Total synthesis of calditol: structural clarification of this typical component of Archaea order Sulfolobales.

Article abstract of DOI:10.1002/1521-3765(20020104)8:1<240::AID-CHEM240>3.0.CO;2-G

The original structure of calditol--that is, an open-chain branched nonitol--has recently been questioned by various research groups and cyclopentane-based structures have been proposed. To unambiguously clear up this confusion, four isomeric cyclopentane

Full text of DOI:10.1002/1521-3765(20020104)8:1<240::AID-CHEM240>3.0.CO;2-G

FULL PAPER
Total Synthesis of Calditol: Structural Clarification of this Typical
Component of Archaea Order Sulfolobales**
Yves Ble¬riot, Edouard Untersteller, BenoÓt Fritz, and Pierre Sinay*[a]
»
Abstract: The original structure of calditol–that is, an open-chain branched
nonitol–has recently been questioned by various research groups and cyclo-
pentane-based structures have been proposed. To unambiguously clear up this
confusion, four isomeric cyclopentane candidates 26 29 have been synthesized. Of
these, compound 27 was found to be fully identical to the natural product present in
Sulfolobus solfataricus (A.T.C.C. 49155). The synthesis of 27 uses a samarium-
diiodide-induced pinacolization reaction of the ketoaldehyde 15 as the critical step.
Keywords: archaea
structure elucidation ¥ sulfolobales
¥ total synthesis
¥
calditol
¥
tetraether structure 1 has been termed diglycerocaldarch-
aeol[5] or GDGT (glycerodialkylglycerol tetraether).[6]
The second type is based on
glycerol on one hand and on a
polyol on the other, for which
the trivial name calditol has
been coined.[7] It may thus be
termed calditoglycerocaldarch-
aeol according to Nishihara et al.,[5] or glycerodialkyl calditol
tetraether (GDCT). The history of this polyol is very
interesting.
Introduction
In addition to prokaryotes and eukaryotes, archae have been
introduced, on the basis of 16S ribosomal RNA sequence
analyses,[1] as the third group of living organisms. Sulfolobus is
a genus of sulfur-oxidizing archae characterized by aerobic
growth at high temperatures and low pH in the presence of
elemental sulfur.[2] Organisms of this genus are usually found
in sulfur-containing habitats such as acidic hot springs and
mud holes. The known species of Sulfolobus include Sulfolo-
bus acidocaldarius, originally discovered in Yellowstone Na-
tional Park (USA) and Sulfolobus solfataricus, originally
discovered in Pisciarelli (Italy), and these have been widely
used in research. Brock et al. suggested that Sulfolobus may
be important geochemical agents in the production of sulfuric
acid from elemental sulfur in high-temperature hydrothermal
systems.[2a] The membranes of extreme thermoacidophiles are
based on two major types of complex macrocyclic tetraethers
in which two polyols are linked together through two
isoprenoid chains.[3] In one type, the hydrophilic portions
are two glycerol units in which the ether bonds are located at
the sn-2 and sn-3 positions of glycerol.[4] The diglycerol
The early history of calditol–Langworthy and De Rosa: In
1974, Langworthy et al.[8] studied the structure of various
lipids extracted from Sulfolobus acidocaldarius (Strain 98-3),
an archae originally isolated by Brock et al.[2] from Locomo-
tive Spring in Yellowstone National Park. One component,
identified as a glycolipid B, after acidic methanolysis to
remove the glucose unit gave a product which was identified
as the polyol dialkyl glycerol triether 2 (Scheme 1). Although
¬
[a] Prof. P. Sinay», Dr. Y. Bleriot, Dr. E. Untersteller, B. Fritz
¬
¬
Departement de Chimie, Associe au CNRS
¬
Ecole Normale Superieure
24 Rue Lhomond, 75231 Paris cedex 05 (France)
Fax : (‡33)1-44-32-33-97
Scheme 1. Isolation of a polyol dialkyl glycerol triether 2 by Langworthy.
E-mail: pierre.sinay@ens.fr
[**] Part of this work was published as a preliminary communication: E.
the structure of this new polyol was not determined at that
time, they suggested that it might be cyclic, and demonstrated
that it was connected through an ether linkage to glycerol.
At about the same time, the Italian group of De Rosa
studied the structure of the second lipid type from Caldariella
acidophila (Strain MT-4), isolated from an acid hot spring in
¬
Untersteller, B. Fritz, Y. Bleriot, P. Sinay» C.R. Acad. Sci. Ser. 2 1999, C,
429 433.
Supporting information for this article is available on the WWW under
http://wiley-vch.de/home/chemistry/ or from the author: 1H and
13CNMR spectra of the synthetic peracetates 26 29 and the natural
product.
240
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Chem. Eur. J. 2002, 8, No. 1

240 246
Agnano, Naples.[9] This archaeon should now be renamed[2c]
Sulfolobus solfataricus (A.T.C.C. 49155). In complete contrast
to Langworthy, they proposed that calditol was a unique
acyclic branched-chain nonitol 3 containing no ether bond,
and the structure of the corresponding calditol glycerol
tetraether 4 was proposed by the Italian group. The stereo-
chemistry of the calditol was not determined.
tetraether lipids from Sulfolobus solfataricus and also detect-
ed several significant differences in comparison with the
spectral data reported by De Rosa et al.[14] The interpretation
of NMR data of their own lipid sample led to the proposed
new structure 6 for calditol. In both structures 5 and 6, a cyclic
polyol is connected to sn-1 glycerol by an ether linkage. These
structures only differ in the configuration at a single stereo-
center.
An improved purification of this so-called glycerol dialkyl
nonitol tetraether (GDNT) has subsequently been report-
ed.[10]
Results and Discussion
To clarify this rather confusing situation, we launched a
programme of chemical synthesis of various stereoisomers. A
key derivative in this piece of work was the protected d-
glucopyranose derived diol 14. In this compound, the hexitol
derivative is connected through an ether linkage to the sn-1
position of di-O-benzylated glycerol. The strategy was then to
convert the diol into a substituted cyclopentane ring by
pinacolization. The synthesis of the key diol 14 is given in
Scheme 2. To alkylate the sn-1 position of glycerol, we first
transformed the sn-3-O-benzyl glycerol (7)[15] into the cyclic
sulfate 9, via the cyclic sulfite 8. Sharpless demonstrated that
cyclic sulfates are easily opened by nucleophilic attack at the
less hindered position.[16] Indeed, phenyl 2,3,6-tri-O-benzyl-1-
thio-b-d-glucopyranose (10)[17] was efficiently alkylated[18]
with cyclic sulfate 9 to give, after acidic hydrolytic removal
of the transient sulfate, the secondary alcohol 11. Benzylation
of this product gave compound 12, which was converted into
the hemiacetal 13 using N-bromosuccinimide in moist ace-
tone, and then into the target intermediate 14 (in 84% yield
from 12) after reduction with lithium aluminum hydride. This
synthetic pathway is of general interest for the efficient
anchoring of a glyceryl appendage onto a secondary alcohol.
As shown in Scheme 3, the glucitol derivative 14 was
submitted to Swern oxidation[19] to afford the unstable
ketoaldehyde 15 which was not isolated. Immediate sama-
rium-diiodide-promoted pinacolization gave an inseparable
mixture of two cis diols, 16 and 17, in a 3:1 ratio (78% yield).
A similar pinacolization reaction has recently been report-
ed.[20]
Structural and chemical investigations–doubts about the
correctness of the original structure of calditol: In 1990,
Jeganathan and Vogel reported the first synthesis of two
1
defined stereoisomers of De Rosa×s nonitol.[11] The H NMR
spectra of the corresponding peracetates were both different
from the one reported by De Rosa et al. for the natural
calditol peracetate. They concluded at this stage that the
natural product was another stereoisomer. In 1995, we
reported the chemical synthesis of another defined peracety-
lated isomer.[12] Comparison of the 13CNMR skeletal
chemical shifts of this synthetic compound with those given
by De Rosa for the nonacetate of calditol revealed odd
discrepancies. From a critical analysis of De Rosa×s structural
work, we detected various significant anomalies, so that we
seriously questioned the correctness of the original structure
assigned to this natural product by the Italian group.[12]
In addition to these synthetic efforts, two independent
structural investigations of calditol also invalidated the
original open-chain structure. SugaÔ et al.,[13] in accordance
with Langworthy×s prediction and on the basis of NMR
analysis, proposed the new structure 5 for calditol, which
could be isolated in pure form from type two lipids of
Sulfolobus acidocaldarius (A.T.C.C. 33909). Arigoni×s group
independently reinvestigated the structure of the calditol
Abstract in French: La structure d×origine du calditol–‡
savoir un nonitol branchÿ en chain droite–a ÿtÿ sÿrieusement
remise en question rÿcemment par plusieurs groupes de
recherche, et des structures cyclopentaniques ont ÿtÿ proposÿes.
