Synthesis of sphingosine relatives. Part 22. Synthesis of sulfobacin A, B and flavocristamide A, new sulfonolipids isolated from Chryseobacterium sp.

Article abstract of DOI:10.1039/a904258j

Sulfobacin A (1), B (2), and flavocristamide A (3), new sulfonolipids isolated from Chryseobacterium sp. were synthesized stereoselectively by starting from L-cysteine.

Full text of DOI:10.1039/a904258j

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Synthesis of sphingosine relatives. Part 22.1 Synthesis of
sulfobacin A, B and flavocristamide A, new sulfonolipids isolated
from Chryseobacterium sp.
Hirosato Takikawa, Dai Nozawa, Akihiro Kayo, Shin-etsu Muto and Kenji Mori*
Department of Chemistry, Science University of Tokyo, Kagurazaka 1-3, Shinjuku-ku,
Tokyo 162-8601, Japan
Received (in Cambridge) 27th May 1999, Accepted 22nd June 1999
Sulfobacin A (1), B (2), and flavocristamide A (3), new sulfonolipids isolated from Chryseobacterium sp. were
synthesized stereoselectively by starting from -cysteine.
1 can be prepared from an aminosulfinic acid A, which is
Introduction
obtainable from the key intermediate B. Since the sulfone
portion of B is a part of the acetonide group, this is considered
a sulfinic acid equivalent. The key intermediate B may be syn-
thesized by diastereoselective coupling of C with D. For the
preparation of optically active E, we adopt enzymatic reso-
lution. This synthetic plan could also be applicable for the syn-
thesis of the other two target compounds (2 and 3).
In 1995 sulfobacin A (1) and B (2), von Willebrand factor
Synthesis of the key intermediates B and E
First we synthesized the intermediate E (= 8b) as follows. 10-
Bromodecan-1-ol
4 was treated with isoamylmagnesium
bromide in the presence of dilithium tetrachlorocuprate
(Li2CuCl4) to give alcohol 5 (Scheme 2). This was then oxidized
to give either the corresponding aldehyde 6 or the carboxylic
acid 7. The aldehyde 6 was treated with the lithium enolate of
ethyl acetate followed by hydrolysis to give ( )-8b (= E). This
racemate was resolved with lipase PS in the presence of vinyl
acetate10 to afford the desired (R)-8b in 28% yield, [α]D23 = Ϫ12.7
(c 1.02 in CHCl3) {lit.11 [α]D20 = Ϫ12.0 (c 1.0 in CHCl3)}. The
enantiomeric purity of (R)-8 was estimated by GLC analysis on
a chiral stationary phase to be ~100% ee. The hydroxy acid (R)-
8b was then converted into the corresponding TBDMS ether 9.
We then prepared the intermediate D (= 12) as follows. Com-
mercially available dec-9-en-1-ol 10a was treated with toluene-
p-sulfonyl chloride (TsCl), which was employed in a Grignard
coupling with isobutylmagnesium bromide in the presence of
Li2CuCl4 to afford 11. Dibromination of 11 was followed by
dehydrobromination12 to give 12.13
receptor antagonists, were isolated by Kamiyama et al. from the
culture broth of Chryseobacterium sp.2 Almost simultaneously,
the isolation of flavocristamide A (3) and B (= sulfobacin A, 1),
DNA polymerase α inhibitors, from the cultured mycelium of
Flavobacterium sp. (= Chryseobacterium sp.) was reported by
Kobayashi et al.3 These compounds are novel sulfonolipids
and are unusual sphingosine derivatives. Similar sulfonolipids,
N-acyl-2-amino-3-hydroxy-15-methylhexadecane-1-sulfonic
acids, were previously found in the cell envelope of gliding
bacteria of the genera Cytophaga, Capnocytophaga, Spora-
cytophaga and Flexibacter.4,5 Although a structurally similar
sulfonolipid was previously synthesized by Kamikawa et al.,6
the synthesis of these sulfonolipids (1, 2 and 3) had not been
reported. We therefore became interested in synthesizing these
three compounds as a part of our work in preparing unusual
sphingosine derivatives.7 Recently, two syntheses of sulfobacins
were reported as preliminary communications. The first one
was carried out by Irako and Shioiri,8 and the second was
accomplished by us.9 Herein we describe our improved syn-
thesis of sulfobacins and the details of the first synthesis of
flavocristamide A (3).
The known aldehyde 1414 (= C) was prepared from -cysteine
hydrochloride 13. At that time we found that the enantiomeric
purity of the obtained 14 (after chromatographic purification)
was 93% ee, and that of the crude 14 was ~100% ee by HPLC
analysis. The decrease of enantiomeric purity could be due to
the partial racemization of aldehyde 14 in the course of the
purification. We therefore decided to employ 14 in the next step
without purification. Diastereoselective addition of lithium
alkynide derived from 12-methyltridec-1-yne (12) to 14 was
performed by Fujisawa’s procedure14 to give the desired anti-
adduct 15 in 65% yield (2 steps) after chromatographic separ-
ation (anti:syn = ca. 6:1). The enantiomeric purity of 15 was
determined by HPLC analysis to be 95% ee. After reduction of
the triple bond, the sulfur atom at the thiazolidine ring was
oxidized with MCPBA to afford the key intermediate 17 (= B).
At this stage an alternative route to 17 was also examined. The
known ester 1815 was oxidized with MCPBA to give 19. First
we attempted to prepare aldehyde 21 by the reduction of 19
with DIBAL-H. Although the reaction proceeded cleanly, the
enantiomeric purity of the resulting 21 (after chromatographic
Results and discussion
Synthetic plan
Scheme 1 shows our synthetic plan for 1. The target compound
J. Chem. Soc., Perkin Trans. 1, 1999, 2467–2477
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Scheme 1 Synthetic plan for 1.
purification) was <20% ee and that of the crude 21 was ca. 60%
ammonia was followed by oxidation with hydrogen peroxide to
ee. The following reduction–oxidation sequence was therefore
chosen. The ester 19 was reduced with LAH, which was fol-
lowed by oxidation with Dess–Martin periodinane16 to give
aldehyde 21. The enantiomeric purity of the resulting 21
(without purification) was estimated to be ~100% ee by HPLC
analysis. This aldehyde 21 was immediately employed in
diastereoselective addition of lithiated 12 to give 22 in 65%
yield under the same conditions as for the preparation of 15.
Although the chemical yield was moderate, the diastereo-
selectivity was excellent (anti:syn = 99:1). Several attempts
were made in vain to improve the yield of 22 by using differ-
ently metallated 12. The triple bond of 22 was then reduced to
give 17. The enantiomeric purity of 17 was estimated to be
97.8% ee by HPLC analysis. Judging from the overall efficiency,
it was concluded that the latter procedure was more efficient
and practical for the preparation of 17.
furnish sulfobacin B (2), [α]D20 = Ϫ10.7 (c 0.14 in MeOH) {lit.2
[α]D23 = Ϫ19 (c 0.14 in MeOH)}. The overall yield of 2 was 28%
prepared in 9 steps starting from 18. Although the reason for
the disagreement in the optical rotation value is not clear, the
1H-NMR, 13C-NMR, IR and mass spectra of synthetic 2 were
in good accord with those reported. Indeed the direct com-
parison of our spectra with the copies of the spectra of the
natural product fully supported the identity of our synthetic 2
as sulfobacin B.
By the same procedure as described above, sulfobacin A (1)
was also synthesized. The aminosultine 23 was acylated with 9
to give 26a. The deprotection of the TBS group of 26a afforded
26b. The resulting 26b was converted to sulfobacin A (1) in 2
steps, [α]D25 = Ϫ15 (c 0.14 in MeOH), {lit.2 [α]D24 = Ϫ35 (c 0.14 in
MeOH), lit.3 [α]D20 = Ϫ7.9 (c 0.18 in MeOH)}. The overall yield
of 1 was 22% prepared in 10 steps starting from 18. The optical
rotation value of synthetic 1 was not in good accord with those
of Kamiyama’s2 and Kobayashi’s.3 To clarify the reason for the
disagreement, we remeasured the optical rotation value of
natural 1 kindly supplied by Kamiyama. It was not identical
with that reported, [α]D18 = Ϫ8.1 (c 0.10 in MeOH). The optical
rotation value of this type of compounds seems to be sensitive
to temperature, pH and/or concentration. In addition, we pre-
pared the sodium salt of 1 according to Kobayashi’s advice and
measured its optical rotation value. This was in good accord
with that of Kobayashi’s, [α]D24 = Ϫ9.0 (c 0.10 in MeOH). The
1H-NMR data of synthetic 1 was also slightly different from
those reported.2,3 We therefore remeasured 1H-NMR spectra of
Kamiyama’s natural 1 and our synthetic 1 under almost the
same conditions. These two spectra were superimposable sup-
porting the conclusion that our synthetic 1 was identical with
Kamiyama’s natural 1. The 13C-NMR, IR and mass spectra of
synthetic 1 were also in good accord with those of Kamiyama’s.
Synthesis of sulfobacin A and B
The next step is one of the key steps in our synthesis. As men-
tioned in the synthetic plan, the sulfone portion of 17 (= B) is a
part of the acetonide group and is thought of as a sulfinic acid
equivalent. Therefore deprotection of the acetonide group
should give the corresponding sulfinic acid. This idea was real-
ized as follows. The cleavage of Boc and acetonide protecting
groups of 17 was achieved by treatment with hydrochloric acid
to give crystalline sultine 23,17 not sulfinic acid (A) (Scheme 3).
The formation of the cyclic sulfinate was not expected but wel-
come to us nevertheless, because it also served as the protection
for the hydroxy group. Moreover, the enantiomeric purity of 23
could be enriched to ~100% ee by recrystallization at this stage.
The orientation of the oxygen atom on the sulfur atom of 23
was determined to be β on the basis of the similarity of its
1H-NMR spectrum to that of 29a (vide infra). The amino group
of 23 was acylated with 7 in the presence of DCC to give the
amide 24. Hydrolysis of the sulfinate portion with aqueous
1
We then measured H-NMR spectrum of the sodium salt of
synthetic 1, and it was in good accord with that of Kobayashi’s.
