Total synthesis of archaeal 36-membered macrocyclic diether lipid

Article abstract of DOI:10.1021/jo962327h

Total synthesis of archaeal 36-membered macrocyclic diether lipid 2 is reported. The synthesis is based upon stereoselective preparation of functionalized isoprenoid chains, ether-linkage formation between the isoprenoid chains with a glycerol derivative,

Full text of DOI:10.1021/jo962327h

1924
J . Org. Chem. 1997, 62, 1924-1933
Articles
Tota l Syn th esis of Ar ch a ea l 36-Mem ber ed Ma cr ocyclic Dieth er
Lip id
Tadashi Eguchi, Kenji Arakawa, Takumi Terachi, and Katsumi Kakinuma*
Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152, J apan
Received December 12, 1996X
Total synthesis of archaeal 36-membered macrocyclic diether lipid 2 is reported. The synthesis is
based upon stereoselective preparation of functionalized isoprenoid chains, ether-linkage formation
between the isoprenoid chains with a glycerol derivative, and the ultimate intramolecular dicarbonyl
coupling using low-valent titanium known as McMurry coupling. This synthetic method has
successfully provided the first practical route to chemically defined archaeal macrocyclic membrane
lipids, which were not available because of the lack of synthetic access. Also described is a highly
stereoselective and convenient synthesis of stereochemically homogeneous archaeal biphytanyl
glycerol lipid 1.
In tr od u ction
chemical features of these archaeal lipids. Recently, we
have postulated the pathway and stereochemistry of the
lipid biosynthesis in the halophiles and the thermoaci-
dophiles.3 Another area of our interest in these lipids
focuses on the biochemical significance of the macrocyclic
molecular structures.4 Several modeling and synthetic
studies of these macrocyclic lipids have been reported in
terms of their thermostability,5 since these membrane
lipids may provide a clue to the development of a heat-
resistant lipid membrane. However, no reports have
appeared on the synthesis of natural macrocyclic ring
possessing branched isoprenoid chains until our prelimi-
nary report on the synthesis of archaeal macrocyclic 36-
membered lipids.4b In this paper, we report full details
of our synthesis of an archaeal macrocyclic membrane
lipid featuring the 36-membered ring, which was first
isolated from extreme thermophiles Methanococcus
jannaschii.2k,l
The archaea (or archaebacteria) including thermo-
philes, halophiles, acidophiles, alkalophiles, and metha-
nogens are a heterogeneous group of prokaryotes.1 Most
of these microorganisms grow under extreme environ-
ments such as high temperature and high acidic and salt-
rich conditions and differ markedly from other prokary-
otes in their 16S ribosomal RNA sequences and in other
important characteristics of cellular composition.1,2 Ar-
chaeal cell membrane lipids are composed of branched
isoprenoid-chain hydrocarbons linked to a glycerol mol-
ecule at the sn-2- and -3-positions by ether linkage. Fatty
acid components found in eubacterial and eucaryal lipids
are completely absent. The isoprenoid hydrocarbon
chains of lipid molecules are frequently joined intramo-
lecularly at the terminal position to form a macrocyclic
ring as large as 36- or 72-membered as shown in Figure
1.2 We have been interested in the chemical and bio-
Resu lts a n d Discu ssion
* To whom correspondence should be addressed. Fax: +81-3-3729-
8498. E-mail: kakinuma@chem.titech.ac.jp.
The basic synthetic plan for 2 was composed of stereo-
selective preparation of appropriate isoprenoid chains,
X Abstract published in Advance ACS Abstracts, March 15, 1997.
(1) (a) Woese, C. R.; Fox, G. E. Proc. Natl. Acad. Sci. U.S.A. 1977,
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U.S.A. 1992, 89, 5685. (d) Kjems, J .; Larsen, N.; Dalgaard, J . Z.;
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S0022-3263(96)02327-4 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Archaeal Macrocyclic Diether Lipid
J . Org. Chem., Vol. 62, No. 7, 1997 1925
F igu r e 1. Typical structures of archaeal membrane lipids 1, 2, and 3a ,b.
subsequent ether-linkage formation with a glycerol de-
rivative, and a crucial intramolecular dicarbonyl coupling
using low-valent titanium known as McMurry coupling.6
Thus, our primary synthetic target was the C20 unit 24.7
The synthesis of the C20 unit 24 was accomplished by
coupling relevant two C10 units, and the essential build-
ing block possessing 10-carbons 12 was prepared in two
methods using either methyl (R)-3-hydroxy-2-methylpro-
pionate (4) or (R)-citronellol benzyl ether (16) as a chiral
starting material.
The first choice of a chiral starting material was
commercially available methyl (R)-3-hydroxy-2-methyl-
propionate (4). Transformation of 4 into a carbon-5 block
5 was carried out by manipulations similar to those
previously reported by Mori et al.8 Thus, a series of
reactions comprising from protection of the hydroxyl
group of 4 with an ethoxy ethyl group (EE), reduction of
the ester group with lithium aluminum hydride, tosyla-
tion of the resulting alcohol, and displacement of the
tosyloxy group with cyanide ion gave nitrile 5 in 98%
overall yield from 4. Exchange of the protecting group
from EE to tert-butyldimethylsilyl (TBDMS), followed by
repeated reduction with DIBAH, afforded the C5 unit 7
in 73% yield.
romethyl)-R-phenylacetate (MTPA) derivative of 9.11 Me-
sylation of 9 followed by displacement of the mesylate
with a phenylthio group and oxidation with m-CPBA
afforded the sulfone 10 in 89% yield. The next step was
the coupling between two C5 units into a C10 unit. The
reaction between the anion derived from 10 with butyl-
lithium and iodide 8 in THF-HMPA at -25 °C smoothly
provided coupling product 11 in 73% yield, which was
subesequently treated with Na(Hg) in methanol to afford
the bifunctional C10 unit 12 in 85% yield. Then, portions
of 12 were subjected to either deprotection of the benzyl
group or TBDMS group to obtain 13a and 14a in 96%
and 79% yield, respectively (Scheme 1).
For the alternative synthesis of the precursory bifunc-
tional C10 unit, we developed a more efficient and
preparative method. The synthesis started from readily
available (R)-citronellol (15) (98% ee) and is summarized
in Scheme 2.12 The readily available (R)-citronellol
benzyl ether 1614 was oxidatively decomposed by ozo-
nolysis, followed by reductive workup of the resulting
ozonide with sodium borohydride to furnish alcohol 17
in 93% yield. The tosylate of alcohol 17, obtained by
treatment with tosyl chloride, was treated with an
acetylide anion derived from propargyl alcohol tetrahy-
The C5 unit 7 was treated with I2-Ph3P-imidazole in
benzene to give in 85% yield iodide 8 as one coupling
precursor. The other coupling partner 10 was also
derived from 7. Treatment of 7 with benzyl 2,2,2-
trichloroacetimidate in the presence of acid catalyst9 gave
a benzyl ether,10 which was then hydrolyzed by acid to
afford alcohol 9 in 88% yield. At this stage, the enan-
tiomeric purity was determined to be 99% ee as judged
from the 1H NMR spectra of (R)-R-methoxy-R-(trifluo-
(11) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(12) Our first attempt to synthesize a C10 unit from (R)-citronellol
involved the asymmetric hydrogenation of readily available (E)-allylic
alcohol i using Noyori’s BINAP-Ru-based catalysts.13 The hydrogena-
tion reactions proceeded smoothly using several BINAP-Ru-based
catalysts; however, the diastereomeric purities of the product ii were
less than 75% in our hands.
(6) (a) McMurry, J . E. Acc. Chem. Res. 1983, 16, 405. (b) McMurry,
J . E. Chem. Rev. 1989, 89, 1513. (c) McMurry, J . E.; Rico, J . G.
Tetrahedron Lett. 1989, 30, 1169.
(7) (a) Heathcock, C. H.; Finkelstein, B. L.; Aoki, T.; Poulter, C. D.
Science 1985, 229, 862. (b) Heathcock, C. H.; Radel, P. A. J . Org. Chem.
1986, 51, 4322. (c) Heathcock, C. H.; Finkelstein, B. L.; J arvi, E. T.;
Radel, P. A.; Hadley, C. R. J . Org. Chem. 1988, 53, 1922.
(8) Mori, K. Tetrahedron 1983, 39, 3107. (b) Mori, K.; Ebata, T.
Tetrahedron 1986, 42, 4413.
(9) Iversen, T.; Bundle, K. R. J . Chem. Soc., Chem. Commun. 1981,
1240.
(10) Benzylation under basic conditions such as NaH-benzyl halide
in DMF or DMSO was not straightforward as migration of the TBDMS
group was observed in ca. 30-40% yield.
(13) (a) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akuta-
gawa, S.; Inoue, I.; Noyori, R. J . Am. Chem. Soc. 1987, 109, 1596. (b)
Takaya, H.; Ohta, T.; Mashima, K.; Noyori, R. Pure Appl. Chem. 1990,
62, 1135. (c) Kitamura, M.; Tokunaga, M.; Noyori, R. J . Org. Chem.
1992, 57, 4053. (d) Heiser, B.; Broger, E. A.; Carameri, Y. Tetrahedron
Asymmetry 1991, 1, 51. (e) Kitamura, M.; Tokunaga, M.; Ohkuma, T.;
Noyori, R. Tetrahedron Lett. 1991, 32, 4163.
(14) Patel, D. V.; VanMiddlesworth, F.; Donaubauer, J .; Gannett,
P.; Sih, C. J . J . Am. Chem. Soc. 1986, 108, 4603.

1926 J . Org. Chem., Vol. 62, No. 7, 1997
Eguchi et al.
