, obsd 352.2613; [R]24 -19.8 (c 0.205,
D
CHCl3).
Meth yl (2S,4′aR,5R,8′aR)-4,4′a,5,5′,6′,7′,8′,8′a-Octah ydr o-
2′,5,5′,5′,8′a -p en ta m eth ylsp ir o[fu r a n -2(3H),1′(4′H)-n a p h -
th a len e]-5-a ceta te (18) a n d Meth yl (2S,4′a R,5R,8′a R)-
Decah ydr o-5,5′,5′,8′a-tetr am eth ylspir o[fu r an -2(3H),1′(2′H)-
n a p h th a len e]-5-a ceta te (19). Thionyl chloride (6.0 µL, 0.08
mmol) was added to a soution of 17b (9.0 mg, 0.025 mmol)
and DMAP (3.1 mg, 0.025 mmol) in pyridine (0.1 mL, 1.23
mmol) at 0 °C. The reaction mixture was stirred under N2
for 30 min, quenched by pouring into ice-water (1 mL), and
extracted with ethyl acetate. The combined organic layers
were dried and evaporated to leave an oil which was chro-
matographed on silica gel (elution with 20:1 hexanes/ethyl
acetate) to give 2.2 mg (26%) of 18 and 4.6 mg (54%) of 19.
For 18: white solid, mp 67-68 °C (from CHCl3); IR (neat,
obsd 320.2353; [R]24 +134.3 (c 0.035, CHCl3). Natural grin-
D
delic acid exhibits [R]24 -132.3 (c 0.034, CHCl3).
D
1
cm-1) 1740, 1455, 1436, 1224, 1093, 1022, 992; H NMR (300
MHz, CDCl3) δ 5.50 (m, 1 H), 3.65 (s, 3 H), 2.74 (d, J ) 14.2
Hz, 1 H), 2.61 (d, J ) 14.2 Hz, 1 H), 2.27-2.17 (series of m, 13
H), 1.76 (s, 3 H), 1.55 (s, 3 H), 1.33 (s, 3 H), 0.89 (s, 3 H), 0.81
(s, 3 H); 13C NMR (75 MHz, CDCl3) ppm 171.9, 134.9, 126.6,
90.6, 81.6, 51.4, 48.0, 42.7, 42.0, 40.7, 38.2, 33.2, 32.9, 32.8,
28.5, 27.4, 24.2, 22.4, 21.3, 18.8; MS m/ z (M+) calcd 334.2501,
obsd 334.2508; [R]24D +125.9 (c 0.085, CHCl3). Natural methyl
Ack n ow led gm en t. Support for this investigation
was provided by the National Science Foundation and
Eli Lilly Co. The authors thank Professor C. C. Liao
for making those arrangements necessary to bring
H.L.W. to The Ohio State University.
1
Su p p or tin g In for m a tion Ava ila ble: 300-MHz H NMR
grindelate exhibits [R]24 -127.1 (c 0.085, CHCl3).
and 75-MHz 13C NMR spectra of those compounds lacking
combustion data (12 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
D
For 19: colorless oil; IR (neat, cm-1) 1740, 1456, 1436, 1094,
1043, 895; 1H NMR (300 MHz, CDCl3) δ 4.78 (s, 1 H), 4.67 (s,
1 H), 3.63 (s, 3 H), 2.58-2.46 (m, 3 H), 2.17-2.02 (m, 3 H),
1.96-1.88 (m, 1 H), 1.74-1.48 (series of m, 6 H), 1.39-1.18
(m, 4 H), 1.29 (s, 3 H), 0.88 (s, 3 H), 0.79 (s, 3 H), 0.76 (s, 3 H);
13C NMR (75 MHz, CDCl3) ppm 171.9, 150.9, 106.7, 91.2, 81.2,
J O960547P