Total Synthesis of Archaeal 72-Membered Macrocyclic Tetraether Lipids

Article abstract of DOI:10.1021/jo972328p

Total synthesis of archaeal 72-membered macrocyclic tetraether lipids 3a and 3b is reported. The synthesis was principally composed of preparation of the functionalized half-sized diether compounds 11 and 15 first followed by appropriate dimerization through Julia coupling and final macrocyclization of the crucial dialdehydes 23 and 31 by McMurry coupling. This strategy appeared to be advantageous for the stereoselective synthesis of both natural 72-membered tetraether lipids 3a and 3b using common synthetic intermediates. In addition, this approach was so designed that its synthetic flexibility would allow construction of unnatural structural variants for physicochemical studies. Also described are the results of differential scanning calorimetric analysis of the synthesized lipids 3a and 3b. Both 3a and 3b showed almost the same phase behavior with the broad endothermic phase transition at -53 °C. The enthalpy of the phase transition, ΛH, was estimated to be 1.8 and 1.9 kcal/mol for 3a and 3b, respectively. The physicochemical as well as polymorphismic properties of 3a and 3b turned out to be indistinguishable despite of their regioisomeric structures. The physical structure of the phases in terms of the chemical structure is also discussed.

Full text of DOI:10.1021/jo972328p

J . Org. Chem. 1998, 63, 2689-2698
2689
Tota l Syn th esis of Ar ch a ea l 72-Mem ber ed Ma cr ocyclic Tetr a eth er
Lip id s
Tadashi Eguchi, Kazuya Ibaragi, and Katsumi Kakinuma*,†
Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152, J apan
Received December 30, 1997
Total synthesis of archaeal 72-membered macrocyclic tetraether lipids 3a and 3b is reported. The
synthesis was principally composed of preparation of the functionalized half-sized diether compounds
11 and 15 first followed by appropriate dimerization through J ulia coupling and final macrocy-
clization of the crucial dialdehydes 23 and 31 by McMurry coupling. This strategy appeared to be
advantageous for the stereoselective synthesis of both natural 72-membered tetraether lipids 3a
and 3b using common synthetic intermediates. In addition, this approach was so designed that
its synthetic flexibility would allow construction of unnatural structural variants for physicochemical
studies. Also described are the results of differential scanning calorimetric analysis of the
synthesized lipids 3a and 3b. Both 3a and 3b showed almost the same phase behavior with the
broad endothermic phase transition at -53 °C. The enthalpy of the phase transition, ∆H, was
estimated to be 1.8 and 1.9 kcal/mol for 3a and 3b, respectively. The physicochemical as well as
polymorphismic properties of 3a and 3b turned out to be indistinguishable despite of their
regioisomeric structures. The physical structure of the phases in terms of the chemical structure
is also discussed.
In tr od u ction
striking features of archaeal membrane lipids are found
in the presence of macrocyclic structures as large as 36-
and 72-membered rings (2 and 3a b) as shown in Figure
1. Concerning to the stereochemistry of these macrocyclic
archaeal lipids, Heathcock and co-workers were success-
ful in showing the absolute stereochemistry of the bi-
phytane of the archaeal tetraether lipid by a synthetic
approach.4 In addition, Arigoni et al. reported recently
that the 72-membered lipids exist as a mixture of
regioisomers in terms of the glycerol arrangements such
as 3a and 3b in several methanogenic and thermophilic
archaebacteria such as Methanobacterium thermoau-
totrophicum, Thermoplasma, and Sulfolobus.5
The physical nature of a membrane composed of these
macrocyclic lipids is quite intriguing.3 The 72-membered
lipids are considered to form a unimolecular membrane
structure, in contrast to the ubiquitous bilayer assembly,
or to constitute a trans-membrane orientation.6 Recently,
Archaea (archaebacteria) have currently been attract-
ing wide attention due to their evolutionary diversity
from eubacteria and eukaryotes.1 Among the major
interests in archaea are unique chemical structures of
the membrane core lipids. Archaeal membrane lipids are
structurally unique in that the glycerol core is linked to
the isoprenoid chains with ethereal bonding as shown in
structure of 1, in contrast to the ester linkages with fatty
acids in eubacterial and eukaryotic membrane lipids.2
These unusual lipids have attracted attention in connec-
tion with their physicochemical properties. Several
modeling and synthetic studies have been reported in
order to investigate the stability, fluidity, and perme-
ability of the archaeal membrane lipids.3 The most
† Fax: +81-3-3729-8498. E-mail: kakinuma@chem.titech.ac.jp.
(1) (a) Woese, C. R.; Fox, G. E. Proc. Natl. Acad. Sci. U.S.A. 1977,
74, 5088. (b) Woese, C. R.; Kandler, O.; Wheelis, M. L. Proc. Natl. Acad.
Sci. U.S.A. 1990, 87, 4576. (c) Delong, E. F. Proc. Natl. Acad. Sci.
U.S.A. 1992, 89, 5685. (d) Kjems, J .; Larsen, N.; Dalgaard, J . Z.;
Garrett, R. A.; Stetter, K. O. Syst. App. Microbiol. 1992, 15, 203. (e)
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1967, 6, 3329. (b) J oo, C. N.; Shier, T.; Kates, M. J . Lipid Res. 1968,
9, 782. (c) De Rosa, M.; Gambacorta, A.; Minale, L.; J . Chem. Soc.,
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217. (e) De Rosa, M.; Gambacorta, A.; Bu’Lock, J . D. Phytochemistry
1976, 15, 143. (f) Langworthy, T. A. Biochim. Biophys. Acta 1977, 487,
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J . D. Phytochemistry 1977, 16, 1961. (h) Tornabene, T. G.; Langworthy,
T. A. Science 1979, 203, 51. (i) De Rosa, M.; Gambacorta, A.; Nicolaus,
B.; Sodano, S.; Bu’Lock, J . D. Phytochemistry 1980, 19, 833. (j)
Kushwaha, S. C.; Kates, M.; Sprott, G. D.; Smith, I. C. P. Biochim.
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1983, 222, 1329. (l) Comita, P. B.; Gagosian, R. B.; Pang, H.; Costello,
C. E. J . Biol. Chem. 1984, 259, 15234. (m) Kates, M. In The
Biochemistry of Archaea (Archaeobacteria); Kates, M., Kushner, D. J .,
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Gambacorta, A.; Gliozzi, A.; De Rosa, M. World J . Microbiol. Biotech.
1995, 11, 115.
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Ourisson, G.; Nakatani, Y. Biochim. Biophys. Acta 1987, 903, 132. (b)
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1003, 151. (c) Stewart, L. C.; Kates, M.; Ekiel, I. H.; Smith, I. C. P.
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Moriya, A.; Yamada, K.; Hosokawa, T.; Higuchi, T.; Kinoshita, M. J .
Am. Chem. Soc. 1990, 112, 3188. (e) Yamauchi, K.; Yamada, K.;
Kinoshita, M.; Kamikawa, T. Bull. Chem. Soc. J pn. 1991, 64, 2088. (f)
Moss, R. A.; Fujita, T.; Okumura, Y. Langmuir 1991, 7, 2415. (g)
Thompson, D. H.; Wong, K. F.; Humphry-Baker, R.; Wheeler, J . J .;
Kim, J .-M.; Rananavare, S. B. J . Am. Chem. Soc. 1992, 114, 9035. (h)
Kim, J .-M.; Thompson, D. H. Langmuir 1992, 8, 637. (i) Moss, R. A.;
Li, J .-M. J . Am. Chem. Soc. 1992, 114, 9227. (j) Yamauchi, K.; Doi, K.;
Kinoshita, M.; Kii, F.; Fukuda, H. Biochim. Biophys. Acta 1992, 1110,
171. (k) He´bert, N.; Beck, A.; Lennox, R. B.; J ust, G. J . Org. Chem.
1992, 57, 1777. (l) Menger, F. M.; Chen, X. Y.; Brocchini, S.; Hopkins,
H. P.; Hamilton, D. J . Am. Chem. Soc. 1993, 115, 6600. (m) Ladika,
M.; Fisk, T. E.; Wu, W. W.; J ons, S. D. J . Am. Chem. Soc. 1994, 116,
12093. (n) Menger, F. M.; Chen, X. Y. Tetrahedron Lett. 1996, 37, 323.
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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.
(5) Gra¨ther O.; Arigoni, D. J . Chem. Soc., Chem. Commun. 1995,
405.
S0022-3263(97)02328-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/01/1998

2690 J . Org. Chem., Vol. 63, No. 8, 1998
Eguchi et al.
F igu r e 1. Typical structures of archaeal membrane lipids 1, 2, and 3a b.
we reported the syntheses of the macrocyclic 36-mem-
bered lipid found in Methanococcus jannaschii and of the
desmethylated analogues of 72-membered lipids.7 Our
continuing efforts have now yielded the first total syn-
thesis of archaeal 72-membered macrocyclic tetraether
lipids, and we wish to report here the full details of the
synthesis.
isomeric monoalkylated benzylglycerol derivatives, which
were easily separable by silica gel column chromatogra-
phy to afford sn-2-O-alkylated benzylglycerol 9 and sn-
3-O-alkylated benzylglycerol 10 in 50 and 44% yields,
respectively.11 The sn-2-O-alkylated glycerol 9 was fur-
ther alkylated via its sodium alkoxide with the mesylate
derivative7d of 4 to afford 2,3-O-disubstituted sn-1-O-
benzylglycerol 11 in 86% yield. Subsequent deprotection
of the TBS group with TBAF afforded half-sized diether
compound 12. The half-sized lipid 12 was converted into
two appropriate coupling precursors, sulfone 13 and
aldehyde 14, which were then coupled together by J ulia
coupling to lead to a precursor of McMurry coupling.
Thus, mesylation of 12 under the usual conditions and
subsequent treatment with thiophenol, followed by m-
CPBA afford the sulfone 13 in 88% yield. The other
coupling partner in the J ulia method, the aldehyde 14,
was prepared from 12 by Swern oxidation in 96% yield.
The sn-3-O-alkylated glycerol 15 was also manipulated
in the same manner as the synthesis of 14 from 11 to
give aldehyde 17 in 86% yield (two steps). It should be
emphasized here that the key intermediates 13, 14, and
17 were prepared from a common precursor.
As shown in Scheme 2, the lithium carbanion prepared
from the sulfone 13 with butyllithium was treated with
the aldehyde 14 in THF at -25 °C to successfully furnish
â-hydroxy sulfone 18.8 After acetylation to 19, a reduc-
tive elimination reaction of 19 was carried out with an
excess amount of SmI2 in THF and HMPA,12 which
proceeded smoothly to give olefin 20 in an excellent yield
(88%) as a mixture of the geometrical isomers. The
isomeric ratio was estimated as 85:15 (E/ Z) by 13C NMR.
Catalytic hydrogenation of the resulting double bond of
20 with Pd/C leading to 21 was somewhat troublesome.
Epimerization of the chiral centers neighboring the
double bond was observed. This may be due to a minute
amount of residual sulfurous impurity from the prior
reaction, because the epimerization ratio varied from
time to time. Thus, to secure the stereochemically
defined hydrogenation, the olefin 20 was subjected to
diimide reduction with potassium azodicarboxylate and
Resu lts a n d Discu ssion
The basic synthetic plan was similar to the preparation
of the desmethylated 72-membered lipids.7e Thus, the
synthesis was principally composed of preparation of the
functionalized half-sized diether compounds 11 and 15
first followed by appropriate dimerization through J ulia
coupling8 and final macrocyclization of the crucial dial-
dehydes 23 and 31 by McMurry coupling.9 This strategy
appeared to be advantageous for the stereoselective
synthesis of both natural 72-membered tetraether lipids
3a and 3b using common synthetic intermediates.