Sch em e 1a
a
Reagents: (a) (1) ethyl vinyl ether, PPTS/THF, (2) LiAlH4; (b) TsCl/Py; (c) NaCN/DMSO; (d) (1) 2 N HCl/THF, (2) TBDMSCl, imidazole/
DMF; (e) (1) DIBAH/toluene, (2) H2O, (3) DIBAH/toluene; (f) I2, Ph3P, imidazole/benzene; (g) BnOC(dNH)CCl3, TfOH/ether; (h) 2 N HCl/
THF; (i) MsCl/pyridine; (j) PhSH, K2CO3/DMF; (k) m-CPBA/CH2Cl2; (l) (1) nBuLi/THF-HMPA, (2) compound 8; (m) 5% Na(Hg)/MeOH;
(n) H2, Pd-C/EtOAc.
Sch em e 2a
a
Reagents: (a) (1) O3/MeOH, (2) NaBH4; (b) TsCl/pyridine; (c) NaCtCCH2OTHP/DMSO; (d) 2 N HCl/THF-MeOH; (e) LiAlH4/THF; (f)
Ti(OiPr)4, D-(-)-DET, BuOOH, molecular sieves 4A/CH2Cl2; (g) Me3Al/CH2Cl2; (h) NaIO4/THF-H2O; (i) NaBH4/MeOH; (j) TBDMSCl,
imidazole/DMF; (k) H2, Pd-C/EtOAc.
t
dropyranyl ether and hydrolyzed with acid to provide
alkynyl alcohol 18 in 71% yield. Reduction of the alkynyl
alcohol to allylic alcohol 19 was efficiently accomplished
with high selectivity using lithium aluminum hydride in
THF at 0 °C. Raising the reaction temperature to 10 °C
or above led to generation of an allenic product in 10-
20% yield, which was essentially useless for further
transformation. The allylic alcohol 19 was subjected to
Sharpless asymmetric epoxidation15 to give epoxide 20
in high yield. Stereoselective epoxide opening with
iodide 21 in 88% yield by treatment with I2-Ph3P-
imidazole in benzene. The other building block 14b was
also transformed into sulfone 22 in 85% yield as described
for the synthesis of 10. In the same fashion as in the
synthesis of 11,7 the iodide 21 and the sulfone 22 were
coupled in 87% yield to obtain the intermediary C20 unit
23, which was subsequently treated with lithium in
ethylamine-THF to afford the desired C20 unit 24 in 59%
yield.
Having the C20 unit in hand, a precursory dialdehyde
29 for McMurry coupling was prepared on the basis of
our synthetic plan by a method similar to our synthesis
of desmethylated analogue of 2.4a Two equivalents of
mesylate 25, derived from the alcohol 24, was treated
with a dialkoxide derived from 1-O-benzyl-sn-glycerol
(26)17 with NaH in DMSO to afford the diether derivative
27 in 56% yield. After deprotection of 27 with diluted
HCl in THF, the resulting diol 28 was oxidized to the
dialdehyde 29 under Swern conditions in 89% yield.
The key reaction of an intramolecular McMurry cou-
pling of dialdehyde 29 was performed under high dilution
conditions. Thus, a solution of dialdehyde 29 in dimethox-
16
trimethylaluminum in CH2Cl2 followed by a series of
reactions with sodium periodate and with sodium boro-
hydride afforded the C10 unit 14b in 84% yield. The
newly formed chiral center of 14b had 95% diastereo-
1
meric purity as judged from H NMR spectra of its (R)-
MTPA ester derivative.11 The other C10 unit 13b was
easily obtained from 14b in excellent yield.
As shown in Scheme 3, the essential building block
13a b for the synthesis of a C20 unit 23 was converted to
(15) (a) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102,
5974. (b) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(16) Suzuki, T.; Saimoto, H.; Tomioka, H.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1982, 23, 3597.
(17) Takano, S.; Seya, K.; Goto, E.; Hirama, M.; Ogasawara, K.
Synthesis 1983, 116.

Synthesis of Archaeal Macrocyclic Diether Lipid
J . Org. Chem., Vol. 62, No. 7, 1997 1927
Sch em e 3a
a
Reagents: (a) I2, Ph3P, imidazole/benzene; (b) MsCl/pyridine; (c) PhSH, K2CO3/DMF; (d) m-CPBA/CH2Cl2; (e) (1) nBuLi/THF-HMPA,
(2) compound 21; (f) Li/EtNH2-THF.
Sch em e 4a
a
Reagents: (a) (1) NaH/DMSO, (2) compound 27; (b) 2 N HCl/THF; (c) Swern oxidation; (d) TiCl3, Zn-Cu/DME; (e) H2, Pd-C.
Sch em e 5a
a
Reagents: (a) H2, [(S)-BINAP]chloro(p-cymene)ruthenium chloride/MeOH; (b) MsCl/pyridine; (c) (1) NaH/DMSO, (2) compound 33;
(d) H2, Pd-C/EtOAc.
yethane was added by a motor-driven syringe pump over
a period of 50-60 h to a refluxing slurry of TiCl3/Zn-Cu
in dimethoxyethane to yield the macrocyclic diether 30
as an essentially single product. The best yield we were
able to obtain in this coupling reaction was 56%, and the
representative yields (50-55%) were obtained from re-
peated runs. The stereochemistry of the resulting double
bond was not rigorously determined but was tentatively
assigned to be E in analogy with the previous reports
that such a macrocyclization by the McMurry coupling
reaction predominantly afforded the E-double bond.6 No
epimerization at the R-position of carbonyl groups was
observed during the McMurry coupling, since degradation
of 30 by ozonolysis followed by sodium borohydride
reduction afforded material that was identical with 28
in all respects of spectroscopic means. Deprotection of
the benzyl group and reduction of the double bond of 30
were performed simultaneously by catalytic hydrogena-
tion over Pd-C to afford the 36-membered diether lipid
2 in 96% yield (Scheme 4).
the cyclized lipid with noncyclized counterpart 1. Al-
though several synthetic studies directing analogues to
the archaeal lipid 1 were reported, the chiralities of the
C-3 position of the phytanyl moieties and the glycerol
part were not taken care of. Surprisingly, nothing has
been discussed for the efficient synthesis of stereochemi-
cally defined 1. Therefore, we describe here a highly
stereoselective synthetic route to 1 using an asymmetric
hydrogenation reaction based on the BINAP-Ru cata-
lyst.13
As shown in Scheme 5, the commercially available
phytol 31 was hydrogenated in 92% yield into phytanol
32 in the presence of [(S)-BINAP]chloro(p-cymene)ruthe-
nium chloride. The absolute stereochemistry of the
newly formed stereogenic center was determined to be
R from its optical rotation,2a and the diastereomeric
purity was 95%.18 By similar manipulation as described
for 2, phytanol 32 was converted to archaeal core lipid 1
via mesylation, etherification with 1-O-benzylglycerol,
We were thus successful in synthesizing the archaeal
36-membered diether lipid with branched isoprenoid
chains by the McMurry coupling. For detailed investiga-
tions of this 36-membered lipid, it is necessary to compare
(18) The diastereomeric excess was determined by the method of
Noyori et al. (ref 13a).

1928 J . Org. Chem., Vol. 62, No. 7, 1997
Eguchi et al.
Sch em e 6a
a
Reagents: (a) (1) Cl2P(dO)O(CH2)2Cl/pyridine, (2) H2O; (b) NMe3/toluene-CH3CN.
(150 mL), and TsCl (60.0 g, 0.315 mol) was added at 0 °C. The
mixture was stirred at room temperature for 15 h. Water and
EtOAc were added. The organic phase was separated, and
the aqueous phase was extracted with EtOAc. The combined
organic phase was successively washed with 2 N HCl, satu-
rated aqueous NaHCO3, and brine, dried (Na2SO4), filtered,
and concentrated to dryness. The residual oil was dissolved
in DMSO (180 mL). NaCN (12.3 g, 0.252 mol) was added, and
the solution was stirred at 50 °C for 14 h. Water and EtOAc
were added, and the organic phase was separated. The
aqueous phase was extracted with EtOAc. The combined
organic phase was washed with brine, dried (Na2SO4), filtered,
and concentrated to dryness. The residue was chromato-
graphed over silica gel with hexane-EtOAc (4:1) to give
cyanide 5 (35.1 g, 98%) as an oil. 1H NMR (270 MHz) δ: 1.09
(d, J ) 7.0, 3H), 1.21 (t, J ) 7.0, 3H), 1.30 (d, J ) 5.0, 3H),
2.12 (m, 1H), 2.37 (ddd, J ) 16.8, 6.7, 2.3, 1H), 2.49 (ddd, J )
16.8, 5.5, 2.3, 1H), 3.21-3.71 (m, 4H), 4.68 (dt, J ) 2.3, 4.9,
1/2H), 4.70 (dt, J ) 2.3, 4.9, 1/2H). IR (neat): 1390, 2250,
and hydrogenation. Thus, we have achieved the synthe-
sis of archaeal lipid 1 starting from phytol in 53% overall
yield.
Our next interest was to focus on the characteristics
of the synthetic macrocyclic diether lipid. Therefore, the
synthesized archaeal macrocyclic lipid 2 and noncyclized
(linear) counterpart 1 were converted into the corre-
sponding phosphocholine derivatives 35 and 36, respec-
tively. The synthetic lipids 2 and 1 were converted to
the phosphodiester derivatives by treatment with an
excess of (â-chloroethyl)phosphoryl dichloride in pyridine.
Subsequent displacement of the chlorine atom by tri-
methylamine in a pressure bottle for 3 days at 50-60 °C
gave the phosphocholine derivatives 35 and 36. The
overall yields of 35 and 36 from 2 and 1 were 60% and
44%, respectively (Scheme 6). Preliminary electron and
optical microscopic studies have revealed that vesicles
were formed in an aqueous dispersion of the synthesized
phosphocholine derivatives 35 and 36 (data not shown).
Investigation of the properties of the synthesized lipids
are in progress and will be reported in due course.
In summary, a total synthesis of an archaeal 36-
membered macrocyclic diether lipid 2 has been achieved
by using intramolecular McMurry coupling as a key
reaction. In addition, we have developed a highly ste-
reoselective and convenient synthesis of archaeal bi-
phytanyl glycerol lipid 1. These results may stimulate
investigations into the characteristics of the thermophilic
archaeal 36-membered macrocyclic diether lipids. Fur-
thermore, extension of this methodology to the synthesis
of archaeal 72-membered macrocyclic tetraether lipids is
currently underway in our laboratory.
