Synthesis of 2,7-Cyclofarnesol and 2,7-Cyclogeranylgeraniol: Prenylogs of β-Cyclogeraniol

Full text of DOI:10.1021/jo9706335

J . Org. Chem. 1997, 62, 7475-7478
7475
Syn th esis of 2,7-Cyclofa r n esol a n d
2,7-Cycloger a n ylger a n iol: P r en ylogs of
â-Cycloger a n iol
Robert M. Coates* and Alan Qingwu J in
The first commited step in the biosynthesis of pacli-
taxel and related diterpenes11 is the enzyme-catalyzed
cyclization of GGPP to a tricyclic taxadiene precursor,
recently established to be taxa-4(5),11(12)-diene (5).12 The
usual mechanism proposed involves macrocyclization to
a verticillene intermediate followed by an H+-induced
cyclization forming the C-ring as the last step.11,13,14
However, an interesting alternative cyclization mecha-
nism proceeding through 2,7-cycloGGPP warrants con-
sideration (eq 1). Thus, macrocyclization of (S)-4-OPP,
bridging to form the A and B rings, and transannular
proton shift (C-11 to C-3) would lead to taxa-4,11-diene.
This mechanism would be consistent with the results of
recent deuterium-labeling experiments with taxadiene
synthase which show intramolecular deuterium transfer
from C-11 to ring C, and it would explain the lack of
incorporation of verticillene.14
Department of Chemistry, University of Illinois, 600 South
Mathews Avenue, Urbana, Illinois 61801
Received April 8, 1997
R- and â-cyclogeraniol (1-OH and 2-OH), monoterpene
alcohols reported to occur as natural products in the leaf
oil of Citrus auranticum L,1 are considered as prototypes
for a cyclogeraniol family of structurally related monot-
erpenes including picrocrocin,2 safranal,3 4-hydroxycy-
clocitral,3 and similar compounds.1b,4 A plausible bio-
synthesis of the cyclogeraniols would be H+-induced
cyclization of geranyl diphosphate, the usual substrate
for monoterpene cyclases,5 to R- and/or â-cyclogeranyl PP
(e.g. 2-OPP) followed by diphosphate hydrolysis. Alter-
natively the cyclogeraniols might arise more directly by
enzymic cyclization of geraniol itself. It is also possible
that some or all members of the cyclogeraniol family of
natural products are actually oxidative metabolites of
carotenoid precursors.
In order to evaluate 2,7-cyclo-GGPP as an intermediate
in taxadiene biosynthesis, we required access to 4-OH.
This paper describes a practical five-step synthesis of this
new diterpene alcohol and the sesquiterpene analog, 2,7-
cyclofarnesol (3-OH), from 3-ethoxy-2-cyclohexenone (6)
(Scheme 1).
Prenylmethyl-(4-methyl-3-pentenyl) and geranyl-
methyl-((E)-4,8-dimethyl-3,7-nonadienyl)lithium reagents
were generated from the corresponding iodides by halogen/
metal exchange with tert-butyllithium in ether-pentane
for 1 h at -78 °C. Addition to 3-ethoxy-2-cyclohexenone
at -78 °C followed by hydrolysis with NH4Cl afforded
3-(prenylmethyl)- and 3-(geranylmethyl)-2-cyclohexenones
(7a , 79%; 7b, 87%), both of which are known com-
pounds.15,16 Excess (1.8-2.0 equiv) tert-butyllithium was
used on the expectation that the second equivalent of the
lithium reagent would be rapidly consumed by a second-
The sesquiterpene and diterpene analogs of â-cycloger-
aniol, 2,7-cyclofarnesol (3-OH) and 2,7-cyclogeranylge-
raniol (4-OH), are to the best of our knowledge unknown
compounds,6 despite their plausible biosynthetic origin
by analogous cyclizations of (E,E)-farnesyl PP and (E,E,E)-
geranylgeranyl PP (GGPP). Although structures based
on 2,7-cyclogeranylgeraniol were initially proposed for
three diterpenes isolated from Magydaris panacifolia,7
the constitutions were revised following total synthesis
1
and detailed H-NMR analysis.8 Many naturally occur-
ring sesquiterpenes and diterpenes related to 6,11-
cyclofarnesol9 and 10,15-cyclogeranylgeraniol10 have been
reported.
(1) (a) Uchida, S. J . Soc. Chem. Ind. J pn, Suppl. Binding 1928, 31,
B. 188; (b) Erman, W. F. Chemistry of the Monoterpenes Part A;
Dekker: New York, 1985; Chapter 5.
