A C10 Chiron Applicable to the Synthesis of Archaebacterial Lipids

Full text of DOI:10.1021/jo961911n

1536
J . Org. Chem. 1997, 62, 1536-1539
examine new routes to key intermediate 5. Although the
synthesis of 53-5,15,16 and the closely related C9 unit17-20
have received fair attention, with results ranging from
a short synthesis of three steps and 10% yield (ee >95%),
to one with a yield of 25%, in 10 steps (racemic), we were
prompted to attempt further improvement. The results
reported in this Note compare favorably as to length,
yield, and optical purity of the final product: five steps,
27% yield, ee >95%.
A C10 Ch ir on Ap p lica ble to th e Syn th esis of
Ar ch a eba cter ia l Lip id s
William F. Berkowitz* and Yanzhong Wu
Department of Chemistry and Biochemistry,
Queens College of the City University of New York,
65-30 Kissena Boulevard, Flushing, New York 11367
Received October 9, 1996
We have adapted Chenevert’s approach,18 i.e. cyclic
hydroboration of 2,6-dimethyl-1,6-heptadiene (8) and
have increased the carbon count to 10 by carbonylation.
Asymmetry was induced by enolization of the resulting
meso-3,7-dimethylcyclooctanone with lithium (+)-bis[(R)-
(1-phenylethyl)]amine21 (11) which afforded the 3S,7R
enol silyl ether. Ozonolysis/reduction of the silyl enol
ether afforded 5a . We have also developed an efficient,
two-step synthesis of diene 8 (Scheme 1).
The membrane lipids1 of archaebacteria may be an
important factor in the unusual adaptation of such
organisms to extremes of temperature, salt concentration,
and pH. Among the most common lipids isolated from
these prokaryotes are derivatives of two2 C2-symmetric,
sn-2,3-bisbiphytanylglycerol tetraethers 1 and 2 (R, R′
) glycoside, phosphate ester, hexitol, etc.1c), containing
a 72-membered ring with 16 configurationally defined
methyl groups Chart 1).
The C40 bisbiphytanediol chains (3) of lipids 1 and 2,
which are octamers of a common C5 (“isopranyl”) unit,
have been synthesized by Heathcock,3 Czeskis,4 and
Kakinuma,5 who coupled two (C20) tetramers (4) head to
head. In turn, the tetramers were assembled by head to
tail coupling of two C10 dimers (5). This C10 unit occurs
in a variety of other substances as well: e.g. the ubiq-
uitous phytol6 side chains of Vitamins E7 and K,8 and
chlorophyll;9 lycopadiene produced by the microalga
Botryococcus braunii;10 and pheromones of pine saw-
flies,11,12 tsetse flies,12,13 red flour beetles,12,14 male stink
bugs,12 mountain ash bentwings, and alfalfa blotch leaf
miners.12
Resu lts a n d Discu ssion
Cross coupling of 4-bromo-2-methyl-1-butene22 (7) with
the Grignard23 reagent of methallyl chloride in the
presence of Li2CuCl424 gave 2,6-dimethyl-1,6-heptadiene
(8) in 65% yield starting from 3-methyl-3-butenol, a
considerable improvement over previous methods.25
Cyclic hydroboration/oxidation of diene 8 with thexyl-
borane26 (Scheme 2) was found by Still27 (and confirmed
by Chenevert18) to give a predominately meso-diol in
73%25 (59%18) yield (meso/d,l ) 15/1). On the other hand,
cyclic hydroboration with thexyl borane followed by
carbonylation28 of the crude product produced meso-3,7-
dimethylcyclooctanone (10) as a pure diastereoisomer in
51% yield. GC-MS showed one other component with M+
154 but of negligible intensity (0-0.2%), and 13C NMR
showed no peaks consistent with the d,l diastereoisomer
(Scheme 2). It is likely that the Still/Chenevert results
were due to the presence of appreciable polymeric borane
The requirement for a means to obtain sufficient
archaebacterial lipid for biomedical study led us to
(1) (a) Langworthy, T. A. Current Topics in Membranes and
Transport; Academic Press: New York, 1982; Vol. 17, p 45. (b)
Langworthy, T. A. The Bacteria; Academic Press: New York, 1985;
Vol. VIII, Chap. 10, p 459. (c) DeRosa, M.; Gambacorta, A. Prog. Lipid
Res. 1988, 27, 153. (d) Sprott, G. D. J . Bioenerg. Biomembr. 1992, 24,
555. (e) De Rosa, M.; Riccio, A. M.; Gambacorta, A.; Trincone, A.; Incani,
O. Biosens. Bioelectron. 1994, 9, 669.
(2) Grather, O.; Arigoni, D. J . Chem. Soc., Chem. Commun. 1995,
406.