The synthesis started with the bifuctionalized C20
isoprenoid unit 47d as shown in Scheme 1. The mono-
TBS ether 4 was oxidized under Swern conditions to give
aldehyde 11 (83%), which was subjected to acetal forma-
tion with sn-1-O-benzylglycerol 610 in the presence of
p-toluenesulfonic acid and MgSO4, followed by deprotec-
tion of the TBS group with TBAF, to give the acetal
product 7 in 93% yield as a diastereomeric mixture in a
ratio of 7:3. After protection of the resulting hydroxyl
group with a MPM group, the acetal derivative 8 was
treated with DIBAL-H to give a mixture of positionally
(6) (a) Gliozzi, A.; Rolandi, R.; De Rosa, M.; Gambacorta, A. J .
Membr. Biol. 1983, 75, 45. (b) De Rosa, M.; Gambacorta, A.; Nicolaus,
B. J . Membr. Sci. 1983, 16, 287. (c) Bruno, S.; Cannistraro, S., Gliozzi,
A.; De Rosa, M.; Gambacorta, A. Eur. Biophys. J . 1985, 13, 647. (d)
De Rosa, M.; Gambacorta, A.; Gliozzi, A. Microbiol. Rev. 1986, 50, 70.
(7) (a) Eguchi, T.; Terachi, T.; Kakinuma, K. Tetrahedron Lett. 1993,
34, 2175. (b) Eguchi, T.; Terachi, T.; Kakinuma, K. J . Chem. Soc.,
Chem. Commun. 1994, 137. (c) Eguchi, T.; Kano, H.; Kakinuma, K.
Chem. Commun. 1996, 365. (d) Eguchi, T.; Arakawa, K.; Terachi, T.;
Kakinuma, K. J . Org. Chem. 1997, 62, 1924. (e) Eguchi, T.; Kano, H.;
Arakawa, K.; Kakinuma, K. Bull. Chem. Soc. J pn. 1997, 70, 2545.
(8) (a) J ulia M.; Paris, J .-M. Tetrahedron Lett. 1973, 4833. (b)
Kocienski, P. J .; Lythgoe, B.; Ruston, S. J . Chem. Soc., Perkin Trans.
1 1978, 829.
(9) (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.
(10) Takano, S.; Seya, K.; Goto, E.; Hirama, M.; Ogasawara, K.
Synthesis 1983, 116.
(11) Takano, S.; Kurotaki, A.; Sekiguchi, Y.; Satoh, S.; Ogasawara,
K. Synthesis 1986, 811.
(12) (a) Ihara, M.; Suzuki, S.; Taniguchi, T.; Fukumoto, K. Synlett
1994, 859. (b) Ihara, M.; Suzuki, S.; Taniguchi, T.; Fukumoto, K.
Tetrahedron 1995, 36, 9873.

Archaeal 72-Membered Macrocyclic Tetraether Lipids
J . Org. Chem., Vol. 63, No. 8, 1998 2691
Sch em e 1a
acetic acid to give 21 in an excellent yield without
epimerization. Deprotection of the MPM groups with
DDQ in CH2Cl2-H2O was performed to afford diol 22 in
90% yield. The key precursor dialdehyde for McMurry
coupling 23 was then prepared from 22 by subsequent
oxidation under Swern conditions in 96% yield.
means that both regioisomeric 72-membered lipids 3a
and 3b were not distinguishable in usual spectroscopic
means. Furthermore, especially in 13C NMR spectra,
both 3a and 3b showed the same symmetrical spectral
pattern, thereby clearly indicating that no epimerization
at the R-positions of carbonyl groups or double bonds
occurred during the synthesis.
The crucial 72-membered ring formation reaction was
performed with the dialdehyde 23 with the aid of a low-
valent titanium coupling known as McMurry coupling.9
The intramolecular coupling of 23 was carried out under
high dilution conditions for a prolonged time. The
reaction proceeded quite smoothly to yield macrocyclic
tetraether 24 in 59% yield as a single isomer of the double
bond as was observed in the case of the 36-membered
ring formation.7d Usually, the yield of this coupling
reaction ranged from 50 to 65%. Finally, reduction of
the double bond of 24 by diimide reduction again,
followed by deprotection of the benzyl group by catalytic
hydrogenation over Pd-C, afforded the 72-membered
tetraether core lipid 3a in 62% yield (two steps). The
EI-MS spectrum of the product 3a , m/z 1301 (M+) and
1283 (M+ - H2O), firmly supported the structure.
The synthesis of the positional isomer 3b started from
the sulfone 13 and the aldehyde 17, and similar manipu-
lations as described above gave the regioisomeric dial-
dehyde 31 as shown in Scheme 3. A McMurry coupling
of the dialdehyde 31 also went smoothly to afford in 66%
yield the cyclized product 32 as a single isomer. Reduc-
tion and deprotection gave the regioisomeric 3b in 70%,
m/z: 1301 (M+), 1283 (M+ - H2O).
As was mentioned above briefly, the membranes of
archaeal tetraether lipids of methanogens and themoaci-
dophiles essentially consist of bipolar monolayer struc-
tures in which each lipid molecule spans the entire
thickness of the membrane. These structures would be
related to the membrane stability at the high growth
temperatures of these archaea.6 The organized struc-
tures of these tetraether lipids are intriguing in terms
of physiological conditions. Several publications dealt
with the structure and polymorphism of a variety of
tetraether lipid mixtures extracted from thermoacido-
philic archaea as studied by X-ray scattering as well as
differential scanning calorimetry.13 While the nature and
characteristic of the lipids comprising a single bipolar
macrocyclic isomer is interesting for various aspects, it
has been beyond current research due to the lack of
availability of such single compounds. The first total
synthesis described above has now allowed us to pursue
a new area of research, and we describe here our
(13) (a) Gliozzi, A.; Paoli, G.; De Rosa, M.; Gambacorta, A. Biochim.
Biophys. Acta 1983, 735, 234. (b) Gulik, A.; Luzzati, V.; De Rosa, M.;
Gambacorta, A. J . Mol. Biol. 1985, 182, 131. (c) Gulik, A.; Luzzati, V.;
De Rosa, M.; Gambacorta, A. Syst. Appl. Microbiol. 1986, 7, 258. (d)
Gliozzi, A.; Bruno, S.; Basak, T. K.; De Rosa, M.; Gambacorta, A. Syst.
Appl. Microbiol. 1986, 7, 266. (e) Gulik, A.; Luzzati, V.; De Rosa, M.;
Gambacorta, A. J . Mol. Biol. 1988, 201, 429. (f) Cavagnetto, F.; Relini,
A.; Mirghani, Z.; Gliozzi, A.; Bertoia, D.; Gambacorta, A. Biochim.
Biophys. Acta 1992, 1106, 273.
The synthesized 72-membered lipids 3a and 3b were
in good agreement with the natural 72-membered lipid
mixture in all spectral properties including IR, mass, and
1H and 13C NMR spectra as well as optical rotations. This

2692 J . Org. Chem., Vol. 63, No. 8, 1998
Eguchi et al.
Sch em e 2a
preliminary results of the differential scanning calori-
metric analysis of the chemically pure synthetic tetra-
ether lipids 3a and 3b.
for the detailed polymorphism of 3a and 3b at the present
time, it seems most likely that the hydrocarbon chains
of both 3a and 3b are stiff and parallel as in a lamellar
structure below the transition temperature and the
ordered structures collapse above the phase transition.
In summary, we have accomplished the first total
synthesis of the 72-membered macrocyclic tetraether
lipids using McMurry coupling. These results may
stimulate investigations to gain more insight into the
characteristics of the thermophilic archaeal macrocyclic
diether lipids. Also described are the preliminary results
of calorimetric analysis of the synthesized tetraether
lipids 3a and 3b. Further characterizations composed
of these lipids are currently in progress and will be
reported in due course.
Differential scanning calorimetric thermograms of the
synthesized 3a and 3b in the absence of water are
depicted in Figure 2. The lipids were immiscible with
water. While the peaks were small and broadened, both
compounds clearly showed the existence of endothermic
phase transition at low temperature. The enthalpy, ∆H,
the corresponding entropy variation, ∆S, and the transi-
tion temperatures, Tc, are collected in Table 1. The facts
that both 3a and 3b indicated almost the same phase
behavior as shown in Figure 2 and Table 1 suggest that
the physicochemical as well as polymorphismic properties
of 3a and 3b are indistinguishable despite of their
regioisomeric structures.
Exp er im en ta l Section
It was reported that a mixture of tetraether lipids, in
which each biphytanyl chain contains 0 to 4 cyclopentane
rings, shows a lamellar phase (Lâ′) in the temperature
range from -19 to 19 °C under dry conditions and the
lamellar structure melts above 19 °C by the X-ray
scattering method.13b In addition, it is known that the
phase transition temperature is shifted toward lower
temperature as the number of cyclopentane rings in the
tetraether structure decreases.13 Calorimetric measure-
ments on 3a and 3b indicated the presence of phase
transitions at low temperature, such as -53 °C, which
might be characteristic of the melting transition in the
absence of water. Although we do not have a rationale
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. Column chromatography was carried out
with Kieselgel 60 (70-230 mesh or 230-400 mesh, Merck).
THF 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.
(3R ,7R ,11S ,15S )-16-[(t er t -Bu t yld im e t h ylsilyl)oxy]-
3,7,11,15-tetr a m eth ylh exa d eca n a l (5). To a stirred solution
of oxalyl chloride (2.69 g, 21.2 mmol) in CH2Cl2 (90 mL) was
slowly added DMSO (4.0 mL, 56.6 mmol) at -78 °C. The

Archaeal 72-Membered Macrocyclic Tetraether Lipids
J . Org. Chem., Vol. 63, No. 8, 1998 2693
Sch em e 3a
Ta ble 1. P h a se Tr a n sition s of th e Lip id s 3a a n d 3ba
lipid
Tc (°C)
∆H (kcal mol-1
)
∆S (cal mol-1 deg-1
)
3a
3b
-53.4
-53.5
1.8
1.9
8.4
8.6
a
Thermograms were scanned at the temperature range from
-80 to 40 °C at a scanning rate of 2 °C/min. The enthalpy, ∆H,
the corresponding entropy variation, ∆S, and the transition
temperatures, Tc, are given for 3a and 3b.