We then moved on to the problem of the inversion of
configuration at C-1 of 16 and 17. Our first approach consisted
of the transformation of the cis diols into the corresponding
separable cyclic sulfates and their subsequent opening with a
nucleophile by an SN2 mechanism. Several nucleophiles such
as lithium acetate, cesium acetate, ammonium benzoate, and
sodium azide were tried in various solvents (DMF, HMPT,
acetonitrile), but only elimination products and/or starting
material were detected and no opening of the sulfate was
observed.
√
Afin de totalement clarifier cette situation plutot confuse,
quatre candidats isomõres structuraux cyclopentaniques 26
29 ont ÿtÿ synthÿtisÿs. Seul l×un d×eux, le composÿ 27, est
totalement identique au produit naturel prÿsent chez Sulfolo-
bus solfataricus (A.T.C.C. 49155). La synthõse de 27 met en jeu
dans l×ÿtape critique une rÿaction de pinacolisation du cÿtoal-
dÿhyde 15, initiÿe par le diiodure de samarium.
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241

P. Sinay» et al.
FULL PAPER
deprotected with potassium
carbonate in 87 92% yield to
afford the pure cis diols 16 and
17, respectively. The structures
of the two cyclopentane rings
were unambiguously establish-
ed at this stage by recording
NOESY spectra of the corre-
sponding acetonides 20 and 21
(Figure 1, Table 1). The dis-
criminating nuclear Overhauser
effects observed were as fol-
lows: 1) irradiation of H-6 of
acetonide 20 gave an NOE with
H-1 and H-4 indicating that H-1
and H-4 are on the same (top)
face of the cyclopentane ring,
and 2) irradiation of one of the
methyl groups of the acetonide
i
ii
BnO
BnO
BnO
OH
O
O
69%
OH
O
S
O
S
O
O
O
7
8
9
BnO
HO
BnO
iii
87%
O
BnO
O
SPh
O
+
9
SPh
BnO
BnO
OBn
OBn
OR
10
11: R = H
iv
93%
12: R = Bn
BnO
BnO
O
BnO
vi
95%
v
O
OBn
OH
O
OH
12
OH
BnO
BnO
BnO
89%
OBn
OBn
OBn
13
14
Scheme 2. Synthesis of glucitol derivative 14. i) SOCl2, Et3N, CH 2Cl2; ii) NaIO4, RuCl3, 08C , C HCl2; iii) a)
nBuLi, THF, HMPA; b) 2m H2SO4; iv) BnBr, NaH, THF; v) NBS, dark, acetone/H2O; vi) LiAlH4, THF.
2
21 gave an NOE with H-4 and H-2 indicating that H-4, H-2
and the hydroxyl groups of the corresponding diol 17 are all
on the same (top) face of the cyclopentane ring. Thus
compound 16 has the diol moiety located under the cyclo-
pentane ring, whereas compound 17 has the diol unit pointing
above the cyclopentane ring.
Scheme 3. Synthesis of cis diols 16 and 17 by pinacol coupling. i) oxalyl
chloride, DMSO, Et3N, CH2Cl2, À 658C; ii) SmI2, tBuOH, THF, À408C.
Figure 1. Nuclear Overhauser effects observed for acetonides 20 and 21.
Benzyl groups (R) are not shown for clarity.
A strategy consisting of the oxidation of the alcohol at C-1,
followed by the reduction of the resulting ketone to the
inverted alcohol was then examined. For this purpose, the
mixture of cis diols 16 and 17 were conveniently separated as
their carbonates 18 and 19 (Scheme 4), which were then
Table 1. Nuclear Overhauser effects observed for acetonides 20 and 21.
Irradiated proton[a]
NOE observed
Acetonide 21
Acetonide 20
CH3 (isopropylidene)
CH3 (isopropylidene)
H-1
H-1, H-6
H-3
H-2
H-4 (weak), H-6, benzyl
H-2 (weak), H-4
H-4, H-6
H-2
H-3
H-4
H-6, H-6'
H-1, benzyl
H-2, H-4, CH3
H-1, H-3 (weak)
H-1, H-4, benzyl
benzyl
H-4, H-6
H-4, CH3
[a] Key NOEs are indicated in bold.
The oxidation of the cis diols 16 and 17 was problematic.
Swern oxidation[19] gave a mixture of elimination products,
whereas the Dess Martin periodinane[21] cleaved the C C
À
bond formed during the pinacol coupling to afford the glucitol
derivative 14 after sodium borohydride reduction. Bromine
oxidation of the diol-derived stannylenes, followed by sodium
borohydride reduction, also gave poor results. Finally, and as
Scheme 4. Protection of the cis diols 16 and 17 as carbonates 18 and 19 and
acetonides 20 and 21. i) 1,1'-carbonyl diimidazole, CH2Cl2; ii) K2CO3,
CH3OH; iii) 2,2 dimethoxypropane, acetone, CSA.
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Chem. Eur. J. 2002, 8, No. 1

Total Synthesis of Calditol
240 246
observed by Adinolfi et al. in a similar case,[22] oxidation was
achieved in a satisfying yield using sodium hypochlorite/
2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO) methodol-
ogy.[23] Subsequent sodium borohydride reduction of the
resulting ketones 22 and 23, probably directed by the tertiary
alcohol, selectively afforded the expected trans diols 24
(Scheme 5) and 25 (Scheme 6). Traces of cis diols were easily
separated after conversion into their corresponding aceto-
nides 20 and 21, respectively. Catalytic hydrogenolysis of the
trans diols 24 and 25 afforded the corresponding heptitols,
which were directly peracetylated to give compounds 26 and
27, respectively. The same sequence was applied to the cis
diols 16 and 17 to afford the peracetylated compounds 28 and
29, respectively (Scheme 5 and 6). Comparison of the 1H and
13CNMR spectra of the peracetates 26 29 with an authentic
sample of peracetylated calditol, kindly provided to us by A.
SugaÔ, showed that the peracetylated natural product and
compound 27 were identical. Furthermore, the optical rota-
tions of both synthetic 27 and natural calditol heptacetate
were very close (natural sample: [a]D ˆ À14.6 (c ˆ 1.56 in
CHCl3), synthetic compound 27: [a]D ˆ À14 (c ˆ 0.27 in
CHCl3)).
ocaldarius (A.T.C.C. 33909) by
SugaÔ et al.[13] is that shown in
Figure 2.
The depicted relative stereo-
structure is indeed that previ-
ously proposed by Gr‰ther and
Arigoni, working on a sample
isolated from Sulfolobus solfataricus (A.T.C.C. 49155), the
same archaeon that had been extensively studied by De Rosa
et al. and initially named Caldariella acidophila. Although no
sample of peracetylated calditol has been available to us from
De Rosa or Arigoni for direct comparison, we consider it
highly probable that the calditol present in various archaea
has the same structure. This work also firmly establishes that
the cyclic part of calditol is connected through an ether
linkage to the sn-1 carbon atom of glycerol. It is worth noting
that kerufarrides[24] and crasserides,[25] which are natural
products of marine origin, contain a cyclopentane-pentol
moiety that is also connected through an ether linkage,
probably to sn-1 position of glycerol.
Figure 2. Structure of calditol.
Experimental Section
Cyclic sulfite 8: Diol 7 (9.0 g, 49.4 mmol) and Et3N (27.7 mL, 198 mmol)
were dissolved in anhydrous CH2Cl2 (100 mL), and the solution was cooled
to 08C. A solution of freshly distilled SOCl2 (5.4 mL, 74.1 mmol) in
anhydrous CH2Cl2 (50 mL) was added dropwise under argon. The reaction
mixture was then stirred at RT for 1 h, diluted with cold Et2O (100 mL),
and washed with cold water (2 Â 100 mL) and brine (100 mL). The organic
phase was dried over MgSO4 and
Conclusion
This synthetic work unambiguously demonstrates for the first
time that the structure of calditol (including its absolute
configuration) isolated from the archaeon Sulfolobus acid-
filtered, and the solvent was removed
in vacuo. Purification by column chro-
matography (EtOAc/cyclohexane 1:6
then 1:4) afforded cyclic sulphite 8
(8.0 g, 78%). This compound was
immediately used in the next step.