2900, 2980 cm-1
. Anal. Calcd for C9H17NO2: C, 63.12; H,
10.01; N, 8.18. Found: C, 63.10; H, 9.73; N, 7.88.
(3S)-4-[(ter t-Bu tyld im eth ylsilyl)oxy]-3-m eth ylbu ta n e-
n itr ile (6). A solution of 5 (34.2 g, 0.200 mol) in 2 N HCl (18
mL) and THF (180 mL) was stirred for 2 h at room temper-
ature. Saturated NaHCO3 and EtOAc were added, and the
organic phase was separated. The aqueous phase was ex-
tracted with EtOAc. The combined organic phase was suc-
cessively washed with brine, dried (Na2SO4), filtered, and
concentrated to dryness. The residual oil was dissolved in
DMF (90 mL). Imidazole (34.0 g, 0.494 mol) and TBDMSCl
(35.4 g, 0.235 mol) were added, and the solution was stirred
for 2 h at room temperature. Water and EtOAc were added,
and the organic phase was separated. The aqueous phase was
extracted with EtOAc. The combined organic phase was
washed with brine, dried (Na2SO4), filtered, and concentrated
to dryness. The residue was chromatographed over silica gel
with hexane-EtOAc (20:1) to give TBDMS ether 6 (39.0 g,
92%) as an oil. [R]27D: +22.7° (c 5.64, CHCl3). 1H NMR (270
MHz) δ: 0.01 (s, 6H), 0.85 (s, 9H), 0.99 (d, J ) 7.0, 3H), 1.91-
2.05 (m, 1H), 2.27 (dd, J ) 16.3, 6.9, 1H), 2.43 (dd, J ) 16.3,
5.6, 1H), 3.36 (dd, J ) 11.1, 7.4, 1H), 3.56 (dd, J ) 11.1, 4.7,
1H). 13C NMR (67.5 MHz) δ: -5.59, -5.54, 15.79, 18.19, 20.85,
25.78, 33.21, 65.98, 118.84. IR (neat): 780, 840, 1100, 1260,
Exp er im en ta l Section
Gen er a l In for m a tion . All reactions, except for catalytic
hydrogenation reactions, were carried out in an inert (Ar or
N2) atmosphere. THF, diethyl ether, and DME were distilled
from sodium/benzophenone ketyl prior to use. Pyridine and
triethylamine were distilled from potassium hydroxide. DMF
was distilled from CaSO4, and benzene, DMSO, CH2Cl2,
HMPA, and toluene were distilled from calcium hydride.
Coupling constants, J , are given in Hz.
1460, 1750, 2250, 2860, 2950 cm-1. Anal. Calcd for C11H23
-
NOSi: C, 61.91; H, 10.86; N, 6.56. Found: C, 61.61; H, 10.58;
N, 6.79.
(3S )-4-[(t er t -B u t y ld im e t h y ls ily l)o x y ]-3-m e t h y lb u -
ta n ol (7). A solution of DIBAH in toluene (1.0 M, 33 mL, 33
mmol) was added dropwise to a solution of 6 (6.4 g, 30 mmol)
in toluene (50 mL) over 15 min at -78 °C, and the mixture
was stirred at -78 °C for 15 min. Saturated aqueous NH4Cl
(9.3 mL) was added, and the mixture was gradually warmed
to room temperature. Ether (100 mL) and 2 N HCl (100 mL)
were added, and the mixture was allowed to stir at room
temperature for 20 min. The organic phase was separated,
and the aqueous phase was extracted with ether. The
(3S)-4-[(1-Eth oxyeth yl)oxy]-3-m eth ylbu ta n en itr ile (5).
A mixture of methyl (R)-3-hydroxy-2-methylpropionate (4)
(24.8 g, 0.210 mol, Aldrich), ethyl vinyl ether (30 mL, 0.315
mol), and PPTS (200 mg) in THF (180 mL) was stirred for 2 h
at room temperature. To this reaction mixture was added
LiAlH4 (7.97 g, 0.210 mol) in small portions at 0 °C, and the
mixture was stirred at 0 °C for 1 h. Water was carefully added.
The insoluble materials were filtered off and washed with
THF. The filtrate and washings were combined and concen-
trated to dryness. The residual oil was dissolved in pyridine

Synthesis of Archaeal Macrocyclic Diether Lipid
J . Org. Chem., Vol. 62, No. 7, 1997 1929
combined organic phase was successively washed with satu-
rated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and
concentrated to dryness. The residue was dissolved in toluene
(50 mL), a solution of DIBAH in toluene (1.0 M, 33 mL, 33
mmol) was added dropwise to the solution over 15 min at -78
°C, and the mixture was stirred at -78 °C for 10 min.
Saturated aqueous NH4Cl (9.3 mL) was added, and the
mixture was gradually warmed to room temperature. Ether
(100 mL) and 2 N HCl (100 mL) were added, and the mixture
was allowed to stir at room temperature for 20 min. The
organic phase was separated, and the aqueous phase was
extracted with ether. The combined organic phase was suc-
cessively washed with saturated aqueous NaHCO3 and brine,
dried (Na2SO4), filtered, and concentrated to dryness. The
resulting residual oil was chromatographed over silica gel with
hexane-EtOAc (5:1) to give alcohol 7 (4.8 g, 73%) as an oil.
[R]27D: -6.96° (c 4.80, CHCl3). 1H NMR (270 MHz) δ: 0.12
(s, 6H), 0.90 (d, J ) 6.9, 3H), 0.91 (s, 9H), 1.58 (m, 2H), 1.78
(m, 1H), 2.84 (br, 1H), 3.43 (dd, J ) 9.9, 6.9, 1H), 3.54 (dd, J
) 9.9, 4.6, 1H), 3.67 (m, 2H). 13C NMR (67.5 MHz) δ: -5.53,
-5.48, 17.27, 18.28, 25.84, 33.89, 37.95, 61.06, 68.75. IR
(neat): 780, 840, 1100, 1260, 1460, 2330, 2860, 2950, 3350
thiophenol (2.88 mL, 28.0 mmol) and K2CO3 (3.88 g, 28.0
mmol) were added. The mixture was stirred for 15 min at
room temperature. Water was added, and the mixture was
extracted with EtOAc. The organic phase was washed with
brine, dried (Na2SO4), filtered, and concentrated to dryness.
To a solution of the resulting residue in CH2Cl2 (150 mL) was
added m-CPBA (14.3 g, 82.9 mmol) at 0 °C, and the mixture
was stirred for 1 h at 0 °C. Saturated aqueous Na2S2O3 was
added, and the organic phase was separated. The aqueous
phase was extracted with CH2Cl2. The combined organic
phase was washed with brine, dried (Na2SO4), filtered, and
concentrated to dryness. The residue was chromatographed
over silica gel with hexane-EtOAc (7:1-3:1) to give sulfone
10 (10.4 g, 89%) as an oil. [R]27D: +2.02° (c 4.87, CHCl3). 1H
NMR (270 MHz) δ: 1.11 (d, J ) 7.0, 3H), 1.55 (m, 1H), 1.77
(m, 1H), 2.28 (m, 1H), 2.95 (dd, J ) 14.1, 7.9, 1H), 3.25 (dd, J
) 14.1, 4.6, 1H), 3.46 (m, 2H), 4.42 (s, 2H), 7.25-7.37 (m, 5H),
7.47-7.65 (m, 3H), 7.86-7.91 (m, 2H). 13C NMR (67.5 MHz)
δ: 19.98, 26.47, 36.19, 62.35, 67.65, 72.91, 127.53, 127.81,
128.28, 128.33, 129.17, 133.43, 138.24, 140.08. IR (neat):
1110, 1150, 1300, 1450, 2860, 2930 cm-1
. Anal. Calcd for
C12H18OS: C, 67.89; H, 6.97. Found: C, 68.12; H, 7.03.
(2S,6S)-8-(Ben zyloxy)-1-[(ter t-bu tyld im eth ylsilyl)oxy]-
2,6-d im eth yl-5-(p h en ylsu lfon yl)octa n e (11). A 50 mL
Schlenk tube was charged with 10 (588 mg, 1.85 mmol) and
degassed THF (10 mL). A solution of n-butyllithium in hexane
(1.68 M, 1.21 mL, 2.04 mmol) was added dropwise, and the
slurry was stirred at -78 °C for 20 min. The mixture was
warmed to room temperature and allowed to stir for 10 min.
The mixture was recooled to -25 °C. HMPA (4.0 mL) was
added, followed by a solution of 8 (606 mg, 1.85 mmol) in
degassed THF (4 mL). The mixture was stirred at -25 °C for
1 h and then at room temperature for 1 h. Saturated aqueous
NH4Cl was added, and the mixture was extracted twice with
EtOAc. The combined organic phase was washed with brine,
dried (Na2SO4), filtered, and concentrated to dryness. The
residue was chromatographed over silica gel with hexane-
EtOAc (10:1) to give sulfone 11 (695 mg, 73%) as an oil. 1H
NMR (270 MHz) δ: 0.12 (s, 6H), 0.86 (d, J ) 6.6, 3H), 0.96 (s,
9H), 1.14 (d, J ) 8.0, 3H), 1.10-2.00 (m, 8H), 3.15 (dt, J )
1.5, 6.8, 1H), 3.32-3.70 (m, 4H), 4.49 (dd, J ) 13.5 11.8, 2H),
7.33-7.47 (m, 5H), 7.51-7.72 (m, 3H), 7.94 (m, 2H). IR
(neat): 840, 1090, 1150, 1350, 1460, 2850, 2950 cm-1. Anal.
Calcd for C29H46O4SSi: C, 67.13; H, 8.94. Found: C, 67.34;
H, 9.17.
(2S,6S)-8-(Ben zyloxy)-1-[(ter t-bu tyld im eth ylsilyl)oxy]-
2,6-d im eth ylocta n e (12a ). A mixture of 11 (3.56 g, 6.86
mmol) and 5% sodium amalgam (41.1 g, 89.3 mmol) in
methanol (70 mL) was stirred for 13 h at room temperature.