(Na2SO4), filtered, and concentrated to dryness. The residue
was chromatographed over silica gel with hexane-EtOAc (50:
1) to give aldehyde 5 (5.02 g, 83%) as an oil: [R]27 +4.45 (c
D
1.22, CHCl3); 1H NMR (300 MHz) δ 0.07 (s, 6H), 0.83-0.90
(m, 18H), 0.98 (d, J ) 5.1 Hz, 3H), 1.00-1.43 (m, 20H), 1.58
(m, 1H), 2.05 (m, 1H), 2.23 (ddd, J ) 2.7, 7.8, 16.1 Hz, 1H),
2.40 (ddd, J ) 1.7, 5.4, 15.6 Hz, 1H), 3.35 (dd, J ) 6.6, 9.8 Hz,
1H), 3.45 (dd, J ) 5.9, 9.8 Hz, 1H), 9.76 (dd, J ) 1.7, 2.7 Hz,
1H); 13C NMR (75 MHz) δ -5.30, 16.79, 18.35, 19.70, 19.75,
20.01, 24.42, 24.48, 25.95, 28.18, 32.73, 33.48, 35.74, 37.05,
37.23, 37.33, 51.05, 68.41, 203.22; IR (neat) 775, 837, 1095,
1252, 1730, 2856, 2927, 2954 cm-1. Anal. Calcd for C26H54O2-
Si: C, 73.17; H, 12.75. Found: C, 73.13; H, 12.93.
F igu r e 2. Differential scanning calorimetric thermograms of
the synthesized lipids 3a and 3b performed at a scan rate of
2 °C/min on warming.
(4R)-4-[(Ben zyloxy)m et h yl]-2-[(2R,6R,10S,14S)-15-h y-
d r oxy-2,6,10,14-t e t r a m e t h ylp e n t a d e ca n yl]-1,3-d ioxo-
la n e (7). A mixture of 5 (4.90 g, 11.5 mmol), 1-O-benzyl-sn-
glycerol 6 (2.40 g, 13.3 mmol), p-toluenesulfonic acid (146 mg,
0.84 mmol), and MgSO4 (1.40 g, 11.7 mmol) in CH2Cl2 (40 mL)
was stirred for 12 h at room temperature. The mixture was
filtered, EtOAc and saturated aqueous NaHCO3 were added
to the filtrate, and the organic phase was separated. The
aqueous phase was extracted three times with EtOAc. The
combined organic layer was washed with brine, dried (Na2-
mixture was stirred for 45 min. A solution of 4 (6.07 g, 14.2
mmol) in CH2Cl2 (26 mL) was added dropwise over 5 min. The
mixture was stirred for 30 min and warmed to -60 °C, and
stirring was continued for 1.5 h. Then, Et3N (9.8 mL, 70.7
mmol) was added dropwise over 5 min. The mixture was
gradually warmed to room temperature, and a saturated
aqueous NH4Cl solution was added. The mixture was ex-
tracted three times with EtOAc. The combined organic phase
was washed with saturated aqueous NH4Cl and brine, dried

2694 J . Org. Chem., Vol. 63, No. 8, 1998
Eguchi et al.
SO4), filtered, and concentrated to dryness. The residue was
dissolved in THF (40 mL), and a solution of TBAF (17.4 mL,
1 M in THF, 17.4 mmol) was added. The mixture was stirred
for 3.5 h at room temperature. After concentration, the residue
was chromatographed over silica gel with hexane-EtOAc (7:
1) to give oily 7 as a 7:3 mixture of diastereomers (5.09 g,
93%): 1H NMR (300 MHz) δ 0.80-0.95 (m, 12H), 0.97-1.74
(m, 25H), 3.38-3.59 (m, 4H), 3.64 (dd, J ) 6.8, 8.0 Hz, 0.3H),
3.79 (dd, J ) 5.4, 8.3 Hz, 0.7H), 3.90 (dd, J ) 6.8, 8.3 Hz, 0.7H),
4.12 (dd, J ) 6.6, 8.3 Hz, 0.3H), 4.18-4.33 (m, 1H), 4.57 (s,
0.6H), 4.58 (s, 1.4H), 4.94 (t, J ) 4.9 Hz, 0.7H), 5.03 (dd, J )
4.4, 5.9 Hz, 0.3H), 7.22-7.35 (m, 5H); 13C NMR (75 MHz) δ
16.60, 19.72, 19.85, 19.93, 24.12, 24.34, 29.21, 32.68, 33.43,
35.72, 37.18, 37.25, 37.28, 37.57, 37.67, 40.98, 41.11, 67.34,
67.37, 68.25, 68.31, 70.45, 71.03, 73.41, 74.30, 74.57, 103.73,
104.28, 127.61, 127.67, 127.69, 128.35, 137.87; IR (neat) 698,
37.45, 55.18, 62.80, 68.64, 69.98, 72.55, 73.46, 75.71, 78.49,
113.66, 127.58, 127.64, 128.35, 129.03, 130.90, 138.00, 158.99;
IR (neat) 698, 735, 820, 1039, 1095, 1173, 1248, 1302, 1363,
1377, 1462, 1514, 1612, 2858, 2925, 2951, 3452 cm-1. Anal.
Calcd for C38H62O5: C, 76.21; H, 10.43. Found: C, 76.28; H,
10.58. 10: [R]27D +1.49 (c 1.00, CHCl3); 1H NMR (300 MHz) δ
0.80-0.95 (m, 12H), 0.97-1.81 (m, 24H), 2.50 (br, 1H), 3.20
(dd, J ) 6.8, 9.0 Hz, 1H), 3.29 (dd, J ) 5.9, 9.0 Hz, 1H), 3.43-
3.59 (m, 6H), 3.80 (s, 3H), 3.99 (m, 1H), 4.43 (s, 2H), 4.56 (s,
2H), 6.87 (dt, J ) 8.8, 2.2 Hz, 2H), 7.22-7.35 (m, 7H); 13C NMR
(75 MHz) δ 17.21, 19.69, 19.76, 24.34, 24.46, 29.88, 32.78,
32.80, 33.44, 34.01, 36.55, 37.32, 37.34, 37.36, 37.39, 37.48,
55.25, 69.52, 69.98, 71.38, 71.79, 72.58, 73.43, 113.68, 127.71,
128.41, 129.10, 130.91, 138.00, 159.00; IR (neat) 698, 735, 820,
1038, 1097, 1111, 1173, 1248, 1302, 1362, 1377, 1456, 1514,
1612, 2858, 2925, 2951, 3452 cm-1
38H62O5: C, 76.21; H, 10.43. Found: C, 76.23; H, 10.72.
1-O-Ben zyl-2-O-[(3R,7R,11S,15S)-16-[(4-m et h oxyb en -
.
Anal. Calcd for
735, 982, 1030, 1103, 1128, 1377, 1456, 2860, 2925, 2951 cm-1
.
C
Anal. Calcd for C30H52O4: C, 75.58; H, 10.99. Found: C,
75.78; H, 11.29.
zyl)oxy]-3,7,11,15-t e t r a m e t h ylh e xa d e ca n yl]-3-O-[(3R ,
7R,11S,15S)-16-[(ter t-b u t yld im et h ylsilyl)oxy]-3,7,11,15-
tetr a m eth ylh exa d eca n yl]-sn -glycer ol (11). To prewashed
NaH (171 mg, 7.13 mmol) was added a solution of 9 (2.13 g,
3.56 mmol) in DMSO (18 mL). The mixture was stirred for 1
h at room temperature, and a solution of the mesylate7d of 4
(1.78 g, 3.52 mmol) in DMSO (13 mL) was added. The mixture
was stirred for 5 h at room temperature. After the solution
was cooled to 0 °C, EtOAc and water were added to the
mixture. The organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic phase
was washed with saturated aqueous NH4Cl and brine, dried
(Na2SO4), filtered, and concentrated to dryness. The residue
was chromatographed over silica gel with hexane-EtOAc
(4R)-4-[(Ben zyloxy)m eth yl]-2-[(2R,6R,10S,14S)-15-[(4-
m eth oxyben zyl)oxy]-2,6,10,14-tetr am eth ylpen tadecan yl]-
1,3-d ioxola n e (8). To prewashed NaH (630 mg, 6.55 mmol)
was added a solution of acetal 7 (4.99 g, 10.5 mmol) in DMF
(30 mL). The mixture was stirred for 30 min at room
temperature, and 4-methoxybenzyl chloride (2.85 mL, 20.9
mmol) was added. After 15 min of stirring at room temper-
ature, the mixture was warmed to 40 °C, and stirring was
continued at the same temperature for 3 h. After the solution
was cooled to 0 °C, hexane and water were added to the
mixture. The layers were separated, and the aqueous layer
was extracted four times with hexane. The organic phase was
washed with saturated aqueous NH4Cl and brine, dried (Na2-
SO4), filtered, and concentrated to dryness. The residue was
chromatographed over silica gel with hexane-EtOAc (100:1-
20:1) to give oily 8 (5.67 g, 91%): 1H NMR (300 MHz) δ 0.80-
0.95 (m, 12H), 0.97-1.78 (m, 24H), 3.20 (dd, J ) 6.8, 9.0 Hz,
1H), 3.30 (dd, J ) 5.9, 9.0 Hz, 1H), 3.44 (dd, J ) 5.9, 9.8 Hz,
0.7H), 3.49 (dd, J ) 4.9, 10.0 Hz, 0.3H), 3.55 (dd, J ) 5.6, 9.8
Hz, 0.7H), 3.58 (dd, J ) 5.4, 10.0 Hz, 0.3H), 3.63 (dd, J ) 7.1,
8.3 Hz, 0.3H), 3.78 (dd, J ) 5.3, 8.0 Hz, 0.7H), 3.80 (s, 3H),
3.89 (dd, J ) 7.1, 8.0, 0.7H), 4.12 (dd, J ) 6.9, 8.3 Hz, 0.3H),
4.18-4.32 (m, 1H), 4.43 (s, 2H), 4.57 (s, 0.6H), 4.58 (s, 1.4H),
4.94 (t, J ) 5.1 Hz, 0.7H), 5.03 (dd, J ) 4.4, 5.6 Hz, 0.3H),
6.87 (dt, J ) 8.8, 2.2 Hz, 2H), 7.22-7.35 (m, 7H); 13C NMR
(75 MHz) δ 17.27, 19.80, 19.94, 20.02, 24.23, 24.40, 24.50,
29.32, 32.82, 33.49, 34.06, 37.31, 37.36, 37.41, 37.66, 37.77,
41.10, 41.21, 55.29, 67.45, 67.48, 70.55, 71.14, 72.63, 73.52,
74.40, 74.66, 75.79, 103.82, 104.37, 113.72, 127.72, 127.76,
127.80, 128.45, 128.51, 129.14, 130.96, 137.98, 159.04; IR
(neat) 698, 737, 820, 978, 1038, 1097, 1173, 1248, 1302, 1362,
1377, 1464, 1514, 1587, 2858, 2925, 2951 cm-1. Anal. Calcd
for C38H60O5: C, 76.47; H, 10.13. Found: C, 76.50; H, 10.37.