OBn
OBn
OBn
OH
ii
BnO
BnO
BnO
O
i
O
40%
O
BnO
O
BnO
BnO
OH
OBn
HO
HO
HO
OBn
OBn
OBn
OBn
OBn
22
24
16
iii
45%
Cyclic sulfate 9: H2O (120 mL), Ru-
Cl3 ¥ 3H2O (1 mg), and then NaIO4
iii
73%
AcO
O
OAc
OAc
OAc
(15 g, 70 mmol) were added to
a
AcO
solution of (8.0 g, 38.5 mmol) in
8
CH3CN (80 mL) and CH2Cl2 (80 mL)
at 08C. The reaction mixture was
stirred at 08Cfor 45 min, diluted with
diethyl ether (150 mL), and the aque-
ous phase was extracted with Et2O
(2 Â 100 mL). Organic extracts were
combined, washed with 5% aq Na2-
S2O3 solution (2 Â 100 mL), and dried
over MgSO4. The solvent was re-
moved under reduced pressure to
afford 9 (8.42 g, 89%) as a brown oil.
MS (CI, NH3): m/z (%): 245 (15)
O
AcO
AcO
OAc
AcO
AcO
OAc
OAc
OAc
OAc
28
26
Scheme 5. Synthesis of peracetylated compounds 26 and 28. i) TEMPO, NaOCl, CH2Cl2, H2O; ii) NaBH4,
CH3OH; iii) H2, 10% Pd/C, EtOAc, CH3OH then Ac2O, pyridine, DMAP.
OH
BnO
OH
BnO
OH
OH
BnO
ii
i
O
O
BnO
BnO
OH
O
BnO
O
BnO
50%
‡
‡
OBn
[M‡H] , 262 (100) [M‡NH4] ; ele-
mental analysis calcd (%) for
C10H12O5S (244.3): C49.17, H: 4.95;
found: C49.54, H 4.82.
BnO
BnO
OBn
OBn
OBn
OBn
OBn
17
25
23
iii
iii
77%
78%
Alcohol 11: Compound 10 (15 g,
27.7 mmol)
and
2,2'-bisquinoline
OAc
AcO
AcO
AcO
OAc
(20 mg) were dissolved in anhydrous
THF (150 mL). The solution was
cooled to À408C, and nBuLi
(17.4 mL, 10.9 mmol, 1.6m in hexane)
was added dropwise until the solution
became orange. Hexamethyl phos-
phoramide (HMPA; 30 mL) was
O
AcO
AcO
O
AcO
OAc
OAc
AcO
OAc
OAc
OAc
29
27
Scheme 6. Synthesis of peracetylated compounds 27 and 29. i) TEMPO, NaOCl, CH2Cl2, H2O; ii) NaBH4,
CH3OH; iii) H2, 10% Pd/C, EtOAc, CH3OH then Ac2O, pyridine, DMAP.
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243

P. Sinay» et al.
FULL PAPER
added dropwise under stirring followed by a solution of cyclic sulfate 9
(6.7 g, 27.7 mmol) in anhydrous THF (10 mL). The reaction mixture was
allowed to warm to RTand acidified to pH 1 with H2SO4 (2m). The reaction
mixture was then heated at reflux for 3 h, cooled to RT, neutralized with
solid NaHCO3, filtered, diluted with Et2O (200 mL), and washed with
water (200 mL). The aqueous layer was extracted with Et2O (2 Â 200 mL).
Organic extracts were combined and dried over MgSO4, and the solvent
removed under reduced pressure. Purification by column chromatography
(EtOAc/cyclohexane 1:4 then 1:2) afforded alcohol 11 (17 g, 87%) as a
white solid. M.p. 60 618C ; a[ ]2D2 ˆ ‡3.8 (c ˆ 0.51 in CHCl3); 1H NMR
(CDCl3, 400 MHz): d ˆ 7.64 7.30 (m, 25H; 5Ph), 4.97 (d, J ˆ 10.7 Hz, 2H;
2CHPh), 4.91 (d, J ˆ 10.7 Hz, 1H; CHPh), 4.78 (d, J ˆ 10.2 Hz, 1H;
CHPh), 4.72 (d, J ˆ 9.7 Hz, 1H; H-1), 4.69 (d, J ˆ 12.0 Hz, 1H; CHPh), 4.63
(d, J ˆ 12.0 Hz, 1H; CHPh), 4.57 (s, 2H; CH2Ph), 3.94 (m, 1H; H-8), 3.90
3.82 (m, 3H; H-6, H-6', H-7), 3.78 (dd, J ˆ 3.8 Hz, 10.2 Hz, 1H; H-7'), 3.72
(appt, J ˆ 8.9 Hz, 1H; H-3), 4.02 (appt, J ˆ 9.3 Hz, 1H; H-4), 3.57 (appt,
J ˆ 9.5 Hz, 1H; H-2), 3.51 (m, 1H; H-5), 3.49 (appd, J ˆ 5.3 Hz, 2H; H-9,
H-9'), 3.05 (d, J ˆ 4.3 Hz, 1H; OH); 13C NMR (CDCl3, 100 MHz): d ˆ
137.99, 137.89, 137.84, 137.83, 133.58 (5Cipso), 131.86 127.41 (5Ph), 87.32
(CH-1), 86.14 (CH-3), 80.69 (CH-2), 78.92 (CH-5), 78.37 (CH-4), 75.67
(CH2Ph), 75.26 (CH2Ph), 74.21 (CH2Ph), 73.36 (CH2Ph), 73.29 (CH2Ph),
70.92 (CH2-9), 69.93 (CH-8), 68.84 (CH2-6); MS (CI, NH3): m/z (%): 724
d-Glucitol derivative 14: Alcohol 13 (5.1 g, 7.3 mmol) was dissolved in
anhydrous THF (80 mL) under argon, the solution was cooled to 08C, and
LiAlH4 (0.55 g, 14.6 mmol) was added portionwise. The reaction mixture
was allowed to warm to RTover 2 h. Ethyl acetate (80 mL) was added, and
the solution acidified to pH 1 with 1m HCl. The aqueous phase was
extracted with EtOAc (3 Â 80 mL), the organic extracts were combined,
dried over MgSO4, and concentrated. Purification by column chromatog-
raphy (EtOAc/cyclohexane 1:5 then 1:2) afforded diol 14 (4.9 g, 95%) as a
colorless oil. [a]2D2 ˆ ‡12.5 (c ˆ 0.56 in CHCl3); 1H NMR (CDCl3,
400 MHz): d ˆ 7.37 7.34 (m, 25H; 5Ph), 4.64 4.53 (m, 10H; 5CH2Ph),
4.02 (m, 1H; H-5), 3.96 (dd, J ˆ 4.4, 5.9 Hz, 1H; H-3), 3.82 (m, 2H; H-1,
H-2), 3.77 (m, 5H; H-1', H-4, H-7, H-7', H-8), 3.69 (dd, J ˆ 4.0, 9.7 Hz, 1H;
H-6), 3.62 (dd, J ˆ 5.3, 9.7 Hz, 1H; H-6'), 3.61 (m, 2H; H-9, H-9'), 3.35 (d,
J ˆ 6.1 Hz, 1H; OH-5), 2.37 (appt, 1H; OH-1); 13C NMR (CDCl3,
100 MHz): d ˆ 138.18, 138.14, 138.02, 138.00, 137.91 (5Cipso), 128.35
127.55 (5Ph), 79.61 (CH-4), 79.38 (CH-2), 79.30 (CH-3), 77.27 (CH-8),
74.50 (CH2Ph), 73.31 (CH2Ph), 73.26 (CH2Ph), 72.69 (CH2Ph), 72.06
(CH2Ph), 71.63 (CH2-7), 71.04 (CH2-6), 70.32 (CH-5), 69.61 (CH2-9), 61.62
‡
(CH2-1); MS (CI, NH3): m/z (%): 724 (100) [M‡NH4] ; elemental analysis
calcd (%) for C44H50O8 (706): C74.87, H 6.99; found: C74.77, H 7.05.
Cis diols 16 and 17: Oxalyl chloride (2.3 mL, 26.7 mmol) was dissolved in
anhydrous THF (180 mL) under argon. The solution was cooled to À788C,
anhydrous DMSO (2.3 mL, 32.0 mmol) was added dropwise, and the
solution stirred for 10 min at À608C. A solution of compound 14 (3.8 g,
5.3 mmol) in anhydrous THF (60 mL) was then added slowly, and the
resulting solution stirred for 10 min at À608C. The reaction mixture was
allowed to warm to À458Cand stirred for 45 min. Anhydrous Et 3N
(7.5 mL, 53.4 mmol) was then added, the solution was stirred for 10 min and
allowed to warm up to RT for 1 h. The resulting white suspension was then
transferred by cannula under argon to a 1m solution of SmI2 in THF
(60 mL) containing degassed tert-butanol (1 mL) at À788C. The reaction
mixture was stirred for 4 h at À408Cand then allowed to warm up to RT. A
semi-saturated aq. NH4Cl solution (80 mL) was added to the reaction
mixture, and the aqueous phase was extracted with EtOAc (3 Â 80 mL).