(3) (a) Heathcock, C. H.; Finkelstein, B. L.; J arvi, E. T.; Radel. P.
A.; Hadley, C. R. J . Org. Chem. 1988, 53, 1922. (b) Heathcock, C. H.;
Radel, P. A. J . Org. Chem. 1986, 51, 4323. (c) Heathcock, C. H.;
Finkelstein, B. L.; Poulter, C. D. Science 1985, 862.
(4) (a) Czeskis, B. A.; Alexeev, I. G.; Moiseenkov, A. M. Russ. Chem.
Bull. 1993, 42, 1246. (b) Czeskis, B. A.; Alexeev, I. G.; Moiseenkov, A.
M. Mendeleev Commun. 1993, 93.
(5) Eguchi, T.; Terachi, T.; Kakinuma, K. J . Chem. Soc., Chem.
Commun. 1994, 137.
(6) Sita, L. R. J . Org. Chem. 1993, 58, 5285 and references therein.
(7) (a) Mercier, C.; Chabardes, P. Pure Appl. Chem. 1994, 66, 1509.
(b) Coffen, D. L.; Cohen, N.; Pico, A. M.; Schmid, R.; Sebastian, M. J .;
Wong, F. Heterocycles 1994, 39, 527.
(8) (a) Lipshutz, B. H.; Bulow, G.; Lowe, R. F., Stevens, K. L. J .
Am. Chem. Soc. 1996, 118, 5512: see reference 11. (b) Guo, J .; Yu, R.;
Gu, D. Yiyao Gongye 1986, 17, 468: a review of Vitamin K synthesis
with 18 references; Chem. Abstr. 1987, 106, R67510s.
(9) Connolly, J . D.; Hill, R. A. Dictionary of Terpenoids: Vol. 2, Di-
and Higher Terpenoids; Chapman and Hall: London, 1991.
(10) Metzger, P.; Largeau, C.; Casadevall, E. Progr. Chem. Org. Nat.
Prod. 1991, 57, 1.
(15) (a) Gramatica, P.; Manitto, Ranzi, M; Delbianco, A.; Francavilla,
M. Experientia 1982, 38, 775. (b) Gramatica, P.; Manitto, P.; Poli, L.
J . Org. Chem. 1985, 50, 4625. (c) Gramatica, P.; Manitto, P.; Speranza,
G. Tetrahedron 1986, 42, 6687. (d) Gramatica, P.; Manitto, P.; Monti,
D.; Speranza, G. Tetrahedron 1987, 43, 4481.
(16) (a) Hickmott, P. W.; Hargreaves, J . R. Ibid. 1967, 23, 3151. (b)
Botta, M.; Castelli, S.; Gambacorta, A. Tetrahedron 1985, 41, 2913.
(c) Gambacorta, A.; Turchetta, S.; Farah, M. E. Gazz. Chim. Ital. 1992,
122, 527.
(17) Be´rube´, G.; Deslongchamps, P. Bull. Soc. Chim. Fr. 1987, 103.
(18) Chenevert, R.; Desjardins, M. J . Org. Chem. 1996, 61, 1219.
(19) Hanessian, S.; Murray, P. J .; Sahoo, S. P. Tetrahedron Lett.
1985, 26, 5623.
(20) See also: Molander, G. A.; Shakya, S. R. J . Org. Chem. 1994,
59, 3445.
(21) (a) Cox, P. J .; Simpkins, N. S. Tetrahedron Asymm. 1991, 2, 1.
(b) Majewski, M.; Gleave, D. M. J . Org. Chem. 1992, 57, 3599. (c) Bunn,
B. J .; Cox., P. J .; Simpkins, N. S. Tetrahedron 1993, 49, 207.
(22) (a) Maercker, A.; Weber, K. Liebigs Ann. Chem. 1972, 756, 43.
(b) Trost, B. M.; Kunz, R. A. J . Am. Chem. Soc. 1975, 97, 7152. (c)
Hao, N. K.; Cheskis, B. A.; Mavrov, M. V.; Moiseenkov, A. M.;
Serebryakov, E. P. Zhur. Org. Khim. 1987, 23, 498.
(23) (a) Derguini-Boumechal, F.; Lorne, R.; Linstrumelle, G. Tetra-
hedron Lett. 1977, 1181. (b) Morisaki, M.; Shibata, M.; Duque, C.;
Imamura, N.; Ikekawa, N. Chem. Pharm. Bull. 1980, 28, 606.
(24) Tamura, M.; Kochi, J . K. Synthesis 1971, 303.