1-O-Ben zyl-2-O-[(3R,7R,11S,15S)-16-[(4-m eth oxyben zy-
l)oxy]-3,7,11,15-tetr a m eth ylh exa d eca n yl]-sn -glycer ol (9)
a n d 1-O-Ben zyl-3-O-[(3R,7R,11S,15S)-16-[(4-m eth oxyben -
zyl)oxy]-3,7,11,15-tetr a m eth ylh exa d eca n yl]-sn -glycer ol
(10). A solution of DIBAH (23.4 mL, 1 M in toluene, 23.4
mmol) was added to a solution of 8 (5.64 g, 9.42 mmol) in
toluene (20 mL) at -78 °C. The mixture was stirred for 20
min at the same temperature and then at 0 °C for 26 h. The
reaction was quenched by addition of saturated aqueous NH4-
Cl. After 10 min, ether and 2 N HCl were added. The etherial
layer was separated, and the aqueous phase was extracted
three times with ether. The combined organic layer was
washed with saturated aqueous NaHCO3 and brine, dried (Na2-
SO4), filtered, and concentrated to dryness. The residue was
purified by flash chromatography over silica gel with hexane-
EtOAc (5:1) to give less mobile product 9 (2.81 g, 50%) and
more mobile product 10 (2.47 g, 44%). 9: [R]27D -3.71 (c 1.38,
CHCl3); 1H NMR (300 MHz) δ 0.80-0.95 (m, 12H), 0.97-1.83
(m, 24H), 2.19 (br, 1H), 3.20 (dd, J ) 6.8, 9.0 Hz, 1H), 3.30
(dd, J ) 6.1, 9.0 Hz, 1H), 3.45-3.76 (m, 7H), 3.78 (s, 3H), 4.42
(s, 2H), 4.55 (s, 2H), 6.87 (dt, J ) 8.8, 2.2 Hz, 2H), 7.22-7.35
(m, 7H); 13C NMR (75 MHz) δ 17.19, 19.65, 19.73, 24.31, 24.42,
29.78, 32.73, 32.75, 33.41, 33.98, 37.03, 37.28, 37.30, 37.34,
(20:1) to give 11 (3.05 g, 86%) as an oil: [R]26 +2.60 (c 1.00,
D
CHCl3); 1H NMR (300 MHz) δ 0.03 (s, 6H), 0.80-0.95 (m, 33H),
0.97-1.81 (m, 48H), 3.20 (dd, J ) 6.8, 9.0 Hz, 1H), 3.30 (dd, J
) 6.1, 9.0 Hz, 1H), 3.35 (dd, J ) 6.6, 9.8 Hz, 1H), 3.41-3.65
(m, 10H), 3.79 (s, 3H), 4.43 (s, 2H), 4.55 (s, 2H), 6.87 (dt, J )
8.8, 2.2 Hz, 2H), 7.22-7.35 (m, 7H); 13C NMR (75 MHz) δ
-5.37, 16.79, 17.20, 18.32, 19.66, 19.69, 19.73, 24.34, 24.45,
25.93, 29.81, 29.90, 32.74, 32.77, 32.80, 33.44, 33.51, 34.02,
35.75, 36.64, 37.10, 37.32, 37.39, 37.51, 55.20, 68.39, 68.86,
69.95, 70.35, 70.80, 72.58, 73.33, 75.74, 77.96, 113.68, 127.44,
127.53, 128.26, 129.04, 130.95, 138.44, 159.02; IR (neat) 696,
735, 775, 837, 1099, 1248, 1362, 1377, 1462, 1514, 1612, 2856,
2927, 2952 cm-1. Anal. Calcd for C64H116O6Si: C, 76.13; H,
11.58. Found: C, 76.28; H, 11.88.
1-O-Ben zyl-2-O-[(3R,7R,11S,15S)-16-[(4-m et h oxyb en -
zyl)oxy]-3,7,11,15-t e t r a m e t h ylh e xa d e ca n yl]-3-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 (12). A solution of TBAF (4.45 mL, 1 M in
THF, 4.45 mmol) was added to a solution of 11 (2.99 g, 2.97
mmol) in THF (20 mL). The mixture was stirred for 10 h at
room temperature and concentrated in vacuo. The residue was
chromatographed over silica gel with hexane-EtOAc (8:1) to
give 12 (2.39 g, 90%) as an oil: [R]24 +0.84 (c 1.00, CHCl3);
D
1H NMR (300 MHz) δ 0.80-0.95 (m, 24H), 0.97-1.80 (m, 49H),
3.19 (dd, J ) 6.8, 9.0 Hz, 1H), 3.30 (dd, J ) 6.1, 9.0 Hz, 1H),
3.37-3.65 (m, 11H), 3.80 (s, 3H), 4.43 (s, 2H), 4.55 (s, 2H),
6.87 (dt, J ) 8.8, 2.2 Hz, 2H), 7.22-7.35 (m, 7H); 13C NMR
(75 MHz) δ 16.64, 17.21, 19.68, 19.71, 19.76, 24.36, 24.39,
24.43, 24.48, 29.82, 29.90, 32.75, 32.79, 32.82, 33.45, 33.48,
34.03, 35.78, 36.63, 37.10, 37.31, 37.36, 37.40, 37.52, 37.54,
55.24, 68.34, 68.88, 69.97, 70.33, 70.80, 72.80, 73.35, 75.76,
77.95, 113.69, 127.48, 127.57, 128.29, 129.08, 130.94, 138.43,
159.02; IR (neat) 698, 735, 820, 1039, 1099, 1111, 1248, 1377,
1462, 1514, 1612, 2858, 2925, 2951, 3465 cm-1. Anal. Calcd
for C58H102O6: C, 77.80; H, 11.48. Found: C, 77.78; H, 11.58.
1-O-Ben zyl-2-O-[(3R,7R,11S,15S)-16-[(4-m et h oxyb en -
zyl)oxy]-3,7,11,15-t e t r a m e t h ylh e xa d e ca n yl]-3-O-[(3R ,
7R,11S,15S)-3,7,11,15-t et r a m et h yl-16-(p h en ylsu lfon yl)-
h exa d eca n yl]-sn -glycer ol (13). To a solution of 12 (1.56 g,
1.74 mmol) and triethylamine (0.361 mL, 2.61 mmol) in CH2-
Cl2 (5 mL) was added methanesulfonyl chloride (0.162 mL, 2.09
mmol) at 0 °C, and the mixture was stirred for 1.5 h at the
same temperature. EtOAc and water were added, and the

Archaeal 72-Membered Macrocyclic Tetraether Lipids
J . Org. Chem., Vol. 63, No. 8, 1998 2695
organic phase was separated. The aqueous phase was ex-
tracted three times with EtOAc. The combined organic phase
was washed with saturated aqueous NH4Cl and brine, dried
(Na2SO4), filtered, and concentrated to dryness. The resulting
residue was dissolved in DMF (10 mL), K2CO3 (337 mg, 2.44
mmol) and thiophenol (0.282 mL, 2.76 mmol) were added, and
the resulting mixture was stirred for 30 h at room tempera-
ture. Water and hexane were added, and the organic phase
was separated. The aqueous phase was extracted five times
with hexane. The combined organic phase was successively
washed with 2 N HCl, saturated aqueous NaHCO3, and brine,
dried (Na2SO4), filtered, and concentrated to dryness. The
residue was dissolved in CH2Cl2 (19 mL), and 3-chloroperben-
zoic acid (1.16 g, 6.75 mmol) was added at 0 °C. The mixture
was stirred for 7 h at 0 °C. A saturated aqueous Na2SO3
solution was added, and the mixture was stirred for 30 min.
The mixture was extracted with EtOAc, and the layers were
separated. The aqueous phase was extracted three times with
EtOAc. The combined organic phase was successively washed
with 10% aqueous NaOH, saturated aqueous Na2SO3, and
brine, dried (Na2SO4), filtered, and concentrated to dryness.
The residue was chromatographed over silica gel with hexane-
EtOAc (10:1) to give phenyl sulfone 13 (1.56 g, 88%) as an oil:
0.04 (s, 6H), 0.80-0.95 (m, 33H), 0.97-1.81 (m, 48H), 3.20 (dd,
J ) 6.6, 9.0 Hz, 1H), 3.30 (dd, J ) 5.9, 9.0 Hz, 1H), 3.35 (dd,
J ) 6.6, 9.5 Hz, 1H), 3.40-3.65 (m, 10H), 3.80 (s, 3H), 4.43 (s,
2H), 4.55 (s, 2H), 6.87 (dt, J ) 8.8, 2.2 Hz, 2H), 7.22-7.35 (m,
7H); 13C NMR (75 MHz) δ -5.36, 16.80, 17.21, 18.35, 19.67,
19.71, 19.75, 24.35, 24.47, 25.96, 29.77, 29.88, 32.75, 32.78,
32.81, 33.44, 33.50, 34.01, 35.75, 36.62, 37.09, 37.32, 37.39,
37.51, 55.22, 68.41, 68.87, 69.95, 70.29, 70.76, 72.58, 73.33,
75.73, 77.92, 113.67, 127.48, 127.56, 128.28, 129.07, 130.91,
138.41, 158.99; IR (neat) 696, 735, 775, 837, 1099, 1248, 1362,
1377, 1462, 1514, 1612, 2856, 2927, 2952 cm-1. Anal. Calcd
for C64H116O6Si: C, 76.13; H, 11.58. Found: C, 75.93; H, 11.82.
1-O-Ben zyl-2-O-[(3R,7R,11S,15S)-16-h yd r oxy-3,7,11,15-
t et r a m et h ylh exa d eca n yl]-3-O-[(3R,7R,11S,15S)-16-[(4-
m eth oxyben zyl)oxy]-3,7,11,15-tetr a m eth ylh exa d eca n yl]-
sn -glycer ol (16). Compound 15 (859 mg, 0.85 mmol) was
treated in the same manner as described for the preparation
of 12 to give 16 (706 mg, 93%) as an oil: [R]25D +0.05 (c 0.717,
CHCl3); 1H NMR (300 MHz) δ 0.80-0.95 (m, 24H), 0.97-1.80
(m, 49H), 3.20 (dd, J ) 6.8, 8.8 Hz, 1H), 3.30 (dd, J ) 6.1, 8.8
Hz, 1H), 3.40 (dd, J ) 6.6, 10.2 Hz, 1H), 3.43-3.64 (m, 10H),
3.80 (s, 3H), 4.43 (s, 2H), 4.55 (s, 2H), 6.87 (dt, J ) 8.8, 2.2
Hz, 2H), 7.22-7.35 (m, 7H); 13C NMR (75 MHz) δ 16.62, 17.20,
19.66, 19.70, 19.75, 24.34, 24.38, 24.40, 24.45, 29.79, 29.87,
32.73, 32.77, 32.80, 33.43, 33.46, 33.99, 35.75, 36.60, 37.06,
37.23, 37.28, 37.34, 37.50, 55.21, 68.33, 68.86, 69.95, 70.27,
70.75, 72.57, 73.32, 75.73, 77.91, 113.66, 127.48, 127.56,
128.27, 129.07, 130.88, 138.38, 158.99; IR (neat) 698, 735, 820,
1039, 1099, 1111, 1248, 1377, 1462, 1514, 1612, 2858, 2925,
[R]21 +5.22 (c 0.58, CHCl3); 1H NMR (300 MHz) δ 0.80-0.97
D
(m, 24H), 0.97-1.82 (m, 47H), 2.07 (m, 1H), 2.92 (dd, J ) 8.1,
14.1 Hz, 1H), 3.08 (dd, J ) 4.4, 14.1 Hz, 1H), 3.20 (dd, J )
6.8, 9.0 Hz, 1H), 3.30 (dd, J ) 5.9, 9.0 Hz, 1H), 3.80 (s, 3H),
4.43 (s, 2H), 4.55 (s, 2H), 6.87 (dt, J ) 8.8, 2.2 Hz, 2H), 7.22-
7.35 (m, 7H), 7.56 (m, 2H), 7.64 (m, 1H), 7.91 (m, 2H); 13C NMR
(75 MHz) δ 17.31, 19.73, 19.77, 19.80, 19.85, 20.04, 23.88,
24.45, 24.53, 24.56, 28.68, 29.78, 29.99, 32.76, 32.87, 32.91,
34.11, 36.72, 36.90, 37.16, 37.19, 37.42, 37.48, 37.62, 55.34,
62.66, 68.97, 70.06, 70.40, 70.87, 72.68, 73.44, 75.84, 78.04,
113.77, 127.58, 127.66, 127.94, 128.38, 129.17, 129.32, 133.56,
138.52, 159.10; IR (neat) 600, 690, 737, 822, 1038, 1088, 1099,
1111, 1149, 1248, 1306, 1378, 1462, 1514, 1612, 2858, 2925,
2951 cm-1. Anal. Calcd for C64H106O7S: C, 75.39; H, 10.48.
