An efficient synthesis of sulfobacin A (flavocristamide B), sulfobacin B, and flavocristamide A

Article abstract of DOI:10.1016/S0040-4020(00)00768-7

Sulfobacin A (flavocristamide B, 1), sulfobacin B (2), and flavocristamide A (3), biologically active sulfonolipids, have been efficiently synthesized utilizing the asymmetric aldol reaction of the Schiff base 8 derived from glycine ester and (+)-2-hydroxy-3-pinanone (HyPN). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00768-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9129±9142
An Ef®cient Synthesis of Sulfobacin A (Flavocristamide B),
Sulfobacin B, and Flavocristamide A
*
Takayuki Shioiri and Naoko Irako
Faculty of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Dedicated to Professor Paul J. Scheuer, a great pioneer of marine natural product chemistry, on the occasion of his 85th birthday
Received 29 May 2000; accepted 16 June 2000
AbstractÐSulfobacin A (¯avocristamide B, 1), sulfobacin B (2), and ¯avocristamide A (3), biologically active sulfonolipids, have been
ef®ciently synthesized utilizing the asymmetric aldol reaction of the Schiff base 8 derived from glycine ester and (1)-2-hydroxy-3-pinanone
(HyPN). q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
of 4 at the amide linkage into the left carboxylic acid 5 and
the right aminodiol 6 is obvious from the retrosynthetic
point of view, and the amide coupling would be attained
Sulfobacins A (1) and B (2) were isolated by Kamiyama and
co-workers1 from the culture broth of Chryseobacterium sp.
(Flavobacterium sp.) NR 2993 in a soil sample collected at
Iriomote Island, Okinawa Prefecture, Japan. Biological
activities of these compounds were revealed to inhibit the
binding of von Willebrand factor to the GPIb/IX receptors
in a competitive manner with IC50s of 0.47 mM for sulfoba-
cin A (1) and 2.2 mM for sulfobacin B (2), respectively.1a
Sulfobacin A (named as ¯avocristamide B) and ¯avocrist-
amide A (3) were also isolated by Kobayashi and co-workers2
from Flavobacterium sp. in the marine bivalve Cristaria
plicata collected in Ishikari Bay, Hokkaido, Japan. Both
¯avocristamides B (1) and A (3) have been found to exhibit
inhibitory activity against DNA polymerase a. The struc-
tures of these compounds 1±3 are related to sulfonolipids
having an aminosulfonic acid moiety and are analogous to
sphingosine, as shown in Fig. 1. Their structural uniqueness
as well as intriguing biological activities led us to synthesize
them in a suitable manner for large scale production. We
now wish to report the details of the ef®cient stereoselective
synthesis of sulfobacins (1 and 2)3 and ¯avocristamide A
(3). Mori, Takikawa, and co-workers also accomplished
their synthesis by a different approach.4
by
use
of
diethylphosphorocyanidate
(DEPC,
(C2H5O)2P(O)CN).5 The left fragment 5 of sulfobacin A
(1) and ¯avocristamide A (3) could be prepared by the
asymmetric reduction of the corresponding b-keto ester 7,
while the right fragment 6 would be constructed by the
asymmetric aldol reaction6 utilizing the Schiff base 8
derived from (1)-2-hydroxy-3-pinanone ((1)-HyPN).7
Figure 1.
Preparation of the side chain
Synthetic strategy
In the synthesis of topostins, DNA topoisomerase I inhibi-
tors,8 we have already synthesized 13-methyl-1-tetradeca-
nol (14a) and 13-methyltetradecanoic acid (16) starting
from 1,10-decanediol (9a) in a straight forward manner, as
outlined in Scheme 2. Analogously, 10-methyl-1-undecanol
(14b) was ef®ciently synthesized from 1,9-nonanediol (9b)
through monobenzylation, oxidation, Wittig reaction, and
catalytic hydrogenation. Both alcohols 14a and 14b were
Scheme 1 shows our synthetic strategy for 1, 2 and 3. The
sulfonic acid part of these compounds would be prepared by
the oxidation of the corresponding thioacetate 4. Bisection
Keywords: sulfonolipids; asymmetric aldol reaction; 2-hydroxy-3-pina-
none; oxidation.
* Corresponding author. Tel.: 181-52-836-3439; fax: 181-52-834-4172;
e-mail: shioiri@phar.nagoya-cu.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00768-7

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T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
Scheme 1.
Scheme 2.
respectively oxidized with pyridinium chlorochromate
(PCC) to give the aldehydes 15a and 15b, which were
respectively utilized for the synthesis of sulfobacins A and
B (1 and 2).
manganese dioxide)9 oxidation, as summarized in Scheme
3.
Synthesis of the left fragment of sulfobacin A (1) and
¯avocristamide A (3)
The aldehyde 19 required for the construction of ¯avocrist-
amide A (3) was prepared from the aldehyde 15b by three
step operations; Horner±Wadsworth±Emmons reaction,
DIBAL (Bui2AlH) reduction, and then CMD (chemical
15-Methyl-3-hydroxyhexadecanoic acid (22), the left frag-
ment of sulfobacin (1) and ¯avocristamide A (3), was also
prepared from 16a in our topostin synthesis,8 the key steps
Scheme 3.

T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
9131
Scheme 4.
Scheme 5.
of which were the addition of acetate unit followed by the
asymmetric reduction of the b-keto ester 20, as summarized
in Scheme 4.
by its conversion to 31 as well as the MTPA ester 32, as
shown in Scheme 6.
With the required right and left fragments in hand, we
constructed the full carbon skeletons of 1, 2 and 3.