Organic extracts were combined and dried over MgSO4, and the solvent
removed under reduced pressure. Purification by column chromatography
(EtOAc/cyclohexane 1:4 then 1:1) afforded an inseparable 3:1 mixture of
the cis diols 16 and 17 (2.9 g, 78%) as a yellow oil.
‡
(100) [M‡NH4] ; elemental analysis calcd (%) for C43H46O7S (706): C
73.06, H 6.56; found: C73.05, H 6.65.
Thiophenyl derivative 12: A solution of alcohol 11 (9 g, 12.7 mmol) in
anhydrous THF (80 mL) was added dropwise to a cooled suspension of
BnBr (1.8 mL, 15.1 mmol) and NaH (624 mg, 15.6 mmol, 60% dispersion in
mineral oil) in anhydrous THF (30 mL). The solution was stirred at RT for
3 h, cooled to 08C, and quenched with CH3OH (100 mL). The solvent was
removed under reduced pressure, and the residue dissolved in Et2O
(200 mL), and washed with water (3 Â 200 mL). The organic layer was
dried over MgSO4, and the solvent was removed under reduced pressure.
Purification by column chromatography (EtOAc/cyclohexane 1:8 then 1:7)
afforded 12 (9.43 g, 93%) as a yellow oil. [a]2D2 ˆ À2.1 (c ˆ 0.93 in CHCl3);
1H NMR (C6D6, 400 MHz): d ˆ 7.82 7.30 (m, 30H; 6Ph), 5.03 (d, J ˆ
10.7 Hz, 1H; CHPh), 4.99 (s, 2H; CH2Ph), 4.81 (d, J ˆ 10.7 Hz, 1H;
CHPh), 4.73 (d, J ˆ 9.1 Hz, 1H; H-1), 4.63 (s, 2H; CH2Ph), 4.56 (d, J ˆ
12.0 Hz, 1H; CHPh), 4.51 (d, J ˆ 12.0 Hz, 1H; CHPh), 4.43 (s, 2H; CH2Ph),
4.16 (dd, J ˆ 5.2, 9.8 Hz, 1H; H-7), 3.91 (dd, J ˆ 4.6, 9.8 Hz, 1H; H-7'),
3.82 3.76 (m, 3H; H-6, H-6', H-8), 3.70 3.60 (m, 5H; H-2, H-3, H-4, H-9,
Carbonates 18 and 19: Diols 16 and 17 (2.4 g, 3.4 mmol) and 1,1'-carbonyl
diimidazole (2.2 g, 13.75 mmol) were dissolved in anhydrous CH2Cl2
(150 mL) under argon. The solution was heated at reflux for 16 h, cooled
to RT, and washed with water (2 Â 100 mL). The organic phase was dried
over MgSO4, and the solvent removed under reduced pressure. Purification
by column chromatography (EtOAc/cyclohexane 1:7 then 1:5) afforded
carbonate 19 (490 mg, 19%) as a colourless oil. [a]2D2 ˆ À10.0 (c ˆ 0.55 in
CHCl3); 1H NMR (C6D6, 400 MHz): d ˆ 7.41 7.20 (m, 25H; 5Ph), 4.82 (dd,
J ˆ 1.8, 3.5 Hz, 1H; H-1), 4.76 (d, J ˆ 12.0 Hz, 1H; CHPh), 4.72 (d, J ˆ
12.0 Hz, 1H; CHPh), 4.59 (m, 3H; 3CHPh), 4.41 (m, 3H; 3CHPh), 4.26
(app d, J ˆ 12.1 Hz, 2H; CH2Ph), 3.89 (m, 2H; H-2, H-3), 3.82 (dd, J ˆ 4.4,
5.7 Hz, 1H; H-4), 3.75 (m, 2H; H-7, H-7'), 3.72 (d, J ˆ 11.2 Hz, 1H; H-6),
3.71 (m, 1H; H-8), 3.58 (m, 2H; H-9, H-9'), 3.51 (d, J ˆ 11.2 Hz, 1H; H-6');
H-9'), 3.31 (m, 1H; H-5); 13CNMR (C D6, 100 MHz): d ˆ 139.95, 139.93,
6
139.66, 139.55, 139.45, 135.49 (6Cipso), 132.65, 129.61, 129.04 127.90 (6Ph),
88.32 (CH-1), 87.40 (CH-2), 81.69 (CH-4), 79.93 (CH-5), 79.08 (CH-3),
78.57 (CH-8), 75.93 (CH2Ph), 75.90 (CH2Ph), 73.93 (CH2Ph), 73.91
(CH2Ph), 73.37 (CH2-7), 72.69 (CH2Ph), 71.08 (CH2-9), 69.74 (CH2-6);
‡
MS (CI, NH3): m/z (%): 724 (100) [M‡NH4] ; elemental analysis calcd (%)
for C50H52O7S (797.03): C75.34, H 6.57; found: C75.31, H 6.60.
Alcohol 13: Compound 12 (5.9 g, 7.4 mmol) was dissolved in acetone/water
(290 mL, 95% v/v). The reaction mixture was cooled to 08Cand NBS
(6.6 g, 36.9 mmol, recrystallized from water) was added in one portion in
the dark. After 3 min of vigorous stirring, sat. aq Na2CO3 solution (200 mL)
was added, and a white precipitate formed. The acetone was evaporated,
and the remaining aqueous white suspension was extracted with CH2Cl2/
cyclohexane (2 Â 200 mL, 50% v/v). Organic extracts were combined and
dried over MgSO4, and the solvent removed under reduced pressure. The
resulting solid was recrystallized from cyclohexane to afford 13 (4.6 g,
89%) as a white solid. Data for the major a anomer: 1H NMR (CDCl3,
400 MHz): d ˆ 7.37 7.30 (m, 25H; 5Ph), 5.23 (appt, J ˆ 3.0 Hz, 1H; H-1),
4.92 (d, J ˆ 10.8 Hz, 1H; CHPh), 4.84 (d, J ˆ 10.8 Hz, 1H; CHPh), 4.79 (d,
J ˆ 11.8 Hz, 1H; CHPh), 4.69 (d, J ˆ 11.8 Hz, 1H; CHPh), 4.63 (d, J ˆ
12.1 Hz, 1H; CHPh), 4.59 (d, J ˆ 12.1 Hz, 1H; CHPh), 4.55 (d, J ˆ 12.2 Hz,
1H; CHPh), 4.51 (s, 2H; CH2Ph), 4.49 (d, J ˆ 12.2 Hz, 1H; CHPh), 4.01 (m,
2H; H-5, H-7), 3.90 (t, J ˆ 9.2 Hz, 1H; H-3), 3.72 3.65 (m, 4H; H-6, H-6',
H-7', H-8), 3.56 (dd, J ˆ 3.0 Hz, J ˆ 9.2 Hz, 1H; H-2), 3.54 (m, 2H; H-9,
H-9'), 3.48 (t, J ˆ 9.2 Hz, 1H; H-4), 2.87 (d, J ˆ 2.2 Hz, 1H; OH); 13CNMR
(CDCl3, 100 MHz): d ˆ 138.63, 138.60, 137.94, 137.90, 137.81 (5Cipso),
128.46 127.51 (5Ph), 91.26 (CH-1), 81.46 (CH-3), 79.77 (CH-2), 78.16
(CH-4), 77.45 (CH-8), 75.47 (CH2Ph), 73.35 (CH2Ph), 73.31 (CH2Ph), 73.21
(CH2Ph), 72.53 (CH2-7), 72.04 (CH2Ph), 70.26 (CH-5), 70.31 (CH2-9), 68.64
13CNMR (CDCl 3, 100 MHz): d ˆ 153.87 (C O), 138.25, 137.99, 137.67,
ˆ
137.18, 136.82 (5Cipso), 128.65 127.51 (5Ph), 87.57 (C-5), 86.82 (CH-4),
83.85 (CH-3), 82.56 (CH-2), 82.18 (CH-1), 76.82 (CH-8), 73.64, 73.41, 73.03,
72.26, 72.11 (5CH2Ph), 71.84 (CH2-7), 69.37 (CH2-9), 68.11 (CH2-6); MS
‡
(CI, NH3): m/z (%): 748 (100) [M‡NH4] ; elemental analysis calcd (%) for
C45H46O9 (730.8): C73.95, H 6.34; found: C73.78, H 6.52.