Found: C, 75.27; H, 10.68.
2951, 3473 cm-1
. Anal. Calcd for C58H102O6: C, 77.80; H,
11.48. Found: C, 77.77; H, 11.72.
1-O-Ben zyl-2-O-[(3R,7R,11S,15S)-15-for m yl-3,7,11,15-
t et r a m et h ylp en t a d eca n yl]-3-O-[(3R,7R,11S,15S)-16-[(4-
m eth oxyben zyl)oxy]-3,7,11,15-tetr a m eth ylh exa d eca n yl]-
sn -glycer ol (17). Compound 16 (546 mg, 0.611 mmol) was
treated in the same manner as described for 14 to give
aldehyde 17 (603 mg, 93%) as an oil: [R]23 +7.20 (c 0.840,
D
CHCl3); 1H NMR (300 MHz) δ 0.80-0.95 (m, 24H), 0.97-1.80
(m, 48H), 2.33 (ddd, J ) 2.0, 6.6, 13.2 Hz, 1H), 3.20 (dd, J )
6.8, 9.0 Hz, 1H), 3.30 (dd, J ) 5.9, 9.0 Hz, 1H), 3.41-3.65 (m,
9H), 3.80 (s, 3H), 4.43 (s, 2H), 4.55 (s, 2H), 6.87 (dt, J ) 8.8,
2.2 Hz, 2H), 7.22-7.35 (m, 7H), 9.61 (d, J ) 2.0 Hz, 1H); 13C
NMR (75 MHz) δ 13.34, 17.20, 19.63, 19.66, 19.70, 19.73, 24.34,
24.39, 24.43, 24.45, 29.81, 29.89, 30.86, 32.63, 32.76, 32.78,
33.43, 34.00, 36.62, 36.98, 37.09, 37.37, 37.45, 37.50, 46.32,
55.21, 68.86, 69.95, 70.32, 70.77, 72.58, 73.33, 75.73, 77.94,
113.68, 127.46, 127.54, 128.27, 129.06, 130.92, 138.42, 159.00,
205.34; IR (neat) 698, 735, 820, 1039, 1101, 1111, 1248, 1377,
1462, 1514, 1612, 1728, 2858, 2925, 2951 cm-1. Anal. Calcd
for C58H100O6: C, 77.97; H, 11.28. Found: C, 78.11; H, 11.38.
3,3′-O-[(3R,7R,11S,15S,18S,22S,26R,30R)-16-H yd r oxy-
3,7,11,15,18,22,26,30-oct a m et h yl-17-(p h en ylsu lfon yl)d o-
tr iacon tan e-1,32-diyl]bis{1-O-ben zyl-2-O-[(3R,7R,11S,15S)-
16-[(4-m et h oxyb en zyl)oxy]-3,7,11,15-t et r a m et h ylh exa -
d eca n yl]-sn -glycer ol} (18). A solution of butyllithium (0.59
mL, 1.47 M in hexane, 0.867 mmol) was added dropwise to a
stirred solution of 13 (807 mg, 0.792 mmol) in THF (7 mL)
over 5 min at -78 °C. After 15 min at -78 °C, the mixture
was warmed to 0 °C, stirred for 15 min, and then recooled to
-25 °C. A solution of 14 (700 mg, 0.784 mmol) in THF (7 mL)
was added. After 1 h at -25 °C, saturated aqueous NH4Cl
was added. The mixture was extracted three times with ether.
The combined organic phase was washed with saturated
aqueous NH4Cl and brine, dried (Na2SO4), filtered, and
concentrated to dryness. The residue was purified by flash
chromatography over silica gel with hexane-ether (4:1) to give
oily 18 (739 mg, 45%) as a mixture of diastereomers: 1H NMR
(300 MHz) δ 0.74-0.97 (m, 48H), 0.97-1.82 (m, 95H), 2.00-
2.40 (m, 1H), 3.05-3.77 (m, 19.7H), 3.20 (dd, J ) 6.8, 9.0 Hz,
2H), 3.30 (dd, J ) 6.1, 9.0 Hz, 2H), 3.80 (s, 6H), 4.10 (m, 0.3H),
4.43 (s, 4H), 4.55 (s, 4H), 6.87 (dt, J ) 8.8, 2.2 Hz, 4H), 7.22-
7.35 (m, 14H), 7.56 (m, 2H), 7.64 (m, 1H), 7.91 (m, 2H); 13C
NMR (75 MHz) δ 17.22, 19.68, 19.71, 19.76, 24.36, 24.48, 29.84,
29.93, 32.79, 32.82, 33.46, 34.03, 36.66, 37.11, 37.34, 37.41,
37.54, 55.24, 68.89, 69.98, 70.35, 70.81, 72.59, 73.36, 75.76,
1-O-Ben zyl-2-O-[(3R,7R,11S,15S)-16-[(4-m eth oxyben zy-
l)oxy]-3,7,11,15-t et r a m et h ylh exa d eca n yl]-3-O-[(3R,7R,
11S,15S)-15-for m yl-3,7,11,15-tetr a m eth ylp en ta d eca n yl]-
sn -glycer ol (14). To a stirred solution of oxalyl chloride (216
mg, 1.70 mmol) in CH2Cl2 (11 mL) was added DMSO (0.24
mL, 3.38 mmol) at -78 °C. The mixture was stirred for 1 h.
A solution of 12 (764 mg, 0.853 mmol) in CH2Cl2 (8 mL) was
added dropwise over 5 min. The mixture was stirred for 15
min at -78 °C and then for 1.5 h at -60 °C. Then, Et3N (0.78
mL, 5.63 mmol) was added dropwise over 5 min. The mixture
was warmed gradually to room temperature, and saturated
aqueous NH4Cl was added. The mixture was extracted three
times 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 (9:1) to give aldehyde 14 (733 mg, 96%)
as an oil: [R]24 +6.85 (c 0.957, CHCl3); 1H NMR (300 MHz) δ
D
0.80-0.95 (m, 24H), 0.97-1.80 (m, 48H), 2.33 (ddd, J ) 2.0,
6.6, 13.2 Hz, 1H), 3.20 (dd, J ) 6.8, 9.0 Hz, 1H), 3.30 (dd, J )
6.0, 9.0 Hz, 1H), 3.41-3.65 (m, 9H), 3.80 (s, 3H), 4.43 (s, 2H),
4.55 (s, 2H), 6.87 (dt, J ) 8.8, 2.2 Hz, 2H), 7.22-7.35 (m, 7H),
9.61 (d, J ) 2.0 Hz, 1H); 13C NMR (75 MHz) δ 13.35, 17.21,
19.64, 19.67, 19.71, 19.75, 24.35, 24.39, 24.44, 24.46, 29.81,
29.89, 30.87, 32.64, 32.78, 32.80, 33.44, 34.02, 36.63, 36.99,
37.09, 37.32, 37.36, 37.39, 37.51, 46.33, 55.22, 68.87, 69.95,
70.32, 70.79, 72.58, 73.34, 75.74, 77.95, 113.68, 127.47, 127.55,
128.28, 129.06, 130.93, 138.43, 159.01, 205.33; IR (neat) 698,
735, 820, 1039, 1099, 1111, 1248, 1377, 1462, 1514, 1612, 1728,
2858, 2925, 2951 cm-1. Anal. Calcd for C58H100O6: C, 77.97;
H, 11.28. Found: C, 78.27; H, 11.58.
1-O-Ben zyl-2-O-[(3R,7R,11S,15S)-16-[(ter t-bu tyld im eth -
y ls ily l)o x y ]-3,7,11,15-t e t r a m e t h y lh e x a d e c a n y l]-3-O -
[(3R,7R,11S,15S)-16-[(4-m eth oxyben zyl)oxy]-3,7,11,15-tet-
r a m eth ylh exa d eca n yl]-sn -glycer ol (15). Compound 10
(915 mg, 1.53 mmol) was treated in the same manner as
described for the preparation of 11 to give 15 (911 mg, 60%)
as an oil: [R]22 +1.90 (c 0.935, CHCl3); 1H NMR (300 MHz) δ
D

2696 J . Org. Chem., Vol. 63, No. 8, 1998
Eguchi et al.
77.97, 113.70, 127.48, 127.57, 128.28, 129.02, 129.07, 130.96,
138.45, 159.04; IR (neat) 696, 733, 820, 1039, 1099, 1111, 1248,
1302, 1377, 1462, 1514, 1612, 2856, 2925, 2951 cm-1. Anal.
Calcd for C122H206O13S: C, 76.60; H, 10.85. Found: C, 76.51;
H, 11.08.
dried (Na2SO4), filtered, and concentrated to dryness. This
procedure was repeated until olefinic signals disappeared from
the 1H NMR. The obtained crude product was chromato-
graphed over silica gel with hexane-EtOAc (20:1) to give 21
(389 mg, 92%) as an oil: [R]23D +2.84 (c 0.895, CHCl3); 1H NMR
(300 MHz) δ 0.80-0.95 (m, 48H), 0.97-1.80 (m, 100H), 3.19
(dd, J ) 6.8, 9.0 Hz, 2H), 3.30 (dd, J ) 5.9,9.0 Hz, 2H), 3.41-
3.65 (m, 18H), 3.80 (s, 6H), 4.43 (s, 4H), 4.55 (s, 4H), 6.87 (dt,
J ) 8.8, 2.2 Hz, 4H), 7.22-7.35 (m, 14H); 13C NMR (75 MHz)
δ 17.21, 19.67, 19.71, 19.75, 24.36, 24.48, 29.81, 29.89, 32.78,
32.81, 33.05, 33.44, 34.01, 34.31, 36.62, 37.09, 37.33, 37.39,
37.52, 37.57, 55.23, 68.87, 69.96, 70.31, 70.77, 72.58, 73.33,
75.74, 77.93, 113.68, 127.48, 127.57, 128.28, 129.08, 130.91,
138.42, 159.00; IR (neat) 696, 735, 820, 1039, 1101, 1111, 1248,
1377, 1462, 1514, 1612, 2856, 2925, 2951 cm-1. Anal. Calcd
for C116H202O10: C, 79.30; H, 11.59. Found: C, 79.17; H, 11.67.