(25) (a) Ansell, M. F.; Thomas, D. A., J . Chem. Soc. 1961, 539 (11%).
(b) Uijttewaal, A. P.; J onkers, F. L.; Gen, A. V.d. J . Org. Chem. 1979,
44, 3157 (15%). (c) Irrgang, B.; Mayr, H. Tetrahedron 1991, 47, 219
(27%).
(26) (a) Brown, H. C.; Negishi, E.-i. J . Am. Chem. Soc. 1972, 94,
3567. (b) Negishi, E.-i.; Brown, H. C. Synthesis 1974, 77.
(27) Still, W. C.; Darst, K. P. J . Am. Chem. Soc. 1980, 102, 7385.
(28) (a) Brown, H. C.; Negishi, E. J . Am. Chem. Soc. 1967, 89, 5477.
(b) Pelter, A.; Smith, K.; Hutchings, M. G.; Rowe, K. J . Chem. Soc.,
Perkin Trans. 1 1975, 129.
(11) (a) Mori, K. The Synthesis of Insect Pheromones. In The Total
Synthesis of Natural Products; ApSimon, J ., Ed.; J . Wiley: New York,
1981; Vol. 4, pp 1-184. (b) Baker, R.; Winton, P.; Tuner, R. W.
Tetrahedron Lett. 1980 21, 1175. (c) Bystrom, S.; Hogberg, H. B.; Norin,
T. Tetrahedron 1981, 37, 2554.
(12) Mori, K. The Synthesis of Insect Pheromones, 1979-1989. In
The Total Synthesis of Natural Products; ApSimon, J ., Ed.; J . Wiley:
New York, 1992; Vol. 9, pp 1-524.
(13) (a) Sonnet, P. E.; Uebel, E. C.; Harris, R. C.; Miller, R. W. J .
Chem. Ecol. 1977, 3, 245. (b) Carlson, D. A.; Langley, P. A.; Huyton,
P. Science (Wash., D.C.) 1978, 201, 750.
(14) Mori, K.; Kuwahara, S.; Ueda, H. Tetrahedron 1983, 39, 2439.
S0022-3263(96)01911-1 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 5, 1997 1537
Ch a r t 1
Sch em e 1
The ring was opened by ozonolysis/reduction,29 and the
Sch em e 2
resulting acid 5a was converted in turn to the hydroxy
ester 5b and diol 5c. Chiral shift reagent, Eu(hfc)3,21b,30
1
induced separation of the H NMR position of diastere-
oisomeric methoxyl groups of optically active hydroxy
ester 5b by 20 Hz. Integrated intensities of the two
peaks indicated an ee of 96-98%. (The proton spectrum
of the enol silyl ether was unaffected by the shift reagent.)
In addition, the optical rotation of diol 5c was the same
sign and of greater magnitude than that reported by
Gramatica15b for diol 5c prepared from (R)-citronellol and
shown to have an ee >95%. Had cyclooctanone 10 been
the trans-dimethyl diastereoisomer, the product enolate,
and thus subsequent products, would have perforce been
racemic. Consequently, hydroxy acid 5a is determined
to be (3R,7S)-3,7-dimethyl-8-hydroxyoctanoic acid, and
the absolute configuration of acid enol silyl ether 12
produced with the R,R base is 3S,7R, with an ee of 98%.
The high ee obtained is consistent with the transition
state model proposed by Majewski,21b and the distinct
differences in the environments of the R and R′ protons
of cyclooctanone 10 in stable conformations.31
Con clu sion s
In conclusion, we have fashioned an improved synthe-
sis of diene 9 and have used it in a sequence involving
(1) cyclic hydroboration/carbonylation, followed by (2)
asymmetric enolization and (3) ozonization of the derived
enol silyl ether 12, to produce C10 chiron 5a in five steps,
with an ee of 98%, applicable to the synthesis of archae-
bacterial lipids and other natural products containing the
C10 diisopranyl unit.
besides the desired (cyclic) borocane 9, and oxidation of
this mixture gave the meso/d,l diol products actually
isolated. Carbonylation, on the other hand, could have
proceeded only from the borocane intermediate, which
resulted from a highly stereoselective cyclic hydrobora-
tion as Still had predicted. We are presently trying to
find ways to minimize the polymeric byproduct of the
hydroboration step.
Exp er im en ta l Section
The key step, asymmetric enolization, using the lithium
salt of (+)-bis[(R)-(1-phenylethyl)]amine (11) proceeded
remarkably well.21 The corresponding enol trimethylsilyl
ether 12 was produced in 85% yield by internal quench-
ing of the enolate with excess trimethylsilyl chloride.