The mixture was filtered, and the residual mercury was
washed with EtOAc. The filtrate and washings were com-
bined, washed with brine, dried (Na2SO4), filtered, and con-
centrated to dryness. The residue was chromatographed over
silica gel with hexane-EtOAc (40:1-10:1) to give 12a (2.20 g,
85%) as an oil. [R]27D: +0.44° (c 1.75, CHCl3). 1H NMR (300
MHz) δ: 0.03 (s, 6H), 0.86 (d, J ) 6.6, 3H), 0.87 (d, J ) 6.6,
3H), 0.89 (s, 9H), 0.95-1.73 (m, 10 H), 3.34 (dd, J ) 9.5, 6.8,
1H), 3.44 (dd, J ) 9.5, 5.9, 1H), 3.49 (t, J ) 6.8, 1H), 3.50 (dd,
J ) 7.2, 6.0, 1H), 4.50 (s, 2H), 7.25-7.34 (m, 5H). 13C NMR
(75 MHz) δ: -5.35, 16.79, 18.35, 19.67, 24.27, 25.96, 29.85,
33.43, 35.74, 36.74, 37.43, 68.38, 68.74, 72.88, 127.44, 127.58,
128.31, 138.69. IR (neat): 850, 1110, 2880, 2950 cm-1. Anal.
Calcd for C23H42O2Si: C, 72.95; H, 11.18. Found: C, 72.84;
H, 11.22.
cm-1
.
Anal. Calcd for C11H26O2Si: C, 60.49; H, 12.00.
Found: C, 60.51; H, 12.30.
(2S)-1-[(ter t-Bu t yld im et h ylsilyl)oxy]-4-iod o-2-m et h -
ylbu ta n e (8). A mixture of 7 (9.5 g, 43.5 mmol), imidazole
(7.4 g, 108.7 mmol), triphenylphosphine (28.5 g, 108.7 mmol),
and I2 (22.1 g, 87.1 mmol) in benzene (300 mL) was stirred
for 1 h at room temperature. Saturated aqueous Na2S2O3 was
added, and the organic phase was separated. The aqueous
phase was extracted with EtOAc. The combined organic phase
was washed with brine, dried (Na2SO4), filtered, and concen-
trated to dryness. The residue was chromatographed over
silica gel with hexane to give iodide 8 (12.1 g, 85%) as an oil.
[R]27D: -10.5° (c 2.35, CHCl3). 1H NMR (270 MHz) δ: 0.04
(s, 6H), 0.88 (d, J ) 5.5, 3H), 0.89 (s, 9H), 1.71 (m, 2H), 2.00
(m, 1H), 3.20 (dt, J ) 9.5, 7.2, 1H), 3.28 (ddd, J ) 9.5, 7.8, 5.9,
1H), 3.43 (dd, J ) 9.2, 5.6, 1H), 3.47 (dd, J ) 9.2, 5.6, 1H). 13
C
NMR (67.5 MHz) δ: -5.42, 5.12, 15.93, 18.26, 25.90, 36.65,
37.58, 67.34. IR (neat): 780, 850, 1100, 1250, 1460, 2850, 2950
cm-1. Anal. Calcd for C11H25OSiI: C, 40.24; H, 7.68. Found:
C, 40.51; H, 7.98.
(2S)-4-(Ben zyloxy)-2-m eth ylbu ta n ol (9). A solution of
alcohol 7 (9.0 g, 41.2 mmol), benzyl 2,2,2-trichloroacetimidate
(15.4 mL, 82.9 mmol), and trifluoromethanesulfonic acid (0.5
mL, 3.3 mmol) in ether (70 mL) was stirred at room temper-
ature for 40 min. Saturated aqueous NaHCO3 was added, and
the organic phase was separated. The aqueous phase was
extracted with ether. The combined organic phase was washed
with brine, dried (Na2SO4), filtered, and concentrated to
dryness. The residue was dissolved in THF (80 mL), 2 N HCl
(50 mL) and methanol (50 mL) were added, and the mixture
was stirred at room temperature for 3.5 h. After removal of
organic solvent, brine and EtOAc were added, and the organic
phase was separated. The aqueous phase was extracted with
EtOAc, and the combined organic phase was washed with
saturated NaHCO3 and brine, dried (Na2SO4), filtered, and
concentrated to dryness. The residue was chromatographed
over silica gel with hexane-EtOAc (10:1-3:1) to give benzyl
ether 9 (7.0 g, 88%) as an oil. [R]27D: -7.85° (c 3.07, CHCl3).
1H NMR (270 MHz) δ: 0.92 (d, J ) 6.7, 3H), 1.49-1.89 (m,
3H), 2.51 (br, 1H), 3.37-3.63 (m, 4H), 4.51 (s, 2H), 7.23-7.40
(m, 5H). 13C NMR (67.5 MHz) δ: 17.12, 33.96, 34.03, 68.00,
68.63, 73.09, 127.67, 127.70, 128.39, 137.97. IR (neat): 740,
1040, 1100, 1370, 1460, 2880, 2940, 3410 cm-1. Anal. Calcd
for C12H18O2: C, 74.19; H, 9.34. Found: C, 73.89; H, 9.35.
(2S )-4-(Be n zyloxy)-1-(p h e n ylsu lfon yl)-2-m e t h ylb u -
ta n e (10). Methanesulfonyl chloride (2.17 mL, 28.0 mmol)
was added to a solution of 9 (4.54 g, 23.4 mmol) in pyridine
(20 mL) at 0 °C, and the mixture was stirred at room
temperature for 3 h. Water and EtOAc were added, and the
organic phase was separated. The aqueous phase was ex-
tracted with EtOAc. The combined organic phase was suc-
cessively washed with 2 N HCl, saturated aqueous NaHCO3,
and brine, dried (Na2SO4), filtered, and concentrated to dry-
ness. The residue was dissolved in DMF (50 mL), and
(3R,7S)-8-[(ter t-Bu tyld im eth ylsilyl)oxy]-2,6-d im eth yl-
1-octa n ol (13a ). A mixture of 12a (1.08 g, 2.85 mmol) and
10% Pd-C (119 mg) in EtOAc (20 mL) was stirred at room
temperature under hydrogen atmosphere for 50 h. The
catalyst was filtered off and washed with EtOAc. The filtrate
and washings were combined and concentrated to dryness. The
residue was purified by chromatography over silica gel with
hexane-EtOAc (10:1) to give 13a (0.79 g, 96%) as an oil.
[R]27D: -0.49° (c 1.73, CHCl3). 1H NMR (300 MHz) δ: 0.04 (s,
6H), 0.87 (d, J ) 6.6, 3H), 0.89 (d, J ) 6.4, 3H), 0.90 (s, 9H),
1.00-1.67 (m, 10H), 3.35 (dd, J ) 9.8, 6.4, 1H), 3.44 (dd, J )
9.8, 5.5, 1H), 3.68 (m, 2H). 13C NMR (75 MHz) δ: -5.36, 16.76,

1930 J . Org. Chem., Vol. 62, No. 7, 1997
Eguchi et al.
18.35, 19.64, 24.26, 25.94, 29.45, 33.40, 35.73, 37.43, 39.91,
61.21, 68.37. IR (neat): 840, 1100, 2860, 2940, 2960, 3350
room temperature for 3 h and then at 50 °C for 4.5 h. Water
was carefully added, and the mixture was diluted with ether
and 2 N HCl. The organic phase was separated, and the
aqueous phase was extracted with ether. The combined
organic layer was washed with saturated NaHCO3 and brine,
dried (Na2SO4), filtered, and concentrated to dryness. The
residue was chromatographed over silica gel with hexane-
EtOAc (4:1) to give allylic alcohol 19 (25.6 g, 94%) as an oil.
[R]28D: +3.63° (c 1.17, CHCl3). 1H NMR (300 MHz) δ: 0.87 (d,
J ) 6.6, 3H), 1.07-1.20 (m, 1H), 1.24-1.67 (m, 6H), 2.02 (m,
2H), 3.49 (t, J ) 6.8, 1H), 3.50 (dd, J ) 6.8, 6.1, 1H), 4.08 (d,
J ) 4.9, 2H), 4.50 (s, 2H), 5.62 (dt, J ) 4.9, 15.3, 1H), 5.69 (dt,
J ) 5.6, 15.1, 1H), 7.26-7.35 (m, 5H). 13C NMR (100 MHz) δ:
19.56, 26.42, 29.67, 32.41, 36.53, 36.68, 63.80, 68.59, 72.85,
127.46, 127.59, 128.32, 128.87, 133.42, 138.61. IR (neat): 698,
cm-1
.
Anal. Calcd for C16H36O2Si: C, 66.60; H, 12.58.
Found: C, 66.52; H, 12.86.
(2S,6R)-8-(Ben zyloxy)-2,6-dim eth yloctan ol (14a). A mix-
ture of 12a (1.09 g, 2.88 mmol) and 2 N HCl (1 mL) in THF (5
mL) and methanol (3 mL) was stirred for 1.5 h at room
temperature. Saturated aqueous NaHCO3 and EtOAc were
added, the organic phase was separated, and the aqueous
phase was extracted with EtOAc. The combined organic layer
was washed with brine, dried (Na2SO4), filtered, and concen-
trated to dryness. The residue was chromatographed over
silica gel with hexane-EtOAc (10:1-2:1) to give 14a (0.60 g,
79%) as an oil. [R]28D: -4.81° (c 1.10, CHCl3). 1H NMR (300
MHz) δ: 0.86 (d, J ) 6.6, 3H), 0.88 (d, J ) 6.6, 3H), 0.96-1.73
(m, 10H), 2.73 (br, 1H), 3.31 (dd, J ) 10.2, 6.6, 1H), 3.41 (dd,
J ) 10.2, 5.9, 1H), 3.47 (t, J ) 7.1, 1H), 3.48 (dd, J ) 7.1, 6.0,
1H), 4.47 (s, 2H), 7.22-7.32 (m, 5H). 13C NMR (75 MHz) δ:
16.58, 19.66, 24.21, 29.81, 33.35, 35.71, 36.67, 37.33, 68.27,
68.69, 72.86, 127.44, 127.58, 128.30, 138.64. IR (neat): 1100,
1460, 2860, 2940, 3380 cm-1. Anal. Calcd for C17H28O2: C,
77.22; H, 10.67. Found: C, 77.48; H, 10.94.