It was therefore concluded that Kamiyama’s group isolated
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Scheme 2 Synthesis of 1 and 2—(1). Reagents, conditions and yields: (a) Me2CH(CH2)2MgBr, Li2CuCl4, THF (96%); (b) PCC, MS 4 Å, CH2Cl2
(78%); (c) Jones’ CrO3, acetone (70%); (d) EtOAc, LDA, THF (79%); (e) LiOH, aq MeOH–THF (86%); (f) lipase PS, vinyl acetate, BHT, 60 ЊC (28%,
~100% ee); (g) TBDMSCl, imidazole, DMF, then dilute HCl (82%); (h) TsCl, pyridine (quantitative); (i) BuiMgBr, Li2CuCl4, THF (94%, 2 steps); (j)
Br2, CH2Cl2; (k) ButOK, 18-crown-6, petroleum ether (72%, 2 steps); (l) BunLi, 12-methyltridec-1-yne (12), HMPA, THF (65% for 15 and 65% for
22); (m) PtO2, H2, EtOAc (97% for 16 and 97% for 17); (n) MCPBA, CHCl3 (95%); (o) MCPBA, CH2Cl2 (99%); (p) LAH, THF (81%); (q) Dess–
Martin periodinane (quantitative).
sulfobacin A as the free sulfonic acid and Kobayashi’s group
isolated flavocristamide B (= sulfobacin A) as its sodium salt.
selectivity was estimated by HPLC analysis to be anti:syn =
96:4. Cleavage of the Boc and the acetonide protecting groups
of 28 gave aminosultines 29a and 29b as a mixture (ca. 4:1) in
1
96% yield. Based on the careful comparison of their H-NMR
Synthesis of flavocristamide A
spectra, the less polar and major product was thought to be
29a, while the other was 29b. MM3 calculations also supported
our hypothesis. This mixture was acylated with 9 and then the
products were separated by silica gel column chromatography
to give amides 30a and 30b in 49% and 14% yield respectively.
In the same manner as mentioned before, the two isomers 30a
and 30b were finally converted to flavocristamide A (3),
[α]D22 = Ϫ21 (c 0.27, MeOH) {lit.2 [α]D20 = Ϫ17 (c 0.27, MeOH)}.
The overall yield of 3 was 19% prepared in 9 steps starting from
18. The sodium salt of 3 was then prepared, [α]D18 = Ϫ16 (c 0.10
The next subject we addressed was the synthesis of flavocrist-
amide A (3). Attempts were initially made to prepare the inter-
mediate 28 by reduction of 22. Although a variety of reduction
conditions were examined, we could not find any appropriate
conditions. We therefore turned our attention to using nucleo-
philic addition of alkenylmetal to 21 and carried out a series
of experiments as shown in Table 1. The same conditions
employed for the synthesis of 17 and 22 gave the desired
diastereomer 28, although the chemical yield was less than 30%
(Scheme 4). We therefore tried to use different alkenylmetals
under various conditions (Table 1). As a result, the conditions
listed in entry 5 were selected as those optimal to obtain 28.
Diastereoselective addition of 12-methyltridec-1-enylmag-
nesium bromide to 21 gave 28 in 67% yield. The diastereo-
1
in MeOH). Although the H-NMR spectrum of synthetic 3
(sulfonic acid) was slightly different from that reported, that of
the sodium salt was in good accord with the reported data. The
13C-NMR, IR and mass spectra of synthetic 3 were also in good
accord with those reported.
J. Chem. Soc., Perkin Trans. 1, 1999, 2467–2477
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Scheme 3 Synthesis of 1 and 2—(2). Reagents, conditions and yields: (a) 6 M HCl, MeOH (80%); (b) 7, DCC, CHCl3 (71%); (c) aq NH3, CHCl3–
MeOH; (d) aq H2O2 (99% for 2 and 98% for 1, 2 steps); (e) 9, DCC, CHCl3 (64%); (f) TBAF, THF (85%).
Table 1 Diastereoselective addition of (E)-12-methyltridec-1-enylmetal to 21
Yieldb
(%)
Ratioc
(anti:syn)
Entry
Metala
Li
Solvent
Additive
Temp./ЊC
Ϫ78
Ϫ78–25
Ϫ78–25
Ϫ78
Time
1
2
3
4
5
6
Et2O
Et2O
Et2O
Et2O–THF
Et2O–THF
Et2O–THF
HMPA
none
HMPA
none
HMPA
none
15 min
12 h
12 h
15 min
15 min
1 h
29d
36f
5g
75
75
0 j
>99:<1
25:75
92:8
86:14
96:4
Al(iBu)2 e
Al(iBu)2
MgBrh
e
MgBrh
Ϫ78
Ϫ78
i
CeCl2
—
a (E)-12-Methyltridec-1-enylmetal was used as the nucleophile. b Isolated yield as a mixtute of syn and anti isomers. c The ratio of anti:syn was
estimated by HPLC analysis of compound 17 after reduction of the double bond. d 21 was not recovered. e Prepared by the treatment of 12 with
i
DIBAL-H. f The amount of recovered 21 was ~60%. g The amount of recovered 21 was >80%. h See Experimental section. Prepared by the same
metal exchange method as entries 4 and 5. j The amount of recovered 21 was ~20%.
In summary, the syntheses of new sulfonolipids sulfobacin A
(1), B (2) and flavocristamide A (3) were achieved by starting
from -cysteine. We have clarified that sulfobacin A (1) and B
(2) isolated by Kamiyama and his co-workers were sulfonic
acids and that flavocristamide A (3) and B (= sulfobacin A, 2)
isolated by Kobayashi and his co-workers were sodium salts.
400 MHz on a JEOL JNM-LA400 spectrometer and at 500
MHz on a JEOL JNM-LA500. The peak for TMS, CDCl3 (at
δ 7.26), DMSO-d6 (at δ 2.49) or CD3OD (at δ 3.30) was used for
the internal standard. Chemical shifts are reported in ppm on
the δ scale, and J values are given in Hz. 13C-NMR spectra were
recorded at 100 MHz on a JEOL JNM-LA400 spectrometer
and at 126 MHz on a JEOL JNM-LA500. The peak for CDCl3
(at δ 77.0), DMSO-d6 (at δ 39.5) or CD3OD (at δ 49.0) was used
as internal standard. Optical rotations were taken with a
JASCO DIP-1000 polarimeter [α]D values are given in 10Ϫ1 deg
cm2 gϪ1. Mass spectra were measured with a JEOL JMS-
SX102A spectrometer. Column chromatography was carried
out on Merck Kieselgel 60 Art 1.07734. TLC analyses were
performed on Merck silica gel plates 60F-254.
Experimental
All mps and bps are uncorrected. All mps were measured on a
Yanaco micro melting point apparatus. IR spectra were meas-
ured on a JASCO A-102 spectrometer as films for oils or as
1
Nujol mulls and KBr disks for solids. H-NMR spectra were
recorded at 90 MHz on a JEOL JNM-EX 90A spectrometer, at
2470
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Scheme 4 Synthesis of 3. Reagents, conditions and yields: (a) (E)-12-methyltridec-1-enylmagnesium bromide, HMPA, THF (67%, 2 steps); (b) 3 M
HCl, MeOH (96%); (c) 9, DCC, DMAP, CHCl3 (49% for 30a and 14% for 30b); (d) TBAF, THF (59% for 31a and 62% for 31b); (e) aq NH3, CHCl3–
MeOH; (f) aq H2O2 (95% based on 31a or 31b, 2 steps).
13-Methyltetradecan-1-ol 5
(C᎐O), 755s; δ (90 MHz; CDCl ) 0.86 (6H, d, J 6.2,
᎐
H 3
CH(CH3)2), 1.10–1.65 (21H, m, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-,
11- and 12-H2 and 13-H), 2.41 (2H, t, J 6.6, 2-H2), 9.76 (1H,
t, J 1.8, CHO). This was employed in the next step without
further purification.
To a stirred and cooled solution of 4 (20.0 g, 84.3 mmol) in dry
THF (200 cm3) was added a solution of (Me)2CH(CH2)2MgBr
in dry THF (1.32 mol dmϪ3; 239 cm3, 316 mmol) followed by a
solution of Li2CuCl4 in dry THF (0.2 mol dmϪ3; 5 cm3, 1 mmol)
at Ϫ78 ЊC under Ar. The resulting mixture was allowed to warm
to room temperature with stirring overnight. After the reaction
mixture was quenched with saturated aq. NH4Cl, it was
extracted with ethyl acetate. The extract was washed with water,
saturated aq. NaHCO3 and brine, dried (MgSO4), and concen-
trated under reduced pressure. The residue was chromato-
graphed on SiO2 to give the alcohol 5 (18.5 g, 96%) as a colorless
oil, nD25 1.4462 (Found: C, 78.47; H, 14.19. C15H32O requires C,
78.87; H, 14.12%); νmax(film)/cmϪ1 3370s (OH), 1055m (C–O),
760s; δH(400 MHz; CDCl3) 0.86 (6H, d, J 6.8, CH(CH3)2), 1.15–
1.65 (24H, m, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- and 12-H2,
13-H and OH), 3.64 (2H, q, J 6.1, 1-H2).
13-Methyltetradecanoic acid 7
To a stirred and cooled solution of 6 (1.00 g, 4.38 mmol) in
acetone (10 cm3) was added Jones’ CrO3 reagent (2.69 mol
dmϪ3; 3.1 cm3, 8.3 mmol) dropwise at 0 ЊC and the reaction
mixture was stirred at room temperature for 1 h. After the reac-
tion mixture was quenched with propan-2-ol, it was extracted
with ethyl acetate. The extract was washed with water and brine,
dried (MgSO4), and concentrated under reduced pressure. The
residue was chromatographed on SiO2 to give the acid 7 (744
mg, 70%) as a colorless solid, mp 43–46 ЊC (lit.,11 52 ЊC);
νmax(Nujol)/cmϪ1 1700s (C᎐O), 930m; δ (90 MHz; CDCl ) 0.86
᎐
H
3
(6H, d, J 6.2, CH(CH3)2), 1.00–1.70 (21H, m, 3-, 4-, 5-, 6-, 7-,
8-, 9-, 10-, 11- and 12-H2 and 13-H), 2.35 (2H, t, J 6.8, 2-H2).
13-Methyltetradecanal 6
A solution of 5 (21.8 g, 95.5 mmol) in dry CH2Cl2 (150 cm3) was
added dropwise to a stirred suspension of PCC (29.0 g, 134
mmol) and powdered MS 4 Å (20 g) in dry CH2Cl2 (150 cm3).
After having been stirred at room temperature for 3 h, the reac-
tion mixture was concentrated under reduced pressure. The
residue in Et2O was filtered through SiO2, and the filtrate was
concentrated under reduced pressure. The residue was chrom-
atographed on SiO2 to give the aldehyde 6 (16.9 g, 78%) as
a colorless oil, nD25 1.4408; νmax(film)/cmϪ1 2720w (CHO), 1725s
Ethyl ( )-3-hydroxy-15-methylhexadecanoate ( )-8a
LDA was prepared from diisopropylamine (11.6 cm3, 81.8
mmol) and BunLi (1.59 mol dmϪ3 in hexane; 51.5 cm3, 81.9
mmol) in dry THF (80 cm3) under Ar. Ethyl acetate (8.0 cm3, 82
mmol) was added dropwise to the LDA solution at Ϫ78 ЊC.
After the mixture was stirred for 30 min at this temperature, a
solution of 6 (16.5 g, 72.9 mmol) in dry THF (100 cm3) was
added dropwise at Ϫ78 ЊC. After having been stirred for 10 min,
J. Chem. Soc., Perkin Trans. 1, 1999, 2467–2477
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the reaction mixture was quenched with saturated aq. NH4Cl
and extracted with ethyl acetate. The extract was washed with
water, saturated aq. NaHCO3 and brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was chrom-
atographed on SiO2 to give the hydroxy ester ( )-8a (18.2 g,
79%) as a colorless oil, nD25 1.4448 (Found: C, 72.69; H, 12.32.