Gen er a l. All air-sensitive reactions were carried out under
argon or nitrogen. Diethyl ether and THF were distilled under
(29) Clark, R. D.; Heathcock, C. H. J . Org. Chem. 1976, 41, 1396.
(30) See the Experimental Section for details.
(31) Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981.

1538 J . Org. Chem., Vol. 62, No. 5, 1997
Notes
nitrogen from sodium and benzophenone. CH2Cl2 was distilled
from CaH2. All amines were distilled from CaH2. Trimethylsilyl
chloride was distilled from CaH2 and used immediately. IR
spectra of solutions in CCl4 or CDCl3 were recorded in cm-1. Gas
chromatographic analyses were performed on a 1 m 2% OV-1
column. GC-MS spectra were performed using a fused silica
capillary column. TLC was carried out on silica gel. Flash32
column chromatography was performed on silica gel 60 (230-
400 mesh ASTM). 1H and 13C NMR spectra were recorded for
CDCl3 solutions using a Bruker DPX 400 spectrometer, and
chemical shifts are reported in ppm downfield from tetrameth-
ylsilane (TMS). Distillations were performed with either a
column packed with glass helices or on an annular Teflon
spinning band column. Elemental analyses were performed by
Galbraith Laboratories, Inc, Knoxville, TN.
mL, 24.0 mmol) was added dropwise with vigorous stirring, and
the mixture was allowed to warm to room temperature during
1 h. The flask was cooled to 0 °C, and aqueous NaOH (15 mL,
3 M) followed by 30% H2O2 (28 mL) were added. This mixture
was stirred for 3 h at room temperature and 20 min at 50 °C.
The solution was then saturated with sodium chloride, and the
organic phase was separated, washed with saturated aqueous
sodium bicarbonate and brine, dried (MgSO4), and filtered. The
solvent was distilled at 1 atm, and the residue was purified by
flash chromatography (silica gel, hexane/ethyl acetate 40/1) and
then distilled to yield 1.58 g (51%) of cis-3,7-dimethylcyclooc-
tanone (10), bp 63.5-64.0 °C/1.5 mmHg. GC-MS showed a
single peak. IR 1696.4; 1H NMR 0.99 (d, J ) 6.4 Hz, 6H), 1.23-
1.37 (m, 3H), 1.40-1.54 (m, 1H), 1.60-1.75 (m, 2H), 2.15-2.22
(m, 4H), 2.53 (q, J ) 18.0 Hz, 8.7 Hz, 2H); 13C NMR 22.44, 22.63,
32.49, 36.42, 50.45, 215.3; mass spectrum m/e (% relative
intensity) 154 (M+, 12), 139 (14), 125 (11), 121 (9), 112 (45), 98
(17), 84 (15), 81 (9), 69 (100), 55 (52), 41 (60), 39 (29), 27 (16).
Anal. Calcd for C10H18O: C, 77.86; H, 11.76. Found: C, 77.51;
H, 11.72.
[((3S,7R)-3,7-Dim et h ylcyclooct en -1-yl)oxy]t r im et h ylsi-
la n e (12). To a cold (-78 °C), 100 mL, flame-dried, three-necked
flask which contained (+)-bis[(R)-(1-phenylethyl)]amine21 (11)
(Fluka, 1.46 g, 6.50 mmol) in dry THF (65 mL) was added
dropwise a solution of n-butyllithium in hexane (6.25 mmol, 2.50
mL of 2.5 M). After 5 min, the cooling bath was removed, and
the temperature was allowed to warm to room temperature
during 35 min and then again lowered to -78 °C. Freshly
distilled TMSCl (3.17 mL, 25.0 mmol) in THF (6 mL) was added
dropwise. The cold mixture was stirred for 8 min, and then cis-
3,7-dimethylcyclooctanone (10) (0.770 g, 5.00 mmol) in THF (15
mL) was added dropwise during 40 min. The resulting solution
was stirred at -78 °C for 3 h, and then Et3N (9 mL) was added.
The solution was allowed to warm to room temperature,
saturated aqueous NaHCO3 (30 mL) was added, and the solvents
were removed under vacuum. The residue was extracted with
pentane (3 × 50 mL), and the combined extracts were washed
with 0.1 M aqueous citric acid (2 × 50 mL) and water (50 mL),
dried (MgSO4), and concentrated under reduced pressure to give
the crude product which was purified by flash chromatography
(SiO2, pentane) to yield 0.96 g (85%) of enol silyl ether 12 (0.96
g, 85%) as a colorless oil. GC-MS showed a single peak.