(4R)-6-(Ben zyloxy)-4-m eth ylh exa n ol (17). Ozone gas
was introduced into a solution of 1614 (17.9 g, 72.6 mmol) in
methanol (30 mL) at -78 °C for 10 h. NaBH4 (3.0 g, 79.3
mmol) was carefully added to the mixture at -78 °C, and the
mixture was gradually warmed to room temperature. The
solvent was removed, and the residue was diluted with ether
and 2 N HCl. The aqueous phase was extracted with ether.
The combined organic phase was successively washed with
saturated NaHCO3 and brine, dried (Na2SO4), filtered, and
concentrated to dryness. The residue was chromatographed
over silica gel with hexane-EtOAc (4:1-2:1) to give alcohol
17 (15.1 g, 93%) as an oil. [R]30D: +1.41° (c 0.92, CHCl3). 1H
NMR (300 MHz) δ: 0.90 (d, J ) 6.6, 3H), 1.10-1.75 (m, 7H),
3.50 (t, J ) 6.8, 1H), 3.51 (dd, J ) 6.8, 6.1, 1H), 3.62 (t, J )
6.6, 2H), 4.50 (s, 2H), 7.26-7.35 (m, 5H). 13C NMR (75 MHz)
δ: 19.46, 29.51, 29.98, 32.82, 36.53, 62.94, 68.43, 72.79, 127.43,
127.56, 128.25, 138.37. IR (neat): 698, 737, 1099, 1365, 1454,
2866, 2931, 3373 cm-1. Anal. Calcd for C14H22O2: C, 75.63;
H, 9.97. Found: C, 75.35; H, 10.04.
737, 970, 1003, 1095, 1365, 1454, 1670, 2858, 2927, 3383 cm-1
.
Anal. Calcd for C17H26O2: C, 77.82; H, 9.99. Found: C, 77.53;
H, 10.01.
(2R,3R,7R)-9-(Ben zyloxy)-2,3-ep oxy-7-m eth yln on a n ol
(20). To a suspension of molecular sieves 4A powder (22.9 g)
in freshly distilled CH2Cl2 (390 mL) was added tetraisopropyl
orthotitanate (14.0 mL, 47.8 mmol) and D-(-)-diethyl tartrate
(10.0 mL, 58.4 mmol) at -25 °C, and the mixture was stirred
at -25 °C for 55 min. A solution of 19 (12.3 g, 46.9 mmol) in
freshly distilled CH2Cl2 (50 mL) was added dropwise at -25
°C over 15 min. After 20 min, tert-butyl hydroperoxide in
decane (5.5 M, 18.0 mL, 99.0 mmol) was added at -25°C over
10 min, and the mixture was stirred for 1.5 h at -25 °C.
Aqueous 10% tartaric acid (200 mL) was added, and the
mixture was stirred at room temperature for 1 h. The mixture
was diluted with EtOAc, and the organic phase was separated.
The aqueous phase was extracted with EtOAc. The combined
organic layer was washed with brine, dried (Na2SO4), filtered,
and concentrated to dryness. The residue was dissolved in
ether (160 mL), and 10% aqueous NaOH (80 mL) was added
at 0 °C. After 1 h of stirring at 0 °C, two phases were
separated, and the aqueous phase was extracted with ether.
The combined organic layer was washed with brine, dried (Na2-
SO4), filtered, and concentrated to dryness. The residue was
chromatographed over silica gel with hexane-EtOAc (2:1) to
give epoxide 20 (11.9 g, 91%) as an oil. [R]26D: +22.19° (c 1.50,
CHCl3). 1H NMR (300 MHz) δ: 0.88 (d, J ) 6.3, 3H), 1.10-
1.73 (m, 9H), 2.46 (t, J ) 6.3, 1H), 2.90 (m, 2H), 3.49 (t, J )
6.8, 1H), 3.50 (dd, J ) 6.8, 6.1, 1H), 3.57 (ddd, J ) 12.5, 6.5,
4.7, 1H), 3.85 (ddd, J ) 12.5, 5.9, 2.5, 1H), 4.49 (s, 2H), 7.23-
7.38 (m, 5H). 13C NMR (75 MHz) δ: 19.38, 23.14, 29.59, 31.62,
36.49, 36.56, 55.87, 58.49, 61.67, 68.41, 72.73, 127.35, 127.48,
128.19, 138.42. IR (neat): 698, 739, 1028, 1099, 1365, 1454,
2862, 2929, 3423 cm-1. Anal. Calcd for C17H26O3: C, 73.35;
H, 9.41. Found: C, 73.25; H, 9.61.
(2S,6R)-8-(Ben zyloxy)-2,6-d im eth ylocta n ol (14b). A so-
lution of trimethylaluminum in hexane (1 M, 165 mL, 165
mmol) was added dropwise to a solution of 20 (14.7 g, 52.8
mmol) in CH2Cl2 (190 mL) at 0 °C during 15 min, and the
mixture was stirred for 3.5 h at 0 °C. Methanol (30 mL) was
carefully added, and the mixture was diluted with ether and
2 N HCl. The organic layer was separated, and the aqueous
phase was extracted with ether. The combined organic layer
was successively washed with saturated aqueous NaHCO3 and
brine, dried (Na2SO4), filtered, and concentrated to dryness.
The residue was dissolved in THF (40 mL) and water (20 mL),
and sodium periodate (14.1 g, 65.9 mmol) was added. The
resulting mixture was stirred for 2.5 h at room temperature.
The mixture was diluted with EtOAc and brine, and the two
phases were separated. The aqueous phase was extracted with
EtOAc. The combined organic layer was washed with brine,
dried (Na2SO4), filtered, and concentrated to dryness. The
residual oil was dissolved in methanol (75 mL), and NaBH4
(2.1 g, 55.5 mmol) was added at 0 °C. After 1 h of stirring at
0 °C, the solvent was removed in vacuo, and the residue was
diluted with ether and 2 N HCl. The organic layer was
successively washed with saturated Na2S2O3, saturated NaH-
CO3, and brine, dried (Na2SO4), filtered, and concentrated to
dryness. The residue was chromatographed over silica gel
with hexane-EtOAc (7:1-5:1) to give alcohol 14b (11.8 g, 84%)
as an oil.
(7R)-9-(Ben zyloxy)-7-m eth yl-2-n on yn -1-ol (18). To a
solution of 17 (32.0 g, 144 mmol) in pyridine (60 mL) was added
p-TsCl (35.5 g, 186 mmol) at 0 °C, and the mixture was stirred
for 3.5 h at 0 °C. Water was added, and the mixture was
extracted with EtOAc. The organic phase was successively
washed with 2 N HCl, saturated aqueous NaHCO3, and brine,
dried (Na2SO4), filtered, and concentrated to dryness to give
a crude tosylate (52.5 g). A suspension of prewashed NaH (5.2
g, 217 mmol) in DMSO (104 mL) was heated at 70 °C for 30
min, and the resulting solution was cooled to room tempera-
ture. Tetrahydro-2-(2-propynyloxy)-2H-pyran (30.5 g, 217
mmol) was added, and the mixture was stirred for 25 min at
room temperature. A solution of the crude tosylate (52.5 g)
in DMSO (35 mL) was added dropwise over 15 min at 10 °C,
and the resulting mixture was stirred for 5 min at 10 °C.
Water was added, and the mixture was extracted four times
with hexane. The combined organic phase was washed with
water, dried (Na2SO4), filtered, and concentrated to dryness.
The residue was treated with 2 N HCl (16 mL) in THF-
methanol (1:1, 200 mL). After removal of the solvent, the
residual oil was applied to chromatography over silica gel with
hexane-EtOAc (5:1-2:1) to give 18 (26.7 g, 71%) as an oil.
[R]28D: +6.21° (c 1.10, CHCl3). 1H NMR (300 MHz) δ: 0.88 (d,
J ) 6.3, 3H), 1.22 (m, 1H), 1.34-1.72 (m, 6H), 2.10 (br, 1H),
2.18 (tt, J ) 2.2, 7.1, 2H), 3.49 (t, J ) 6.8, 1H), 3.50 (dd, J )
6.8, 6.1, 1H), 4.20 (dt, J ) 5.5, 2.0, 2H), 4.50 (s, 2H), 7.25-
7.34 (m, 5H). 13C NMR (100 MHz) δ: 18.94, 19.50, 25.94, 29.38,
36.18, 36.58, 51.34, 68.48, 72.87, 78.39, 86.46, 127.49, 127.60,
128.33, 138.54. IR (neat): 698, 737, 1016, 1097, 1365, 1454,
2224, 2285, 2864, 2927, 3386 cm-1
.
Anal. Calcd for
C17H24O2: C, 78.42; H, 9.29. Found: C, 78.12; H, 9.03.
(2E,7R)-9-(Ben zyloxy)-7-m eth yl-2-n on en -1-ol (19).
A
solution of 18 (27.0 g, 104 mmol) in THF (40 mL) was added
dropwise to a suspension of LiAlH4 (4.1 g, 108 mmol) in THF
(130 mL) at 10 °C over 20 min. The mixture was stirred at

Synthesis of Archaeal Macrocyclic Diether Lipid
J . Org. Chem., Vol. 62, No. 7, 1997 1931
(2S,6S)-8-(Ben zyloxy)-1-[(ter t-bu tyld im eth ylsilyl)oxy]-
2,6-d im eth ylocta n e (12b). A mixture of 14b (10.0 g, 37.8
mmol), TBDMSCl (7.0 g, 46.4 mmol), and imidazole (6.5 g, 95.5
mmol) in DMF (80 mL) was stirred for 1.5 h at room
temperature. Water was added, and the mixture was ex-
tracted several times with hexane. The combined organic
layer was washed with brine, dried (Na2SO4), filtered, and
concentrated to dryness. The residue was chromatographed
over silica gel with hexane-EtOAc (10:1) to give 12b (14.1 g,
99%) as an oil.