C19H38O3 requires C, 72.56; H, 12.18%); νmax(film)/cmϪ1 3470m
mg, 82%) as a colorless oil, [α]D23 ϩ1.35 (c 1.07 in CHCl3); nD26
1.4479; νmax(film)/cmϪ1 1715s (C᎐O), 1255s (TBDMS), 1100m,
᎐
940m, 840s, 780s; δH(400 MHz; CDCl3) 0.10 (3H, s, SiMe), 0.11
(3H, s, SiMe), 0.86 (6H, d, J 6.6, CH(CH3)2), 0.90 (9H, s, SiBut),
1.10–1.60 (23H, m, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- and
14-H2 and 15-H), 2.49 (1H, dd, J 15.3 and 5.5, 2-Ha), 2.56 (1H,
dd, J 15.3 and 5.1, 2-Hb), 4.08 (1H, quintet, J 5.7, 3-H). This
was employed in the next step without further purification.
(OH), 1720s (C᎐O), 1180s, 1025m, 755m; δ (400 MHz; CDCl )
᎐
H
3
0.86 (6H, d, J 6.6, CH(CH3)2), 1.10–1.60 (26H, m, 4-, 5-, 6-, 7-,
8-, 9-, 10-, 11-, 12-, 13- and 14-H2, 15-H and OCH2CH3), 2.39
(1H, dd, J 16.6 and 9.0, 2-Ha), 2.50 (1H, dd, J 16.6 and 3.0,
2-Hb), 2.92 (1H, d, J 3.9, OH), 3.99 (1H, m, 3-H), 4.17 (2H, q,
J 7.2, OCH2CH3).
Dec-9-enyl toluene-p-sulfonate 10b
To a solution of dec-9-en-1-ol 10a (21.7 g, 139 mmol) in pyri-
dine (43 cm3) and CH2Cl2 (60 cm3), toluene-p-sulfonyl chloride
(53.0 g, 208 mmol) was added at 0 ЊC. The mixture was stirred
for 12 h at 4 ЊC. This mixture was poured into water and
extracted with n-hexane. The extract was washed with water,
dilute aq. HCl and brine, dried (MgSO4), and concentrated
under reduced pressure to give the crude tosylate 10b (44.2 g,
quantitative), νmax(film)/cmϪ1 3080m (C᎐CH ), 1645m (C᎐C),
1600m (Ar), 1500m (Ar), 1360s (SO2), 1190s (SO2), 1180s (SO2);
δH(90 MHz; CDCl3) 1.10–1.70 (12H, m, 2-, 3-, 4-, 5-, 6-, 7-H2),
1.90–2.20 (2H, m, 8-H2), 2.45 (3H, s, ArMe), 4.02 (2H, t, J 6.1,
1-H2), 4.93 (1H, br d, J 1.2 and 17.3, 10-H), 4.96 (1H, br d, J 1.2
and 10.1, 10-H), 5.87 (1H, ddt, J 6.7, 10.1 and 17.3, 9-H), 7.34
(2H, d, J 8.4, Ar-H), 7.79 (2H, d, J 8.4, Ar-H). This was
employed in the next step without further purification.
( )-3-Hydroxy-15-methylhexadecanoic acid ( )-8b
To a stirred solution of ( )-8a (16.4 g, 52.2 mmol) in THF (100
cm3) and MeOH (50 cm3) was added aq. LiOH (1 mol dmϪ3;
60 cm3, 60 mmol) at room temperature. After having been
stirred overnight, the reaction mixture was concentrated under
reduced pressure. The residue was poured into ethyl acetate,
acidified with dilute aq. HCl to pH 3, and extracted with ethyl
acetate. The extract was washed with water and brine, dried
(MgSO4), and concentrated under reduced pressure. The resi-
due was recrystallized from hexane to give the hydroxy acid ( )-
8b (12.8 g, 86%) as colorless plates, mp 59–61 ЊC; νmax(KBr)/
᎐
᎐
2
cmϪ1 3470m (OH), 2900s (CH), 2690m, 2580m, 1720s (C᎐O),
᎐
910m; δH(400 MHz; CDCl3) 0.86 (6H, d, J 6.6, CH(CH3)2),
1.10–1.60 (23H, m, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- and
14-H2 and 15-H), 2.47 (1H, dd, J 16.6 and 9.0, 2-Ha), 2.58 (1H,
dd, J 16.6 and 3.2, 2-Hb), 4.02 (1H, m, 3-H); these spectral data
were identical with those reported for (R)-8b.11
12-Methyltridec-1-ene 11
A dry THF solution of isobutylmagnesium bromide was pre-
pared from isobutyl bromide (20.0 cm3, 184 mmol) and mag-
nesium (5.39 g, 222 mmol) in dry THF (165 cm3). The resulting
Grignard reagent and Li2CuCl4 (0.10 mol dmϪ3 in THF; 18 cm3,
1.8 mmol) were added successively to a solution of tosylate 10b
(44.2 g, 142 mmol) in dry THF (200 cm3) at Ϫ78 ЊC under Ar.
This mixture was allowed to warm to room temperature with
stirring overnight. After quenching with saturated aq. NH4Cl, it
was extracted with n-hexane. The extract was washed with
water, saturated aq. NaHCO3 and brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was chrom-
atographed on SiO2 and distilled to give the alkene 11 (25.5 g,
94% from 10a) as a colorless oil, bp 84 ЊC/3.6 mmHg; nD25 1.4341
(Found: C, 85.80; H, 14.33. C14H28 requires C, 85.63; H,
14.37%); νmax(film)/cmϪ1 3080m (C᎐CH ), 2975s (C᎐CH), 2940s
(R)-3-Hydroxy-15-methylhexadecanoic acid (R)-8b
To a stirred solution of ( )-8b (2.00 g, 6.98 mmol) and 2,6-di-
tert-butyl-4-methylphenol (20 mg) in vinyl acetate (30 cm3) was
added lipase PS (1.00 g), and the mixture was stirred at 60 ЊC
for 48 h. After cooling, the mixture was filtered and the filtrate
was concentrated under reduced pressure. The residue was
chromatographed on SiO2, and the resulting solid was recrystal-
lized from hexane to give the hydroxy acid (R)-8b (562 mg, 28%)
as colorless plates, mp 55–57 ЊC; [α]D23 Ϫ12.7 (c 1.02 in CHCl3)
{lit.11 [α]D20 = Ϫ12.0 (c 1.0 in CHCl3)} (Found: C, 70.82; H, 11.86.
C17H34O3 requires C, 71.28; H, 11.96%); IR and 1H NMR spec-
tra were identical with those of ( )-8b.
᎐
᎐
᎐
2
(CH), 2850s (CH), 1645m (C᎐C), 995m (CH᎐CH ), 910s
᎐
2
(CH᎐CH ); δ (90 MHz; CDCl ) 0.89 (6H, d, J 6.1, CH(CH ) ),
᎐
2
H
3
3 2
1.26 (17H, br s, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-H2 and 12-H), 1.90–
2.20 (2H, m, 3-H2), 4.93 (1H, br d, J 10.2, 1-H), 4.97 (1H, br d,
J 17.2, 1-H), 5.83 (1H, ddt, J 6.7, 10.2 and 17.2, 2-H).
Determination of the enantiomeric purity of (R)-8b
A small amount of (R)-8b was converted to the methyl ester by
treatment with diazomethane. The resulting methyl ester was
analyzed by GLC to determine its enantiomeric purity. GLC
analysis [column: Chirasil-DEX CB (0.25 mm × 25 m, 180 ЊC;
carrier gas: He, pressure 110 kPa)]. tR/min 50.0 [no peak, methyl
ester of (S)-8b], 51.0 [100%, methyl ester of (R)-8b]. The
enantiomeric purity of (R)-8b was estimated to be ~100% ee.
12-Methyltridec-1-yne 12
To a solution of 11 (2.71 g, 13.8 mmol) in dry CH2Cl2 (30 cm3),
bromine (0.78 cm3, 15.2 mmol) was added and the mixture was
stirred for 10 min at 0 ЊC. After quenching with saturated
aq. Na2S2O3, it was extracted with n-hexane. The extract was
washed with water and brine, dried (MgSO4), and concentrated
under reduced pressure to give 1,2-dibromo-12-methyltridecane
(5.00 g, quantitative) as a colorless oil. This was employed in
the next step without further purification. A small amount of
this was chromatographed on SiO2 to give an analytical sample
as a colorless oil, nD25 1.4496 (Found: C, 47.40; H, 7.75. C14H28Br2
requires C, 47.21; H, 7.92%); νmax(film)/cmϪ1 2940s (CH), 2860s
(CH), 1460m (CH), 1430m, 1380m (CH), 1365m (CH); δH(400
MHz; CDCl3) 0.86 (6H, d, J 6.6, CH(CH3)2), 1.15–1.60 (17H,
m, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-H2 and 12-H), 1.73–1.83 (1H, m,
3-H), 2.10–2.21 (1H, m, 3-H), 3.63 (1H, t, J 10.1, 1-H), 3.85
(1H, dd, J 4.4 and 10.1, 1-H), 4.17 (1H, m, 2-H). To a solution
of the dibromide (5.00 g, 14.0 mmol) in petroleum ether (70
cm3), ButOK (4.65 g, 41.4 mmol) and 18-crown-6 (11 mg, 0.041
mmol) were added and the mixture was stirred for 2 h under
(R)-3-(tert-Butyldimethylsilyloxy)-15-methylhexadecanoic acid 9
To a stirred solution of (R)-8b (210 mg, 0.733 mmol) and
imidazole (200 mg, 2.94 mmol) in DMF (5 cm3) was added
TBDMSCl (400 mg, 2.65 mmol) at room temperature. After
having been stirred at room temperature for 3 h, the reaction
mixture was poured into water and extracted with ethyl acetate.
The extract was washed with water, and concentrated under
reduced pressure. The residue was diluted with THF (5 cm3).