4-Br om o-2-m eth yl-1-bu ten e22 (7). The method of Bose was
used.33 To a mixture of 3-methyl-3-butene-1-ol (6) (50.5 mL,
0.500 mol), triphenylphosphine (144 g, 0.550 mol), and dry CH2-
Cl2 (100 mL) cooled in an ice bath was added N-bromosuccin-
imide (97.9 g, 0.550 mol) in several portions with vigorous
stirring. Stirring was continued for 3 h at room temperature.
Then, hexane (300 mL) was added to the flask, and the mixture
was filtered through a short silica gel pad, which was washed
with hexane (200 mL). The solvents were removed by distilla-
tion at 1 atm, and the residue was distilled under reduced
pressure to yield 55.9 g (75%) of 4-bromo-2-bromo-1-butene (8),
bp 63-65 °C/90 mmHg (lit.22a bp 40 °C, 40 mmHg), and GC-MS
showed a single peak. IR 3080.7, 1649.7, 1450.2, 897.6; 1H NMR
1.75 (s, 3H), 2.58 (t, J ) 7.4 Hz, 2H), 3.48 (t, J ) 7.3 Hz, 2H),
4.78, 4.86 (s,s, 2H); 13C NMR 21.94, 30.80, 40.90, 112.68, 142.4;
mass spectrum m/e (% relative intensity) 150 (M+, 81Br, 13), 148
(M+, 79Br, 14), 135 (0.4), 133 (0.5), 95 (2.3), 93 (2.5), 82 (1.3), 80
(1.3), 70 (5.5), 69 (100), 68 (9.1), 67 (16), 55 (20), 53 (21), 41 (81),
39 (46), 27 (22).
2,6-Dim eth yl-1,6-h eptadien e (8).25 Kochi’s coupling method
was employed.23,24 The Grignard reagent prepared from 3-chloro-
2-methyl-1-propene (59.2 mL, 0.60 mol) in dry THF (200 mL)
was siphoned into a 1-L three-necked flask which contained
4-bromo-2-bromo-1-butene (7) (44.8 g, 0.30 mol), Li2CuCl4 (30
mL of 0.1 M solution in THF, 3.00 mmol), and dry THF (200
mL) at -78 °C. The mixture was stirred for 1 h at -78 °C and
then for 6 h at 0 °C and 18 h at room temperature. Then,
saturated NaCl (100 mL) was added, and the resulting mixture
was filtered through a short pad of Celite 545, which was washed
with ether (150 mL). The aqueous layer was separated and
extracted with ether (3 × 50 mL). The combined organic extracts
were washed with brine and dried, and the solvent was removed
by distillation at 1 atm. The residue was distilled to yield 32.43
g (87%) of 2,6-dimethyl-1,6-heptadiene (8), bp 135-136 °C (lit.25a
bp 138-139 °C) and GC-MS showed a single peak. IR 3073.4,
[R]25 D +120 (c 2.32, CHCl3); IR 1656.0, 1252.0, 847.4; 1H NMR
0.13 (s, 9H), 0.95 (d, J ) 5.0 Hz, 3H), 0.97 (d, J ) 4.8 Hz, 3H),
1.08-1.18 (m, 1H), 1.20-1.40 (m, 2H), 1.52-1.62 (m, 2H), 1.70-
1.80 (m, 2H), 1.88-1.98 (m, 1H), 2.2-2.3 (m, 1H), 2.60 (q, J )
14.0 Hz, 4.9 Hz, 1H), 4.45 (d, J ) 7.6 Hz, 1H); 13C NMR 0.41,
21.63, 23.59, 24.81, 32.08, 33.79, 34.28, 37.18, 39.82, 113.44,
150.06; mass spectrum m/e (% relative intensity) 226 (M+, 15),
211 (28.6), 197 (9.2), 184 (23.4), 183 (63.9), 169 (15.3), 157 (93.2),
144 (12.9), 130 (14.5), 121 (6.2), 115 (13.8), 99 (3.8), 93 (5.5), 75
(47), 73 (100), 55 (12.0), 45 (17.5), 39 (6.9). Anal. Calcd for
1
1649.3, 1648.8; H NMR 1.57 (p, J ) 7.6 Hz, 2H), 1.72 (s, 6H),
2.00 (t, J ) 7.7 Hz, 4H), 4.68, 4.71 (s,s, 4H); 13C NMR 22.41,
25.56, 37.38, 109.83, 145.94; mass spectrum m/e (% relative
intensity) 124 (M+, 2), 109 (24), 96 (14), 81 (20), 68 (100), 57
(12), 53 (18), 41 (61).