(3R,7S)-8-[(ter t-Bu tyld im eth ylsilyl)oxy]-2,6-d im eth yl-
1-octa n ol (13b). By the same manner as described for the
synthesis of 13a , compound 12b (14.1 g, 37.2 mmol) was
converted to 13b (11.0 g, 97%) as an oil.
(2S,6R)-1-[(ter t-Bu tyldim eth ylsilyl)oxy]-8-iodo-2,6-dim -
eth ylocta n e (21). A mixture of 13a b (1.57 g, 5.44 mmol),
imidazole (0.92 g, 13.5 mmol), triphenylphosphine (3.55 g, 13.5
mmol), and iodine (2.75 g, 10.8 mmol) in benzene (60 mL) was
stirred at room temperature for 30 min. Saturated aqueous
Na2S2O3 was added, and the mixture was extracted with
EtOAc. The organic layer was successively washed with brine,
dried (Na2SO4), filtered, and concentrated to dryness. The
residue was chromatographed over silica gel with hexane-
was extracted with EtOAc. The organic phase was succes-
sively washed with saturated NaHCO3 and brine, dried (Na2-
SO4), filtered, and concentrated to dryness. The residue was
chromatographed over silica gel with hexane-EtOAc (20:1-
10:1) to give sulfone 23 (4.89 g, 87%) as an oil. 1H NMR (300
MHz) δ: 0.04 (s, 6H), 0.77 (d, J ) 6.3, 3H), 0.82 (d, J ) 6.3,
3H), 0.85 (d, J ) 6.6, 3H), 0.90 (s, 9H), 1.01 (d, J ) 7.1, 3H),
0.93-1.90 (m, 22H), 2.20 (m, 1H), 2.87 (dt, J ) 1.7, 5.6, 1H),
3.34 (dd, J ) 9.8, 6.6, 1H), 3.42 (dd, J ) 9.8, 5.7, 1H), 3.48 (m,
2H), 4.49 (s, 2H), 7.22-7.37 (m, 5H), 7.58 (m, 3H), 7.88 (m,
2H). IR (neat): 840, 1080, 1140, 1250, 1300, 1460, 2850, 2920
cm-1
. Anal. Calcd for C39H66O4SSi: C, 71.07; H, 10.09.
Found: C, 71.29; H, 10.29.
(3R,7R,11S,15S)-16-[(ter t-Bu tyld im eth ylsilyl)oxy]-3,7,-
11,15-tetr a m eth ylh exa d eca n ol (24). A small portion of Li
(80 mg, 10 mmol) was added to a solution of 23 (130 mg, 0.20
mmol) in THF (5 mL) and ethylamine (10 mL) at -78 °C, and
the mixture was stirred at -78 °C for 2 h. The excess Li was
destroyed by addition of isoprene and methanol. The mixture
was diluted with brine and extracted with EtOAc. The organic
layer was successively washed with 2 N HCl, saturated
NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated
to dryness. The residue was chromatographed over silica gel
with hexane-EtOAc (10:1) to give 24 (50 mg, 59%) as an oil.
[R]28D: +0.45° (c 1.38, CHCl3). 1H NMR (300 MHz) δ: 0.04 (s,
6H), 0.82-0.91 (m, 12H), 0.90 (s, 9H), 1.00-1.68 (m, 24H), 3.35
(dd, J ) 9.8, 6.6, 1H), 3.45 (dd, J ) 9.8, 5.8, 1H), 3.69 (m, 2H).
13C NMR (75 MHz) δ: -5.36, 16.79, 18.34, 19.66, 19.76, 24.35,
24.39, 24.43, 25.95, 29.51, 32.73, 32.78, 33.50, 35.74, 37.30,
37.36, 37.48, 39.93, 61.18, 68.43. IR (neat): 760, 840, 1090,
1250, 1460, 2850, 2920, 3340 cm-1. Anal. Calcd for C26H56O2-
Si: C, 72.83; H, 13.16. Found: C, 72.55; H, 13.14.
1-O-Ben zyl-2,3-b is-O-[(3R,7R,11S,15S)-16-[(ter t-b u t yl-
d im et h ylsilyl)oxy]-3,7,11,15-t et r a m et h ylh exa d eca n yl]-
sn -glycer ol (27). Methanesulfonyl chloride (1.00 mL, 12.9
mmol) was added to a mixture of 24 (4.42 g, 10.3 mmol) in
pyridine (25 mL) at 0 °C, and the solution was stirred at 0 °C
for 2.5 h. Water (60 mL) was added, and the mixture was
extracted with EtOAc. The organic phase was successively
washed with 2 N HCl, saturated aqueous NaHCO3, and brine,
dried (Na2SO4), filtered, and concentrated to dryness. The
methanesulfonate residue was used for the next step without
further purification. To a suspension of prewashed NaH (104
mg, 4.33 mmol) in DMSO (2 mL) was added a solution of 1-O-
benzyl-sn-glycerol (26) (213 mg, 1.17 mmol) in DMSO (3 mL)
at room temperature. The mixture was stirred at room
temperature for 1 h, and a solution of mesylate (1.24 g, 2.45
mmol) in DMSO (14 mL) was added at room temperature. The
mixture was stirred at room temperature for 2 days. Water
was added, and the mixture was extracted with EtOAc. The
EtOAc (50:1) to give iodide 21 (2.00 g, 92%) as an oil. [R]28
:
D
-9.08° (c 1.44, CHCl3). 1H NMR (300 MHz) δ: 0.04 (s, 6H),
0.86 (d, J ) 6.8, 3H), 0.87 (d, J ) 6.4, 3H), 0.89 (s, 9H), 0.95-
1.43 (m, 7H), 1.55 (br, 1H), 1.63 (m, 1H), 1.87 (m, 1H), 3.16
(ddd, J ) 9.8, 7.8, 7.1, 1H), 3.25 (ddd, J ) 9.8, 7.8, 5.4, 1H),
3.35 (dd, J ) 9.8, 6.3, 1H), 3.44 (dd, J ) 9.8, 5.9, 1H). 13C
NMR (75 MHz) δ: -5.34, 5.40, 16.77, 18.36, 18.74, 24.14, 25.96,
33.35, 33.83, 35.71, 36.55, 40.90, 68.35. IR (neat): 780, 840,
1090, 1250, 1460, 2850, 2930 cm-1. Anal. Calcd for C16H35
OSiI: C, 48.23; H, 8.85. Found: C, 48.03; H, 8.99.
-
(2S,6R)-8-(Ben zyloxy)-1-(p h en ylsu lfon yl)-2,6-d im eth y-
locta n e (22). A mixture of 14a b (11.0 g, 41.6 mmol) and
methanesulfonyl chloride (4.0 mL, 51.6 mmol) in pyridine (30
mL) was stirred for 3.5 h at 0 °C. Water was added, and the
mixture was extracted with EtOAc. The organic phase was
successively washed with 2 N HCl, saturated aqueous NaHCO3
and brine, dried (Na2SO4), filtered, and concentrated to dry-
ness. The resulting residue was dissolved in DMF (100 mL),
and K2CO3 (5.9 g, 42.7 mmol) and thiophenol (5.2 mL, 51.0
mmol) were added to the mixture, which was further stirred
for 4 h at room temperature. Water was added, and the
mixture was extracted four times with hexane. The combined
organic layer was washed with brine, dried (Na2SO4), filtered,
and concentrated to dryness. The residual oil was treated with
m-CPBA (25.0 g (85%), 123 mmol) in CH2Cl2 (120 mL) for 7 h
at 0 °C. Saturated aqueous Na2S2O3 (150 mL) was added, and
the mixture was extracted with EtOAc. The organic layer was
successively washed with 10% aqueous NaOH and brine, dried
(Na2SO4), filtered, and concentrated to dryness. The residue
was chromatographed over silica gel with hexane-EtOAc (20:
1) to give sulfone 22 (15.4 g, 95%) as an oil. [R]30D: +3.49° (c
1.69, CHCl3). 1H NMR (300 MHz) δ: 0.83 (d, J ) 6.6, 3H),
1.06 (d, J ) 6.6, 3H), 1.14-1.43 (m, 7H), 1.46-1.73 (m, 2H),
2.07 (m, 1H), 2.91 (dd, J ) 14.1, 7.8, 1H), 3.07 (dd, J ) 14.1,
4.6, 1H), 3.47 (t, J ) 6.9, 1H), 3.48 (dd, J ) 6.9, 5.7, 1H), 4.48
(s, 2H), 7.26-7.34 (m, 5H), 7.52-7.63 (m, 3H), 7.89-7.92 (m,
2H). 13C NMR (75 MHz) δ: 19.48, 19.84, 23.54, 28.44, 29.60,
36.52, 36.72, 36.81, 62.38, 68.46, 72.78, 127.38, 127.49, 127.72,
128.23, 129.15, 133.42, 138.52, 140.03. IR (neat): 534, 567,
600, 1088, 1147, 1306, 1446, 2858, 2927 cm-1. Anal. Calcd
for C23H32O3S: C, 71.09; H, 8.30. Found: C, 70.93; H, 8.48.
(2S,6R,10S,14R)-16-(Ben zyloxy)-1-[(ter t-bu tyld im eth yl-
silyl)oxy]-2,6,10,14-tetr a m eth yl-8-(p h en ylsu lfon yl)h exa -
d eca n e (23). A 300 mL Schlenk tube was charged with
sulfone (22) (3.30 g, 8.49 mmol) and degassed THF (50 mL).