Then to the solution was added aq. HCl (0.2 mol dmϪ3; 1 cm3)
and the mixture was stirred at room temperature overnight. The
reaction mixture was poured into water and extracted with
ethyl acetate. The extract was washed with water and brine,
dried (MgSO4), and concentrated under reduced pressure. The
residue was chromatographed on SiO2 to give the acid 9 (246
2472
J. Chem. Soc., Perkin Trans. 1, 1999, 2467–2477

View Article Online
reflux. This mixture was poured into water and extracted with
n-hexane. The extract was washed with dilute aq. HCl, water
and brine, dried (MgSO4), and concentrated under reduced
pressure. The residue was chromatographed on SiO2 and dis-
tilled to give the alkyne 12 (1.93 g, 72%) as a colorless oil, bp
75 ЊC/1.6 mmHg; nD25 1.4381 (Found: C, 86.56; H, 13.61. C14H26
trated under reduced pressure. The residue was chromato-
graphed on SiO2 to give the alcohol 17 (182 mg, 95%) as a
colorless oil, [α]D20 Ϫ21.2 (c 1.03 in CHCl3); nD24 1.4720; vmax(film)/
cmϪ1 3530s (OH), 1710s (C᎐O), 1370s, 1320s (SO ), 1170s,
᎐
2
1140s, 1100s (C–O), 1070s; δH(400 MHz; CDCl3) 0.86 (6H, d,
J 6.6, CH(CH3)2), 1.12–1.38 (23H, m, 2Ј-, 3Ј-, 4Ј-, 5Ј-, 6Ј-, 7Ј-,
8Ј-, 9Ј-, 10Ј-, 11Ј-, 12Ј-H2 and 13Ј-H), 1.50 (9H, s, OCMe3), 1.66
(3H, s, acetonide), 1.69 (3H, s, acetonide), 2.04 (1H, m, OH),
3.15 (1H, dd, J 8.3 and 13.4, SO2CHH), 3.51 (1H, dd, J 6.8 and
13.4, SO2CHH), 4.17 (1H, m, 4-H), 4.25 (1H, m, 1Ј-H).
requires C, 86.52; H, 13.48%); νmax(film)/cmϪ1 3340m (C᎐CH),
᎐
᎐
᎐
2140w (C᎐C); δ (90 MHz; CDCl ) 0.86 (6H, d, J 6.2,
᎐
H
3
CH(CH3)2), 1.00–1.65 (17H, m, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-H2
and 12-H), 1.93 (1H, t, J 2.7, 1-H), 2.05–2.30 (2H, m, 3-H2).
tert-Butyl (R)-4-methoxycarbonyl-2,2-dimethyl-1,1-dioxo-1ꢀ6,3-
thiazolidine-3-carboxylate 19
tert-Butyl (4R,1ЈR)-4-(1Ј-hydroxy-13Ј-methyltetradec-2Ј-ynyl)-
2,2-dimethyl-1,3-thiazolidine-3-carboxylate 15
To a stirred solution of 18 (10.1 g, 36.7 mmol) in CHCl3 (150
cm3) was added MCPBA (70% purity; 19.0 g, 110 mmol) at
0 ЊC. After having been stirred at room temperature for 12 h,
the reaction mixture was poured into 10% aq. Na2SO3 and
extracted with CHCl3. The extract was washed with saturated
aq. NaHCO3, water and brine, dried (MgSO4), and concen-
trated under reduced pressure. The residue was chromato-
graphed on SiO2 to give the ester 19 (11.1 g, 99%) as a white
solid. A small portion of 19 was further purified by recrystal-
lization from n-hexane to give an analytical sample as colorless
plates, mp 61–62 ЊC; [α]D23 Ϫ43.1 (c 1.43 in CHCl3) (Found: C,
46.82; H, 6.69; N, 4.56. C12H21O6NS requires C, 46.89; H,
6.89; N, 4.56%); νmax(KBr)/cmϪ1 1765s (C᎐O), 1715s (C᎐O);
To a stirred solution of 12 (1.39 g, 7.17 mmol) in dry THF (10
cm3), BunLi (1.54 mol dmϪ3 in n-hexane; 4.89 cm3, 7.53 mmol)
was added dropwise at Ϫ10 ЊC under Ar. After stirring for 30
min at 0 ЊC, a solution of 14 (0.88 g, 3.59 mmol) in dry THF (10
cm3) and HMPA (3.74 cm3) was added dropwise to this mixture
at Ϫ78 ЊC. It was stirred for 15 min at Ϫ78 ЊC, quenched with
saturated aq. NH4Cl, and extracted with ethyl acetate. The
extract was washed with water and brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was chrom-
atographed on SiO2 to give the alcohol 15 (1.03 g, 65%) as a
colorless oil, [α]D20 Ϫ26.2 (c 1.41 in CHCl3); nD24 1.4849; νmax(film)/
cmϪ1 3450m (OH), 2230w (C᎐C), 1690s (C᎐O), 1460m, 1365s,
᎐
᎐
᎐
1170s; δH(90 MHz; CDCl3) 0.85 (6H, d, J 6.1, CH(CH3)2), 1.05–
1.40 (18H, m, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј-, 11Ј-, 12Ј-H2 and 13Ј-H
and OH), 1.49 (9H, s, OCMe3), 1.78 (3H, s, acetonide), 1.80
(3H, s, acetonide), 2.21 (2H, m, 4Ј-H), 3.21 (2H, m, SCH2),
4.44 (1H, m, 4-H), 4.76 (1H, m, 1Ј-H) [Found: (HRFAB-MS)
(M Ϫ H)ϩ 440.3185. C25H46NO3S requires m/z 440.3198].
᎐
᎐
δH(90 MHz; CDCl3) 1.47 (9H, s, OCMe3), 1.73 (6H, s, aceton-
ide), 3.42 (2H, d like, J 7.4, SO2CH2), 3.79 (3H, s, OMe), 4.81
(1H, br, NCH).
Determination of the enantiomeric purity of 19
The enantiomeric purity of the resulting 19 was estimated by
HPLC analysis. HPLC analysis [column, Chiralcel OD (4.6
mm × 25 cm); solvent, n-hexane–PriOH (9:1); flow, 0.4 cm3
minϪ1; detector at 210 nm]: tR/min 39.80 [100%, (R)-19], 33.41
[no peak, (S)-19]. The enantiomeric purity of 19 was estimated
to be ~100% ee.
Determination of the enantiomeric and diastereomeric purity of
15
The enantiomeric purity of the resulting 15 was estimated by
HPLC analysis. HPLC analysis [column, Chiralcel OD (4.6
mm × 25 cm); solvent, n-hexane–EtOH (100:1); flow, 0.3 cm3
minϪ1; detector at 210 nm]: tR/min 17.67 [2.46%, (4S,1ЈS)-15],
19.16 [97.54%, (4R,1ЈR)-15]. The enantiomeric purity of 15 was
estimated to be 95.1% ee. The diastereomeric purity of the
resulting 15 was estimated by weighing the isolated isomers.
The diastereomeric purity of 15 was estimated to be ca. 65% de.
tert-Butyl (R)-4-hydroxymethyl-2,2-dimethyl-1,1-dioxo-1ꢀ6,3-
thiazolidine-3-carboxylate 20
A solution of 19 (4.00 g, 13.0 mmol) in THF (100 cm3) was
added dropwise to a stirred and cooled suspension of LAH
(990 mg, 26.0 mmol) in THF (50 cm3) at Ϫ20 ЊC, and the reac-
tion mixture was stirred for 10 min. The excess LAH was des-
troyed by the addition of water (1 cm3), 15% aq. NaOH (1 cm3),
and water (3 cm3) at 0 ЊC. After having been stirred for 1 h, the
mixture was filtered. The filtrate was concentrated under
reduced pressure. The residue was recrystallized from hexane to
give the alcohol 20 (2.95 g 81%) as colorless plates, mp 112–
114 ЊC; [α]D24 Ϫ18.1 (c 1.15 in CHCl3) (Found: C, 47.33; H, 7.44;
N, 4.99. C11H21O5NS requires C, 47.30; H, 7.58; N, 5.01%);
νmax(Nujol)/cmϪ1 3540m (OH), 3370w, 1690s (C᎐O); δ (400
tert-Butyl (4R,1ЈR)-4-(1Ј-hydroxy-13Ј-methyltetradecyl)-2,2-
dimethyl-1,3-thiazolidine-3-carboxylate 16
A mixture of 15 (3.23 g, 7.35 mmol) and PtO2 (300 mg) in ethyl
acetate (25 cm3) was stirred for 36 h at room temperature under
H2. This mixture was filtered through Celite and concentrated
under reduced pressure. The residue was chromatographed on
SiO2 to give the alcohol 16 (3.17 g, 97%) as a colorless oil, [α]D20
Ϫ17.4 (c 1.88 in CHCl3); nD24 1.4761; νmax(film)/cmϪ1 3460s (OH),
᎐
H
1695s (C᎐O), 1670s, 1355s, 1175s; δ (90 MHz; CDCl ) 0.85
᎐
H
3
MHz; CDCl3) 1.51 (9H, s, OCMe3), 1.67 (3H, s, acetonide),
1.68 (3H, s, acetonide), 2.34 (1H, br, OH), 3.27 (1H, dd, J 13.7
and 8.5, SO2CHH), 3.47 (1H, dd, J 13.7 and 2.4, SO2CHH),
3.75–3.90 (2H, m, CH2OH), 4.40 (1H, m, NCH).
(6H, d, J 6.4, CH(CH3)2), 1.00–1.35 (23H, m, 2Ј-, 3Ј-, 4Ј-, 5Ј-,
6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј-, 11Ј-, 12Ј-H2 and 13Ј-H), 1.48 (9H, s,
OCMe3), 1.78 (6H, s, acetonide), 2.15 (1H, m, OH), 2.85–3.25
(2H, m, SCH2), 3.93 (1H, m, 4-H), 4.31 (1H, m, 1Ј-H) [Found:
(HRFAB-MS) (M Ϫ H)ϩ 444.3516. C25H50NO3S requires m/z
444.3511].
Determination of the enantiomeric purity of 20
The enantiomeric purity of the resulting 20 was estimated by
HPLC analysis. HPLC analysis [column, Chiralcel OD (4.6
mm × 25 cm); solvent, n-hexane–PriOH (9:1); flow, 0.5 cm3
minϪ1; detector at 210 nm]: tR/min 24.7 [100%, (R)-20], 26.9 [no
peak, (S)-20]. The enantiomeric purity of 20 was estimated to
be ~100% ee.
tert-Butyl (4R,1ЈR)-4-(1Ј-hydroxy-13Ј-methyltetradecyl)-2,2-
dimethyl-1,1-dioxo-1ꢀ6,3-thiazolidine-3-carboxylate 17 (from
16)
To a stirred solution of 16 (178 mg, 0.401 mmol) in CHCl3 (3
cm3) was added MCPBA (70% purity; 311 mg, 1.26 mmol) at
0 ЊC. After having been stirred at room temperature for 4 h,
the reaction mixture was poured into 10% aq. Na2SO3 and
extracted with CHCl3. The extract was washed with saturated
aq. NaHCO3, water and brine, dried (MgSO4), and concen-
tert-Butyl (R)-4-formyl-2,2-dimethyl-1,1-dioxo-1ꢀ6,3-
thiazolidine-3-carboxylate 21
To a stirred solution of 20 (2.90 g, 10.5 mmol) in dry CH2Cl2
J. Chem. Soc., Perkin Trans. 1, 1999, 2467–2477
2473

View Article Online
(50 cm3) was added a suspension of Dess–Martin periodinane
(6.69 g, 15.1 mmol) in dry CH2Cl2 (50 cm3) at room temper-
ature. After having been stirred for 10 min, the reaction mixture
was poured into Et2O (400 cm3). A solution of saturated aq.
NaHCO3 (100 cm3) and 10% aq. Na2S2O3 (100 cm3) was added
to this mixture. After having been stirred for 10 min, it was
extracted with ether. The extract was washed with saturated aq.