C
13H26OSi: C, 68.96; H, 11.57. Found: C, 68.58; H, 11.32.
r a c-[(3,7-Dim et h ylcyclooct en -1-yl)oxy]t r im et h ylsila n e
(12). Corey’s method was employed.34 To a cold (-78 °C), 25-
mL, flame-dried, three-necked flask which contained diisopro-
pylamine (0.14 mL, 1.1 mmol) in dry THF (2 mL) was added
n-butylithium (1.1 mmol, 0.44 mL of 2.5 M solution in hexane)
by syringe. After addition of n-butyllithium was complete, the
mixture was stirred for 10 min at -78 °C. Freshly distilled
TMSCl (0.89 mL, 7.0 mmol) in THF (2 mL) was added dropwise,
followed by cis-3,7-dimethylcyclooctanone (10) (0.154 g, 1.0
mmol) in THF (2 mL). The resulting solution was stirred at
-78 °C for 20 min, and while still at -78 °C Et3N (2 mL) and
saturated aqueous NaHCO3 (5 mL) were added. The mixture
was allowed to warm to room temperature, and the solvents were
removed under reduced pressure. The residue was extracted
with ether (3 × 10 mL), and the combined ether extracts were
washed with 0.1 M aqueous citric acid (2 × 10 mL) and water
(10 mL) and dried (MgSO4). The solvents were removed under
reduced pressure to give the crude product which was purified
by flash chromatography (SiO2, pentane) to yield 0.20 g (88%)
of racemic [(3,7-dimethyl-1-cycloocten-1-yl)oxy]trimethylsilane
(12). GC-MS showed a single peak. IR 1655.0, 1251.9; 1H NMR
0.13 (s, 9H), 0.95 (d, J ) 5.0 Hz, 3H), 0.97 (d, J ) 4.8 Hz, 3H),
cis-3,7-Dim eth ylcycloocta n on e (10). An oven dried, three-
neck flask was fitted with an L-shaped solid-addition tube, an
injection septum, a magnetic stirring bar, and a vacuum/nitrogen
inlet. Into the sidearm was placed dry, finely divided sodium
cyanide (1.08 g, 22.0 mmol).28b The apparatus was then evacu-
ated and filled with nitrogen, which was maintained at a positive
pressure until the oxidation step was complete. Tetrahydrofuran
(200 mL) and borane-THF (22.0 mL of 1.0 M, 22.0 mmol) were
introduced, and the temperature was lowered to -25 °C. By
syringe, 2,3-dimethylbut-2-ene (2.62 mL, 22.0 mmol) was slowly
added to the stirred solution. Stirring was continued for 2 h at
0 °C, and then the temperature was lowered to -78 °C and 2,6-
dimethyl-1,6-heptadiene (8, 2.48 g, 20.0 mmol) was added during
15 min. The cooling bath was removed after addition of the
diene, and the mixture was allowed to warm to room tempera-
ture and stirred for 20 h.
The solid addition sidearm was then rotated so that the
sodium cyanide was introduced. The mixture was stirred for 2
h, during which time most of the sodium cyanide dissolved. The
mixture was cooled to -78 °C, trifluoroacetic anhydride28b (3.38
(32) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(33) Bose., A. K.; Lal, B. Tetrahedron Lett. 1973, 3937.
(34) Corey, E. J .; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.

Notes
J . Org. Chem., Vol. 62, No. 5, 1997 1539
1.08-1.18 (m, 1H), 1.20-1.40 (m, 2H), 1.52-1.62 (m, 2H), 1.70-
1.80 (m, 2H), 1.88-1.98 (m, 1H), 2.2-2.3 (m, 1H), 2.60 (q, J )
14.0 Hz, 4.9 Hz, 1H), 4.45 (d, J ) 7.6 Hz, 1H); 13C NMR 0.41,
21.63, 23.59, 24.81, 32.08, 33.79, 34.28, 37.18, 39.82, 113.44,
150.06; mass spectrum m/e (% relative intensity) 226 (M+, 15),
211 (27), 197 (9), 184 (23), 183 (64), 169 (15), 157 (93), 144 (13),
130 (15), 121 (6), 115 (14), 99 (4), 93 (6), 75 (47), 73 (100), 55
(12), 45 (18), 39 (7).