A solution of n-butyllithium in hexane (1.57 M, 5.60 mL, 8.79
mmol) was added dropwise, and the slurry was stirred at -78
°C for 15 min. The mixture was stirred at 0 °C for 15 min
and recooled to -25 °C. HMPA (20 mL) was added to the
mixture. After 5 min, a solution of iodide 21 (3.38 g, 8.49
mmol) in degassed THF (25 mL) was added over 10 min at
-25 °C, and the mixture was stirred at the same temperature
for 1 h. Saturated aqueous NH4Cl was added, and the mixture
organic phase was washed with water, dried (Na2
SO4), filtered,
and concentrated to dryness. The residue was chromato-
graphed over silica gel with hexane-EtOAc (20:1) to give 27
(656 mg, 56%) as an oil. [R]26
D: +0.68° (c 1.56, CHCl3). 1H
NMR (300 MHz) δ: 0.04 (s, 12H), 0.83-0.90 (m, 24H), 0.89 (s,
18H), 0.94-1.73 (m, 48H), 3.32-3.64 (m, 13H), 4.55 (s, 2H),
7.26-7.34 (m, 5H).
13C NMR (67.5 MHz) δ: -5.34, 16.81,
18.35, 19.69, 19.71, 19.76, 24.39, 24.48, 25.97, 29.81, 29.90,
29.94, 32.76, 32.82, 33.52, 35.76, 36.64, 37.10, 37.41, 37.53,
68.42, 68.87, 69.97, 70.31, 70.78, 73.35, 77.95, 127.48, 127.57,
128.29, 138.42. IR (neat): 780, 840, 1090, 1250, 1460, 2850,
2920 cm-1
. Anal. Calcd for C62H122O5Si2: C, 74.18; H, 12.25.
Found: C, 74.31; H, 12.27.
1-O-Ben zyl-2,3-bis-O-[(3R,7R,11S,15S)-16-h yd r oxy-3,7,-
11,15-tetr a m eth ylh exa d eca n yl]-sn -glycer ol (28). A mix-
ture of 27 (51 mg, 0.051 mmol) and 2 N HCl (0.3 mL) in THF
(3 mL) was stirred for 5 h at room temperature. Saturated
aqueous NaHCO3 was added, and the mixture was extracted
with EtOAc. The organic layer was washed with brine, dried
(Na2SO4), filtered, and concentrated to dryness. The residue
was chromatographed over silica gel with hexane-EtOAc (4:
1) to give diol 28 (40.0 mg, quantitative) as an oil. [R]28
:
D
-2.45° (c 0.86, CHCl3). 1H NMR (300 MHz) δ: 0.84 (d, J )
6.8, 6H), 0.85 (d, J ) 6.3, 6H), 0.87 (d, J ) 6.6, 6H), 0.91 (d, J
) 6.8, 6H), 0.96-1.70 (m, 48H), 1.80 (br, 2H), 3.36-3.64 (m,
13H), 4.55 (s, 2H), 7.26-7.34 (m, 5H). 13C NMR (75 MHz) δ:

1932 J . Org. Chem., Vol. 62, No. 7, 1997
Eguchi et al.
16.61, 19.64, 19.66, 19.72, 24.31, 24.35, 24.37, 29.75, 29.83,
32.69, 32.73, 33.44, 35.71, 36.56, 37.02, 37.26, 37.31, 37.46,
37.47, 68.22, 68.82, 69.91, 70.23, 70.72, 73.29, 77.88, 127.44,
127.53, 128.24, 138.33. IR (neat): 1040, 1120, 1380, 1460,
2850, 2920, 3400 cm-1. Anal. Calcd for C50H94O5: C, 77.46;
H, 12.22. Found: C, 77.41; H, 12.51.
1110, 1380, 1460, 2850, 2920, 3440 cm-1
.
EI-MS m/z: 650
(M+), 620, 557. High-resolution EI-MS: calcd for C43H86O3
650.6577, found 650.6603. Anal. Calcd for C43H86O3: C, 79.32;
H, 13.31. Found: C, 79.60; H, 13.31.
(3R ,7R ,11R )-3,7,11,15-T e t r a m e t h y lh e x a d e c a n -1-o l
(P h yta n ol) (32). A mixture of phytol (31) (12.9 g, 43.5 mmol)
and [(S)-(-)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]chlo-
ro(p-cymene)ruthenium chloride (97 mg) in degassed methanol
(40 mL) was placed in a stainless steel autoclave under argon
atmosphere. High purity hydrogen gas (99.999 99% purity)
was introduced into the reaction apparatus (90 kgf/cm2
mixture was stirred at room temperature for 4 days. The
mixture was concentrated in vacuo, and the residue was
chromatographed over silica gel with hexane-EtOAc (10:1) to
1-O-Ben zyl-2,3-b is-O-[(3R,7R,11S,15S)-16-for m yl-3,7,-
11,15-tetr a m eth ylh exa d eca n yl]-sn -glycer ol (29). Dim-
ethyl sulfoxide (180 µL, 2.54 mmol) was added to a solution of
(COCl)2 (2 M in CH2Cl2, 1.00 mL, 2.00 mmol) in CH2Cl2 (11
mL) at -78 °C, and the mixture was stirred at the same
temperature for 35 min. To this mixture was added dropwise
a solution of 28 (299 mg, 0.386 mmol) in CH2Cl2 (9 mL) at
-78 °C. The mixture was stirred at -78 °C for 20 min and
then at -25 °C for 2 h. The mixture was recooled to -78 °C,
and Et3N (0.90 mL, 6.5 mmol) was added dropwise. The
reaction mixture was gradually warmed to room temperature.
Water was added, and the mixture was extracted with EtOAc.
The organic layer was successively washed with 2 N HCl,
saturated aqueous NaHCO3, and brine, dried (Na2SO4), fil-
tered, and concentrated to dryness. The residue was purified
by flash chromatography over silica gel with hexane-EtOAc
(20:1) to give 29 (264 mg, 89%) as an oil. [R]26D: +10.81° (c
1.30, CHCl3). 1H NMR (300 MHz) δ: 0.84 (d, J ) 7.8, 6H),
0.85 (d, J ) 6.3, 6H), 0.87 (d, J ) 6.1, 6H), 1.09 (d, J ) 7.1,
6H), 0.99-1.75 (m, 46H), 2.34 (m, 2H), 3.44-3.65 (m, 9H), 4.55
(s, 2H), 7.27-7.34 (m, 5H), 9.61 (d, J ) 2.0, 2H). 13C NMR
(75 MHz) δ: 13.34, 19.63, 19.66, 19.70, 19.73, 24.34, 24.39,
24.43, 29.67, 29.80, 29.87, 30.84, 32.63, 32.78, 36.61, 36.98,
37.07, 37.31, 37.35, 37.41, 37.50, 46.33, 68.86, 69.94, 70.28,
70.76, 73.32, 77.92, 127.47, 127.55, 128.27, 138.40, 205.40. IR
(neat): 1120, 1380, 1460, 1730, 2850, 2930 cm-1. Anal. Calcd
for C50H90O5: C, 77.87; H, 11.76. Found: C, 77.78; H, 11.81.
(2S,7R ,11R ,15S,19S,22S,26S,30R ,34R )-2-(Be n zyloxy-
m eth yl)-7,11,15,19,22,26,30,34-octa m eth yl-1,4-d ioxa cyclo-
h exa tr ia con t-20-en e (30). Powdered TiCl3 (1.0 g, 6.5 mmol)
and Zn-Cu couple (1.0 g, 15.4 mmol) were placed in a 200
mL Schlenk tube. DME (50 mL) was added, and the mixture
was refluxed for 1.5 h. A solution of 29 (264 mg, 0.343 mmol)
in DME (50 mL) was added to the refluxing slurry via a motor-
driven syringe pump over a 50 h period. After an additional
18 h of refluxing, the reaction mixture was cooled to room
temperature. The mixture was treated with 20% aqueous K2-
CO3 (70 mL) at room temperature for 3 h and then extracted
with EtOAc. The organic layer was washed with brine, dried
(Na2SO4), filtered, and concentrated to dryness. The residue
was purified by flash chromatography over silica gel with
). The
give phytanol (32) (11.9 g, 92%) as an oil. [R]29
D: +2.29° (c
1.02, CHCl3) (lit.2a [R]29D +2.4°). 1H NMR (300 MHz) δ: 0.84-
0.91 (d, J ) 6.6, 15H) 1.00-1.67 (m, 25H), 3.62-3.75 (m, 2H).
13C NMR (75 MHz) δ: 19.66, 19.74, 19.76, 22.62, 22.72, 24.35,
24.44, 24.78, 27.96, 29.49, 32.78, 37.26, 37.29, 37.36, 37.42,
37.47, 39.34, 39.93, 61.24. IR (neat): 737, 760, 1009, 1057,
1365, 1377, 1464, 2870, 2925, 2954, 3330 cm-1
.
1-O-Ben zyl-2,3-bis-O-[(3R,7R,11R)-3,7,11,15-tetr a m eth -
ylh exa d eca n -1-yl]-sn -glycer ol (34). Methanesulfonyl chlo-
ride (0.72 mL, 9.26 mmol) was added to a mixture of phytanol
(32) (2.12 g, 7.12 mmol) in pyridine (10 mL) at 0 °C, and the
solution was stirred at 0 °C for 2 h. Water (10 mL) was added,
and the mixture was extracted with EtOAc. The organic phase
was successively washed with 2 N HCl, saturated NaHCO3,
and brine, dried (Na2SO4), filtered, and concentrated to dryness
to give crude mesylate 33 as an oil. This methanesulfonate
was used for the next step without further purification. To a
suspension of prewashed NaH (252 mg, 10.5 mmol) in DMSO
(3 mL) was added a solution of 1-O-benzyl-sn-glycerol (26) (580
mg, 3.18 mmol) in DMSO (3 mL). After 1 h, a solution of the
mesylate (2.46 g, 6.52 mmol) in DMSO (7 mL) was added. The
mixture was stirred for 67 h at 40 °C. Saturated aqueous NH4-
Cl (15 mL) was added, and the mixture was extracted with
EtOAc. The organic phase was washed with water, dried (Na2-
SO4), filtered, and concentrated to dryness. The residue was
chromatographed over silica gel with hexane-EtOAc (50:1) to
give 34 (1.49 g, 63%) as an oil. [R]28D: +2.85° (c 0.64, CHCl3).