(2) (a) Kuhn, R.; Winterstein, A. Chem. Ber. 1934, 67, 344. (b)
Simonsen, J . L. The Terpenes; Cambridge University Press: Cam-
bridge, England, 1953; Vol. I, 114-122.
(3) Zarghami, N. S.; Heine, D. E. Phytochemistry 1971, 10, 2755.
(4) CRC Handbook of Terpenoids: Monoterpenoids; Dev, S., Ed.;
CRC Press: Boca Raton, FL, 1982.
(10) (a) Dev, S.; Misra, R. In CRC Handbook of Terpenoids: Diter-
penoids; Dev, S., Ed.; CRC Press: Boca Raton, FL, 1985; Vol. I, pp
166-173. (b) Teresa, J . de P.; Caballero, E.; Caballero, C.; Medarde,
M.; Barrero, A. F.; Grande, M. Tetrahedron Lett. 1978, 3491. (c)
Blackman, A. J .; Wells, R. J . Ibid. 1976, 2729.
(11) For reviews, see: (a) Gue´ritte-Voegelein, F.; Gue´nard, D.; Potier,
P. J . Nat. Prod. 1987, 50, 9. (b) Kingston, D. G. I.; Molinero, A. A.;
Rimoldi, J . M. Progr. Chem. Org. Nat. Prod. 1993, 61, 1-192. (c) Floss,
H. G.; Mocek, U. In Taxol®: Science and Applications; Suffness, M.,
Ed.; CRC Press: Boca Raton, FL, 1995; pp 191-208.
(12) (a) Koepp, A. E.; Hezari, M.; Zajicek, J .; Vogel, B. S.; LaFever,
R. E.; Lewis, N. G.; Croteau, R. J . Biol. Chem. 1995, 270, 8686. (b)
Rubenstein, S. M.; Williams, R. M. J . Org. Chem. 1995, 60, 7215.
(13) Harrison, J . W.; Scrowston, R. M.; Lythgoe, B. J . Chem. Soc. C
1966, 1933.
(5) Croteau, R. Chem. Rev. 1987, 87, 929-954.
(6) The following secondary reference works were searched: (a)
Chem. Abstr. 1907-1995, Vols. 1-123. (b) Encyclopedia of the Terpe-
noids; Glasby, J . S., Ed.; Wiley: Manchester, UK, 1982. (c) Nat. Prod.
Rep., 1984-1996, Vols. 1-13. (d) Terpenoids and Steroids, Specialist
Periodical Reports; Chemical Society: London, 1971-1983, Vols. 1-12.
(7) Teresa, J . de P.; Grande, C.; Grande, M. Tetrahedron Lett. 1978,
4563.
(8) (a) Nagano, H.; Masunaga, Y.; Matsuo, Y.; Shiota, M. Bull. Chem.
Soc. J pn. 1987, 60, 707. (b) Teresa, J . de P.; Grande, C.; Moran, J . R.;
Grande, M. Chem. Lett. 1984, 247. (c) Bruno, M.; Lamartina, L.;
Lentini, F.; Pascual, C.; Savona, G. Tetrahedron Lett. 1984, 25, 4287.
(9) (a) Dictionary of Natural Products; Chapman and Hall: London,
1994; see Vol 7, pp 164-165, 206. (b) Takeda, R.; Naoki, H.; Iwashita,
T.; Mizukawa, K.; Hirose, Y.; Isida, T.; Inoue, M. Bull. Chem. Soc. J pn.
1983, 56, 1125. (c) Suzuki, K. T.; Suzuki, N.; Nozoe, S. J . Chem. Soc.,
Chem. Commun. 1971, 527.
(14) Lin, X.; Hezari, M.; Koepp, A. E.; Floss, H. G.; Croteau, R.
Biochemistry 1996, 35, 2968.
(15) Hagiwara, H.; Uda, H. J . Chem. Soc., Perkin Trans. 1 1984,
91.
(16) (a) Douglas, G. H.; Graves, J . M. H.; Hartley, D.; Hughes, G.
A.; McLoughlin, B. J .; Siddall, J .; Smith, H. J . Chem. Soc. 1963, 5072.
(b) Emmick, T. L. German Offn. Patent 1, 965, 306; Chem. Abstr. 1970,
73, 55787z. (c) Grove, J . F.; J ennings, R. C.; J ohnson, A. W.; White, A.