(2S,6R)-2,6-Dim eth yl-1,8-octan ediol (5c). To LiAlH4 (0.100
g, 2.50 mmol) in dry ether (10 mL) was added methyl 8-hydroxy-
(3R,7S)-3,7-dimethyloctanoate (5b) (50.0 mg, 0.250 mmol) in dry
ether (10 mL) during a period of 7 min. The resulting mixture
was stirred for 4 h and then cooled to 0 °C, and a mixture of
ether (4 mL) and methanol (4 mL) was added dropwise, followed
by HCl (10 mL, 1 M). The aqueous layer was extracted with
ether (3 × 10 mL), and the combined organic phases were
washed with saturated NaHCO3 and brine and dried. The
solvent was evaporated under reduced pressure to crude product
which was purified by flash chromatography (SiO2, hexane/
EtOAc, 2:1) to yield 42.6 mg (98%) of diol 5c as a colorless oil.
8-Hydr oxy-(3R,7S)-3,7-dim eth yloctan oic Acid (5a). Heath-
cock’s method was employed.29 [((3S,7R)-3,7-Dimethylcycloocten-
1-yl)oxy]trimethylsilane (12) (0.800 g, 3.54 mmol) in methanol
(20 mL) and CH2Cl2 (20 mL) was treated with excess O3 at -78
°C until the solution turned blue. After purging with nitrogen,
the cold solution was reduced with excess sodium borohydride
(1.34 g, 35.4 mmol), allowed to warm to room temperature, and
stirred overnight. After the solvent was evaporated on a rotary
evaporator, the residue was stirred with HCl (20 mL, 10%) and
extracted with ether (3 × 50 mL). The combined ether extracts
were washed with brine and dried (MgSO4), and the solvent was
evaporated to give the crude product, which was purified by flash
chromatography (SiO2, hexane/acetone, 1:1) to yield 0.632 g
GC-MS showed a single peak. [R]25 -7.0 (c 2.1, CHCl3); lit.15b
D
1
[R]25 -6.3 (c 9.5, CHCl3). IR 3639.0, 3628.3, 1028.7; H NMR
D
0.91 (t, J ) 7.0 Hz, 6H), 1.04-1.48 (m, 9H), 1.55-1.70 (m, 3H),
3.42 (q, J ) 10.5 Hz, 5.9 Hz, 1H), 3.51 (q, J ) 10.4 Hz, 6.5 Hz,
1H), 3.65-3.75 (m, 2H); 13C NMR 16.62, 19.68, 24.25, 29.45,
33.35, 35.76, 37.38, 39.89, 61.21, 68.33; mass spectrum m/e (%
relative intensity) 144 (0.1), 137 (0.3), 126 (5), 123 (7),112 (2),
109 (15), 99 (7), 97 (7), 81 (46), 70 (38), 69 (82), 56 (36), 55 (100),
43 (39), 41 (73), 39 (18), 31 (56). Anal. Calcd for C10H22O2: C,
68.92; H, 12.72. Found: C, 68.63, H; 12.40.
(95%) of 8-hydroxy-(3R,7S)-3,7-dimethyloctanoic acid (5a ): [R]25
D
-3.6 (c 2.42, CHCl3). IR 3625.9, 2800-3400(br), 1707.6, 1030.2;
1H NMR 0.92 (d, J ) 6.8 Hz, 3H), 0.97 (d, J ) 6.7 Hz, 3H), 1.02-
1.48 (m, 7H), 1.62 (m, 1H), 1.96 (m, 1H), 2.16 (q, J ) 15.0 Hz,
8.0 Hz, 1H), 2.34 (q, J ) 15.0 Hz, 6.1 Hz, 1H), 3.47 (m, 2H),
5.0-6.5 (s,br, 1H); 13C NMR 16.57, 19.78, 24.21, 30.13, 33.12,
35.65, 36.87, 41.45, 68.25, 178.85; mass spectrum m/e (% relative
intensity) 159(3), 158(25), 152(1), 139(3), 129(2), 115(8), 111(8),
110(13), 101(8), 97(22), 95(9), 87(100), 83(10), 81(9), 69(51),
55(57), 45(16), 41(44), 31(20), 28(22), 18(19). Anal. Calcd for
r a c-Meth yl 8-Hyd r oxy-3,7-d im eth ylocta n oa te (5b). Ra-
cemic [(3,7-dimethylcycloocten-1-yl)oxy]trimethylsilane (12) (0.200
g, 0.880 mmol) in methanol (5 mL) and CH2Cl2 (5 mL) was
ozonized as above29 (the ozonide was reduced with 0.400 g of
sodium borohydride, 10.6 mmol). Workup gave crude racemic
8-hydroxyl-3,7-dimethyloctanoic acid. Without further purifica-
tion, this acid was dissolved in methanol (15 mL), and p-
toluenesulfonic acid (8 mg) was added. The resulting solution
was heated to reflux for 15 h. The solvent was evaporated under
reduced pressure, and the residue was extracted into ether (50
mL) and washed with saturated aqueous NaHCO3 (40 mL) and
brine and dried. The solvent was evaporated under reduced
pressure to crude product which was purified by flash chroma-
tography (SiO2, hexane/EtOAc, 6:1) to yield 0.16 g (90%) of 5b.