Further elution afforded carbonate 18 (1.7 g, 67%) as a colourless oil.
[a]2D2 ˆ ‡30.1 (c ˆ 1.02 in CHCl3); 1H NMR (C6D6, 400 MHz): d ˆ 7.44
7.19 (m, 25H; 5Ph), 4.76 (d, J ˆ 11.7 Hz, 1H; CHPh), 4.68 (d, J ˆ 12.0 Hz,
1H; CHPh), 4.64 (d, J ˆ 12.0 Hz, 1H; CHPh), 4.63 (d, J ˆ 11.7 Hz, 1H;
CHPh), 4.59 (d, J ˆ 11.7 Hz, 1H; CHPh), 4.51 (d, J ˆ 5.4 Hz, 1H; H-1), 4.45
(s, 2H; CH2Ph), 4.35 (appt, J ˆ 8.7 Hz, 1H; H-3), 4.30 (d, J ˆ 11.7 Hz, 1H;
CHPh), 4.26 (d, J ˆ 12.0 Hz, 1H; CHPh), 4.15 (d, J ˆ 12.0 Hz, 1H; CHPh),
3.94 (m, 2H; H-7, H-7'), 3.83 (m, 1H; H-8), 3.73 (d, J ˆ 8.6 Hz, 1H; H-4),
3.67 (appd, J ˆ 4.6 Hz, 2H; H-9, H-9'), 3.61 (dd, J ˆ 5.4, 8.7 Hz, 1H; H-2),
3.36 (d, J ˆ 10.1 Hz, 1H; H-6), 3.38 (d, J ˆ 10.1 Hz, 1H; H-6'); 13CNMR
ˆ
(C6D6, 100 MHz): d ˆ 154.52 (C O), 139.88, 139.51, 139.43, 138.41, 138.07
(5Cipso), 129.27 128.12 (5Ph), 85.96 (C-5), 85.39 (C-3), 81.55 (CH-4), 79.91
(CH-2), 78.36 (CH-8), 77.52 (CH-1), 74.12 (CH2Ph), 74.01 (CH2Ph), 73.93
(CH2Ph), 72.76 (CH2Ph), 72.64 (CH2-7), 72.59 (CH2Ph), 70.58 (CH2-9),
‡
(CH2-6); MS (CI, NH3): m/z (%): 722 (100) [M‡NH4] ; elemental analysis
calcd (%) for C44H48O8 (704.86): C74.97, H 6.86; found: C74.89, H 6.80.
244
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0801-0244 $ 17.50+.50/0
Chem. Eur. J. 2002, 8, No. 1

Total Synthesis of Calditol
240 246
‡
70.34 (CH2-6); MS (CI, NH3): m/z (%): 748 (100) [M‡NH4] ; elemental
analysis calcd (%) for C45H46O9 (730.8): C73.95, H 6.34; found: C73.83, H
6.50.
1H; H-3), 3.93 (dd, J ˆ 4.4, 10.4 Hz, 1H; H-7), 3.89 (dd, J ˆ 5.0, 10.4 Hz,
1H; H-7'), 3.88 (d, J ˆ 9.5 Hz, 1H; H-6), 3.80 (m, 1H; H-8), 3.71 (d, J ˆ
9.5 Hz, 1H; H-6'), 3.65 (appd, J ˆ 5.4 Hz, 2H; H-9, H-9'), 3.40 (s, 1H; OH-
5), 2.90 (d, J ˆ 4.4 Hz, 1H; OH-1); 13CNMR (C 6D6, 100 MHz): d ˆ 139.87,
139.61, 139.58, 139.47, 138.84, (5Cipso), 129.15 128.10, (5Ph), 88.28 (CH-4),
87.94 (CH-2), 84.40 (CH-3), 79.11 (C-5), 78.36 (CH-8), 77.58 (CH-1), 74.18
(CH2Ph), 73.92 (CH2Ph), 72.70 (CH2-6, CH2Ph), 72.60 (CH2Ph), 72.53
(CH2Ph), 71.56 (CH2-7), 70.97 (CH2-9); MS (CI, NH3): m/z (%): 722 (100)
Acetonide 20: Camphorsulphonic acid (3 mg) and 2,2-dimethoxypropane
(2 mL, 16 mmol) were added to a solution of diol 16 (207 mg, 0.29 mmol) in
acetone (18 mL) under argon. The solution was stirred at RT for 17 h, and
the reaction mixture then neutralized with Et3N. The solvent was removed
in vacuo and purification by column chromatography (EtOAc/cyclohexane
1:5) afforded acetonide 20 (175 mg, 80%) as a colorless oil. [a]2D0 ˆ À10.8
(c ˆ 1.0 in CHCl3); 1H NMR (C6D6, 400 MHz): d ˆ 7.50 7.19 (m, 25H;
5Ph), 5.03 (d, J ˆ 12.0 Hz, 2H; CH2Ph), 4.81 (m, 3H; 3CHPh), 4.71 (dd,
J ˆ 7.5, 8.9 Hz, 1H; H-3), 4.63 (d, J ˆ 4.1 Hz, 1H; H-1), 4.62 (d, J ˆ 11.9 Hz,
1H; CHPh), 4.48 (s, 2H; CH2Ph), 4.33 (appq, 2H; CH2Ph), 4.15 (dd, J ˆ
4.8, 9.7 Hz, 1H; H-7), 4.04 (appq, J ˆ 4.8 Hz, 1H; H-8), 3.97 (dd, J ˆ 4.1,
8.9 Hz, 1H; H-2), 3.94 (d, J ˆ 7.3 Hz, 1H; H-4), 3.84 (dd, J ˆ 4.8, 9.7 Hz,
1H; H-7'), 3.81 (dd, J ˆ 4.5, 10.1 Hz, 1H; H-9),3.73 (dd, J ˆ 4.5, 10.1 Hz,
1H; H-9'), 3.53 (d, J ˆ 9.5 Hz, 1H; H-6), 3.49 (d, J ˆ 9.5 Hz, 1H; H-6'), 1.69,
1.44 (2s, 6H; 2CH3); 13CNMR (C 6D6, 100 MHz): d ˆ 138.80, 139.59, 139.67,
140.21, 140.22, (5Cipso), 129.17 127.90 (5Ph), 112.74 (C(CH3)2), 87.20 (CH-
3), 85.24 (C-5), 83.39 (CH-4), 80.76 (CH-1), 80.21 (CH-2), 78.65 (CH-8),
74.22 (CH2-6), 74.10 (CH2Ph), 73.88 (CH2Ph), 73.59 (CH2Ph), 72.79
(CH2Ph), 72.32 (CH2Ph), 71.79 (CH2-7), 71.67 (CH2-9), 27.55, 27.59
‡
[M‡NH4] , 290 (15); elemental analysis calcd (%) for C44H48O8 (704.8): C
74.97, H 6.86; found: C74.91, H 6.98.
Trans diol 24: Diol 16 (36 mg, 0.05 mmol) was dissolved in CH2Cl2 (1 mL)
and potassium bromide (4 mg, 0.034 mmol), TEMPO (40 mg, 0.25 mmol),
and water (50 mL) were added. The solution was cooled to 08Cand a large
excess of NaOCl (0.2 mL, technical solution diluted with water and
adjusted to pH 9 just before use) was added dropwise. Some more NaOCl
and TEMPO were added to complete the reaction. After 50 min, the
reaction mixture was diluted with CH2Cl2 (5 mL) and washed with
saturated aq. Na2S2O3 solution (5 mL) and water (5 mL). The organic
phase was dried over MgSO4, and the solvent removed under reduced
pressure to afford the crude ketone 22 as an orange oil. The ketone 22 was
then dissolved in CH3OH (5 mL), the solution was cooled to 08Cand
NaBH4 (6 mg, 0.15 mmol) was added. After 1 h, the solvent was
removed under reduced pressure. Purification by column chromatography
(EtOAc/cyclohexane 1:2) afforded the trans diol 24 (15 mg, 40%) as a
colorless oil.
‡
(2CH3); MS (CI, NH3): m/z (%): 762 (100) [M‡NH4] ; elemental analysis
calcd (%) for C47H52O8 (744.9): C75.78, H 7.03; found: C75.71, H 7.16.