NaHCO3 and brine, dried (MgSO4), and concentrated under
reduced pressure to give the crude aldehyde 21 (2.93 g, quanti-
Determination of the enantiomeric purity of 17
The enantiomeric purity of the resulting 17 was estimated by
HPLC analysis. HPLC analysis [column, Chiralcel OD (4.6
mm × 25 cm); solvent, n-hexane–EtOH (20:1); flow, 0.5 cm3
minϪ1; detector at 210 nm]: tR/min 15.36 [1.12%, (4S,1ЈS)-17],
20.41 [98.88%, (4R,1ЈR)]. The enantiomeric purity of 17 was
estimated to be 97.8% ee.
(2S,4R,5R)-4-Amino-5-(12Ј-methyltridecyl)-1,2-oxathiolane
2-oxide 23
tative), νmax(film)/cmϪ1 2850w (CHO), 1740s (C᎐O), 1690s
᎐
(C᎐O); δ (90 MHz; CDCl ) 1.51 (9H, s, OCMe ), 1.72 (3H, s,
᎐
H
3
3
To a solution of 17 (1.01 g, 2.12 mmol) in MeOH (10 cm3) was
added aq. HCl (6.0 mol dmϪ3; 1 cm3), and the reaction mixture
was stirred for 12 h at 60 ЊC. After the reaction mixture was
concentrated under reduced pressure, the residue was diluted
with CHCl3, and washed with saturated aq. NaHCO3, water
and brine, dried (Na2SO4), and concentrated under reduced
pressure. The residue was chromatographed on SiO2 and
recrystallized from n-hexane–CHCl3 to give the amine 23 (0.541
g, 80%) as colorless plates, mp 75–77 ЊC; [α]D21 ϩ94.6 (c 1.05
in CHCl3) (Found: C, 64.14; H, 10.88; N, 4.36. C17H35NO2S
requires C, 64.30; H, 11.11; N, 4.41%); νmax(KBr)/cmϪ1 3395m
acetonide), 1.76 (3H, s, acetonide), 3.30–3.60 (2H, m, SO2CH2),
4.45–4.70 (1H, m, NCH), 9.50 (1H, s, CHO). This was
employed in the next step without further purification.
Determination of the enantiomeric purity of 21
A small amount of 21 was reduced with NaBH4 to 20 and the
resulting 20 was analyzed by HPLC. HPLC analysis [column,
Chiralcel OD (4.6 mm × 25 cm); solvent, n-hexane–PriOH
(9:1); flow, 0.5 cm3 minϪ1; detector at 210 nm]: tR/min 23.4
[100%, (R)-20], 26.3 [no peak, (S)-20]. The enantiomeric purity
of 21 was estimated to be ~100% ee.
(NH), 3300w (NH), 1605w, 1115s (S᎐O); δ (400 MHz; CDCl )
᎐
H
3
0.86 (6H, d, J 6.6, CH(CH3)2) 1.12–1.56 (23H, m, 1Ј-, 2Ј-, 3Ј-,
4Ј-, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј-, 11Ј-H2 and 12Ј-H), 1.66 (2H, br s,
NH2), 2.97 (1H, dd, J 2.9 and 13.2, 3-Hβ), 3.28 (1H, dd, J 7.9
and 13.2, 3-Hα), 3.47 (1H, m, 4-H), 4.84 (1H, dt, J 4.6 and 7.8,
5-H).
tert-Butyl (4R,1ЈR)-4-(1Ј-hydroxy-13Ј-methyltetradec-2Ј-ynyl)-
2,2-dimethyl-1,1-dioxo-1ꢀ6,3-thiazolidine-3-carboxylate 22
To a stirred solution of 12 (273 mg, 1.41 mmol) in dry THF
(3 cm3), BunLi (1.54 mol dmϪ3 in n-hexane; 1.01 cm3, 1.55
mmol) was added dropwise at 0 ЊC under Ar. After having been
stirred for 30 min at 0 ЊC, a solution of 21 (260 mg, 0.937 mmol)
in dry THF (2 cm3) and HMPA (0.426 cm3) was added dropwise
to this solution at Ϫ78 ЊC. It was stirred for 15 min at Ϫ78 ЊC,
quenched with saturated aq. NH4Cl and extracted with ethyl
acetate. The extract was washed with water and brine, dried
(MgSO4), and concentrated under reduced pressure. The resi-
due was chromatographed on SiO2 to give the alcohol 22 (289
mg, 65% based on 20) as a colorless oil, [α]D25 Ϫ30.7 (c 1.33
in CHCl3); nD25 1.4849 (Found: C, 63.47; H, 9.99; N, 2.82.
C25H45NO5S requires C, 63.66; H, 9.62; N, 2.97%); νmax(film)/
Determination of the enantiomeric purity of 23
The enantiomeric purity of the resulting 23 was estimated by
HPLC. HPLC analysis [column, Chiralcel OD (4.6 mm × 25
cm); solvent, n-hexane–EtOH–diethylamine (10:1:0.01); flow,
0.4 cm3 minϪ1; detector at 210 nm]: tR/min 29.4 [100%,
(4R,5R)], 26.4 [no peak, (4S,5S)-23]. The enantiomeric purity
of 23 was estimated to be ~100% ee.
(2S,4R,5R)-4-(13Ј-Methyltetradecanoylamino)-5-(12Љ-methyl-
tridecyl)-1,2-oxathiolane 2-oxide 24
cmϪ1 3510m (OH), 2240w (C᎐C), 1700s (C᎐O); δ (400 MHz;
᎐
To a solution of 23 (108 mg, 0.340 mmol) and 7 (87 mg, 0.36
mmol) in dry CH2Cl2 (8 cm3) was added DCC (74 mg, 0.36
mmol), and the reaction mixture was stirred for 12 h. The reac-
tion mixture was poured into water and extracted with ethyl
acetate. The extract was washed with saturated aq. NaHCO3
and brine, dried (MgSO4), filtered through Celite and concen-
trated under reduced pressure. The residue was chromato-
graphed on SiO2 to give the amide 24 (131 mg, 71%) as a white
solid, mp 83–85 ЊC; [α]D21 ϩ60.3 (c 1.03 in CHCl3) (Found:
C, 71.04; H, 11.54; N, 2.75. C32H63NO3S requires C, 70.92;
H, 11.72; N, 2.59%); νmax(KBr)/cmϪ1 3320m (NHCO), 1645s
᎐
᎐
H
CDCl3) 0.85 (6H, d, J 6.6, CH(CH3)2), 1.12–1.30 (17H, m, 5Ј-,
6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј-, 11Ј-, 12Ј-H2 and 13Ј-H), 1.50 (9H, s,
OCMe3), 1.66 (3H, s, acetonide), 1.70 (3H, s, acetonide), 2.18
(2H, dt, J 2.0 and 7.2, 4Ј-H), 3.06 (1H, m, OH), 3.35 (1H, dd,
J 8.5 and 13.8, SO2CHH), 3.63 (1H, dd, J 6.9 and 13.8,
SO2CHH), 4.40 (1H, ddd, J 2.9, 6.9 and 8.5, 4-H), 4.93 (1H, dt,
J 2.0 and 6.9, 1Ј-H).
Determination of the diastereomeric purity of 22
The diastereomeric purity of the resulting 22 was estimated by
HPLC analysis. HPLC analysis [column, Pegasil Silica 60-5 (4.6
mm × 25 cm); solvent, n-hexane–THF (10:1); flow, 1.0 cm3
minϪ1; detector at 210 nm]: tR/min 18.31 [99.30%, (4R,1ЈR)],
30.27 [0.70%, (4R,1ЈS)]. The diastereomeric purity of 22 was
estimated to be 98.6% de.
(NHCO), 1535m (NHCO), 1120m (S᎐O), 1110m; δ (500 MHz;
᎐
H
CDCl3) 0.86 (12H, d, J 6.7, CH(CH3)2), 1.14 (4H, m, 12Ј- and
11Љ-H2), 1.25 (34H, m, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј-, 11Ј-, 1Љ-, 2Љ-,
3Љ-, 4Љ-, 5Љ-, 6Љ-, 7Љ-, 8Љ-, 9Љ- and 10Љ-H2), 1.40–1.71 (6H, m, 3Ј-,
4Ј-H2 and 13Ј- and 12Љ-H), 2.16 (2H, t, J 7.6, 2Ј-H2), 3.03–3.10
(2H, m, 3-H2), 4.85–4.90 (2H, m, 4- and 5-H), 6.95 (1H, d, J 9.2,
NH).
tert-Butyl (4R,1ЈR)-4-(1Ј-hydroxy-13Ј-methyltetradecyl)-2,2-
dimethyl-1,1-dioxo-1ꢀ6,3-thiazolidine-3-carboxylate 17 (from
Ammonium (2R,3R)-3-hydroxy-2-(13Ј-methyltetradecanoyl-
amino)-15-methylhexadecanesulfinate 25
22)
A mixture of 22 (285 mg, 0.604 mmol) and PtO2 (6 mg) in ethyl
acetate (3 cm3) was stirred for 12 h at room temperature under
H2. This solution was filtered through Celite and the filtrate was
concentrated under reduced pressure. The residue was chrom-
atographed on SiO2 to give the alcohol 17 (278 mg, 97%) as
a colorless oil, [α]D23 Ϫ21.9 (c 1.05 in CHCl3); nD25 1.4772 (Found:
C, 63.05; H, 10.60; N, 3.02. C25H49NO5S requires C, 63.12; H,
To a solution of 24 (19 mg, 0.035 mmol) in CHCl3 (0.8 cm3) and
MeOH (0.8 cm3) was added 29% aq. NH3 (0.4 cm3), and the
reaction mixture was stirred at room temperature for 12 h. Then
the reaction mixture was concentrated under reduced pressure
to give the crude sulfinate 25 (20 mg, quantitative), δH(400 MHz;
CD3OD) 0.87 (12H, d, J 6.6, CH(CH3)2), 1.15–1.60 (44H, m,
4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 3Ј-, 4Ј-, 5Ј-, 6Ј-, 7Ј-, 8Ј-,
9Ј-, 10Ј-, 11Ј-, 12Ј-H2 and 15-, 13Ј-H), 2.17–2.20 (2H, m, 2Ј-H2),
2.42–2.46 (1H, m, 1-H), 2.63–2.69 (1H, m, 1-H), 3.60–3.68 (1H,
1
10.38; N, 2.94%). Its IR and H NMR spectra were identical
with those of 17 from 16.
2474
J. Chem. Soc., Perkin Trans. 1, 1999, 2467–2477

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m, 3-H), 4.12 (1H, m, 2-H). This was employed in the next step
2Ј-H), 2.34 (1H, dd, J 15.6 and 2.4, 2Ј-H), 3.09 (2H, m, 3-H2),
without further purification.
3.39 (1H, m, 4-OH), 3.97 (1H, m, 3Ј-H), 4.85 (1H, m, 4-H), 4.91
(1H, m, 5-H), 7.27 (1H, m, NH).