Asymmetric aldol reaction for the right fragment
Synthesis of sulfobacin B (2)
We have already developed optically active 2-hydroxy-3-
pinane (HyPN) as an ef®cient chiral auxiliary for the synth-
esis of optically active amines and amino acids by asym-
The amino alcohol 24 obtained from the aldol adduct 23 was
smoothly condensed with the carboxylic acid 16a by use of
DEPC to give the amide 35, as shown in Scheme 7. After
protection of its hydroxyl group with tert-butyldimethylsilyl
chloride (TBSCl), the resulting ester 36 was reduced with
NaBH4±LiCl to give the alcohol 37. Initial attempts to
convert the hydroxyl group to the sulfonic acid via the bro-
mide were failed. Furthermore, replacement of the hydroxyl
group with the O-mesyl (O-Ms) one, followed by treatment
with potassium thioacetate afforded the aziridine 39 as the
major product and the desired thioacetate 38 was obtained in
only 10% yield. However, the Mitsunobu reaction11 of the
alcohol 37 with thioacetic acid smoothly proceeded to give
the thioacetate 38 in almost quantitative yield. Oxidation of
38 with peroxytri¯uoroacetic acid afforded sulfobacin B (2).
Alternatively, the thioacetate was ®rst reduced with LiAlH4
to give the thiol 40, which was oxidized with peroxytri¯uoro-
acetic acid to produce 2. The synthetic sulfobacin B (2)
([a]1D8ˆ218.7 (c 0.14, MeOH)) was indistinguishable from
the natural one by comparison of [a]2D4ˆ219 (c 0.14,
metric alkylation.7 Solladie-Cavallo and co-workers6
Â
extended the utility of HyPN to the asymmetric aldol reac-
tion, which we adopted for the synthesis of the right frag-
ment of 1, 2 and 3, as shown in Scheme 5. Thus the aldehyde
15a was allowed to react with the titanium enolate generated
from the Schiff base (1)-8 derived from (1)-HyPN7 and
titanium chlorotriethoxide to give the erythro aldol adduct
23 in an ef®cient and completely stereoselective manner.
Removal of the chiral auxiliary was easily carried out
under acidic conditions to give the right fragment 24 of 1
and 2. Analogously, the right fragment 26 of 3 was prepared
from the aldehyde 19. Unambiguous proof for the erythro
con®guration of these aldol adducts 24 and 26 were
obtained by their respective conversion to the oxazolidines
28 and 30 and their 1H NMR analysis, shown in Scheme 5.
The absolute con®guration of 24 was determined by the
modi®ed Moshers method10 through its conversion to the
MTPA esters 32 and 33, while that of 26 was established
1
MeOH),1a IR and H NMR spectra, and TLC.

9132
T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
Scheme 6.
Synthesis of sulfobacin A (1)
Synthesis of ¯avocristamide A (3)
The above synthetic route used for the synthesis of sulfoba-
cin B (2) was applied to the synthesis of sulfobacin A (1).
The aldol adduct 24 was smoothly condensed with the
carboxylic acid 22 with DEPC to give the amide 41. After
treatment with TBSCl, the reduction with NaBH4±LiCl
afforded the desired alcohol 42 in only 37% yield accom-
panied with the diol which was produced by the deprotec-
tion of the TBS group of the left part, shown in Scheme 8.
The synthesis of ¯avocristamide A (3) was carried out
analogously to the synthesis of sulfobacin A (2), as shown
in Scheme 10. The Boc derivative 34 obtained from 26 was
successively treated with TBSCl, NaBH4±LiCl, MsCl, and
potassium thioacetate afforded the thioacetate 50, which
underwent the acidic deprotection of the Boc group
followed by condensation with the carboxylic acid 22 to
give the amide 51. It is known that the oxidation of the
double bond having various oxygen substituents in the
allylic position generally proceeds slowly, but the free hy-
droxyl substituent in the allyl group facilitates the oxidation
because of the formation of the hydrogen bond between the
hydroxyl group and peroxyacid oxygen.12 Thus the hydrox-
yl group of 51 was ®rst protected as the acetyl one, and then
the resulting acetate 52 was oxidized with potassium mono-
peroxysulfate (OXONEw) and treated with potassium car-
bonate in aqueous methanol. After neutralization,
¯avocristamide A (3) was obtained in quantitative yield.
The synthetic ¯avocristamide A, [a]2D6ˆ218.7 (c 0.27,
MeOH), was identi®ed with the natural one, [a]2D6ˆ217
(c 0.27, MeOH),2 by spectral (IR, 1H NMR, and 13C
NMR) comparisons and TLC.
This unsatisfactory result led us to investigate another route,
summarized in Scheme 9. After acidic removal of the chiral
auxiliary, the amino group was protected with di-tert-butyl
dicarbonate (Boc2O) and then the hydroxyl group was
protected with TBSCl. The resulting ester 43 was reduced
with NaBH4±LiCl to give the primary alcohol 44 in quanti-
tative yield. Mesylation of 44 followed by treatment with
potassium thioacetate quantitatively afforded the thioacetate
45. After removal of the Boc group, condensation with the
carboxylic acid 22 smoothly gave the amide 46. Direct
oxidation of 46 or the reduction followed by the oxidation
produced sulfobacin A (1), [a]1D8ˆ231.6 (c 0.14, MeOH),
which was identical with the natural one ([a]24ˆ235 (c
1
0.14, MeOH))1a in every respect (IR, H NMR and 13C
NMR spectra, and TLC).
Thus we have completed the total synthesis of sulfobacin A

T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
9133
Scheme 7.
(1, ¯avocristamide B), sulfobacin B (2), and ¯avocristamide
A (3) in an ef®cient manner. The method employed here
showed have a broader applicability in synthesis.
were measured with a SHIMADZU FT IR-8100 spectro-
meter. All melting and boiling points were uncorrected.
1H and 13C NMR spectra were recorded on a JEOL EX-
270 or a-500 spectrometer with tetramethylsilane (TMS)
or CHCl3 as an internal standard. Mass spectra were
obtained on a JEOL SX 102A or AX 505HA spectrometer.
Optical rotations were measured with a JASCO DIP-1000
digital polarimeter. Silica gel (BW-820MH or BW-200)
purchased from Fuji Silysia Chemical Co. Ltd. was used
for column chromatography. Tetrahydrofuran (THF) was
Experimental
Melting points were determined on a YANAGIMOTO
micro melting point apparatus (hot plate). Distillation was
carried out by a Kugelrohr apparatus. Infrared (IR) spectra
Scheme 8.

9134
T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
Scheme 9.
Scheme 10.