F. Chem. Ind. 1974, 8, 346.
S0022-3263(97)00633-6 CCC: $14.00 © 1997 American Chemical Society

7476 J . Org. Chem., Vol. 62, No. 21, 1997
Sch em e 1. P r ep a r a tion of 3-OH a n d 4-OH
Notes
ary reaction with the tert-butyl iodide produced in the
exchange reaction.17 In some cases, small amounts (5-
10%) of the chromatographically inseparable 3-tert-butyl-
2-cyclohexenone were detected as an impurity in the
cyclohexenone products by GC and 1H NMR analysis,
presumably owing to reaction of unconsumed tert-butyl-
lithium with 3-ethoxy-2-cyclohexenone. Since this byprod-
uct evidently did not react with Me2CuLi, it was unaf-
fected by the subsequent carboxylation and phosphoryla-
tion reactions, and when present, it was easily separated
from the more polar enol phosphates during chromato-
graphic purification. When prenylmethyl bromide was
used instead of the iodide in the exchange with tert-
butyllithium, mixtures of 7a and 3-tert-butyl-2-cyclohex-
enone (4:1 to 10:1) were formed even after allowing an
extended reaction time (3 h at -23 °C) for destruction of
the excess tert-butyllithium with tert-butyl bromide.
Conjugate addition of Me2CuLi (1.1 equiv) in ether
(-30 °C, 12 min) followed by in situ carboxylation of the
resulting enolate with methyl cyanoformate (3 equiv, -78
°C then rt)18 afforded â-keto esters 8a ,b accompanied by
small amounts (14% and 11%) of enol carbonates 11a ,b
resulting from competing O-carboxylation. Since the
â-keto esters proved to be mixtures of easily equilibrated
epimers and enol tautomer, purification by chromatog-
raphy resulted in substantial losses. Consequently the
crude product from the conjugate addition-carboxylation
step was used for enol phosphorylation without purifica-
tion.
Me2CuLi (1.4 equiv) in ether (-23 °C, 3 h) furnished the
tetrasubstituted R,â-enoates 10a ,b (77% and 86%), which
were reduced with LiAlH4 in ether to (()-2,7-cyclofarnesol
(3-OH, 82%) and (()-2,7-cyclogeranylgeraniol (4-OH,
86%).
The diphosphate ester of (()-4-OH and its dideuterio
derivative obtained by LiAlD4 reduction of 10b were
prepared by SN2 displacement of the corresponding allylic
chlorides20 with (Bu4N)3 HP2O7.21 The lack of significant
incorporation of (()-4-OPP-d2 into taxadiene in incuba-
tions with taxadiene synthase effectively rules out the
alternative cyclization mechanism via 2,7-cycloGGPP (eq
1).22 Nevertheless, 2,7-cyclofarnesol (3-OH), 2,7-cycloger-
anylgeraniol (4-OH), their 3,4- or exocyclic double bond
isomers, and related metabolites remain plausible can-
didates for new types of naturally occurring sesquiter-
penes and diterpenes. The syntheses and characteriza-
tion data presented here for these prenylogs of â-cyclo-
geraniol should facilitate the identification of the com-
pounds from plant sources.
Exp er im en ta l Section
Gen er a l Asp ects.23 1H and 13C NMR spectra were recorded
in CDCl3 at 400 MHz (or 500 MHz) and 101 MHz (or 126 MHz).
Mass spectra were recorded on a Varian 70-4F or 70-VSE mass
spectrometer. All reagents were used as purchased unless
otherwise described. Prenylmethyl bromide was converted into
the iodide with NaI in acetone according to a published
procedure.24 Geranylmethyl iodide was prepared from geranyl-
methanol25 with I2, Ph3P, and imidazole (88%).26 Samples were
prepared for combustion analysis by bulb-to-bulb distillation at
0.1 mmHg (bath temperatures 100-190 °C). CuI was purified
by a published procedure.27
3-[(E )-4,8-Dim e t h yl-3,7-n on a d ie n yl]-2-cycloh e xe n -1-
on e (7b). A solution of geranylmethyl iodide (1.41 g, 5.1 mmol)
in ether (35 mL) at -78 °C was stirred and cooled at -78 °C as
tert-butyllithium (1.6 M, 5.75 mL, 9.2 mmol) in pentane was
added. After 1 h, enone 6 (0.86 g, 6.1 mmol) in ether (7 mL)
was added. After 50 min at -78 °C, saturated aqueous NH4Cl
(50 mL) was added at -78 °C and the mixture was allowed to
warm up to rt. The aqueous layer was extracted with ether (2
Installation of the C2 methyl group was accomplished
by cuprate coupling of the enol phosphates.19 Reaction
of the unpurified esters 8a ,b with NaH and (EtO)2P(O)Cl
in THF (rt, 8 h) afforded enol phosphates 9a ,b (52% and
62% from 7a ,b). The cuprate coupling reaction with
(20) Collington, E. W.; Meyers, A. I. J . Org. Chem. 1971, 36, 3044.
(21) Woodside, A. B.; Huang, Z.; Poulter, C. D. Organic Syntheses;
Wiley: New York, 1993; Collect. Vol. VIII, p 616.