(2R,3R)-3-Hydroxy-2-(13Ј-methyltetradecanoylamino)-15-
methylhexadecanesulfonic acid (sulfobacin B) 2
Ammonium (2R,3R,3ЈR)-3-hydroxy-2-(3Ј-hydroxy-15Ј-methyl-
hexadecanoylamino)-15-methylhexadecanesulfinate 27
To a suspension of 25 (20 mg) in water (2.0 cm3) was added 30%
aq. H2O2 (0.4 cm3), and the reaction mixture was stirred for 12 h
at room temperature. After the reaction mixture was concen-
trated under reduced pressure, the residue was chromato-
graphed on SiO2 to give the sulfonic acid 2 (20 mg, 99% based
on 24) as a white solid, mp 201–203 ЊC; [α]D22 Ϫ10.7 (c 0.14 in
CH3OH); νmax(KBr)/cmϪ1 3300m (OH and NH), 2940s (CH),
2860s (CH), 1650m (NHCO), 1550m (NHCO), 1470m (CH),
1385w (CH), 1365w (CH), 1200m (SO2), 1065m (SO2), 800w,
720w (CH); δH(400 MHz; DMSO) 0.83 (12H, d, J 6.8,
CH(CH3)2), 1.12 (4H, m, 14- and 12Ј-H2), 1.22 (34H, m, 4-, 5-,
6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј- and 11Ј-
H2), 1.38–1.51 (6H, m, 3Ј-, 4Ј-H2 and 15- and 13Ј-H), 2.01
(2H, t, J 7.1, 2Ј-H2), 2.64 (1H, dd, J 14.2 and 4.4, 1-Ha), 2.76
(1H, dd, J 14.2 and 6.1, 1-Hb), 3.50 (1H, m, 3-H), 3.85 (1H,
m, 2-H), 4.83 (1H, d, J 5.6, OH), 7.62 (1H, d, J 8.5, NH);
δC(100 MHz; DMSO) 22.5, 25.3, 25.4, 26.8, 27.4, 28.6, 28.9,
29.1, 29.2, 29.3, 33.3, 35.8, 51.1, 51.8, 71.7, 171.6 [Found:
(HRFAB-MS) (M Ϫ H)Ϫ, 574.4517. C32H64NO5S requires m/z
574.4505].
To a solution of 26b (27 mg, 0.046 mmol) in CHCl3 (1 cm3) and
MeOH (1 cm3) was added 29% aq. NH3 (0.5 cm3), and the
reaction mixture was stirred at room temperature for 12 h. Then
the reaction mixture was concentrated under reduced pressure
to give the crude sulfinate 27 (30 mg, quantitative), δH(400 MHz;
CD3OD) 0.87 (12H, d, J 6.6, CH(CH3)2), 1.02–1.57 (46H, m, 4-,
5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 4Ј-, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-,
10Ј-, 11Ј-, 12Ј-, 13Ј-, 14Ј-H2 and 15-, 15Ј-H), 2.32 (2H, d, J 6.6,
2Ј-H), 2.46 (1H, dd, J 13.4 and 3.7, 1-H), 2.62 (1H, dd, J 13.4
and 9.0, 1-H), 3.60 (1H, m, 3-H), 3.95 (1H, m, 3Ј-H), 4.16 (1H,
m, 2-H). This was employed in the next step without further
purification.
(2R,3R,3ЈR)-3-Hydroxy-2-(3Ј-hydroxy-15Ј-methylhexadecan-
oylamino)-15-methylhexadecanesulfonic acid (sulfobacin A) 1
To a suspension of 27 (30 mg) in water (1.5 cm3) was added 30%
aq. H2O2 (0.4 cm3), and the reaction mixture was stirred for 12 h
at room temperature. After the reaction mixture was con-
centrated under reduced pressure, the residue was chromato-
graphed on SiO2 to give the sulfonic acid 1 (28 mg, 98% based
on 26b) as a white solid, mp 233–235 ЊC; [α]D22 Ϫ15 (c 0.14 in
CH3OH); νmax(KBr)/cmϪ1 3310m (OH and NH), 2940s (CH),
2860s (CH), 1645m (NHCO), 1550m (NHCO), 1470m (CH),
1410w, 1385w (CH), 1370w (CH), 1290w, 1195m (SO2), 1065m
(SO2), 800w, 725w (CH); δH(400 MHz; DMSO) 0.83 (12H, d,
J 6.6 CH(CH3)2), 1.12 (4H, m, 14- and 14Ј-H2), 1.22 (38H, m,
4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј-,
11Ј-, 12Ј- and 13Ј-H2), 1.30–1.53 (4H, m, 4Ј-H2 and 15-, 15Ј-H),
2.05–2.15 (2H, m, 2Ј-H2), 2.69–2.72 (2H, m, 1-H2), 3.43 (1H, m,
3-H), 3.73 (1H, m, 3Ј-H), 3.89 (1H, m, 2-H), 4.66 (1H, d, J 4.4,
3Ј-OH), 4.78 (1H, d, J 5.6, 3-OH), 7.65 (1H, d, J 8.5, NH);
δC(100 MHz; DMSO) 22.5, 25.1, 25.4, 26.8, 27.4, 29.1, 29.21,
29.26, 29.32, 33.3, 36.6, 44.7, 51.0, 51.7, 63.9, 67.5, 71.8, 170.2
[Found: (HRFAB-MS) (M Ϫ H)Ϫ, 618.4778. C34H68NO6S
requires m/z 618.4768].
(2S,4R,5R,3ЈR)-4-(3Ј-tert-Butyldimethylsilyloxy-15Ј-methyl-
hexadecanoylamino)-5-(12Љ-methyltridecyl)-1,2-oxathiolane
2-oxide 26a
To a solution of 23 (150 mg, 0.472 mmol) and 9 (218 mg,
0.543 mmol) in dry CH2Cl2 (15 cm3) was added DCC (107
mg, 0.519 mmol), and the reaction mixture was stirred for
30 min. The reaction mixture was poured into water and
extracted with ethyl acetate. The extract was washed with
saturated aq. NaHCO3 and brine, dried (MgSO4), filtered
through Celite and concentrated under reduced pressure. The
residue was chromatographed on SiO2 to give the amide 26a
(210 mg, 64%) as a colorless oil, [α]D22 ϩ40.5 (c 0.97 in CHCl3);
nD26 1.4730 (Found: C, 68.54; H, 11.85; N, 1.66. C40H81NO4SSi
requires C, 68.61; H, 11.66; N, 2.00%); vmax(film)/cmϪ1 3305m
(NHCO), 1650m (NHCO), 1530m (NHCO); δH(500 MHz;
CDCl3) 0.04 (3H, s, SiMe), 0.07 (3H, s, SiMe), 0.85–0.89
(21H, m, CH(CH3)2 and But), 1.14 (4H, m, 14Ј- and 11Љ-H2),
1.25 (38H, m, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј-, 11Ј-, 12Ј-, 13Ј-, 1Љ-,
2Љ-, 3Љ-, 4Љ-, 5Љ-, 6Љ-, 7Љ-, 8Љ-, 9Љ- and 10Љ-H2), 1.45–1.74 (4H,
m, 4Ј-H2 and 15Ј- and 12Љ-H), 2.26 (1H, dd, J 14.4 and 6.4,
2Ј-Ha), 2.34 (1H, dd, J 14.4 and 4.3, 2Ј-Hb), 2.98 (1H, d,
J 13.1, 3-Hβ), 3.14 (1H, dd, J 13.1 and 7.7, 3-Hα), 4.08 (1H, m,
3Ј-H), 4.79–4.87 (2H, m, 4- and 5-H), 7.17 (1H, d, J 9.2,
NH).
Sodium salt of 1
To 1 (7.0 mg, 0.011 mmol) was added aq. Na2CO3 (8.1 mmol
dmϪ3; 0.70 cm3), and the mixture was concentrated under
reduced pressure. The residue in CHCl3 was filtered through
Celite, and the filtrate was concentrated under reduced pressure
to give the sodium salt of 1, [α]D18 Ϫ9.0 (c 0.10 in CH3OH); δH(400
MHz; CD3OD) 0.92 (12H, d, J 6.1, CH(CH3)2), 1.18–1.43
(44H, m, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 4Ј-, 5Ј-, 6Ј-,
7Ј-, 8Ј-, 9Ј-, 10Ј-, 11Ј-, 12Ј-, 13Ј- and 14Ј-H2), 1.57 (2H, m, 15-
and 15Ј-H), 2.37 (2H, m, 2Ј-H2), 3.08 (1H, dd, J 14.6 and 8.8,
1-Ha), 3.17 (1H, dd, J 14.4 and 3.4, 1-Hb), 3.69 (1H, m, 3Ј-H),
4.01 (1H, m, 3-H), 4.29 (1H, m, 2-H).
(2S,4R,5R,3ЈR)-4-(3Ј-Hydroxy-15Ј-methylhexadecanoylamino)-
5-(12Љ-methyltridecyl)-1,2-oxathiolane 2-oxide 26b
To a solution of 26a (106 mg, 0.151 mmol) in THF (6 cm3) was
added TBAF (1.00 mol dmϪ3 in THF; 0.167 cm3, 0.167 mmol)
at 0 ЊC, and the reaction mixture was stirred for 45 min at room
temperature. The mixture was poured into water and extracted
with ethyl acetate. The extract was washed with water and brine,
dried (MgSO4), and concentrated under reduced pressure. The
residue was chromatographed on SiO2 to give the alcohol 26b
(75 mg, 85%) as a white solid, mp 85–88 ЊC; [α]D20 ϩ49.6 (c 0.68
in CHCl3) (Found: C, 69.79; H, 11.72; N, 2.39. C34H67NO4S
requires C, 69.69; H, 11.53; N, 2.39%); νmax(KBr)/cmϪ1 3350m
tert-Butyl (4R,1ЈR,2ЈE)-4-(1Ј-hydroxy-13Ј-methyltetradec-2Ј-
enyl)-2,2-dimethyl-1,1-dioxo-1ꢀ6,3-thiazolidine-3-carboxylate 28
To a suspension of magnesium (1.62 g, 66.7 mmol) in dry Et2O
(60 cm3), a solution of 1,2-dibromoethane (11.0 g, 58.6 mmol)
in dry benzene (20 cm3) was added dropwise over 30 min and
the resulting solution was stirred for 30 min. To a solution of
(E)-1-iodo-12-methyltridec-1-ene (9.50 g, 29.4 mmol), which
was prepared by hydroalumination of 12 followed by cleavage
of the aluminium–carbon bond by iodine, in dry Et2O was
added dropwise ButLi (1.56 mol dmϪ3 in pentane; 41.5 cm3,
64.7 mmol) at Ϫ80 ЊC, and the solution was stirred for 1 h. The
above described freshly prepared solution of magnesium brom-
ide was added. The resulting heterogeneous mixture was stirred
(OH), 1630m (NHCO), 1550m (NHCO), 1105 (S᎐O); δ (500
᎐
H
MHz; CDCl3) 0.86 (12H, d, J 6.5, CH(CH3)2), 1.14 (4H, m, 14Ј-
and 11Љ-H2), 1.25 (38H, m, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј-, 11Ј-, 12Ј-,
13Ј-, 1Љ-, 2Љ-, 3Љ-, 4Љ-, 5Љ-, 6Љ-, 7Љ-, 8Љ-, 9Љ- and 10Љ-H2), 1.17–1.72
(4H, m, 15Ј-, 12Љ-H and 4Ј-H), 2.25 (1H, dd, J 15.6 and 9.2,
J. Chem. Soc., Perkin Trans. 1, 1999, 2467–2477
2475

View Article Online
for 1 h and transferred via cannula into a solution of 21 (2.93 g,
10.5 mmol) in THF (100 cm3) and HMPA (3.6 cm3) at Ϫ80 ЊC.