T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
9135
dried by distillation from benzophenone ketyl. Diethyl ether
(Et2O) was dried by distillation from lithium aluminum
hydride. Other solvents were distilled and stored over
noacetate (2.4 ml, 12.1 mmol). After 15 min of stirring at
room temperature, 15b (1.90 g, 9.56 mmol) in THF (4 ml)
was added dropwise at 08C. The mixture was stirred at room
temperature for 4 h. Water (40 ml) was added, and the
mixture was extracted with Et2O (2£60 ml) and AcOEt
(60 ml). The organic extracts were washed with saturated
aqueous NaCl, and dried over MgSO4. Concentration in
vacuo gave a colorless oil, which was puri®ed by silica
gel column chromatography with hexane±AcOEt (20:1) to
give 17 (2.21 g, 86%) as a colorless oil. IR nmax (®lm): 2926,
Ê
molecular sieves (4 A).
3-Methyltetradecanoic acid (16a). Prepared from 1,10-
decanediol (9a) according to the literature.8
The compounds 10b±14b. Prepared from 1,9-nonanediol
(9b) analogously to the preparation of 14a.8
1
1725, 1655, 1466, 1266, 1179, 1046, 982 cm21. H NMR
8-Benzyloxy-1-octanol (10b). Bp 1608C/5 mmHg. IR nmax
(®lm): 3374, 2930, 1497, 1455, 1364, 1206, 1100,
(CDCl3) d: 0.861 (d, 6H, Jˆ6.6 Hz), 1.16±1.30 and 1.26 (m
and brs, 17H), 1.31±1.55 (m, 3H), 2.19 (q, 2H, t, Jˆ6.9 Hz),
4.18 (q, 2H, Jˆ6.9 Hz), 5.18 (d, 1H, Jˆ15.8 Hz), 6.95 (dt,
1H, Jˆ6.9, 15.5 Hz). Anal. Calcd for C17H32O2: C, 76.06; H,
12.02. Found: C, 75.78; H, 12.26.
1
753 cm21. H NMR (CDCl3) d: 1.33 (brs, 8H), 1.53±1.64
(m, 5H, 1H disappeared with D2O), 3.46 (t, 2H, Jˆ6.6 Hz),
3.63 (t, 2H, Jˆ6.6 Hz), 4.50 (s, 2H), 7.26±7.35 (m, 5H).
HRMS Calcd for C15H24O2: 236.1776. Found: 236.1760.
13-Methyl-2-tetradecenol (18). To a solution of 17 (1.97 g,
7.34 mmol) in THF (18 ml) under argon at 2158C was
added dropwise a solution of DIBAL (1.01 M in toluene,
18 ml, 18.2 mmol). The reaction mixture was stirred at 08C
for 1 h, and 1N aqueous KHSO4 (40 ml) was added drop-
wise. The mixture was ®ltered though the pad of celite and
washed with Et2O (100 ml). The ®ltrate was extracted with
AcOEt (2£100 ml). The extracts were dried over MgSO4.
Concentration in vacuo gave the residue, which was puri®ed
by silica gel column chromatography with hexane±AcOEt
(2:1) to give 18 (1.63 g, 98%) as a colorless oil. IR nmax
8-Benzyloxy-1-decanal (11b). IR nmax (®lm): 2932, 1725,
1
1455, 1364, 1102, 737, 698 cm21. H NMR (CDCl3) d:
1.335 and 1.62 (brs and brs, 10H), 2.42 (dt, 2H, Jˆ1.7,
7.3 Hz), 3.46 (t, 2H, Jˆ6.6 Hz), 4.50 (s, 2H), 7.24±7.38
(m, 5H), 9.76 (t, 1H, Jˆ1.7 Hz).
12-Benzyloxy-2-methyl-4-dodecene (13b). Bp 170±
1758C/5 mmHg. IR nmax (®lm): 2928, 1470, 1464, 1455,
1
1366, 1113, 1103, 1028, 733 cm21. H NMR (CDCl3) d:
0.889 (d, 6H, Jˆ6.6 Hz), 1.31 (brs, 8H), 1.52±1.64 (m,
3H), 1.86±2.02 (m, 4H), 3.46 (t, 2H, Jˆ6.6 Hz), 4.50 (s,
2H), 5.31±5.44 (m, 2H), 7.26±7.35 (m, 5H). Anal. Calcd for
C20H32O: C, 83.27; H, 11.18. Found: C, 83.10; H, 10.98.
1
(®lm): 3326, 2924, 1466, 1366, 1089, 1005, 968 cm21. H
NMR (CDCl3) d: 0.862 (d, 6H, Jˆ6.6 Hz), 1.16±1.39 and
1.26 (m and brs, 16H), 1.49±1.56 (m, 2H, 1H disappeared
with D2O), 2.00±2.07 (m, 2H), 4.09 (br, 2H, d, Jˆ5.0 Hz,
disappeared with D2O), 5.58±5.76 (m, 2H). Anal. Calcd for
C15H30O: C, 79.58; H, 13.36. Found: C, 79.28; H, 13.52.
11-Methyl-1-dodecanol (14b). Bp 1208C/5 mmHg. IR nmax
1
(®lm): 3328, 2926, 1468, 1383, 1057, 722 cm21. H NMR
(CDCl3) d: 0.862 (d, 6H, Jˆ6.6 Hz), 1.14±1.37 (m, 17H),
1.47±1.59 (m, 3H, 1H disappeared with D2O), 3.64 (br, 2H,
t, Jˆ6.6 Hz with D2O). Anal. Calcd for C13H28O: C, 77.93;
H, 14.08. Found: C, 77.62; H, 14.02.
13-Methyl-2-tetradecenal (19). To a solution of 18
(122 mg, 0.495 mmol) in CH2Cl2 (5 ml) at room tempera-
ture was added CMD9 (440 mg, 5.06 mmol). After stirring
for 18 h at room temperature, the mixture was ®ltered
through the pad of celite and washed with CHCl3 (40 ml).