(17) (a) Seebach, D.; Neumann, H. Chem. Ber. 1974, 107, 847. (b)
Neumann, H.; Seebach, D. Tetrahedron Lett. 1976, 4839. (c) Bailey,
W. F.; Punzalan, E. R. J . Org. Chem. 1990, 55, 5404. We thank a
reviewer for calling our attention to ref 17c, which also describes
optimized conditions for preparation of primary alkyllithiums by iodine/
lithium exchange.
(18) Crabtree, S. R.; Chu, W. L. A.; Mander, L. N. In Encyclopedia
of Reagents for Organic Synthesis; Paquette, L. A.; et al., Eds.; Wiley:
Chichester, UK, 1995; pp 3466-3469.
(19) Alderdice, M.; Sum, F. W.; Weiler, L. Organic Syntheses;
Wiley: New York, 1990; Collect. Vol. VII, p 351.
(22) The preparation and characterization of (()-4-OPP as well as
the incubation with taxadiene synthase will be reported separately:
Hezari, M.; Croteau, R.; J in, A. Q.; Coates, R. M.; Oliver, J . S.
Manuscript in preparation.
(23) Steiger, A.; Pyun, H.-J .; Coates, R. M. J . Org. Chem. 1992, 57,
3444.
(24) Crandall, J . K.; Magaha, H. S. J . Org. Chem. 1982, 47, 5368.
(25) Leopold, E. J . Organic Syntheses; Wiley: New York, 1990;
Collect Vol. VII, p 258.
(26) Marshall, J . A.; DeHoff, B. S. Tetrahedron 1987, 43, 4849.
(27) Kauffman, G. B.; Teter, L. A. Inorg. Synth. 1963, Vol VII, 10.

Notes
J . Org. Chem., Vol. 62, No. 21, 1997 7477
× 50 mL). The combined ethereal extracts were washed with
saturated NH4Cl (1 × 50 mL), dried (Na2SO4), and concentrated.
Purification of the residue by flash chromatography on silica gel
(20% EtOAc in hexane) gave 1.08 g (87%) of the enone 7b as a
pale yellow oil. Although 7b is known,16 no characterization
(10% EtOAc in hexane) to isolate the two products for charac-
terization. Enol carbonate 11a (7 mg, 14%): IR (neat) νmax 2932,
1761, 1442, 1258 cm-1; 1H NMR (500 MHz) δ 1.01 (s, 3 H), 1.24-
1.38 (m, 3 H), 1.46-1.53 (m, 1 H), 1.59 (s, 3 H), 1.67 (s, 3 H),
1.75 (quintet, 2 H, J ) 5.7 Hz), 1.91 and 1.96 (AB q of t, J AB
13.5 Hz, J AX ) J BX ) 6.4 Hz), 2.12 and 2.16 (AB q of t, J AB
)
)
data were reported: IR (neat) νmax 2925, 1671 cm-1 1H NMR
;
(400 MHz) δ 1.57 (s, 3 H), 1.58 (d, 3 H, J ) 0.9 Hz), 1.65 (d, 3 H,
J ) 1.0 Hz), 1.92-2.07 (br m, 6 H), 2.14-2.36 (br m, 8 H), 5.06
(m, 2 H), 5.86 (quintet, 1 H, J ) 1.2 Hz); 13C NMR (101 MHz) δ
16.0, 17.6, 22.7, 25.4, 25.6, 26.5, 29.7, 37.3, 38.0, 39.5, 122.5,
124.0, 125.7, 136.3, 166.2, 200.0; GCMS (EI) m/z 246.20. Anal.
Calcd for C17H26O: C, 82.87; H, 10.64. Found: C, 82.50; H,
10.62.
17.3 Hz, J AX ) 6.1 Hz, J BX ) 7.0 Hz), 3.79 (s, 3 H), 5.07 (br t, 1
H, J ) 7.0 Hz), 5.25 (s, 1 H); 13C NMR (126 MHz) δ 17.6, 19.4,
22.7, 25.7, 26.4, 34.0, 34.8, 42.6, 54.8, 123.0, 124.8, 131.3, 147.6,
154.1. â-Keto ester 8a (22 mg): IR (neat) νmax 2922, 1713, 1434,
1226 cm-1. Ma jor d ia ster eom er (67%): 1H NMR (400 MHz)
δ 1.05 (s, 3 H), 1.30 (ddd, 1 H, J ) 11.5, 5.4, 3.4 Hz), 1.42 (ddd,
1 H, J ) 13.2, 9.3, 5.1 Hz), 1.58 (s, 3 H), 1.66 (s, 3 H), 1.81-1.98
(m, 5 H), 2.30 (m, 2 H), 2.65 (m, 1 H), 3.28 (s, 1 H), 3.69 (s, 3 H),
5.04 (tt, J ) 7.1, 1.3 Hz); 13C NMR (101 MHz) δ 17.4, 21.4, 21.8,
22.0, 25.5, 33.3, 39.5, 40.1, 41.3, 51.6, 66.0, 123.6, 131.8, 206.8.