IR 3640.0, 1739.9, 1197.0, 1166.9, 1028.9; 1H NMR 0.93 (t, J )
7.0 Hz, 6H), 1.05-1.45 (m, 7H), 1.55-1.65 (m, 1H), 1.90-2.00
(m, 1H), 2.21 (q, J ) 14.7 Hz, 8.1 Hz, 1H), 2.31 (q, J ) 14.7 Hz,
6.1 Hz, 1H), 3.38-3.53 (m, 2H), 3.67 (s, 3H); 13C NMR 16.58,
19.80, 24.25, 30.32, 33.18, 35.71, 36.95, 41.62, 51.40, 68.29, 173.8;
mass spectrum m/e (% relative intensity) 172 (36), 157 (4), 152
(4), 139 (5), 129 (9), 128 (4), 115 (8), 112 (5), 111 (12), 110 (16),
109 (8), 101 (100), 97 (17), 87 (7), 81 (7), 74 (36), 69 (44), 59 (17),
55 (30), 43 (12), 41 (18).
C
10H20O3: C, 63.80; H, 10.71. Found: C, 63.76; H, 10.88.
Meth yl 8-Hyd r oxy-(3R,7S)-3,7-d im eth ylocta n oa te (5b).
A mixture of 8-hydroxy-(3R,7S)-3,7-dimethyloctanoic acid (5a )
(0.632 g, 3.36 mmol), methanol (50 mL), and p-toluenesulfonic
acid (20 mg) was refluxed for 24 h. The solvent was evaporated
under reduced pressure, and the residue was extracted with
ether (3 × 30 mL), washed with saturated aqueous NaHCO3 (40
mL) and brine, and dried (MgSO4). The solvent was evaporated
under reduced pressure to yield crude product which was
purified by flash chromatography (SiO2, hexane/EtOAc, 6:1) to
yield 0.665 g (98%) of methyl 8-hydroxy-(3R,7S)-3,7-dimethyl-
octanoate (5b) as a colorless oil. GC-MS showed a single peak.
Addition of 6.5 mg of chiral shift reagent tris(3-heptafluo-
robutyryl-d-camphorato)europium(III) (Eu(hfc)3) to 3.7 mg of the
racemic hydroxy ester 5b in 0.7 mL of CDCl3 gave rise to two
diastereomeric complexes. The methyl group (δ 3.67, s, COOCH3)
was split into a doublet (δ 4.16, 4.11) with a 1:1 ratio and base
line separation.
Ack n ow led gm en t. This work was supported by
PSC-CUNY Faculty Research Award 6-66291. We are
especially grateful to our colleague Prof. David C. Locke
for the GC-MS spectra, and the New York State Urban
Development Corp., under the Higher Education Ap-
plied Technology Program, for purchase of the GC-MS
instrument. We also gratefully acknowledge support
from the National Science Foundation (CHE-9408535)
for funds used for the purchase of the 400 MHz NMR
spectrometer.
When Eu(hfc)3 was similarly added to optically active hydroxy
ester 5b, the methyl group (δ 3.67, s) was split into a doublet (δ
4.15, 4.10) with a 99:1 ratio (ee ) 98%). [R]25 -3.91 (c 15.0,
D
CHCl3). IR 3640.6, 3638.5, 1740.4, 1028.2; 1H NMR 0.93 (t, J )
7.0 Hz, 6H), 1.05-1.45 (m, 7H), 1.55-1.65 (m, 1H), 1.90-2.00
(m, 1H), 2.21 (q, J ) 14.7 Hz, 8.1 Hz, 1H), 2.31 (q, J ) 14.7 Hz,
6.1 Hz, 1H), 3.38-3.53 (m, 2H), 3.67 (s, 3H); 13C NMR 16.58,
19.80, 24.25, 30.32, 33.18, 35.71, 36.95, 41.62, 51.40, 68.29,
173.81; mass spectrum m/e (% relative intensity) 172 (36), 157
(4), 152 (4), 139 (5), 129 (9), 128 (4), 115 (8), 112 (5), 111 (12),
110 (16), 109 (8), 101 (100), 97 (17), 87 (7), 81 (7), 74 (36), 69
(44), 59 (17), 55 (30), 43 (12), 41 (18). Anal. Calcd for
C
11H22O3: C, 65.31; H, 10.96. Found: C, 64.93; H, 11.23.
J O961911N