The ®ltrate was concentrated in vacuo to give a colorless oil,
which was puri®ed by silica gel column chromatography
with hexane±Et2O (10:1) to furnish 19 (109 mg, 98.2%)
as a colorless oil. IR nmax (®lm): 2926, 1696, 1468, 1385,
13-Methyl-1-tetradecanal (15a). To a stirred suspension of
PCC (1.58 g, 7.18 mmol) in CH2Cl2 (20 ml) was added
dropwise a solution of alcohol 14a (1.00 g, 4.38 mmol) in
CH2Cl2 at room temperature, and the reaction mixture was
stirred for 2 h. After hexane (40 ml) was added, the mixture
was allowed to settle and then passed through a short pad of
silica gel. Removal of the solvent under reduced pressure
afforded a crude aldehyde 15a, which was puri®ed by silica
gel column chromatography with hexane±AcOEt (10:1) to
give the aldehyde 15a (858 mg, 87%) as a colorless oil, IR
nmax (®lm): 2926, 2855, 1728, 1468, 1410, 1385, 1366,
1
1366, 1140, 974 cm21. H NMR (CDCl3) d: 0.862 (d, 6H,
Jˆ6.6 Hz), 1.14±1.27 and 1.26 (m and brs, 16H), 1.43±1.56
(m, 1H), 2.29±2.37 (m, 2H), 6.12 (dd, 1H, Jˆ7.9, 5.8 Hz),
6.85 (dt, 1H, Jˆ6.6, 15.8 Hz), 9.51 (d, 1H, Jˆ7.9 Hz).
(3R)-Ethyl-3-hydroxy-15-methylhexadecanoate
Prepared from 16a according to the literature.8
(22).
1
722 cm21. H NMR (CDCl3) d: 0.861 (d, 6H, Jˆ6.6 Hz),
1.26 (br, 18H), 1.43±1.66 (m, 3H), 2.42 (dt, 2H, Jˆ2.0,
7.3 Hz), 9.77 (t, 1H, Jˆ2.0 Hz).
N-(1)-(1R,2R,5R)-2-Hydroxy-3-pinanylidene-(2R,3R)-2-
ethoxycarbonyl-3-hydroxy-14-methylpentadecylamine
(23). To a solution of the iminoglycinate (1)-87a (649 mg,
2.56 mmol) in CH2Cl2 (1.5 ml) at 08C was dropwise added a
solution of ClTi(OEt)3 (1.28 g, 5.86 mmol) in CH2Cl2
(2.25 ml), a solution of the aldehyde 15a (650 mg,
2.88 mmol) in CH2Cl2 (1.25 ml), and Et3N (1.51 ml,
10.8 mmol). After stirring at 08C for 5 h, cold saturated
aqueous NaCl (50 ml) and AcOEt (60 ml) were added.
The mixture was ®ltered though the pad of celite and the
®ltrate was extracted with AcOEt (60 ml). The extracts
11-Methyl-1-dodecanal (15b). Prepared analogously from
alcohol 14b. IR nmax (®lm): 2924, 2714, 1728, 1468 cm21
.
1H NMR (CDCl3) d: 0.862 (d, 6H, Jˆ6.6 Hz), 1.26 (br,
16H), 1.47±1.63 (m, 1H), 2.42 (dt, 2H, Jˆ2.0, 7.3 Hz),
9.77 (d, 1H, Jˆ1.7 Hz).
Ethyl 13-methyl-2-tetradecenoate (17). To suspension of
NaH (60%, 480 mg, 12.0 mmol) in anhydrous THF (10 ml)
under argon was added dropwise at 08C triethyl phospho-

9136
T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
were dried over MgSO4. Concentration in vacuo gave the
residue, which was puri®ed by silica gel column chromato-
graphy with hexane±Et2O (1:2) to give 23 (1.13 g, 92%) as
a pale yellow oil, [a]2D7ˆ162.6 (c 1.04, CHCl3). IR nmax
(®lm): 3385, 2924, 1733, 1657, 1468, 1397, 1183, 1161,
CH3I (0.06 ml, 0.96 mmol). After stirring at room tempera-
ture for 20 h, water (40 ml) was added, and the mixture was
extracted with benzene±AcOEt (1:2, 60 ml). The extracts
were dried over Na2SO4. Concentration in vacuo gave the
residue, which was puri®ed by silica gel column chromato-
graphy with hexane±Et2O (1:3!0:1) to give the methyl
ester 28 (88 mg, 80%) as a pale orange solid, IR nmax
(nujol): 3270, 2914, 1767, 1744, 1470, 1217, 1117, 972,
1
1105, 1084, 911, 735 cm21. H NMR (CDCl3) d: 0.861 (d,
6H, Jˆ6.6 Hz), 0.84±0.87 (m, 3H), 1.25 (brs, 25H), 1.33
and 1.51 and 1.43±1.63 (s and s and m, 9H), 2.04±2.11 (m,
2H), 2.34±2.38 (m, 1H), 2.56±2.63 (m, 2H), 4.08±4.15 and
4.19 (m and q, 4H, Jˆ7.0 Hz). HRMS Calcd for C29H53O4N:
479.3974. Found: 479.3968.
1
953 cm21. H NMR (CDCl3) d: 0.862 (d, 6H, Jˆ6.6 Hz),
1.26 (brs, 20H), 1.43±1.61 (m, 3H), 3.81 (s, 3H), 4.39 (dd,
1H, Jˆ2.0, 8.6 Hz), 4.76 (dd, 1H, Jˆ4.3, 8.6 Hz), 5.32 (br,
1H).
(2R,3R)-3-Hydroxy-2-ethoxycarbonyl-15-methylpenta-
decylammonium chloride (24). To a solution of the Schiff
base 23 (1.33 g, 2.78 mmol) in THF (4 ml) at room tempera-
ture was added dropwise 1N aqueous HCl (25 ml). The
reaction mixture was stirred at room temperature for 68 h.
Removal of the solvent under reduced pressure afforded the
crude 24 as a white solid, which was used for the next
reactions.