3,3′-O-[(3R,7R,11S,15S,18S,22S,26R,30R)-3,7,11,15,18,
22,26,30-Octa m eth yld otr ia con ta n e-1,32-d iyl]bis{1-O-ben -
zyl-2-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} (22). To a stirred solution of
21 (344 mg, 0.196 mmol) in CH2Cl2 (7.2 mL) and H2O (0.4 mL)
was added 2,3-dichloro-5,6-dicyanobenzoquinone (145 mg,
0.637 mmol) at room temperature. The mixture was stirred
for 30 min. EtOAc and water were added, the organic phase
was separated, and the aqueous phase was extracted four
times with EtOAc. The combined organic phase was washed
with saturated aqueous NaHCO3 and brine, dried (Na2SO4),
filtered, and concentrated to dryness. The residue was chro-
3,3′-O-[(3R,7R,11S,15S,18S,22S,26R,30R)-16-Acet oxy-
3,7,11,15,18,22,26,30-oct a m et h yl-17-(p h en ylsu lfon yl)d o-
tr iacon tan e-1,32-diyl]bis{1-O-ben zyl-2-O-[(3R,7R,11S,15S)-
16-[(4-m et h oxyb en zyl)oxy]-3,7,11,15-t et r a m et h ylh exa -
d eca n yl]-sn -glycer ol} (19). A mixture of 18 (728 mg, 0.380
mmol), acetic anhydride (0.50 mL, 5.3 mmol), DMAP (64 mg,
0.53 mmol), and pyridine (5 mL) was stirred for 13 h at room
temperature. EtOAc and water were added. The organic
phase was separated, and the aqueous phase was extracted
three times with EtOAc. The combined organic phase was
successively washed with 2 N HCl, saturated aqueous NaH-
CO3, and brine, dried (Na2SO4), filtered, and concentrated to
dryness. The residue was chromatographed over silica gel
with hexane-EtOAc (8:1) to give â-acetoxy sulfone 19 (562 mg,
74%) as an oil: 1H NMR (300 MHz) δ 0.72-0.97 (m, 48H),
0.97-1.80 (m, 95H), 2.04 (s 1.1H), 2.07 (s, 0.9H), 2.09-2.35
(m, 1H), 2.10 (s, 0.7H), 2.14 (s, 0.3H), 3.14 (m, 0.35H), 3.20
(dd, J ) 6.8, 9.0 Hz, 2H), 3.30 (dd, J ) 6.1, 9.0 Hz, 2H), 3.35-
3.67 (m, 18.65H), 3.80 (s, 6H), 4.43 (s, 4H), 4.58 (s, 4H), 4.95-
5.06 (m, 0.33H), 5.18-5.21 (m, 0.67H), 6.87 (dt, J ) 8.8, 2.2
Hz, 4H), 7.22-7.35 (m, 14H), 7.56 (m, 2H), 7.64 (m, 1H), 7.92
(m, 2H); 13C NMR (75 MHz) δ 17.22, 19.70, 19.76, 24.36, 24.47,
29.82, 29.92, 32.78, 32.82, 33.45, 34.02, 36.65, 37.11, 37.33,
37.40, 37.55, 55.24, 68.88, 69.98, 70.33, 70.78, 72.59, 73.35,
75.75, 77.95, 113.69, 127.48, 127.56, 128.29, 128.83, 129.07,
130.94, 138.44, 159.02; IR (neat) 696, 735, 820, 1038, 1101,
1111, 1248, 1306, 1377, 1462, 1514, 1612, 1747, 2858, 2925,
2951 cm-1. Anal. Calcd for C124H208O14S: C, 76.18; H, 10.72.
Found: C, 75.97; H, 10.85.
matographed over silica gel with hexane-EtOAc (5:1) to give
1
22 (266 mg, 90%) as an oil: [R]23 -0.04 (c 0.680, CHCl3); H
D
NMR (300 MHz) δ 0.80-0.94 (m, 48H), 0.97-1.72 (m, 100H),
3.37-3.64 (m, 22H), 4.55 (s, 4H), 7.22-7.35 (m, 10H); 13C NMR
(75 MHz) δ 16.64, 19.71, 19.76, 24.35, 24.39, 24.42, 24.48,
29.81, 29.89, 32.74, 32.81, 33.05, 33.47, 34.31, 35.77, 36.62,
37.08, 37.22, 37.36, 37.42, 37.53, 37.56, 68.36, 68.88, 69.96,
70.30, 70.77, 73.34, 77.93, 127.48, 127.57, 128.28, 138.41; IR
3,3′-O -[(3R ,7R ,11S ,15S ,18S ,22S ,26R ,30R )-3,7,11,15,
18,22,26,30-Octa m eth yld otr ia con t-16-en e-1,32-d iyl]bis{1-
O-ben zyl-2-O-[(3R,7R,11S,15S)-16-[(4-m eth oxyben zyl)oxy]-
3,7,11,15-tetr a m eth ylh exa d eca n yl]-sn -glycer ol} (20). To
a stirred solution of SmI2 in THF (0.1 M, 30.3 mL, 3.03 mmol)
was slowly added HMPA (1.52 mL, 8.69 mmol) at room
temperature. After 35 min, a solution of 19 (546 mg, 0.279
mmol) in THF (9 mL) was added and the mixture was stirred
for 1.5 h at room temperature. Ether and 2 N HCl were added.
The mixture was extracted three times with ether. The
combined organic phase was successively washed with 2 N
HCl, saturated aqueous NaHCO3, and brine, dried (Na2SO4),
filtered, and concentrated to dryness. The residue was chro-
matographed over silica gel with hexane to hexane-EtOAc
(200:1 to 10:1) to afford oily 20 (432 mg, 88%) as a mixture of
geometrical isomers (E/Z ) 85:15): 1H NMR (300 MHz) δ
0.80-0.97 (m, 48H), 0.97-1.80 (m, 94H), 2.02 (m, 1.7H), 2.38
(m, 0.3H), 3.20 (dd, J ) 6.8, 9.0 Hz, 2H), 3.30 (dd, J ) 6.1, 9.0
Hz, 2H), 3.41-3.65 (m, 18H), 3.80 (s, 6H), 4.43 (s, 4H), 4.55
(s, 4H), 5.02 (dd, J ) 1.8, 7.2 Hz, 0.3H), 5.18 (dd, J ) 2.2, 4.7
Hz, 1.7H), 6.87 (dt, J ) 8.8, 2.2 Hz, 4H), 7.22-7.35 (m, 14H);
13C NMR (75 MHz) δ 17.20, 19.69, 19.73, 21.15, 24.34, 24.46,
24.48, 24.71, 29.81, 29.90, 31.20, 32.74, 32.77, 32.80, 33.44,
34.01, 36.63, 36.67, 37.09, 37.32, 37.39, 37.53, 55.22, 68.87,
69.96, 70.33, 70.77, 72.58, 73.33, 75.74, 77.94, 113.68, 127.45,
127.54, 128.27, 129.06, 130.93, 133.57, 134.55, 138.42, 159.00;
IR (neat) 696, 735, 820, 1039, 1101, 1111, 1248, 1377, 1462,
(neat) 696, 733, 1113, 1377, 1462, 2858, 2925, 2951 cm-1
.
Anal. Calcd for C100H186O8: C, 79.20; H, 12.36. Found: C,
79.50; H, 12.37.
3,3′-O-[(3R,7R,11S,15S,18S,22S,26R,30R)-3,7,11,15,18,
22,26,30-Octa m eth yld otr ia con ta n e-1,32-d iyl]bis{1-O-ben -
zyl-2-O-[(3R,7R,11S,15S)-15-for m yl-3,7,11,15-tetr a m eth yl-
p en ta d eca n yl]-sn -glycer ol} (23). To a stirred solution of
oxalyl chloride (51 mg, 0.40 mmol) in CH2Cl2 (7 mL) was added
DMSO (92 µL, 1.3 mmol) at -78 °C. After 1 h, a solution of
22 (122 mg, 0.081 mmol) in CH2Cl2 (6 mL) was added dropwise
over 5 min. The mixture was stirred for 10 min at -78 °C
and then for 1.5 h at -60 °C. Then, Et3N (0.22 mL, 1.6 mmol)
was added dropwise over 5 min. The mixture was gradually
warmed to room temperature, and saturated aqueous NH4Cl
was added. The mixture was extracted three times with
EtOAc. The combined organic phase was washed with satu-
rated aqueous NH4Cl and brine, dried (Na2SO4), filtered, and
concentrated to dryness. The residue was chromatographed
over silica gel with hexane-EtOAc (20:1) to give 23 (114 mg,
1
93%) as an oil: [R]25 +7.81 (c 0.650, CHCl3); H NMR (300
D
MHz) δ 0.80-0.90 (m, 42H), 0.97-1.74 (m, 104H), 2.33 (ddd,
J ) 2.0, 6.6, 13.2, 2H), 3.37-3.64 (m, 18H), 4.55 (s, 4H), 7.22-
7.35 (m, 10H), 9.61 (d, J ) 2.0, 2H); 13C NMR (75 MHz) δ 13.35,
19.64, 19.67, 19.71, 19.74, 24.34, 24.40, 24.43, 24.48, 29.80,
29.87, 30.85, 32.64, 32.79, 33.04, 34.30, 36.62, 36.98, 37.08,
37.16, 37.32, 37.36, 37.41, 37.52, 37.55, 46.33, 68.86, 69.94,
70.29, 70.76, 73.32, 77.92, 127.47, 127.56, 128.27, 138.40,
205.37; IR (neat) 665, 698, 735, 1115, 1377, 1462, 1730, 2858,
1514, 1612, 2858, 2925, 2951 cm-1
116H200O10: C, 79.39; H, 11.49. Found: C, 79.69; H, 11.78.
3,3′-O -[(3R ,7R ,11S ,15S ,18S ,22S ,26R ,30R )-3,7,11,15,
.
Anal. Calcd for
C
18,22,26,30-Octa m eth yld otr ia con ta n e-1,32-d iyl]bis{1-O-
ben zyl-2-O-[(3R,7R,11S,15S)-16-[(4-m eth oxyben zyl)oxy]-
3,7,11,15-tetr a m eth ylh exa d eca n yl]-sn -glycer ol} (21). Po-
tassium azodicarboxylate (3.89 g, 24.0 mmol) was added to a
solution of 20 (421 mg, 0.240 mmol) in methanol (5 mL) and
EtOAc (10 mL). A solution of acetic acid (2.76 mL, 48.0 mmol)
in methanol (2 mL) and EtOAc (4 mL) was added dropwise
over 30 min at room temperature. The suspension was stirred
until the bright yellow color disappeared. Hexane and water
were added, and the mixture was extracted three times with
hexane. The combined organic phase was washed with water,
2925, 2951 cm-1
. Anal. Calcd for C100H182O8: C, 79.41; H,
12.13. Found: C, 79.45; H, 12.26.
(2S ,7R ,11R ,15S ,19S ,22S ,26S ,30R ,34R ,39S ,43R ,47R ,
51S,55S,58S,62S,66R,70R)-2,39-Bis[(b en zyloxy)m et h yl]-
7,11,15,19,22,26,30,34,43,47,51,55,58,62,66,70-h exa d eca -
m eth yl-1,4,37,40-tetr a oxa cyclod oh ep ta con t-56-en e (24).