Min or d ia ster eom er (29%): 1H NMR (400 MHz) δ 0.96 (s, 3
H), 2.11 (ddd, 1 H, J ) 14.9, 10.7, 4.6 Hz), 2.77 (ddd, 1 H, J )
14.2, 10.0, 6.8 Hz), 3.21 (br s, 1 H), 3.68 (s, 3 H), 5.04 (tt, 1 H,
J ) 7.1, 1.3 Hz); 13C NMR (101 MHz) δ 21.5, 21.7, 23.5, 32.3,
38.2, 38.9, 41.5, 51.7, 67.2, 124.0, 131.4, 206.9. E n ol for m
(4%): 1H NMR (400 MHz) δ 1.16 (s, 3 H), 3.72 (s, 3 H), 13.0 (s,
1 H).
3-(4-Meth yl-3-p en ten yl)-2-cycloh exen -1-on e (7a ). Enone
7a was prepared as described above from prenylmethyl iodide
(209 mg, 0.99 mmol) to give 140 mg (79%) of 7a . The spectro-
scopic data match the published data:15 IR (neat) νmax 2926, 1673
cm-1 1H NMR (500 MHz) δ 1.59 (s, 3 H), 1.66 (s, 3 H), 1.96
;
(quintet, 2 H, J ) 6.4 Hz), 2.19 (m, 4 H), 2.27 (t, 2 H, J ) 5.9
Hz), 2.34 (t, 2 H, J ) 6.7 Hz), 5.05 (m, 1 H), 5.86 (br s, 1 H); 13
C
NMR (126 MHz) δ 17.7, 22.7, 25.53, 25.64, 29.7, 37.3, 38.0, 122.7,
125.8, 132.8, 166.2, 200.0.
Enone 7a was also prepared from prenylmethyl bromide as
described for 7b. When the solution containing t-BuLi (1.8
equiv) and the bromide was stirred for 2 h at -23 °C before
addition of enone 6, 7a was contaminated by 9% of 3-tert-butyl-
2-cyclohexenone which was inseparable from 7a by flash chro-
matography. When the lithiation reaction was stirred for 2 h
at -78 °C, the enone product contained 23% of the tert-butyl
byproduct. The presence of this impurity was detected by GC
(8.8 min compared to 9.9 min for 7a ) and 1H NMR analysis (by
characteristic peaks at 1.12 (s, 9 H) and 5.92 ppm (br s, 1 H)).
cis- a n d tr a n s-Meth yl 6-[(E)-4,8-Dim eth yl-3,7-n on a d ie-
n yl]-6-m eth yl-2-oxocycloh exa n eca r boxyla te (8b). A sus-
pension of CuI (724 mg, 3.80 mmol) in ether (10 mL) was stirred
and cooled at 0 °C as ethereal methyllithium (1.4 M, 5.42 mL,
7.59 mmol) was added. After 10 min at 0 °C, the solution was
cooled to -28 °C (1:1 H2O-acetone, dry CO2) and enone 7b (850
mg, 3.45 mmol) in ether (10 mL) was added. After 12 min at
-28 °C, the temperature was lowered to -78 °C, and a solution
of methyl cyanoformate (440 mg, 5.18 mmol) in ether (10 mL)
was added. After 2 h at -78 °C, the mixture was allowed to
warm slowly to rt over 4 h. Saturated aqueous NH4Cl (contain-
ing 5% of concentrated NH4OH, 30 mL) was added, and the
mixture was stirred open to air for 1 h. The aqueous layer was
extracted with ether (3 × 30 mL), and the combined ethereal
solutions were washed with saturated NaCl (1 × 40 mL), dried
(Na2SO4), and concentrated to give a yellow oil (1.18 g). The
crude mixture of â-keto ester epimers, and enol carbonate was
directly used in the enol phosphorylation. The two products
were isolated after a previous smaller scale run carried out with
200 mg (0.81 mmol) of enone 7b. Column chromatography on
silica gel (15% EtOAc in hexane) afforded the two products for
characterization. Enol carbonate 11b (29 mg, 11%): IR (neat)
Meth yl 2-[(Dieth ylp h osp h or yl)oxy]-6-[(E)-4,8-d im eth yl-
3,7-n on adien yl]-6-m eth yl-1-cycloh exen e-1-car boxylate (9b).