Acetonide 21: This compound was synthesized from 17 by the procedure
described for 20 and was obtained as a colorless oil. [a]2D2 ˆ ‡6.2 (c ˆ 0.7 in
CHCl3); 1H NMR (C6D6, 400 MHz): d ˆ 7.45 7.19 (m, 25H; 5Ph), 4.96 (d,
J ˆ 12.0 Hz, 1H; CHPh), 4.94 (d, J ˆ 2.5 Hz, 1H; H-1), 4.92 (d, J ˆ 12.0 Hz,
1H; CHPh), 4.83 (d, J ˆ 12.0 Hz, 1H; CHPh), 4.73 (d, J ˆ 12.0 Hz, 1H;
CHPh), 4.68 (d, J ˆ 12.0 Hz, 1H; CHPh), 4.62 (d, J ˆ 12.0 Hz, 1H; CHPh),
4.49 (dd, J ˆ 7.1, 9.5 Hz, 1H; H-3), 4.50 4.41 (m, 4H; 2CH2Ph), 4.35 (dd,
J ˆ 2.5, 7.1 Hz, 1H; H-2), 4.32 (d, J ˆ 9.5 Hz, 1H; H-4), 4.19 (dd, J ˆ 4.3,
10.3 Hz, 1H; H-7), 4.00 (dd, J ˆ 5.1, 10.3 Hz, 1H; H-7'), 3.97 (d, J ˆ 10.3 Hz,
1H; H-6), 3.91 (m, 1H; H-8), 3.90 (d, J ˆ 10.3 Hz, 1H; H-6'), 3.71 (m, J ˆ
5.3 Hz, 2H; H-9, H-9'), 1.57, 1.52 (2s, 6H; 2CH3); 13CNMR (C 6D6,
100 MHz): d ˆ 140.01, 139.84, 139.55, 139.35, 139.11 (5Cipso), 129.02 127.84
(5Ph), 113.68 (C(CH3)2), 90.87 (CH-4), 88.39 (C-5), 87.46 (CH-4), 86.15
(CH-2), 84.57 (CH-1), 78.46 (CH-8), 74.15 (CH2Ph), 73.90 (CH2Ph), 73.37
(CH2Ph), 72.71 (CH2Ph), 72.26 (CH2Ph), 72.00 (CH2-7), 71.03 (CH2-9),
70.72 (CH2-6), 29.16, 27.43 (2CH3); MS (CI, NH3): m/z (%): 762 (100)
Data for cyclopentanone 22: 1H NMR (C6D6, 400 MHz): d ˆ 7.43 7.17 (m,
25H; 5Ph), 5.18 (d, J ˆ 11.8 Hz, 1H; CHPh), 4.83 (d, J ˆ 11.8 Hz, 1H;
CHPh), 4.75 (appd, J ˆ 11.9 Hz, 2H; CH2Ph), 4.51 (appd, J ˆ 3.8 Hz, 2H;
CH2Ph), 4.42 (m, 1H; H-4), 4.41 (m, 3H; 3CHPh), 4.38 (d, J ˆ 6.5 Hz, 1H;
H-2), 4.36 (d, J ˆ 11.9 Hz, 1H; CHPh), 4.32 (dd, J ˆ 0.8, 6.5 Hz, 1H; H-3),
3.88 (dd, J ˆ 4.5, 10.0 Hz, 1H; H-7), 3.83 (d, J ˆ 8.9 Hz, 1H; H-6), 3.82 (dd,
J ˆ 4.5, 5.6 Hz, 1H; H-7'), 3.72 (s, 1H; OH), 3.65 (m, 1H; H-8), 3.61 3.55
(m, 3H; H-9, H-9', H-6'); 13CNMR (C 6D6, 100 MHz): d ˆ 209.77 (C O),
ˆ
139.42, 139.31, 139.16, 138.74, 138.50, (5Cipso), 129.13 128.25 (5Ph), 85.06,
83.82, 80.78, 77.76 (CH-2, CH-3, CH-4, CH-8), 77.64 (C-5), 74.10, 73.98,
73.44, 73.40, 72.65, 72.42, 71.98, 70.25 (5CH2Ph, CH2-6, CH2-7, CH2-9); MS
‡
(CI, NH3): m/z (%): 720 (8) [M‡NH4 ], 290 (100); HRMS (CI ‡ , NH3):
‡
m/z (%): calcd for C44H49O8 [M‡NH4] : 720.3536; found: 720.3542.
Data for trans diol 24: [a]2D0 ˆ ‡5.2 (c ˆ 0.3 in CHCl3); 1H NMR (C6D6,
400 MHz): d ˆ 7.49 7.18 (m, 25H; 5Ph), 4.96 (d, J ˆ 12.0 Hz, 1H; CHPh),
4.87 (d, J ˆ 11.9 Hz, 1H; CHPh), 4.79 (d, J ˆ 11.9 Hz, 1H; CHPh), 4.88 (d,
J ˆ 12.0 Hz, 1H; CHPh), 4.57 (s, 2H; CH2Ph), 4.46 (appt, J ˆ 5.8 Hz, 1H;
H-1), 4.43 (s, 2H; CH2Ph), 4.39 (d, J ˆ 12.0 Hz, 1H; CHPh), 4.32 (appt, J ˆ
7.0 Hz, 1H; H-3), 4.29 (d, J ˆ 12.0 Hz, 1H; CHPh), 4.07 (m, 2H; H-2, H-4),
3.93 (dd, J ˆ 4.5, 10.2 Hz, 1H; H-7), 3.85 (dd, J ˆ 4.3, 10.2 Hz, 1H; H-7'),
3.72 (s, 2H; H-6, H-6'), 3.70 (m, 1H; H-8), 3.63 (m, 2H; H-9, H-9'), 3.57 (s,
1H; OH-5), 2.98 (d, J ˆ 5.6 Hz, 1H; OH-1); 13CNMR (C 6D6, 100 MHz):
d ˆ 139.74, 139.72, 139.61, 139.32, 138.73 (5Cipso), 129.15 128.07 (5Ph),
87.18 (CH-2), 86.01 (CH-3), 83.43 (CH-4), 83.09 (CH-1), 78.10 (C-5), 77.94
(CH-8), 74.25 (CH2Ph), 73.96 (CH2Ph), 73.67 (CH2-6), 73.07 (CH2Ph),
72.62 (CH2Ph), 72.60 (CH2Ph), 71.57 (CH2-7), 70.57 (CH2-9); MS (CI,
‡
[M‡NH4] ; elemental analysis calcd (%) for C47H52O8 (744.9): C75.78, H
7.03; found: C75.67, H 7.15.
Cis diol 16: Carbonate 18 (545 mg, 0.75 mmol) was dissolved in CH3OH
(50 mL). Potassium carbonate (309 mg, 2.24 mmol) was added under
argon, and the reaction mixture stirred at RT. After 20 h, the reaction
mixture was stirred with ion exchange resin IR-120 (2 g) for 30 min and
then filtered. The solvent was removed under reduced pressure, and the
residue was purified by column chromatography (EtOAc/cyclohexane 1:2)
to afford the cis diol 16 (505 mg, 98% yield) as a colorless oil. [a]2D2 ˆ ‡7.4
(c ˆ 0.51 in CHCl3); 1H NMR (C6D6, 400 MHz): d ˆ 7.43 7.19 (m, 25H;
5Ph), 4.69 (d, J ˆ 11.8 Hz, 1H; CHPh), 4.67 (s, 2H; CH2Ph), 4.66 (d, J ˆ
11.0 Hz, 1H; CHPh), 4.62 (d, J ˆ 11.0 Hz, 1H; CHPh), 4.52 (d, J ˆ 11.8 Hz,
1H; CHPh), 4.44 (s, 2H; CH2Ph), 4.43 (m, 1H; H-3), 4.42 (d, J ˆ 12.0 Hz,
1H; CHPh), 4.35 (d, J ˆ 12.0 Hz, 1H; CHPh), 4.32 (dd, J ˆ 6.1, 8.1 Hz, 1H;
H-1), 4.11 (d, J ˆ 6.0 Hz, 1H; H-4), 4.02 (dd, J ˆ 4.5, 10.2 Hz, 1H; H-7),
3.94 (m, 2H; H-2, H-7'), 3.81 (m, 1H; H-8), 3.66 (appd, J ˆ 5.2 Hz, 2H;
H-9, H-9'), 3.58 (d, J ˆ 9.4 Hz, 1H; H-6), 3.53 (d, J ˆ 9.4 Hz, 1H; H-6'), 3.52
(s, 1H; OH-5), 3.19 (d, J ˆ 8.1 Hz, 1H; OH-1); 13CNMR (C 6D6, 100 MHz):
d ˆ 139.80, 139.54, 139.41, 139.24, 139.13, (5Cipso), 129.08 128.14 (5Ph),
88.47 (CH-3), 83.76 (CH-4), 82.22 (CH-2), 78.12 (C-5), 78.11 (CH-8), 74.01
(CH2Ph), 73.93 (CH2Ph), 73.02 (CH2Ph), 72.81 (CH2Ph), 72.66 (CH2Ph),
72.60 (CH2-6), 71.76 (CH2-7), 71.53 (CH-1), 70.88 (CH2-9); MS (CI, NH3):
‡
NH3): m/z (%): 722 (100) [M‡NH4] , 290 (80); HRMS (CI ‡ , NH3): m/z
‡
calcd for C44H49O8 [M‡H] : 705.3427; found: 705.3434.