After having been stirred for 10 min, the reaction mixture was
quenched with saturated aq. NH4Cl and extracted with ethyl
acetate. The extract was washed with water, saturated aq.
NaHCO3 and brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was chromatographed on SiO2 to
give the alcohol 28 (3.34 g, 67% based on 21) as a colorless oil,
[α]D25 Ϫ18.2 (c 0.95 in CHCl3); nD25 1.4778 (Found: C, 63.26; H,
9.63; N, 2.95. C25H47O5NS requires C, 63.39; H, 10.00; N,
2.96%); νmax(film)/cmϪ1 3510m (OH), 1705s (C᎐O); δ (500
MHz; CDCl3) 0.86 (6H, d, J 6.4, CH(CH3)2), 1.10–1.40 (17H,
m, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј-, 11Ј- and 12Ј-H2 and 13Ј-H), 1.50
(9H, s, OCMe3), 1.66 (3H, s, acetonide), 1.70 (3H, s, acetonide),
2.02 (2H, q, J 7.2, 4Ј-H2), 2.20 (1H, m, OH), 3.17 (1H, dd,
J 13.5 and 8.3, SO2CHH), 3.50 (1H, dd, J 13.5 and 5.9,
SO2CHH), 4.33 (1H, m, 4-H), 4.66 (1H, m, 1Ј-H), 5.38 (1H, dd,
J 15.4 and 6.6, 2Ј-H), 5.76 (1H, dt, J 15.4 and 7.2, 3Ј-H).
ture was poured into water and extracted with ethyl acetate.
The extract was washed with saturated aq. NaHCO3 and brine,
dried (MgSO4), and concentrated under reduced pressure. The
residue was chromatographed on SiO2 to give the amide 30a
(38 mg, 49%) as a colorless oil and 30b (11 mg, 14%) as a wax.
Isomer 30a, [α]D20 ϩ60.1 (c 0.70 in CHCl3); nD25 1.4511 (Found: C,
68.66; H, 11.31; N, 2.08. C40H79O4NSSi requires C, 68.81; H,
11.41; N, 2.01%); νmax(film)/cmϪ1 3360m (NH), 1670s (NHCO),
1540m (NHCO), 1265m (TBDMS), 1130s (S᎐O), 850s, 790s;
᎐
δH(500 MHz; CDCl3) 0.05 (3H, s, SiMe), 0.07 (3H, s, SiMe),
0.86 (12H, d, J 6.4, CH(CH3)2), 0.88 (9H, s, SiBut), 1.10–1.60
(40H, m, 4Ј-, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј-, 11Ј-, 12Ј-, 13Ј-, 14Ј-, 4Љ-,
5Љ-, 6Љ-, 7Љ-, 8Љ-, 9Љ-, 10Љ- and 11Љ-H2, 12Љ-H and 15Ј-H), 2.05
(2H, q, J 7.2, 3Љ-H2), 2.27 (1H, dd, J 14.4 and 6.4, 2Ј-Ha), 2.37
(1H, dd, J 14.4 and 4.4, 2Ј-Hb), 2.97 (1H, dd, J 13.4 and 1.8,
3-Hβ), 3.20 (1H, dd, J 13.4 and 7.5, 3-Hα), 4.08 (1H, m, 3Ј-H),
4.86 (1H, m, 4-H), 5.31 (1H, m, 5-H), 5.44 (1H, dd, J 15.3
and 6.7, 1Љ-H), 5.83 (1H, dt, J 15.3 and 7.2, 2Љ-H), 7.24 (1H, d,
J 9.2, NH). Isomer 30b, [α]D20 ϩ74.4 (c 0.63 in CHCl3) (Found:
C, 68.90; H, 11.36; N, 2.08. C40H79O4NSSi requires C, 68.81;
H, 11.41; N, 2.01%); νmax(film)/cmϪ1 3300w (NH), 1640m
᎐
H
Determination of the enantiomeric and diastereomeric purity of
28
(NHCO), 1540m (NHCO), 1250m (TBDMS), 1120m (S᎐O),
᎐
The enantiomeric purity of the resulting 28 was estimated by
HPLC analysis. HPLC analysis [column, Chiralcel OD (4.6
mm × 25 cm); solvent, n-hexane–EtOH (20:1); flow, 0.4 cm3
minϪ1; detector at 210 nm]: tR/min 21.4 [0.98%, (4S,1ЈS)-28],
23.2 [99.02%, (4R,1ЈR)-28]. The enantiomeric purity of 28 was
estimated to be 98.0% ee. The diastereomeric purity of the
resulting 28 was estimated by HPLC analysis. HPLC analysis
[column, Pegasil Silica 60-5 (4.6 mm × 25 cm); solvent,
n-hexane–THF (10:1); flow, 1.0 cm3 minϪ1; detector at 210 nm]:
tR/min 29.0 [96.56%, (4R,1ЈR)], 34.8 [3.44%, (4R,1ЈS)]. The
diastereomeric purity of 28 was estimated to be 93.1% de.
835s, 775s, 720s; δH(500 MHz; CDCl3) 0.08 (3H, s, SiMe), 0.09
(3H, s, SiMe), 0.84 (12H, d, J 6.4, CH(CH3)2), 0.89 (9H, s,
SiBut ), 1.10–1.55 (40H, m, 4Ј-, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј-, 11Ј-,
12Ј-, 13Ј-, 14Ј-, 4Љ-, 5Љ-, 6Љ-, 7Љ-, 8Љ-, 9Љ-, 10Љ- and 11Љ-H2, 12Љ-H
and 15Ј-H), 2.04 (2H, q, J 7.2, 3Љ-H2), 2.30 (1H, dd, J 15.5 and
4.4, 2Ј-Ha), 2.46 (1H, dd, J 15.5 and 4.3, 2Ј-Hb), 3.19 (1H, dd,
J 12.7 and 9.2, 3-Hβ), 3.32 (1H, dd, J 12.7 and 6.1, 3-Hα), 3.96
(1H, m, 3Ј-H), 4.75 (1H, t, J 7.6, 5-H), 4.97 (1H, m, 4-H), 5.63
(1H, dd, J 15.4 and 8.4, 1Љ-H), 5.82 (1H, dt, J 15.4 and 7.2,
2Љ-H), 6.92 (1H, d, J 7.6, NH).
(2S,4R,5R,3ЈR,1ЉE)-4-(3Ј-Hydroxy-15Ј-methylhexadecanoyl-
amino)-5-(12Љ-methyltridec-1Љ-enyl)-1,2-oxathiolane 2-oxide 31a
(2S,4R,5R,1ЈE)-4-Amino-5-(12Ј-methyltridec-1Ј-enyl)-1,2-oxa-
thiolane 2-oxide 29a and its (2R,4R,5R,1ЈE) isomer 29b
To a solution of 30a (362 mg, 0.518 mmol) in THF (10 cm3)
was added TBAF-2.5H2O (300 mg), and the reaction mixture
was stirred at room temperature for 10 min. The mixture was
poured into water and extracted with CHCl3. The extract was
washed with brine and dried (MgSO4), and concentrated under
reduced pressure. The residue was chromatographed on SiO2,
and the solid was recrystallized from hexane to give the pure
alcohol 31a (178 mg, 59%) as colorless needles, mp 87–89 ЊC;
[α]D20 ϩ61.9 (c 0.89 in CHCl3) (Found: C, 69.79; H, 11.09; N, 2.73.
C34H65O4NS requires C, 69.93; H, 11.22; N, 2.40%); νmax(KBr)/
cmϪ1 3350s (OH and NH), 1630s (NHCO), 1550s (NHCO),
1110s (SO2), 970s, 900s, 760s; δH(500 MHz; CDCl3) 0.89 (12H,
d, J 6.5, CH(CH3)2), 1.10–1.60 (40H, m, 4Ј-, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-,
10Ј-, 11Ј-, 12Ј-, 13Ј- 14Ј-, 4Љ-, 5Љ-, 6Љ-, 7Љ-, 8Љ-, 9Љ-, 10Љ- and 11Љ-
H2, 12Љ-H and 15Ј-H), 2.05 (2H, q, J 7.2, 3Љ-H2), 2.27 (1H, dd,
J 15.7 and 9.5, 2Ј-Ha), 2.36 (1H, dd, J 15.7 and 2.8, 2Ј-Hb), 3.08
(1H, dd, J 13.5 and 2.0, 3-Hβ), 3.12 (1H, dd, J 13.5 and 6.3,
3-Hα), 3.36 (1H, d, J 4.0, OH), 3.98 (1H, m, 3Ј-H), 4.91 (1H, m,
4-H), 5.35–5.45 (2H, m, 1Љ-H and 5-H), 5.84 (1H, dt, J 15.0 and
7.0, 2Љ-H), 7.32 (1H, d, J 9.5, NH).
To a solution of 28 (55 mg, 0.12 mmol) in MeOH (5 cm3) was
added aq. HCl (1.0 mol dmϪ3; 2 cm3), and the reaction mixture
was stirred at 60 ЊC overnight. After the reaction mixture was
concentrated under reduced pressure, the residue was chrom-
atographed on SiO2 to give the mixture of 29a and 29b (total 35
mg, 96%). The ratio of 29a and 29b was determined to be 4:1
based on 1H NMR analysis. This was employed in the next step
without further purification. A small amount of this mixture
was carefully chromatographed on SiO2 to give the analytical
samples of 29a and 29b. Isomer 29a (colorless oil), [α]D25 ϩ85.3 (c
1.03 in CHCl3); nD24 1.4879; vmax(film)/cmϪ1 3390m (NH), 3310m
(NH), 1670m (C᎐C), 1600m, 1120s (S᎐O); δ (400 MHz;
᎐
᎐
H
CDCl3) 0.85 (6H, d, J 6.8, CH(CH3)2), 1.10–1.60 (17H, m, 4Ј-,
5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј- and 11Ј-H2 and 12Ј-H), 1.80 (2H, br s,
NH2), 2.07 (2H, q, J 6.7, 3Ј-H2), 2.93 (1H, dd, J 12.9 and 3.8,
3-Hβ), 3.41 (1H, dd, J 12.9 and 7.6, 3-Hα), 3.48 (1H, m, 4-H),
5.19 (1H, dd, J 7.6 and 4.6, 5-H), 5.39 (1H, dd, J 15.1 and 7.6,
1Ј-H), 5.89 (1H, dt, J 15.1 and 6.8, 2Ј-H). Isomer 29b (wax), [α]D25
ϩ79.1 (c 0.36 in CHCl3); vmax(Nujol)/cmϪ1 3380m (NH), 1620w,
1550w, 1520w, 1090m (S᎐O); δ (400 MHz; CDCl ) 0.85 (6H, d,
᎐
H
3
J 6.6, CH(CH3)2), 1.10–1.70 (19H, m, 4Ј-, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-,
10Ј- and 11Ј-H2, 12Ј-H and NH2), 2.00–2.20 (2H, m, 3Ј-H2),
2.93 (1H, dd, J 12.2 and 10.7, 3-Hβ), 3.25 (1H, dd, J 12.2 and
5.6, 3-Hα), 4.07 (1H, m, 4-H), 4.43 (1H, t, J 8.3, 5-H), 5.57 (1H,
dd, J 15.3 and 8.6, 1Ј-H), 5.86 (1H, dt, J 15.3 and 6.7, 2Ј-H).