Enol phosphate 9b was prepared according to Weiler’s procedure
with some modifications.19 NaH (300 mg of 50% dispersion in
mineral oil, 6.3 mmol) was washed with THF (3 × 5 mL) and
suspended on THF (10 mL). A solution of â-keto ester 8b (1.18
g, 3.68 mmol assuming 100% purity) in THF (10 mL) was added,
and after 50 min at rt, diethyl chlorophosphate (763 mg, 4.42
mmol) in THF (10 mL) was added. After 8 h at rt, saturated
aqueous NH4Cl (40 mL) was added, and the product was
extracted with ether (4 × 50 mL). The combined ethereal
extracts were washed with saturated NaHCO3 (1 × 80 mL) and
saturated NaCl (1 × 80 mL), dried (Na2SO4), and concentrated.
Purification by flash chromatography on silica gel (35% EtOAc
in hexane) gave 9b as a yellow oil (0.98 g, 62% from enone 7b):
IR (neat) νmax 2938, 1725, 1672 cm-1; 1H NMR (400 MHz) δ 1.15
(s, 3 H), 1.31 (t, 6 H, J ) 7.0 Hz), 1.35 (m, 1 H), 1.43 (m, 2 H),
1.56 (s, 3 H), 1.58 (s, 3 H), 1.60 (m, 1 H), 1.74 (m, 2 H), 1.93 (m,
4 H), 2.02 (m, 2 H), 2.40 (t, 2 H, J ) 6.2 Hz), 3.72 (s, 3 H), 4.12
(m, 4 H), 5.06 (m, 2 H); 13C NMR (101 MHz) δ 15.7, 15.9, 16.0,
17.5, 18.2, 22.5, 25.5, 26.1, 26.5, 27.4, 33.2, 36.9, 39.5, 40.0, 51.3,
64.1 (d, J ) 3.8 Hz), 64.2 (d, J ) 3.1 Hz), 124.16, 124.18, 125.2
(d, J ) 8.5 Hz), 131.1, 134.7, 147.6 (d, J ) 7.7 Hz), 167.7 (d, J
) 1.6 Hz).
Meth yl 2-[(Dieth ylp h osp h or yl)oxy]-6-(4-m eth yl-3-p en -
t en yl)-6-m et h yl-1-cycloh exen e-1-ca r b oxyla t e (9a ). Enol
phosphorylation of the 11a + 8a mixture (547 mg) as described
above gave 348 mg (52%, 2 steps) of enol phosphate 9a : IR (neat)
νmax 2929, 1728, 1679 cm-1; 1H NMR (400 MHz) δ 1.16 (s, 3 H),
1.33 (tt, 6 H, J ) 7.1, 1.2 Hz), 1.32-1.39 (m, 1 H), 1.43 (dd, 1 H,
J ) 11.0, 2.0 Hz), 1.44 (br d, 1 H, J ) 11.3 Hz), 1.58 (s, 3 H),
1.66 (s, 3 H), 1.58-1.65 (m, 1 H), 1.76 (quintet, 2 H, J ) 6.1
Hz), 1.93 (dt, 2 H, J ) 10.0, 6.8 Hz), 2.42 (br t, 2 H, J ) 6.1 Hz),
3.73 (s, 3 H), 4.13 (m, 4 H), 5.05 (m, 1 H); 13C NMR (126 MHz)
δ 16.02, 16.08, 17.5, 18.4, 22.7, 25.7, 26.2, 27.6, 33.4, 37.0, 40.2,
51.4, 64.28 (d, J ) 4.6 Hz), 64.33 (d, J ) 3.7 Hz), 124.5, 125.4
(d, J ) 8.3 Hz), 131.3, 147.8 (d, J ) 7.4 Hz), 167.8 (d, J ) 1.8
Hz).
Meth yl 2,6-Dim eth yl-6-[(E)-4,8-dim eth yl-3,7-n on adien yl]-
1-cycloh exen e-1-ca r boxyla te (10b). Enoate 10b was pre-
pared according to Weiler’s procedure.19 A suspension of CuI
(508 mg, 2.67 mmol) in ether (10 mL) was stirred and cooled at
0 °C as methyllithium (1.4 M in ether, 3.8 mL, 5.4 mmol) was
added. After 10 min, the colorless solution was cooled to -23
°C (∼1:1 H2O-acetone, dry CO2) and enol phosphate 9b (871
mg, 1.91 mmol) in ether (8 mL) was added. After 3 h at -23
°C, saturated aqueous NH4Cl (containing 5% concd NH4OH, 30
mL) was added, and the mixture was stirred open to air for 1 h.