Ethyl (2R,3R)-(4-methoxybenzyloxycarbonyl)amino-3-
hydroxy-15-methyl-4-hexadecenoate (29). Prepared
analogously from 26. IR nmax (®lm): 3434, 2926, 1723,
1615, 1586, 1516, 1466, 1248, 1175, 1051, 920,
1
824 cm21. H NMR (CDCl3) d: 0.883 (d, 6H, Jˆ6.6 Hz),
1.27 and 1.15±1.32 (brs and m, 19H), 1.49±1.59 (m, 1H),
2.12±2.18 (m, 2H), 3.2±3.4 (br, 1H), 3.83 and 3.72±3.84 (s
and m, 4H), 4.23 (q, 2H, Jˆ7.3 Hz), 4.51 (br, 1H), 5.07 (s,
2H), 5.44 (dd, 1H, Jˆ6.3, 15.5 Hz), 5.61 (br, 1H), 5.71±
5.79 (m, 1H), 6.90 (d, 2H, Jˆ8.6 Hz), 7.32 (d, 2H,
Jˆ8.6 Hz).
N-(1)-(1R,2R,5R)-2-Hydroxy-3-pinanylidene-(2R,3R)-2-
ethoxycarbonyl-3-hydroxy-14-methyl-3-pentadecenyl-
amine (25). Prepared analogously from 13-methyl-2-tetra-
decenal (19). [a]D22ˆ145.2 (c 1.05, CHCl3). IR nmax (®lm):
3347, 1742, 1659, 1438, 1368, 1179, 1161, 1020, 970,
2-Methoxycarbonyl-3-(12-methyl-1-tridecenyl)oxazoli-
din-5-one (30). Prepared analogously from 29. IR nmax
(®lm): 3342, 2926, 1767, 1464, 1366, 1217, 1121, 972,
1
924 cm21. H NMR (CDCl3) d: 0.861 and 0.873 (d and s,
9H, Jˆ6.6 Hz), 1.15±1.38 and 1.22 and 1.33 (m and brs and
s, 23H), 1.43±1.52 and 1.50 (m and s, 4H), 1.98±2.10 (m,
4H), 2.30±2.36 (m, 1H), 2.39 (br, 1H, disappeared with
D2O), 2.54 (brs, 2H), 3.11 (br, 1H, disappeared with
D2O), 4.15±4.22 (m, 3H), 4.56 (t, 1H, Jˆ6.6 Hz), 5.46
(dd, 1H, Jˆ7.3, 15.5 Hz), 5.73±5.84 (m, 1H). Anal. Calcd
for C29H51NO4: C, 72.91; H, 10.76; N, 2.93. Found: C,
72.64; H, 10.91; N, 2.89.
914, 878 cm21 1H NMR (CDCl3) d: 0.856 (d, 6H,
.
Jˆ6.6 Hz), 1.25 and 1.15±1.53 (brs and m, 19H), 2.04±
2.07 (m, 2H), 3.74 (s, 3H), 4.75 (d, 1H, Jˆ8.6 Hz), 5.17
(t, 1H, Jˆ8.2 Hz), 5.36 (dd, 1H, Jˆ8.0, 15.2 Hz), 5.68 (brs,
1H), 5.94 (dt, 1H, Jˆ6.9, 15.2 Hz).
Ethyl (2R,3R)-2-tert-butoxycarbonylamino-3-hydroxy-
15-methylhexadecanoate (31). (i) From 24. To a suspen-
sion of the above crude 24 (2.78 mmol) in DMF (10 ml) at
08C was added dropwise Et3N (3.00 ml, 21.5 mmol) and
Boc2O (1.28 g, 5.84 mmol) in DMF (10 ml). After the
mixture was stirred at room temperature for 20 h, water
(100 ml) was added, and extracted with Et2O (150 ml).
The extracts were washed with saturated aqueous NaCl
(50 ml), and dried over Na2SO4. Concentration in vacuo
gave the residue, which was puri®ed by silica gel column
chromatography with hexane±AcOEt (5:1) to give 31
(1.04 g, 87%) as a colorless oil, [a]1D6ˆ217.3 (c 1.00,
CHCl3). IR nmax (®lm): 3432, 2926, 1722, 1699, 1505,
Ethyl (2R,3R)-4-methoxybenzyloxycarbonyl)amino-3-
hydroxy-15-methylhexadecanoate (27). To a stirred solu-
tion of the above crude 24 (200 mg, 0.493 mmol) in Et3N
(10 ml) was added PMZ-SDP (300 mg, 0.986 mmol). The
reaction mixture was stirred at 08C for 0.5 h and then at
room temperature for 16.5 h. Removal of the solvent
under reduced pressure afforded the residue, which was
puri®ed by silica gel column chromatography with hex-
ane±Et2O (1:1) to give 27 (183 mg, 75%) as a white solid,
IR nmax (nujol): 3407, 2917, 1738, 1680, 1514, 1466, 1258,
1204, 1076, 1026, 818 cm21. 1H NMR (CDCl3) d: 0.861 (d,
6H, Jˆ6.6 Hz), 1.25 and 1.13±2.17 (brs and m, 26H), 2.56
(br, 1H, disappeared with D2O), 3.81 (s, 3H), 3.80±3.90 (m,
1H), 4.23 (q, 2H, Jˆ5.3 Hz), 4.43 (br, 1H), 5.05 (s, 2H),
5.63 (br, 1H), 6.89 (d, 2H, Jˆ8.6 Hz), 7.30 (d, 2H,
Jˆ8.6 Hz).
1
1468, 1368, 1252, 1167, 1028 cm21. H NMR (CDCl3) d:
0.861 (d, 6H, Jˆ6.6 Hz), 1.25 (brs, 21H), 1.45 and 1.40±
1.68 (s and m, 14H), 2.72 (d, 1H, Jˆ5.9 Hz, disappeared
with D2O), 3.89 (br, 1H), 4.18±4.30 (m, 2H), 4.37 (br, 1H),
5.46 (br, 1H). Anal. Calcd for C24H47NO5: C, 67.09; H,
11.03; N, 3.26. Found: C, 66.86; H, 10.97; N, 3.21.