Trans diol 25: This compound was obtained from diol 14 by the procedure
described for diol 24 and was obtained as a colorless oil. [a]2D2 ˆ ‡10.2 (c ˆ
0.56 in CHCl3); 1H NMR (CDCl3, 400 MHz): d ˆ 7.40 7.30 (m, 25H; 5Ph),
4.72 4.53 (m, 10H; 5CH2Ph), 4.17 (t, J ˆ 5.1 Hz, 1H; H-2), 4.04 (m, 2H;
H-1, H-3), 3.93 (d, J ˆ 9.7 Hz, 1H; H-6), 3.78 3.71 (m, 5H; H-4, H-6', H-7,
H-7', H-8), 3.59 (m, 2H; H-9, H-9'), 3.03 (s, 1H; OH-5), 2.87 (d, J ˆ 5.5 Hz,
1H; OH-1); 13C NMR (CDCl3, 100 MHz): d ˆ 138.50, 138.17, 138.03,
137.75, 137.73 (5Cipso), 128.45 127.49 (5Ph), 88.80 (C-4), 87.74 (C-3), 80.21
(C-5), 76.97 (C-8), 75.73 (CH-1), 73.67 (CH2Ph), 73.32 (CH2Ph), 72.23
(CH2Ph), 72.09 (CH2Ph), 71.97 (CH2Ph), 70.83 (CH2-7), 70.33 (CH2-6),
‡
m/z (%): 722 (100) [M‡NH4] ; elemental analysis calcd (%) for C44H48O8
(704.8): C74.97, H 6.86; found: C74.85, H 7.00.
‡
70.05 (CH2-9); MS (CI, NH3): m/z (%): 722 (100) [M‡NH4] ; HRMS
Cis diol 17: This compound was synthesized from carbonate 19 by the
‡
(CI ‡ , NH3): m/z calcd for C44H52NO8 [M‡NH4] : 722.3693; found:
procedure described for diol 16 and was obtained as a colorless oil. [a]D22
ˆ
722.3681.
‡9.0 (c ˆ 0.1 in CHCl3); 1H NMR (C6D6, 400 MHz): d ˆ 7.48 7.17 (m,
25H; 5Ph), 4.91 (d, J ˆ 11.9 Hz, 1H; CHPh), 4.76 (s, 2H; CH2Ph), 4.69 (d,
J ˆ 11.9 Hz, 1H; CHPh), 4.64 (d, J ˆ 2.1 Hz, 2H; CH2Ph), 4.44 (s, 2H;
CH2Ph), 4.30 (d, J ˆ 11.9 Hz, 2H; CH2Ph), 4.27 (m, 1H; H-2), 4.26 (appt,
J ˆ 4.5 Hz, 1H; H-1), 4.15 (d, J ˆ 5.4 Hz, 1H; H-4), 4.11 (appt, J ˆ 5.4 Hz,
Calditol isomer heptacetate 26: The diol 24 (7 mg, 0.01 mmol) was
dissolved in CH3OH (5 mL). Hydrogenolysis with 10% Pd/Cwas
performed for 17 h by which time TLC(EtOAc/CH 3OH/H2O 3:3:1)
showed one non-UV active spot. The solution was filtered through Celite
Chem. Eur. J. 2002, 8, No. 1
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
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245

P. Sinay» et al.
FULL PAPER
and eluted with CH3OH, and the solvent removed under reduced pressure.
The residue was then dissolved in anhydrous pyridine (1 mL) under argon,
Acknowledgement
and the solution cooled to 08C . AcO (0.5 mL) and DMAP (1 mg) were
2
We would like to thank Prof. P. Vogel and Prof. D. Arigoni for helpful
comments and Dr A. SugaÔ for giving us a sample of peracetylated calditol.
added. The reaction mixture was allowed to warm to RTand was stirred for
4 h. The solvent was then removed under reduced pressure and co-
evaporated with toluene (3 Â 5 mL). Purification by flash chromatography
(EtOAc/cyclohexane 1:1 then EtOAc) afforded the heptacetate 26 (4 mg,
73%) as a colorless oil. [a]D20 ˆ ‡15.2 (c ˆ 0.3 in CHCl3); 1H NMR (CDCl3,
400 MHz): d ˆ 5.80 (m, 1H; H-1), 5.26 (m, 2H; H-2, H-3), 5.17 (m, 1H;
H-8), 4.60 (d, J ˆ 12.0 Hz, 1H; H-6), 4.49 (d, J ˆ 12.0 Hz, 1H; H-6'), 4.33
(dd, J ˆ 4.1, 11.9 Hz, 1H; H-7), 4.15 (dd, J ˆ 6.4, 11.9 Hz, 1H; H-7'), 4.09
(dd, J ˆ 1.7, 2.7 Hz, 1H; H-4) 3.90 (dd, J ˆ 5.0, 10.3 Hz, 1H; H-9), 3.64 (dd,
J ˆ 4.7, 10.7 Hz, 1H; H-9'), 2.15 (s, 3H; OAc), 2.14 (s, 3H; OAc), 2.13 (s,
3H; OAc), 2.12 (s, 3H; OAc), 2.11 (2s, 6H; 2OAc), 2.10 (s, 3H; OAc);
13C NMR (CDCl3, 100 MHz): d ˆ 170.61, 170.42, 170.19, 169.96, 169.74,
[1] a) G. E. Fox, L. J. Magrum, W. E. Balch, R. S. Wolfe, C. R. Woese,
Proc. Natl. Acad. Sci. US 1977, 74, 4537 4541; b) C. R. Woese, G. E.
Fox, Proc. Natl. Acad. Sci. US 1977, 74, 5088 5090; c) C. R. Woese,
L. J. Magrum, G. E. Fox, J. Mol. Evol. 1978, 11, 245 252.
[2] a) T. D. Brock, K. M. Brock, R. T. Belly, R. L. Weiss, Arch. Mikrobiol.
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[3] a) M. De Rosa, A. Gambacorta, B. Nicolaus, B. Chappe, P. Albrecht,
Biochim. Biophys. Acta 1983, 753, 249 256; b) T. A. Langworthy, J. L.
Pond in Thermophiles: General, Molecular, and Applied Microbiology
(Ed.:T. D. Brock), Wiley, New York, 1986, pp. 107 135; c) M.
De Rosa, A. Gambacorta, Prog. Lipid Res. 1988, 27, 153 175; d) B.
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De Rosa, Biochem. J. 1990, 266, 785 791.
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1976, 3, 165 166; b) T. A. Langworthy, Biochim. Biophys. Acta 1977,
487, 37 50; c) M. De Rosa, S. De Rosa, A. Gambacorta, J. Chem. Soc.
Chem. Commun. 1977, 514 515; d) M. De Rosa, S. De Rosa, A.
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1965.
[5] M. Nishihara, M. Morii, Y. Koga, J. Biochem. 1987, 101, 1007 1015.
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M. De Rosa, Biochem. J. 1990, 266, 785 791.
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istry 1980, 19, 249 254.
[8] T. A. Langworthy, W. R. Mayberry, P. F. Smith, J. Bacteriol. 1974, 119,
106 116.
[9] M. De Rosa, S. De Rosa, A. Gambacorta, L. Minale, J. D. Bu×lock,
Phytochemistry 1977, 16, 1961 1965.
[10] S.-L. Lo, C. E. Montague, E. L. Chang, J. Lipid Res. 1989, 30, 944 949.
[11] S. Jeganathan, P. Vogel, Tetrahedron Lett. 1990, 31, 1717 1720.
[12] A. J. Fairbanks, P. Sinay», Tetrahedron Lett. 1995, 36, 893 896.
[13] A. SugaÔ, A. Sakuma, I. Fukuda, N. Kurosawa, Y. H. Itoh, K. Kon, S.