The aqueous layer was extracted with ether (3 × 30 mL), and
the combined organic layers were washed with saturated aque-
ous NaCl (1 × 40 mL), dried (Na2SO4), and concentrated.
Purification by flash chromatography on silica gel (5% EtOAc
in hexane) gave 523 mg (86%) of ester 10b as a yellow oil: IR
(neat) νmax 2929, 1725 cm-1; 1H NMR (400 MHz) δ 1.10 (s, 3 H),
1.30-1.45 (m, 4 H), 1.58 (s, 3 H), 1.60 (s, 3 H), 1.60-1.66 (m, 1
ν
max 2932, 1761, 1442, 1255 cm-1; 1H NMR (200 MHz) δ 1.02 (s,
3 H), 1.26-1.56 (br m, 6 H), 1.59 (s, 6 H), 1.68 (s, 3 H), 1.75 (m,
2 H), 1.86-2.20 (m, 6 H), 3.78 (s, 3 H), 5.09 (m, 2 H), 5.26 (s, 1
H). â-Keto ester 8b (97 mg) was a mixture of two diastereomers
and the enol tautomer in a 74:21:5 ratio based on 1H NMR
integrations. Ma jor d ia ster eom er : 1H NMR (400 MHz) δ 1.05
(s, 3 H), 1.29 (ddd, 1 H, J ) 11.7, 5.4, 4.2 Hz), 1.56 (s, 3 H), 1.58
(s, 3 H), 1.66 (s, 3 H), 1.80-2.06 (m, 8 H), 2.29 (dt, 2 H, J )
12.5, 5.9 Hz), 2.63 (dd, 1 H, J ) 14.2, 6.3 Hz), 3.27 (s, 1 H), 3.68
(s, 3 H), 5.05 (m, 2 H); 13C NMR (101 MHz) δ 15.7, 17.5, 21.4,
21.7, 22.0, 25.6, 26.5, 33.3, 39.44, 39.50, 40.0, 41.3, 51.6, 66.1,
123.4, 124.0, 131.2, 135.4, 169.1, 206.8. Min or d ia ster e-
om er : 1H NMR (400 MHz) δ 0.96 (s, 3 H), 1.43 (dt, 1 H, J )
13.7, 4.9 Hz), 2.10 (ddd, 1 H, J ) 14.6, 10.5, 4.6 Hz), 2.76 (ddd,
1 H, J ) 14.2, 10.0, 6.8 Hz), 3.21 (br s, 1 H), 3.66 (s, 3 H), 5.05
(m, 1 H); 13C NMR (101 MHz) δ 15.6, 17.4, 21.51, 21.54, 23.5,
26.5, 27.2, 32.3, 38.1, 38.9, 41.5, 51.7, 67.2, 123.8, 124.1, 131.2,
135.0, 169.0, 206.8. En ol for m : 1H NMR (400 MHz) δ 1.15 (s,
3 H), 3.75 (s, 3 H), 13.0 (s , 1 H).
Meth yl 6-(4-Meth yl-3-p en ten yl)-6-m eth yl-2-oxocycloh ex-
a n eca r boxyla te (8a ). The procedure described above with
enone 7a (379 mg) gave a yellow oil (673 mg), which was directly
used without purification in the enol phosporylation. A 62-mg
portion was subjected to column chromatography on silica gel

7478 J . Org. Chem., Vol. 62, No. 21, 1997
Notes
1
H), 1.66 (s, 3 H), 1.68 (s, 3 H), 1.88-2.08 (m, 9 H), 3.73 (s, 3 H),
5.08 (m, 2 H); 13C NMR (101 MHz) δ 15.9, 17.7, 18.5, 21.5, 22.6,
25.7, 26.2, 26.7, 31.2, 33.9, 36.2, 39.7, 40.3, 51.1, 124.4, 124.7,
131.3, 134.6, 135.0, 135.1, 171.1; GCMS (EI) m/z 318.25. Anal.
Calcd for C21H34O2: C, 79.19; H, 10.76. Found: C, 79.30; H,
10.42.
4.9 Hz, J BX ) 5.3 Hz), 5.09 (m, 2 H); H NMR (D2O exchange)
the same except for 0.95 (t, 1 H) absent, and 4.06, 4.16 (AB q, J
) 11.5 Hz); 13C NMR (101 MHz) δ 15.9, 17.7, 19.1, 19.8, 22.9,
25.7, 26.4, 32.6, 34.9, 37.1, 39.7, 40.3, 58.8, 124.3, 124.8, 131.3,
134.6, 134.7, 137.5; GCMS (EI) m/z 290. Anal. Calcd for
C
20H34O: C, 82.69; H, 11.80. Found: C, 82.43; H, 12.08.