2-Methoxycarbonyl-3-(12-methyltridecanyl)oxazolidin-
5-one (28). To a stirred solution of 27 (176 mg,
0.357 mmol) in dioxane (6 ml) was added dropwise 1N
NaOH at 08C. After stirring at room temperature for 21 h,
water (20 ml) was added. The aqueous layer was washed
with Et2O (40 ml), and acidi®ed with 1N HCl and extracted
with AcOEt (40 ml). The extracts were dried over MgSO4
and concentration in vacuo gave the oxazolidone as a white
solid. To a stirred solution of the above oxazolidone in DMF
(1.5 ml) was added KHCO3 (65 mg, 0.65 mmol) and then
(ii) From 34. A mixture of 34 (105 mg, 0.25 mmol) and 5%
Pd±C (40 mg) in AcOEt (5 ml) under an atmosphere of H2
was stirred at room temperature for 7.5 h. The mixture was
®ltered though the pad of celite and the ®ltrate was concen-
tration in vacuo to give a colorless oil, which was puri®ed by
silica gel column chromatography with hexane±AcOEt
(5:1) and then AcOEt only to give 31 (94 mg, 89.5%) as a
colorless oil. [a]D25ˆ216.6 (c 1.00, CHCl3). IR nmax (®lm):
3437, 2926, 1722, 1700, 1505, 1468, 1368, 1256, 1167,

T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
9137
1
1028 cm21. H NMR (CDCl3) d: 0.860 (d, 6H, Jˆ6.6 Hz),
from 26. [a]2D4ˆ230.1 (c 1.19, CHCl3). IR nmax (®lm):
1028, 970, 864 cm21. H NMR (CDCl3) d: 0.862 (d, 6H,
Jˆ6.6 Hz), 1.26 and 1.25±1.31 (brs and m, 19H), 1.45 (s,
9H), 1.49±1.57 (m, 1H), 2.01±2.04 (m, 1H), 3.10 (brs, 1H),
4.17±4.26 (m, 3H), 4.45 (br, 2H), 5.38±5.46 (m, 2H), 5.69±
5.77 (m, 1H).
1.25 (brs, 21H), 1.45 and 1.40±1.55 (s and m, 14H), 2.70
(brs, 1H), 3.90 (br, 1H), 4.19±4.28 (m, 2H), 4.35 (br, 1H),
5.43 (br, 1H). These data were identical with that of 31 from
24.
3441, 2926, 1721, 1505, 1468, 1368, 1252, 1167, 1057,
1
Ethyl (2R,3R)-2-tert-butoxycarbonylamino-3-(a-methoxy-
a-tri¯uoromethylphenylacetoxy)-15-methylhexadecano-
ate (32). To a solution of 31 (45 mg, 0.105 mmol) in CH2Cl2
(1 ml) at 08C was added MTPA (45 mg, 0.192 mmol), DCC
(44 mg, 0.21 mmol) and DMAP (10 mg, 0.082 mmol). The
reaction mixture was stirred at 08C for 0.5 h and at room
temperature for 1 h. After addition of Et2O (10 ml), the
mixture was ®ltered though the pad of celite and the ®ltrate
was successively washed with 10% aqueous citric acid,
water, saturated aqueous NaHCO3, water, saturated aqueous
NaCl, and dried over Na2SO4. Concentration in vacuo gave
the residue, which was puri®ed by silica gel column chro-
matography with hexane±AcOEt (8:1) to give the MTPA
ester 32 (68 mg, quant.) as a colorless oil, IR nmax (®lm):
3474, 3374, 2926, 1750, 1717, 1499, 1368, 1252, 1169,
Ethyl
(2R,3R)-3-hydroxy-2-(13-methyltetradecan-
amido)-15-methylhexadecanoate (35). To a solution of
the above crude 24 (4.23 mmol) and the carboxylic acid
16a (450 mg, 1.86 mmol) in DMF (7 ml) at 2108C was
dropwise added DEPC (0.31 ml, 2.04 mmol) and then
Et3N (0.64 ml, 4.59 mmol). Then reaction mixture was stir-
red at 2108C for 1 h, and then at room temperature for 16 h.
After dilution with AcOEt±benzene (2:1, 120 ml), the
whole was successively washed with saturated aqueous
NaHCO3, water, saturated aqueous NaCl, dried over
Na2SO4, and concentrated in vacuo. The residue was puri-
®ed by silica gel column chromatography with hexane±
Et2O (1:1) to give 35 (949 mg, 92%) as a white solid, mp
57.5±598C (hexane±Et2O), [a]2D8ˆ223.6 (c 1.0, CHCl3). IR
nmax (nujol): 3303, 2918, 1736, 1651, 1543, 1377, 1202,
1021, 718 cm21. For (2)-(S)-MTPA ester 32, H NMR
1
(CDCl3) d: 0.863 (d, 6H, Jˆ6.1 Hz), 1.22 and 1.25 (t and
brs, 21H, Jˆ7.3 Hz), 1.44 (s, 9H), 1.71±1.78 (m, 5H), 3.52
(s, 3H), 4.13 (q, 2H, Jˆ7.3 Hz), 4.59±4.60 (m, 1H), 5.10 (d,
1H, Jˆ8.5 Hz), 5.34±5.37 (m, 1H), 7.41±7.42 (m, 3H),
1121, 720 cm21 1H NMR (CDCl3) d: 0.86 (d, 12H,
.
Jˆ6.6 Hz), 1.25 and 1.20±1.65 (br and m, 47H), 2.27 (t,
2H, Jˆ7.3 Hz), 3.33 (d, 1H, Jˆ7.3 Hz, disappeared with
D2O), 3.94 (brs, 1H), 4.20±4.29 (m, 2H), 4.67 (dd, 1H,
Jˆ6.6, 3.0 Hz), 6.42 (d, 1H, Jˆ6.9 Hz). Anal. Calcd for
C34H67NO4: C, 73.73; H, 12.19; N, 2.53. Found: C, 73.23;
H, 12.15; N, 2.80.