Powdered TiCl3 (0.3 g, 1.95 mmol) and Zn-Cu couple (0.3 g,
4.45 mmol) were placed in a Schlenk tube. DME (45 mL) was
added, and the mixture was refluxed for 2 h. A solution of
dialdehyde 23 (101 mg, 0.068 mmol) in DME (5 mL) was added
to the refluxing slurry via a motor-driven syringe pump over

Archaeal 72-Membered Macrocyclic Tetraether Lipids
J . Org. Chem., Vol. 63, No. 8, 1998 2697
a 45 h period. After an additional 18 h reflux period, the
reaction mixture was cooled to room temperature and 20%
aqueous K2CO3 solution (30 mL) was added. The resulting
mixture was stirred for 4 h. The organic phase was separated,
and the aqueous phase was extracted 10 times with ether. The
combined organic extract was washed with saturated aqueous
NH4Cl and brine, dried (Na2SO4), filtered, and concentrated
to dryness. The residue was chromatographed over silica gel
with hexane-EtOAc (20:1) to give 24 (58 mg, 59%) as an oil:
[R]26D +7.08 (c 1.273, CHCl3); 1H NMR (300 MHz) δ 0.80-0.97
(m, 48H), 0.97-1.68 (m, 98H), 2.02 (m, 2H), 3.43-3.65 (m,
18H), 4.55 (s, 4H), 5.16 (dd, J ) 2.2, 4.6, 2H), 7.22-7.35 (m,
10H); 13C NMR (75 MHz) δ 19.74, 19.77, 19.80, 19.82, 21.33,
24.39 24.45, 24.50, 24.78, 29.76, 29.83, 32.77, 32.80, 32.82,
33.05, 34.29, 36.62, 36.83, 37.09, 37.35, 37.39, 37.45, 37.51,
37.59, 37.63, 68.81, 69.89, 70.30, 70.96, 73.35, 77.94, 127.49,
127.58, 128.30, 134.65, 138.41; IR (neat) 696, 733, 1115, 1377,
1458, 2858, 2925, 2951 cm-1; EI-MS m/z 1479 (M+), 1387, 1282,
91. Anal. Calcd for C100H182O6: C, 81.13; H, 12.39. Found:
C, 81.30; H, 12.50.
2,3′-O-[(3R,7R,11S,15S,18S,22S,26R,30R)-16-Acet oxy-
3,7,11,15,18,22,26,30-oct a m et h yl-17-(p h en ylsu lfon yl)d o-
tr ia con ta n e-1,32-d iyl]-2′,3-bis-O-[(3R,7R,11S,15S)-16-[(4-
m eth oxyben zyl)oxy]-3,7,11,15-tetr a m eth ylh exa d eca n yl-
]bis(1-O-ben zyl-sn -glycer ol) (27). Compound 26 (681 mg,
0.356 mmol) was treated in the same manner as described for
the preparation of 19 to give â-acetoxy sulfone 27 (503 mg,
72%) as an oil: 1H NMR (300 MHz) δ 0.72-0.97 (m, 48H),
0.97-1.80 (m, 95H), 2.04 (s, 1.1H), 2.07 (s, 0.9H), 2.09-2.35
(m, 1H), 2.11 (s, 0.7H), 2.15 (s, 0.3H), 3.14 (m, 0.35H), 3.20
(dd, J ) 6.8, 9.0 Hz, 2H), 3.30 (dd, J ) 6.1, 9.0 Hz, 2H), 3.36-
3.67 (m, 1.65H), 3.79 (s, 6H), 4.43 (s, 4H), 4.55 (s, 4H), 4.95-
5.06 (m, 0.33H), 5.18-5.21 (m, 0.67H), 6.87 (dt, J ) 8.8, 2.2
Hz, 4H), 7.22-7.35 (m, 14H), 7.56 (m, 2H), 7.64 (m, 1H), 7.93
(m, 2H); 13C NMR (75 MHz) δ 17.22, 19.68, 19.71, 19.76, 24.35,
24.46, 29.81, 29.89, 32.77, 32.81, 33.44, 34.01, 36.62, 37.09,
37.32, 37.38, 37.40, 37.53, 55.21, 68.87, 69.95, 70.30, 70.76,
72.58, 73.33, 75.73, 77.93, 113.67, 127.48, 127.56, 128.28,
128.83, 129.07, 129.12, 130.91, 138.42, 159.00; IR (neat) 696,
735, 820, 1038, 1099, 1111, 1248, 1306, 1377, 1462, 1514, 1612,
1747, 2858, 2925, 2951 cm-1. Anal. Calcd for C124H208O14S:
C, 76.18; H, 10.72. Found: C, 76.28; H, 10.91.
2,3′-O-[(3R,7R,11S,15S,18S,22S,26R,30R)-3,7,11,15,18,
22,26,30-Octa m eth yld otr ia con t-16-en e-1,32-d iyl]-2′,3-bis-
O-[(3R,7R,11S,15S)-16-[(4-m eth oxyben zyl)oxy]-3,7,11,15-
tetr am eth ylh exadecan yl]bis(1-O-ben zyl-sn -glycer ol) (28).
Compound 27 (493 mg, 0.252 mmol) was treated in the same
manner as described for the preparation of 20 to give oily 28
(385 mg, 87%) as a mixture of geometrical isomers (E/Z ) 85:
15): 1H NMR (300 MHz) δ 0.80-0.97 (m, 48H), 0.97-1.80 (m,
94H), 2.02 (m, 1.7H), 2.38 (m, 0.3H), 3.20 (dd, J ) 6.8, 9.0 Hz,
2H), 3.30 (dd, J ) 6.1, 9.0 Hz, 2H), 3.41-3.65 (m, 18H), 3.80
(s, 6H), 4.43 (s, 4H), 4.55 (s, 4H), 5.02 (dd, J ) 1.8, 7.2 Hz,
0.3H), 5.18 (dd, J ) 2.2, 4.7 Hz, 1.7H), 6.87 (dt, J ) 8.8, 2.2
Hz, 4H), 7.22-7.35 (m, 14H); 13C NMR (75 MHz) δ 17.21,
19.70, 19.75, 21.17, 24.35, 24.47, 24.50, 24.72, 29.81, 29.89,
31.57, 32.75, 32.78, 32.81, 33.44, 34.01, 36.63, 36.70, 37.09,
37.25, 37.39, 37.53, 55.21, 68.87, 69.95, 70.31, 70.77, 72.58,
73.33, 75.74, 77.94, 113.68, 127.47, 127.55, 128.27, 129.06,
130.91, 133.57, 134.56, 138.42, 159.00; IR (neat) 696, 735, 820,
1039, 1101, 1111, 1248, 1377, 1462, 1514, 1612, 2858, 2925,
2951 cm-1. Anal. Calcd for C116H200O10: C, 79.39; H, 11.49.
Found: C, 79.33; H, 11.79.
(2S ,7R ,11R ,15S ,19S ,22S ,26S ,30R ,34R ,39S ,43R ,47R ,
51S,55S,58S,62S,66R,70R)-2,39-Bis[(b en zyloxy)m et h yl]-
7,11,15,19,22,26,30,34,43,47,51,55,58,62,66,70-h exa d eca -
m eth yl-1,4,37,40-tetr aoxacyclodoh eptacon tan e (25). Com-
pound 24 (96 mg, 0.064 mmol) was treated in the same manner
as described for the preparation of 21 to give 25 (77 mg, 80%)
1
as an oil: [R]25 +1.61 (c 1.00, CHCl3); H NMR (300 MHz) δ
D
0.80-0.92 (m, 48H), 0.97-1.68 (m, 104H), 3.43-3.65 (m, 18H),
4.55 (s, 4H), 7.22-7.35 (m, 10H); 13C NMR (75 MHz) δ 19.76,
19.80, 19.82, 24.38, 24.46, 29.74, 29.84, 32.80, 32.82, 33.05,
34.30, 36.62, 37.05, 37.37, 37.46, 37.51, 68.79, 69.89, 70.31,
70.97, 73.35, 77.94, 127.49, 127.58, 128.30, 138.41; IR (neat)
696, 733, 1115, 1377, 1462, 2858, 2925, 2951 cm-1; EI-MS m/z
1481 (M+), 1389 (M+ - CH2Ph), 1284, 91. Anal. Calcd for
C
100H184O6: C, 81.01; H, 12.51. Found: C, 80.75; H, 12.69.
(2S ,7R ,11R ,15S ,19S ,22S ,26S ,30R ,34R ,39S ,43R ,47R ,
51S ,55S ,58S ,62S ,66R ,70R )-2,39-B is(h y d r o x ym e t h yl)-
7,11,15,19,22,26,30,34,43,47,51,55,58,62,66,70-h exa d eca -
m et h yl-1,4,37,40-t et r a oxa cyclod oh ep t a con t a n e (3a ).
A
mixture of 25 (73 mg, 0.049 mmol) and 10% Pd-C (22 mg) in
EtOAc (15 mL) was stirred for 3.5 h under an atmospheric
pressure of hydrogen at 40 °C. The mixture was filtered, and
the filtrate was concentrated to dryness. The residue was
chromatographed over silica gel with hexanes-EtOAc (5:1) to
2,3′-O-[(3R,7R,11S,15S,18S,22S,26R,30R)-3,7,11,15,18,
22,26,30-Oct a m et h yld ot r ia con t a n e-1,32-d iyl]-2′,3-b is-O-
[(3R,7R,11S,15S)-16-[(4-m eth oxyben zyl)oxy]-3,7,11,15-tet-
r a m eth ylh exa d eca n yl]bis(1-O-ben zyl-sn -glycer ol) (29).
Compound 28 (377 mg, 0.215 mmol) was treated in the same
manner as described for the preparation of 21 to give 29 (324
give 3a (50 mg, 78%) as an oil: [R]25 +8.68 (c 1.68, CHCl3);
D
1H NMR (300 MHz) δ 0.80-0.92 (m, 48H), 0.97-1.68 (m,
104H), 2.21 (br, 2H), 3.42-3.74 (m, 18H); 13C NMR (75 MHz)
δ 19.74, 19.80, 19.82, 24.34, 24.43, 29.75, 29.86, 32.75, 33.02,
34.26, 36.53, 37.01, 37.33, 37.48, 63.03, 68.56, 70.05, 71.02,
78.32; IR (neat) 1051, 1117, 1377, 1462, 2858, 2925, 2951, 3452
cm-1; EI-MS m/z 1301 (M+), 1283 (M+ - H2O), 1271, 650.