1H NMR (300 MHz) δ: 0.83-0.88 (10 × d, 30H), 1.00-1.68
(m, 48H), 3.41-3.67 (m, 9H), 4.56 (s, 2H), 7.26-7.34 (m, 5H).
13C NMR (67.5 MHz) δ: 19.75, 22.63, 22.72, 24.37, 24.48, 24.78,
27.96, 29.80, 29.89, 32.80, 36.62, 37.09, 37.27, 37.40, 37.45,
37.50, 39.36, 68.86, 69.94, 70.30, 70.78, 73.33, 77.93, 127.48,
127.57, 128.28, 138.42. IR (neat): 1115, 1380, 1376, 1460,
2860, 2920, 2950 cm-1. Anal. Calcd for C50H94O3: C, 80.79;
H, 12.75. Found: C, 80.59; H, 12.82.
hexane-EtOAc (25:1) to give 30 (141 mg, 56%) as an oil. [R]23
:
D
+6.66° (c 1.16, CHCl3). 1H NMR (300 MHz) δ: 0.83 (d, J )
6.3, 6H), 0.84 (d, J ) 6.3, 6H), 0.87 (d, J ) 6.6, 6H), 0.94 (d, J
) 6.8, 6H), 0.98-1.70 (m, 46H), 2.02 (br, 2H), 3.45-3.65 (m,
9H), 4.55 (s, 2H), 5.11 (m, 2H), 7.25-7.34 (m, 5H). 13C NMR
(75 MHz) δ: 19.77, 19.85, 21.82, 24.48, 25.05, 29.60, 29.72,
32.75, 32.83, 32.87, 36.64, 36.98, 37.23, 37.36, 37.46, 37.47,
37.76, 68.58, 69.70, 70.28, 71.43, 73.35, 77.94, 127.50, 127.57,
128.30, 134.97, 138.37. IR (neat): 696, 733, 968, 1117, 1377,
1462, 2858, 2925 cm-1. EI-MS m/z: 738 (M+), 647, 632, 555.
High-resolution EI-MS: calcd for C50H90O3 738.6890, found
738.6918. Anal. Calcd for C50H90O3: C, 81.24; H, 12.27.
Found: C, 81.31; H, 12.49.
2,3-Di-O-[(3R,7R,11R)-3,7,11,15-t et r a m et h ylh exa d ec-
a n yl]-sn -glycer ol (1). A mixture of 34 (2.03 g, 2.74 mmol)
and 10% Pd-C (1.11 g) in EtOAc (20 mL) was stirred for 29 h
at 40 °C under hydrogen atmosphere. The catalyst was
filtered through a pad of Celite and washed with EtOAc. The
filtrate and washings were combined and concentrated to
dryness. The residue was purified by flash chromatography
over silica gel with hexane-EtOAc (20:1) to give 1 (1.63 g, 92%)
as an oil. [R]25
D: +8.66° (c 1.07, CHCl3). 1H NMR (300 MHz)
δ: 0.83-0.89 (m, 30H) 1.00-1.69 (m, 48H), 2.21 (t, J ) 6.0,
1H), 3.44-3.76 (m, 9H). 13C NMR (75 MHz) δ: 19.66, 19.69,
19.76, 22.62, 22.72, 24.34, 24.46, 24.79, 27.96, 29.83, 29.86,
32.78, 36.57, 37.05, 37.27, 37.34, 37.38, 37.44, 37.48, 39.36,
63.08, 68.63, 70.14, 70.94, 78.28. IR (neat): 1051, 1117, 1365,
(2R,7R,11R,15S,19S,22S,26S,30R,34R)-2-(H yd r oxym e-
t h yl)-7,11,15,19,22,26,30,34-oct a m et h yl-1,4-d ioxa cyclo-
h exa tr ia con ta n e (2). A mixture of 30 (80 mg, 0.11 mmol)
and 10% Pd-C (80 mg) in EtOAc (5 mL) was stirred for 3 days
under hydrogen atmosphere at room temperature. The cata-
lyst was filtered through a pad of Celite and washed with
EtOAc. The filtrate and washings were combined and con-
centrated to dryness. The residue was purified by flash
chromatography over silica gel with hexane-EtOAc (10:1) to
give 2 (68 mg, 96%) as an oil. [R]26D: +8.17° (c 1.16, CHCl3).
1H NMR (300 MHz) δ: 0.84-0.89 (m, 24H) 1.00-1.68 (m,
52H), 2.20 (br, 1H), 3.46-3.73 (m, 9H). 13C NMR (75 MHz) δ:
19.76, 1985, 19.93, 19.97, 20.02, 20.08, 23.96, 24.26, 24.34,
24.42, 29.72, 29.77, 32.41, 32.46, 32.50, 32.59, 32.66, 32.77,
33.03, 33.56, 34.16, 36.53, 36.67, 36.90, 36.99, 37.17, 37.19,
37.26, 63.02, 68.52, 70.00, 71.18, 71.23, 78.37. IR (neat): 1050,
1376, 1464, 2868, 2925, 2952, 3471 cm-1
. Anal. Calcd for
C43H88O3: C, 79.07; H, 13.58. Found: C, 78.91; H, 13.57.
(2R,7R,11R,15S,19S,22S,26S,30R,34R)-7,11,15,19,22,26,-
30,34-Octam eth yl-2-[[[(N,N,N-tr im eth ylam in o)eth yl]ph os-
p h on yl]m eth yl]-1,4-d ioxa cycloh exa tr ia con ta n e (35). To
a solution of 2 (113 mg, 0.173 mmol) in pyridine (1 mL) was
added (â-chloroethyl)phosphonyl dichloride (40 µL, 0.31 mmol)
at 0 °C. The mixture was stirred for 2.5 h at room tempera-
ture. Water (5 mL) was added, and the mixture was stirred
at room temperature for 1 h. Then, the mixture was acidified
by addition of 2 N HCl and extracted four times with CHCl3.
The combined organic layer was dried (Na2SO4), filtered, and
concentrated to dryness. The obtained residue was chromato-

Synthesis of Archaeal Macrocyclic Diether Lipid
J . Org. Chem., Vol. 62, No. 7, 1997 1933
graphed over silica gel with CHCl3-MeOH (20:1-7:1) to give
a waxy residue (172 mg). The residue was dissolved in toluene
(10 mL) and CH3CN (5 mL), and the solution was transferred
into a pressure bottle. The mixture was cooled to -78 °C, and
dry trimethylamine (10 mL) was introduced. The mixture was
heated at 50-60 °C for 3 days. After removal of the solvent,
the residue was chromatographed over silica gel with CHCl3-
methanol (8:1) to CHCl3-methanol-H2O (65:15:1) to give 35
(85 mg, 60%) as a hygroscopic wax. 1H NMR (300 MHz, CDCl3:
CD3OD ) 8:1) δ: 0.85-0.90 (m, 24H), 1.00-1.50 (m, 44H),
1.53-1.67 (m, 8H), 3.23 (s, 9H), 3.45-3.56 (m, 3H), 3.58-3.66
(m, 6H), 3.88 (t, J ) 5.6, 2H), 4.26 (br, 2H). 13C NMR (75 MHz,
CDCl3:CD3OD ) 4:1) δ: 19.29, 19.34, 19.44, 19.47, 19.53, 19.57,
19.63, 19.67, 19.81, 23.58, 23.63, 23.77, 23.82, 23.95, 24.00,
24.14, 29.36, 29.40, 29.44, 29.60, 31.85, 31.87, 32.07, 32.09,
32.15, 32.30, 32.34, 32.38, 32.50, 32.69, 32.96, 32.98, 33.70,
33.73, 36.20, 36.25, 36.39, 36.46, 36.49, 36.56, 36.63, 36.74,
36.76, 36.80, 36.89, 36.94, 36.98, 37.01, 37.07, 37.13, 37.18,
53.92, 58.70 (d, J ) 4.4), 64.86 (d, J ) 5.6), 66.18, 66.23, 66.26,
68.41, 69.72, 70.54, 77.67 (d, J ) 8.6). High-resolution FAB-
MS: calcd for C48H99O6NP (M+ + H) 816.7210, found 816.7210.
2,3-Bis-O-[(3R,7R,11R)-3,7,11,15-tetr am eth ylh exadecan -
1-yl]-sn -glycer o-1-p h osp h och olin e (36). By the same man-
ner as described in the synthesis of 35, the compound 1 (206
mg, 0.315 mmol) was converted to 36 (109 mg, 44%) as a
hygroscopic wax. 1H NMR (400 MHz) δ: 0.83-0.88 (m, 30H),
1.00-1.41 (m, 40H), 1.46-1.64 (m, 8H), 3.24 (s, 9H), 3.45-
3.50 (m, 3H), 3.54-3.66 (m, 6H), 3.88 (t, J ) 6.0, 2H), 4.25
(br, 2H). 13C NMR (100 MHz, CDCl3-CD3OD ) 8:1) δ: 19.39,
19.47, 22.36, 22.45, 24.15, 24.24, 24.55, 27.71, 29.60, 29.71,
32.54, 32.71, 36.44, 36.88, 37.04, 37.19, 37.32, 39.13, 53.98,
58.71 (d, J ) 3.6), 64.81 (d, J ) 5.4), 66.14, 68.61, 69.87, 70.49,
77.77 (d, J ) 7.3). High-resolution FAB-MS: calcd for
C
48H101O6NP (M+ + H) 818.7367, found 818.7385.
Ack n ow led gm en t. The authors are grateful to
Takasago Co. Ltd. and Daiso Co. Ltd for providing chiral
starting materials. This work was supported in part
by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports and Culture.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 1, 2, 5-14a b, 17-24, 27-30, 32, and
34-36, 1H NMR spectra of MTPA esters of 9 and 14b, and
mass spectra for compounds 2, 30, and 35 (56 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.
J O962327H