1
7.41±7.54 (m, 2H). For (1)-(R)-MTPA ester 32, H NMR
(CDCl3) d: 0.865 (d, 6H, Jˆ6.7 Hz), 1.23±1.25 and 1.25 (m
and brs, 21H), 1.44 (s, 9H), 1.59±1.71 (m, 5H), 3.54 (s, 3H),
4.18 (q, 2H, Jˆ7.3 Hz), 4.63±4.64 (m, 1H), 5.20 (d, 1H,
Jˆ7.9 Hz), 5.30±5.40 (m, 1H), 7.39±7.41 (m, 3H), 7.41±
7.54 (m, 2H).
Ethyl (2R,3R)-3-tert-butyldimethylsiloxy-2-(13-methyl-
tetradecanamido)-15-methylhexadecanoate (36). To a
stirred solution of 35 (493 mg, 0.891 mmol) in DMF
(3.5 ml) was added imidazole (340 mg, 4.99 mmol) and
TBSCl (537 ml, 3.56 mmol). The mixture was stirred at
room temperature for 63 h, and quenched with 1 M aqueous
KHSO4 (40 ml). After extraction with Et2O (120 ml), the
extracts were washed with saturated aqueous NaCl
(40 ml), dried over Na2SO4, and concentrated in vacuo.
The residue was puri®ed by silica gel column chromato-
graphy with hexane±AcOEt (10:1) to give the protected
Ethyl (2R,3R)-2-acetylamino-3-(a-methoxy-a-tri¯uoro-
methylphenylacetoxy)-15-methylhexadecanoate (33). To
a stirred solution of 32 (35 mg, 0.054 mmol) in CH2Cl2
(0.9 ml) at room temperature was added dropwise TFA
(0.2 ml, 2.60 mmol). The reaction mixture was stirred at
room temperature for 1.5 h. Removal of the solvent under
reduced pressure afforded a colorless oil. To a stirred solu-
tion of the above colorless oil in pyridine (5 ml) was added
Ac2O (1 ml) at room temperature. The reaction mixture was
stirred at room temperature for 17 h. After removal of the
volatiles, AcOEt (30 ml) was added. The mixture was
washed with 0.5N HCl, water, saturated aqueous
NaHCO3, saturated aqueous NaCl, and dried over Na2SO4.
Concentration in vacuo gave the residue, which was puri®ed
by silica gel column chromatography with hexane±AcOEt
(2:1) to give the acetate 33 (32 mg, quant.) as a colorless oil,
IR nmax (®lm): 3297, 2926, 1750, 1665, 1541, 1466, 1375,
1271, 1170, 1021, 720 cm21. For (2)-(S)-MTPA ester 33,
1H NMR (CDCl3) d: 0.863 (d, 6H, Jˆ6.6 Hz), 1.25 (brs,
21H), 1.41±1.92 (m, 5H), 1.96 (s, 3H), 3.51 (s, 3H), 4.16 (q,
2H, Jˆ7.1 Hz), 4.88 (dd, 1H, Jˆ3.0, 7.3 Hz), 5.27 (dt, 1H,
Jˆ6.3, 3.0 Hz), 6.05 (d, 1H, Jˆ7.9 Hz), 7.41±7.71 (m, 5H).
For (1)-(R)-MTPA ester 33, 1H NMR (CDCl3) d: 0.863 (d,
6H, Jˆ6.6 Hz), 1.25 (brs, 21H), 1.26±1.64 (m, 5H), 1.98 (s,
3H), 3.52 (s, 3H), 4.20 (q, 2H, Jˆ7.3 Hz), 4.89 (dd, 1H,
Jˆ2.6, 7.9 Hz), 5.32 (dt, 1H, Jˆ5.3, 3.0 Hz), 6.19 (d, 1H,
Jˆ7.9 Hz), 7.23±7.40 (m, 5H).
compound 36 (566 mg, 95%) as
a colorless oil,
[a]2D7ˆ225.3 (c 1.51, CHCl3). IR nmax (®lm): 3434, 3306,
2926, 1742, 1651, 1466, 1256, 1190, 1107, 837, 777 cm21
.
1H NMR (CDCl3) d: 0.040 and 0.051 (s£2, 6H), 0.859 and
0.870 (d and s, 21H, Jˆ5.6 Hz), 1.26 (brs, 43H), 1.44±1.66
(m, 4H), 2.22 (t, 2H, Jˆ7.9 Hz), 3.90 (dt, 1H, Jˆ6.9,
2.6 Hz), 4.15±4.28 (m, 2H), 4.63 (dd, 1H, Jˆ2.6, 7.9 Hz),
6.21 (d, 1H, Jˆ7.6 Hz). Anal. Calcd for C40H81NO4Si: C,
71.90; H, 12.22; N, 2.10. Found: C, 71.93; H, 12.14; N, 1.91.
N-[(10R,20R)-10-Hydroxymethyl-20-tert-butyldimethyl-
siloxy-14-methylpentadecanyl]-13-methyltetradecan-
amide (37). To a stirred solution of the above compound 36
(350 mg, 0.524 mmol) in THF (1 ml) at 2108C was added
LiCl (105 mg, 2.47 mmol), NaBH4 (96 mg, 2.54 mmol),
followed by dropwise addition of EtOH (2 ml). The reaction
mixture was stirred at 2108C for 1 h, and then at room
temperature for 22 h. Citric acid (10%, 20 ml) was added,
and the mixture was extracted with AcOEt (40 ml). The
extracts were dried over Na2SO4. Concentration in vacuo
gave the residue, which was puri®ed by silica gel column
Ethyl (2R,3R)-2-tert-butoxycarbonylamino-3-hydroxy-
15-methyl-4-hexadecenoate (34). Prepared analogously

9138
T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
chromatography with hexane±AcOEt (5:1!3:1!2:1) to
give the alcohol 37 (312 mg, 97%) as a colorless oil
[a]2D7ˆ211.8 (c 1.02, CHCl3). IR nmax (®lm): 3299, 2926,
colorless oil and the thioacetate 38 (5 mg, 10%) as a color-
less oil. The aziridine 39; [a]2D3ˆ114.9 (c 0.505, CHCl3). IR
1H NMR (CDCl3) d: 0.022 and 0.049 (s£2, 6H), 0.857 and
0.860 (s and d, 21H, Jˆ6.6 Hz), 1.25 and 1.16±1.26 (s and
m, 38H), 1.43±1.56 (m, 6H), 2.22 (t, 2H, Jˆ7.0 Hz), 3.86±
3.88 (m, 1H), 4.11 (d, 2H, Jˆ4.9 Hz), 4.20±4.26 (m, 1H).