Ando, T. Itoh, Lipids 1995, 30, 339 344.
[14] D. Arigoni, O. Gr‰ther, Zur Strucktur und Biosynthese der tetra-
etherlipide der Archae, Diss. ETH Nr 10860, 1994, Z¸rich (Switzer-
land).
ˆ
169.59, 169.47 (7C O), 83.02 (C-5), 81.72 (CH-4), 77.79 (CH-3), 76.54 (CH-
1), 69.91 (CH-2), 69.05 (CH2-9), 62.37 (CH2-7), 61.81 (CH2-6), 21.24, 20.95,
20.84, 20.83, 20.77, 20.73, 20.71 (7CH3); MS (CI, NH3): m/z (%): 722 (100)
‡
‡
[M‡NH4] ; HRMS (CI ‡ ,
C
H): m/z calcd for C23H33O15 [M‡H] :
4
549.1819; found: 549.1815.
Calditol heptacetate 27: This compound was obtained from diol 17 by the
procedure described for compound 26 and was obtained as a colorless oil.
[a]2D0 ˆ À14.4 (c ˆ 0.27 in CHCl3); 1H NMR (CDCl3, 400 MHz): d ˆ 5.48
(dd, J ˆ 1.8, 4.6 Hz, 1H; H-1), 5.45 (dd, J ˆ 4.6, 8.4 Hz, 1H; H-3), 5.37 (dd,
J ˆ 4.6, 8.4 Hz, 1H; H-2), 5.16 (m, 1H; H-8), 4.93 (d, J ˆ 12.8 Hz, 1H; H-6),
4.53 (d, J ˆ 12.8 Hz, 1H; H-6'), 4.36 (dd, J ˆ 4.0, 11.8 Hz, 1H; H-7), 4.22
4.18 (m, 2H; H-4, H-7'), 3.81 (m, 2H; H-9, H-9'), 2.17 (s, 3H; OAc), 2.14 (s,
3H; OAc), 2.13 (s, 3H; OAc), 2.12 (s, 3H; OAc), 2.11 (s, 3H; OAc), 2.06 (s,
3H; OAc), 2.05 (s, 3H; OAc); 13C NMR (CDCl3, 100 MHz): d ˆ 170.66,
ˆ
170.35, 170.32, 170.00, 169.88, 169.75, 169.13 (7C O), 86.98 (C-5), 85.42
(CH-4), 80.21 (CH-3), 73.03 (CH-1), 72.78 (CH-2), 69.96 (CH-8), 69.94
(CH2-7), 62.43 (CH2-9), 58.73 (CH2-6), 21.89, 20.94, 20.87, 20.73, 20.63,
‡
20.59, 20.55 (7CH3); HRMS (CI ‡ , C H): calcd for C23H33O15 [M‡H] :
4
549.1819; found: 549.1823.
Calditol isomer heptacetate 28: This compound was synthesized from diol
16 by the procedure described for compound 26 and was obtained as a
colorless oil. [a]2D0 ˆ ‡17.9 (c ˆ 0.7 in CHCl3); 1H NMR (CDCl3, 400 MHz):
d ˆ 5.66 (dd, J ˆ 0.8, 5.4 Hz, 1H; H-1), 5.37 (dd, J ˆ 2.7, 6.2 Hz, 1H; H-3),
5.25 (dd, J ˆ 5.4, 5.9 Hz, 1H; H-2), 5.19 (m, 1H; H-8), 4.92 (d, J ˆ 12.8 Hz,
1H; H-6), 4.33 (dd, J ˆ 3.9, 11.8 Hz, 1H; H-7), 4.20 (d, J ˆ 12.8 Hz, 1H;
H-6'), 4.17 (dd, J ˆ 6.9, 11.8 Hz, 1H; H-7'), 3.89 (dd, J ˆ 4.7, 10.1 Hz, 1H;
H-9), 3.81 (dd, J ˆ 0.6, 2.4 Hz, 1H; H-4), 3.56 (dd, J ˆ 4.3, 10.1 Hz, 1H;
H-9'), 2.17 (s, 3H; OAc), 2.15 (s, 3H; OAc), 2.14 (s, 3H; OAc), 2.12 (s, 3H;
OAc), 2.11 (s, 3H; OAc), 2.09 (s, 3H; OAc), 2.08 (s, 3H; OAc); 13CNMR
(CDCl3, 100 MHz): d ˆ 170.66, 170.22, 170.17, 169.74, 169.69, 169.61,
[15] P. J. Edwards, D. A. Entwistle, S. V. Ley, D. R. Owen, E. J. Perry,
Tetrahedron: Asymmetry 1994, 5, 553 556.
ˆ
169.57 (7C O), 83.09 (CH-4), 82.55 (C-5), 82.32 (CH-3), 73.18 (CH-2),
71.59 (CH-1), 69.98 (CH-8), 69.08 (CH2-9), 62.51 (CH2-7), 61.77 (CH2-6),
[16] a) Y. Gao, K. B. Sharpless, J. Am. Chem. Soc. 1988, 110, 7538 7539;
b) B. Moon Kim, K. B. Sharpless, Tetrahedron Lett. 1989, 30, 655 658.
[17] M. S. Motawia, C. E. Olsen, K. Enevoldsen, J. Marcussen, B. L.
Moeller, Carbohydr. Res. 1995, 277, 109 123.
[18] W. Klotz, R. R. Schmidt, Synthesis 1996, 687 689.
[19] A. J. Mancuso, S.-L. Huang, D. Swern, J. Org. Chem. 1978, 43, 2480
2482.
[20] M. Adinolfi, G. Barone, A. Iadonisi, L. Mangoni, Tetrahedron Lett.
1998, 39, 2021 2024.
[21] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155 4156.
[22] M. Adinolfi, G. Barone, A. Iadonisi, L. Mangoni, R. Manna,
Tetrahedron 1997, 53, 11767 11780.
[23] P. L. Anelli, S. Banfi, F. Montanari, S. Quici, J. Org. Chem. 1989, 54,
2970 2972.
[24] M. Ishibashi, C.-M. Zeng, J. Kobayashi, J. Nat. Prod. 1993, 56, 1856
1860.
[25] V. Costantino, E. Fattorusso, A. Mangoni, J. Org. Chem. 1993, 58,
186 191.
ˆ
21.22, 20.95, 20.87, 20.71, 20.68, 20.49, 20.47 (7CH3C O); elemental
analysis calcd (%) for C23H32O15 (548.5): C50.36, H 5.88; found: C50.26,
H 6.02.
Calditol isomer heptacetate 29: This compound was synthesized from diol
17 by the procedure described for compound 26 and was obtained as a
colorless oil. [a]2D0 ˆ À6.3 (c ˆ 0.35 in CHCl3); 1H NMR (CDCl3, 400 MHz):
d ˆ 5.59 (d, J ˆ 7.7 Hz, 1H; H-1), 5.48 (ddd, J ˆ 0.9, 4.5, 7.7 Hz, 1H; H-2),
5.17 (m, 1H; H-8), 5.12 (dd, J ˆ 2.9, 4.5 Hz, 1H; H-3), 4.66 (d, J ˆ 12.1 Hz,
1H; H-6'), 4.62 (d, J ˆ 12.1 Hz, 2H; H-6, H-6'), 4.33 (m, 2H; H-4, H-7), 4.17
(dd, J ˆ 5.9, 11.9 Hz, 1H; H-7'), 3.90 (dd, J ˆ 5.0, 10.7 Hz, 1H; H-9), 3.78
(dd, J ˆ 4.5, 10.7 Hz, 1H; H-9'), 2.14 (s, 3H; OAc), 2.13 (s, 3H; OAc), 2.11
(4s, 12H; 4OAc), 2.07 (s, 3H; OAc); 13C NMR (CDCl3, 100 MHz): d ˆ
ˆ
170.55, 170.28, 170.26, 169.94, 169.85, 169.69, 169.67 (7C O), 84.85 (C-5),
82.81 (CH-4), 78.25 (CH-2), 77.81 (CH-3), 75.52 (CH-1), 69.72 (CH-8),
69.21 (CH2-9), 62.19 (CH2-7), 61.85 (CH2-6), 21.53, 20.86, 20.78, 20.72,
ˆ
20.70, 20.66, 20.64 (7CH3C O); elemental analysis calcd (%) for C23H32O15
(548.5): C50.36, H 5.88; found: C50.20, H 5.96.
Received: August 8, 2001 [F3480]
246
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0801-0246 $ 17.50+.50/0
Chem. Eur. J. 2002, 8, No. 1