Met h yl 2,6-Dim et h yl-6-(4-m et h yl-3-p en t en yl)-1-cyclo-
h exen e-1-ca r boxyla te (10a ). Methyl cuprate addition to enol
phosphate 9a (152 mg) as described above gave 75 mg (77%) of
2,6-Dim eth yl-6-(4-m eth yl-3-pen ten yl)-1-cycloh exen em eth -
a n ol (3-OH). Reduction of ester 10a (85 mg) as described above
gave 62 mg (82%) of 3-OH: IR (neat) νmax 3351, 2913, 1455, 1377,
1
ester 10a : IR (neat) νmax 2934, 1722 cm-1; H NMR (500 MHz)
1001 cm-1 1H NMR (500 MHz) δ 1.03 (s, 3 H), 1.32 (m, 2 H),
;
δ 1.10 (s, 3 H), 1.32-1.44 (m, 3 H), 1.59 (s, 3 H), 1.65 (s, 3 H),
1.54-1.69 (m, 3 H), 1.90 (dt, 2 H, J ) 11.5, 5.7 Hz), 1.97 (m, 2
H), 3.71 (s, 3 H), 5.05 (tt, 1 H, J ) 7.1, 1.2 Hz); 13C NMR (126
MHz) δ 17.5, 18.6, 21.5, 22.8, 25.7, 26.3, 31.2, 34.0, 36.2, 40.4,
51.1, 124.9, 131.0, 134.99, 135.15, 171.2; GCMS (EI) m/z 250.
Anal. Calcd for C16H26O2: C, 76.75; H, 10.47. Found: C, 79.60;
H, 10.21.
1.42 (ddd, 1 H, J ) 13.7, 11.9, 4.9 Hz), 1.58 (s, 3 H), 1.66 (s, 3
H), 1.76 (s, 3 H), 1.53-1.64 (m, 3 H), 1.73-1.81 (m, 1 H), 1.85-
2.03 (m, 3 H), 4.06 and 4.16 (AB q, 2H, J ) 11.5 Hz), 5.07 (m, 1
H); 1H NMR (D2O exchange) the same except for 4.73 (br s); 13
C
NMR (126 MHz) δ 17.6, 19.1, 19.8, 23.0, 25.7, 26.4, 32.7, 35.0,
37.1, 40.4, 58.7, 125.0, 131.1, 134.6, 137.5; GCMS (EI) m/z 204
(M - 18). Anal. Calcd for
Found: C, 81.31; H, 12.15.
C15H26O: C, 81.02; H, 11.78.
2,6-Dim et h yl-6-[(E)-4,8-d im et h yl-3,7-n on a d ien yl]-1-cy-
cloh exen em eth a n ol (4-OH). The alcohol was prepared ac-
cording to Paquette’s procedure with slight modification.28
A
Ack n ow led gm en t. A.Q.J . is grateful to the Univer-
sity of Illinois for the award of University Fellowships,
1996-1998. We thank the National Institutes of Health
for financial support of this work through Grant GM
13956.
suspension of LiAlH4 (202 mg, 5.32 mmol) in ether (10 mL) was
stirred at rt as ester 10b (431 mg, 1.35 mmol) in ether (5 mL)
was added. After 2 h at rt, H2O (0.20 mL), 15% NaOH (0.20
mL), and H2O (0.60 mL) were added in succession.29 The solid
was filtered and washed thoroughly with ether. Concentration
of the filtrate and purification of the residue by flash chroma-
tography (10% EtOAc in hexane) afforded 339 mg (86%) of 4-OH
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of â-keto esters 8a ,b (cis/trans mixtures), enol phos-
phates 9a ,b, (()-3-OH, and (()-4-OH (12 pages). This mater-
ial 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.
as a yellow oil: IR (neat) νmax 3377, 2927, 1456, 1375, 1002 cm-1
;
1H NMR (400 MHz) δ 0.95 (t, 1 H, J ) 5.2 Hz), 1.04 (s, 3 H),
1.29-1.48 (m, 4 H), 1.58 (s, 3 H), 1.60 (s, 3 H), 1.55-1.66 (m, 1
H), 1.68 (s, 3 H), 1.77 (s, 3 H), 1.72-1.84 (m, 1 H), 1.86-2.09
(m, 8 H), 4.07 and 4.18 (AB of ABX, 2 H, J AB ) 11.5 Hz, J AX
)
(28) Belmont, D. T.; Paquette, L. A. J . Org. Chem. 1985, 50, 4102.
(29) Fieser, L. F.; Fieser, M. Reagents Org. Synth. 1967, 1, 584.
J O9706335