Anal. Calcd for C86H172O6: C, 79.32; H, 13.31. Found: C,
79.04; H, 13.60.
mg, 86%) as an oil: [R]23 +3.63 (c 0.420, CHCl3); 1H NMR
D
(300 MHz) δ 0.80-0.95 (m, 48H), 0.97-1.80 (m, 100H), 3.19
(dd, J ) 6.8, 9.0 Hz, 2H), 3.30 (dd, J ) 6.1, 9.0 Hz, 2H), 3.41-
3.65 (m, 18H), 3.80 (s, 6H), 4.43 (s, 4H), 4.55 (s, 4H), 6.87 (dt,
J ) 8.8, 2.2 Hz, 4H), 7.22-7.35 (m, 14H); 13C NMR (75 MHz)
δ 17.21, 19.68, 19.71, 19.76, 24.35, 24.48, 29.80, 29.88, 32.78,
32.81, 33.05, 33.44, 34.01, 34.31, 36.62, 37.09, 37.32, 37.38,
37.41, 37.52, 37.56, 55.22, 68.87, 69.95, 70.29, 70.76, 72.58,
73.33, 75.73, 77.92, 113.67, 127.48, 127.56, 128.28, 129.08,
130.91, 138.41, 158.99; IR (neat) 696, 733, 820, 1039, 1099,
2,3′-O-[(3R,7R,11S,15S,18S,22S,26R,30R)-16-H yd r oxy-
3,7,11,15,18,22,26,30-oct a m et h yl-17-(p h en ylsu lfon yl)d o-
tr ia con ta n e-1,32-d iyl]-2′,3-bis-O-[(3R,7R,11S,15S)-16-[(4-
m et h oxyb en zyl)oxy]-3,7,11,15-t et r a m et h ylh exa d eca n -
yl]bis(1-O-ben zyl-sn -glycer ol) (26). Sulfone 13 (700 mg,
0.686 mmol) and aldehyde 17 (559 mg, 0.625 mmol) were
treated in the same manner as described for the preparation
of 18 to give â-hydroxy sulfone 26 (700 mg, 59%) as an oil: 1H
NMR (300 MHz) δ 0.74-0.97 (m, 48H), 0.97-1.82 (m, 95H),
2.00-2.40 (m, 1H), 3.05-3.77 (m, 19.7H), 3.20 (dd, J ) 6.8,
9.0 Hz, 2H), 3.30 (dd, J ) 5.9, 9.0 Hz, 2H), 3.78 (s, 6H), 4.10
(m, 0.3H), 4.43 (s, 4H), 4.55 (s, 4H), 6.87 (dt, J ) 8.8, 2.2 Hz,
4H), 7.22-7.35 (m, 14H), 7.56 (m, 2H), 7.64 (m, 1H), 7.91 (m,
2H); 13C NMR (75 MHz) δ 17.20, 19.66, 19.69, 19.74, 24.34,
24.44, 29.79, 29.87, 32.75, 32.79, 33.43, 33.99, 36.61, 37.07,
37.30, 37.36, 37.51, 55.20, 68.85, 69.94, 70.29, 70.75, 72.56,
73.32, 75.72, 77.91, 113.65, 127.45, 127.54, 128.27, 128.32,
129.00, 129.06, 129.20, 138.40, 158.99; IR (neat) 696, 733, 820,
1039, 1099, 1111, 1248, 1302, 1377, 1462, 1514, 1612, 2856,
2925, 2951 cm-1. Anal. Calcd for C122H206O13S: C, 76.60; H,
10.85. Found: C, 76.54; H, 11.04.
1111, 1248, 1377, 1462, 1514, 1612, 2856, 2925, 2951 cm-1
.
Anal. Calcd for C116H202O10: C, 79.30; H, 11.59. Found: C,
79.05; H, 11.70.
2,3′-O-(3R,7R,11S,15S,18S,22S,26R,30R)-3,7,11,15,18,
22,26,30-Oct a m et h yld ot r ia con t a n e-1,32-d iyl]-2′,3-b is-O-
[(3R,7R,11S,15S)-16-h yd r oxy-3,7,11,15-tetr a m eth ylh exa -
d eca n yl]bis(1-O-b en zyl-sn -glycer ol) (30). Compound 29
(288 mg, 0.164 mmol) was treated in the same manner as
described for the preparation of 22 to give diol 30 (228 mg,
1
92%) as an oil: [R]23 +0.54 (c 0.580, CHCl3); H NMR (300
D
MHz) δ 0.80-0.94 (m, 48H), 0.97-1.72 (m, 100H), 3.37-3.64
(m, 22H), 4.55 (s, 4H), 7.22-7.35 (m, 10H); 13C NMR (75 MHz)
δ 16.63, 19.70, 19.76, 24.34, 24.39, 24.47, 29.79, 29.86, 32.73,
32.79, 33.03, 33.46, 34.30, 35.75, 36.60, 37.06, 37.28, 37.34,
37.41, 37.50, 37.55, 68.33, 68.86, 69.94, 70.26, 70.75, 73.32,
77.91, 127.47, 127.56, 128.27, 138.37; IR (neat) 696, 733, 1113,

2698 J . Org. Chem., Vol. 63, No. 8, 1998
1377, 1462, 2858, 2925, 2951 cm-1
Anal. Calcd for
Eguchi et al.
.
70.98, 73.35, 77.95, 127.48, 127.57, 128.29, 138.42; IR (neat)
696, 735, 1115, 1377, 1462, 2858, 2925, 2951 cm-1; EI-MS m/z
1481 (M+), 1389 (M+ - CH2Ph), 1284, 91. Anal. Calcd for
100H184O6: C, 81.01; H, 12.51. Found: C, 80.71; H, 12.81.
(2S ,7R ,11R ,15S ,19S ,22S ,26S ,30R ,34R ,38S ,43R ,47R ,
51S,55S,58S,62S,66R,70R)-2,38-Bis(h yd r oxym e t h yl)-7,
11,15,19,22,26,30,34,43,47,51,55,58,62,66,70-h e xa d e ca -
m eth yl-1,4,37,40-tetr aoxacyclodoh eptacon tan e (3b). Com-
pound 33 (74 mg, 0.050 mmol) was treated in the same manner
C
100H186O8: C, 79.20; H, 12.36. Found: C, 79.14; H, 12.60.
2,3′-O-[(3R,7R,11S,15S,18S,22S,26R,30R)-3,7,11,15,18,
22,26,30-oct a m et h yld ot r ia con t a n e-1,32-d iyl]-2′,3-b is-O-
[(3R,7R,11S,15S)-15-for m yl-3,7,11,15-t et r a m et h ylp en t a -
d eca n yl]b is(1-O-b en zyl-sn -glycer ol) (31). Compound 30
(196 mg, 0.129 mmol) was treated in the same manner as
described for the preparation of 23 to give dialdehyde 31 (179
C
mg, 92%) as an oil: [R]23 +9.05 (c 0.775, CHCl3); 1H NMR
D
(300 MHz) δ 0.80-0.90 (m, 42H), 0.97-1.74 (m, 104H), 2.33
(ddd, J ) 2.0, 6.6, 13.2 Hz, 2H), 3.37-3.64 (m, 18H), 4.55 (s,
4H), 7.22-7.35 (m, 10H), 9.61 (d, J ) 2.0 Hz, 2H); 13C NMR
(75 MHz) δ 13.35, 19.65, 19.67, 19.71, 19.75, 24.35, 24.39,
24.44, 24.48, 29.79, 29.87, 30.85, 32.64, 32.79, 33.04, 34.30,
36.62, 36.98, 37.08, 37.16, 37.32, 37.36, 37.41, 37.50, 37.55,
46.33, 68.86, 69.94, 70.28, 70.76, 73.32, 77.92, 127.47, 127.55,
128.27, 138.40, 205.35; IR (neat) 698, 735, 1115, 1377, 1462,
1728, 2858, 2925, 2951 cm-1. Anal. Calcd for C100H182O8: C,
79.41; H, 12.13. Found: C, 79.19; H, 12.32.
as described for the preparation of 3a to give 3b (52 mg, 80%)
1
as an oil: [R]25 +9.06 (c 1.74, CHCl3); H NMR (300 MHz) δ
D
0.80-0.92 (m, 48H), 0.97-1.68 (m, 104H), 2.18 (br, 2H), 3.42-
3.74 (m, 18H); 13C NMR (75 MHz) δ 19.76, 19.82, 19.85, 24.36,
24.44, 29.77, 29.81, 32.77, 33.04, 34.28, 36.55, 37.03, 37.35,
37.50, 63.03, 68.58, 70.07, 71.04, 78.35; IR (neat) 1049, 1115,
1377, 1462, 2858, 2925, 2952, 3452 cm-1; EI-MS m/z 1301 (M+),
1283 (M+ - H2O), 1271, 650. Anal. Calcd for C86H172O6: C,
79.32; H, 13.31. Found: C, 79.38; H, 13.43.
Differ en cia l Sca n n in g Ca lor im etr y (DSC) Mea su r e-
m en t. All calorimetric measurements were performed on a
SEIKO SSC-5200 differential scanning calorimeter. Each lipid
(10-15 mg) was placed in an aluminum pan, and the pan was
sealed to prevent adsorption of water during measurements.
All thermograms were run at a scanning rate of 2 °C/min from
-80 to 40 °C. Determinations of the transition points and of
the enthalpy of the phase were performed on line by means of
a microprocessor connected to the calorimeter.
(2S ,7R ,11R ,15S ,19S ,22S ,26S ,30R ,34R ,38S ,43R ,47R ,
51S,55S,58S,62S,66R,70R)-2,38-Bis[(b en zyloxy)m et h yl]-
7,11,15,19,22,26,30,34,43,47,51,55,58,62,66,70-h exa d eca -
m eth yl-1,4,37,40-tetr a oxa cyclod oh ep ta con t-20-en e (32).
Compound 31 (147 mg, 0.097 mmol) was treated in the same
manner as described for the preparation of 24 to give cyclic
compound 32 (94 mg, 66%) as an oil: [R]24 +7.06 (c 1.03,
D
CHCl3); 1H NMR (300 MHz) δ 0.80-0.97 (m, 48H), 0.97-1.68
(m, 98H), 2.02 (m, 2H), 3.43-3.65 (m, 18H), 4.55 (s, 4H), 5.16
(dd, J ) 2.2, 4.6 Hz, 2H), 7.22-7.35 (m, 10H); 13C NMR (75
MHz) δ 19.75, 19.80, 19.82, 21.33, 24.39 24.45, 24.78, 29.74,
29.84, 32.77, 32.80, 32.82, 33.05, 34.29, 36.64, 36.83, 37.09,
37.36, 37.39, 37.44, 37.50, 37.60, 68.78, 69.89, 70.32, 70.97,
73.35, 77.95, 127.48, 127.57, 128.29, 134.65, 138.42; IR (neat)
696, 733, 1115, 1377, 1462, 2858, 2925, 2951 cm-1; EI-MS m/z
1479 (M+), 1387, 1282, 91. Anal. Calcd for C100H182O6: C,
81.13; H, 12.39. Found: C, 80.94; H, 12.69.
Ack n ow led gm en t. The authors are grateful to Prof.
Y. Koga, University of Occupational and Environmental
Health, J apan, for providing us a natural 72-membered
lipid specimen. We thank Nihon Surfactant Kogyo K.
K. for DSC study. This work was supported in part by
a Grant-in-Aid for Scientific Research from the Ministry
of Education, Science, Sports, and Culture, J apan.
(2S ,7R ,11R ,15S ,19S ,22S ,26S ,30R ,34R ,38S ,43R ,47R ,
51S,55S,58S,62S,66R,70R)-2,38-Bis[(b en zyloxy)m et h yl]-
7,11,15,19,22,26,30,34,43,47,51,55,58,62,66,70-h exa d eca -
m eth yl-1,4,37,40-tetr aoxacyclodoh eptacon tan e (33). Com-
pound 32 (90 mg, 0.061 mmol) was treated in the same manner
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 5, 7-33, 3a , and 3b, 13C NMR spectra for com-
pounds 21-25, 29-33, 3a , and 3b, and mass spectra for
compounds 3a and 3b (44 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.
as described for the preparation of 25 to give 33 (80 mg, 88%)
1
as an oil: [R]24 +1.92 (c 2.46, CHCl3); H NMR (300 MHz) δ
D
0.80-0.92 (m, 48H), 0.97-1.68 (m, 104H), 3.43-3.65 (m, 18H),
4.55 (s, 4H), 7.22-7.35 (m, 10H); 13C NMR (75 MHz) δ 19.76,
19.80, 19.82, 24.38, 24.46, 29.75, 29.84, 32.78, 32.80, 33.05,
34.30, 36.64, 37.07, 37.37, 37.46, 37.51, 68.78, 69.89, 70.32,
J O972328P