(2R,4R,5R,3ЈR,1ЉE)-4-(3Ј-Hydroxy-15Ј-methylhexadecanoyl-
amino)-5-(12Љ-methyltridec-1Љ-enyl)-1,2-oxathiolane 2-oxide 31b
In the same manner as described above, 30b (112 mg, 0.160
mmol) was converted into the pure alcohol 31b (58 mg, 62%) as
colorless plates, mp 84–86 ЊC; [α]D20 ϩ51.9 (c 0.30 in CHCl3)
(Found: C, 69.65; H, 11.17; N, 2.63. C34H65O4NS requires C,
69.93; H, 11.22; N, 2.40%); νmax(KBr)/cmϪ1 3300s (OH and
NH), 1645s (NHCO), 1550s (NHCO), 1515m, 1130s (SO2),
1110s (SO2), 970m; δH(500 MHz; CDCl3) 0.86 (12H, d, J 6.5,
CH(CH3)2), 1.10–1.60 (40H, m, 4Ј-, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-, 10Ј-,
11Ј-, 12Ј-, 13Ј-, 14Ј-, 4Љ-, 5Љ-, 6Љ-, 7Љ-, 8Љ-, 9Љ-, 10Љ- and 11Љ-H2,
12Љ-H and 15Ј-H), 2.07 (2H, q, J 7.2, 3Љ-H2), 2.28 (1H, dd,
J 15.4 and 8.8, 2Ј-Ha), 2.40 (1H, dd, J 15.4 and 2.5, 2Ј-Hb), 2.73
(2S,4R,5R,3ЈR,1ЉE)-4-(3Ј-tert-Butyldimethylsilyloxy-15Ј-
methylhexadecanoylamino)-5-(12Љ-methyltridec-1Љ-enyl)-1,2-
oxathiolane 2-oxide 30a and its (2R,4R,5R,3ЈR,1ЉE) isomer 30b
To a solution of 29 (35 mg, 0.11 mmol), 9 (49 mg, 0.12 mmol)
and DMAP (14 mg, 0.11 mmol) in dry CH2Cl2 (1 cm3) was
added DCC (27 mg, 0.13 mmol), and the reaction mixture
was stirred for 8 h at room temperature. The reaction mix-
2476
J. Chem. Soc., Perkin Trans. 1, 1999, 2467–2477

View Article Online
(1H, d, J 4.0, OH), 3.33 (1H, dd, J 12.7 and 8.3, 3-Hβ), 3.37
(1H, dd, J 12.7 and 6.0, 3-Hα), 3.97 (1H, m, 3Ј-H), 4.85 (1H, t,
J 7.3, 5-H), 4.90 (1H, quintet, J 7.0, 4-H), 5.65 (1H, dd, J 15.4
and 8.0, 1Љ-H), 5.84 (1H, dt, J 15.4 and 7.3, 2Љ-H), 6.23 (1H, d,
J 7.5, NH).
MHz; CD3OD) 0.87 (12H, d, J 6.6, CH(CH3)2), 1.13–1.48
(38H, m, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 4Ј-, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-,
10Ј-, 11Ј-, 12Ј-, 13Ј- and 14Ј-H2), 1.52 (2H, m, 15- and 15Ј-H),
2.04 (2H, m, 6-H2), 2.29 (1H, m, 2Ј-Ha), 3.00 (1H, dd, J 14.4
and 8.8, 1-Ha), 3.11 (1H, dd, J 14.4 and 3.4, 1-Hb), 3.95 (1H, m,
3Ј-H), 4.17 (1H, t, J 6.2, 3-H), 4.31 (1H, m, 2-H), 5.47 (1H, dd,
J 15.4 and 6.8, 4-H), 5.74 (1H, dt, J 15.4 and 7.2, 5-H).
Ammonium (2R,3R,3ЈR)-3-hydroxy-2-(3Ј-hydroxy-15Ј-methyl-
hexadecanoylamino)-15-methylhexadec-4-enesulfinate 32
To a solution of 31a (77 mg, 0.13 mmol) in CHCl3 (3 cm3) and
MeOH (4 cm3) was added 29% aq. NH3 (2 cm3), and the reac-
tion mixture was stirred at room temperature overnight. Then
the reaction mixture was concentrated under reduced pressure
to give the crude sulfinate 32 (78 mg, 95%), δH(500 MHz;
CD3OD) 0.87 (12H, d, J 6.7, CH(CH3)2), 1.15–1.45 (38H, m,
7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 4Ј-, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-,
10Ј-, 11Ј-, 12Ј-, 13Ј- and 14Ј-H2), 1.52 (2H, m, 15- and 15Ј-H),
2.04 (2H, q, J 7.0, 6-H2), 2.27 (1H, dd, J 14.3 and 7.5, 1-Ha),
2.31 (1H, dd, J 14.3 and 5.2, 1-Hb), 2.48 (1H, dd, J 13.4 and 4.1,
2Ј-Ha), 2.57 (1H, dd, J 13.4 and 9.2, 2Ј-Hb), 3.94 (1H, m, 3Ј-H),
4.07 (1H, t, J 6.1, 3-H), 4.23 (1H, m, 2-H), 5.46 (1H, dd, J 15.4
and 6.9, 4-H), 5.70 (1H, dt, J 15.4 and 6.7, 5-H). In the same
manner as described above, compound 31b (10 mg, 0.017
mmol) was also converted into the crude sulfinate 32 (12 mg,
quantitative). This was employed for the next step without
further purification.
Acknowledgements
We thank Dr T. Kamiyama (Nippon Roche Co.) for his kind
supply of natural sulfobacins and the copies of various
spectra of sulfobacins. We also thank Professor J. Kobayashi
(Hokkaido University) for his kind supply of the copies of
various spectra of flavocristamide A and his suggestion con-
cerning the sodium salt of flavocristamides. Our thanks are
due to Professor T. Sugai (Keio University) for his advice on
the enzymatic resolution. We thank Dr Y. Hirose (Amano
Pharmaceutical Co.) for the gift of the enzyme. This work
was supported by a Grant-in-Aid for Scientific Research in a
Priority Area from the Ministry of Education, Science, Sports
and Culture, of the Japanese Government.
References
1 Part 21. K. Otaka and K. Mori, Eur. J. Org. Chem., 1999, in the
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(2R,3R,3ЈR)-3-Hydroxy-2-(3Ј-hydroxy-15Ј-methylhexa-
decanoylamino)-15-methylhexadec-4-enesulfonic acid
(flavocristamide A) 3
2 T. Kamiyama, T. Umino, T. Satoh, S. Sawairi, M. Shirane, S.
Ohshima and K. Yokose, J. Antibiot., 1995, 48, 924.
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54, 3640.
To a suspension of 32 (78 mg) in water (10 cm3) was added 30%
H2O2 (0.1 cm3), and the reaction mixture was stirred at room
temperature overnight. After the reaction mixture was concen-
trated under reduced pressure, the residue was chromato-
graphed on SiO2 to give the sulfonic acid 3 (78 mg, 95% based
on 31a) as a white solid, mp 210–213 ЊC; [α]D22 Ϫ21 (c 0.27 in
CH3OH); νmax(film)/cmϪ1 3300m (OH and NH), 2940m (CH),
2870m (CH), 1640s (NHCO), 1550s (NHCO), 1470s, 1390m,
1370m, 1200s, 1060s (SO3), 970m, 805m, 725m; δH(500 MHz;
CD3OD) 0.87 (12H, d, J 6.7, CH(CH3)2), 1.13–1.48 (38H, m,
7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 4Ј-, 5Ј-, 6Ј-, 7Ј-, 8Ј-, 9Ј-,
10Ј-, 11Ј-, 12Ј-, 13Ј- and 14Ј-H2), 1.52 (2H, m, 15- and 15Ј-H),
2.05 (2H, m, 6-H2), 2.33 (1H, dd, J 14.6 and 8.4, 2Ј-Ha), 2.38
(1H, dd, J 14.6 and 3.7, 2Ј-Hb), 2.89 (1H, dd, J 14.3 and 9.9,
1-Ha), 3.19 (1H, dd, J 14.3 and 2.2, 1-Hb), 3.97 (1H, m, 3Ј-H),
4.07 (1H, t, J 6.3, 3-H), 4.39 (1H, m, 2-H), 5.46 (1H, dd, J 15.4
and 6.9, 4-H), 5.74 (1H, dt, J 15.4 and 6.8, 5-H). δC(126 MHz;
CD3OD) 23.0, 26.8, 28.55, 28.58, 29.2, 30.4, 30.5, 30.7, 30.81,
30.83, 30.9, 31.07, 31.1, 33.5, 38.1, 38.4, 40.26, 40.28, 44.7, 52.3,
52.4, 69.8, 74.9, 130.4, 135.4 [Found: (HRFAB-MS) (M Ϫ H)Ϫ
616.4612. C34H66NO6S requires m/z 616.4611].
16 D. B. Dess and I. C. Martin, J. Org. Chem., 1983, 48, 4155.
17 For recent works on the synthesis of sultines, see: (a) S. Yolka,
R. Fellous, L. Lizzani-Cuvelier and M. Loiseau, Tetrahedron Lett.,
1998, 39, 991; (b) T. J. Connolly and T. Durst, Tetrahedron Lett.,
1997, 38, 1337; (c) C. M. Marson and P. R. Giles, J. Org. Chem.,
1995, 60, 8067.
Sodium salt of 3
To 3 (5.5 mg, 0.0089 mmol) was added aq. Na2CO3 (8.1 mmol
dmϪ3; 0.55 cm3), and the mixture was concentrated under
reduced pressure. The residue in CHCl3 was filtered through
Celite, and the filtrate was concentrated under reduced pressure
to give the sodium salt of 3, [α]D18 Ϫ16 (c 0.10 in CH3OH); δH(400
Paper 9/04258J
J. Chem. Soc., Perkin Trans. 1, 1999, 2467–2477
2477