Anal. Calcd for C38H70NO2Si: C, 75.05; H, 12.76; N, 2.30.
Found: C, 74.92; H, 12.55; N, 2.17.
nmax (®lm): 2926, 1673, 1468, 1256, 1115, 837, 776 cm21
.
1
1644, 1549, 1468, 1256, 1086, 837, 776 cm21. H NMR
(CDCl3) d: 0.083 and 0.087 (s£2, 6H), 0.861 and 0.900 (d
and s, 21H, Jˆ6.6 Hz), 1.25 (brs, 38H), 1.47±1.59 (m, 6H),
2.08 (br, 1H), 2.22 (t, 2H, Jˆ7.3 Hz), 3.58 (dd, 1H, Jˆ2.6,
11.6 Hz), 3.89±3.97 (m, 2H), 4.05 (dd, 1H, Jˆ3.0, 11.6 Hz),
6.32 (d, 1H, Jˆ2.5 Hz). Anal. Calcd for C38H79NO3Si: C,
72.89; H, 12.72; N, 2.24. Found: C, 72.74; H, 12.67; N, 2.28.
N-[(10R,20R)-10-Mercaptomethyl-20-tert-butyldimethyl-
siloxy-14-methylpentadecanyl]-13-methyltetradecan-
amide (40). To a solution of the thioacetate 38 (70 mg,
0.102 mmol) in Et2O (0.5 ml) was added LiAlH4 (7 mg,
0.148 mmol) at 08C. The reaction mixture was stirred at
08C for 15 min. HCl (3N, 5 ml) was added, the mixture
was extracted with AcOEt (40 ml). The extracts were
dried over MgSO4. Concentration in vacuo gave a colorless
oil 40 (56 mg, 85%), which was used for the next reaction
directly. 1H NMR (CDCl3) d: 0.065 (s, 6H), 0.859 and 0.897
(d and s, 21H, Jˆ6.6 Hz), 0.912±1.25 and 1.252 (m and brs,
38H), 1.28±1.64 (m, 6H), 2.09 (s, 1H), 2.20 (t, 2H,
Jˆ7.6 Hz), 2.69±2.79 (m, 1H), 3.80±3.82 (m, 1H), 4.08±
4.10 (m, 1H), 5.71 (d, 1H, Jˆ8.9 Hz).
S-(2R,3R)-3-tert-Butyldimethylsiloxy-2-(13-methyltetra-
decanamido)-15-methylhexadecanyl thioacetate (38). To
a stirred solution of PPh3 (225 mg, 0.858 mmol) in THF
(2 ml) at 08C under argon was added dropwise (i-PrOCON)2
(0.165 ml, 0.838 mmol). After the mixture was stirred at
08C for 5 h, a solution of the alcohol 37 (259 mg,
0.414 mmol) and thioacetic acid (0.065 ml, 0.909 mmol)
in THF (1 ml) was added. The reaction mixture was stirred
at 08C for 1 h, and then at room temperature for 22 h. After
dilution with AcOEt (80 ml), the whole was washed with
saturated aqueous NaHCO3, water, saturated aqueous NaCl,
dried over MgSO4, and concentrated in vacuo. The residue
was puri®ed by silica gel column chromatography with ben-
zene±hexane±Et2O (40:21:1!8:5:1) to give the thioacetate
38 (281 mg, 99%) as a colorless oil. This compound was
unstable, so it was used for the next reaction immediately.
IR nmax (®lm): 3303, 2926, 1698, 1648, 1466, 1119,
Sulfobacin B (2). Method A:
To a stirred solution of the thioacetate 38 (95 mg,
0.139 mmol) in TFA (0.35 ml) was added dropwise 30%
aqueous H2O2 (0.12 ml). The reaction mixture was stirred
at room temperature for 1 h. Removal of the solvent under
reduced pressure afforded the residue, which was puri®ed by
silica gel column chromatography with CHCl3±MeOH±
H2O (65:10:1!65:25:3) to give sulfobacin B (2) (32 mg,
40%) as a white solid, mp 218±2208C, [a]1D8ˆ218.7 (c
0.14, MeOH) [lit.1 [a]D24ˆ219 (c 0.14, MeOH)] IR nmax
1
837 cm21. H NMR (CDCl3) d: 0.060 and 0.067 (s£2,
6H), 0.859 and 0.931 (d and s, 15H, Jˆ6.6 Hz), 1.251 and
1.16±1.25 (s and m, 38H), 1.43±1.56 (m, 6H), 2.09 (td, 2H,
Jˆ2.3, 7.0 Hz), 2.33 (s, 3H), 2.98 (dd, 1H, Jˆ3.6, 14.2 Hz),
3.14 (dd, 1H, Jˆ10.9, 14.2 Hz), 3.77±3.78 (m, 1H), 4.07±
4.11 (m, 1H), 5.74 (d, 1H, Jˆ8.6 Hz).
(2R)-1-(13-Methyltetradecanoyl)-2-((R)-1-tert-butyl-
dimethylsiloxy-13-methyltetradecanyl)aziridine (39). To
a solution of the alcohol 37 (52 mg, 0.083 mmol) in CH2Cl2
(0.3 ml) at 08C was added Et3N (0.025 ml, 0.179 mmol) and
MsCl (0.015 ml, 0.194 mmol). The mixture was stirred at
08C for 0.5 h. After dilution with AcOEt (30 ml), the whole
was washed with water, dried over Na2SO4, and concen-
trated in vacuo. The residue was puri®ed by silica gel
short column chromatography with hexane±AcOEt (3:1)
to give the mesylate (50 mg, 86%) as a pale yellow oil.
This compound was unstable, so it was used for the next
reaction immediately. For the mesylate, IR nmax (®lm):
3287, 2926, 1740, 1667, 1466, 1374, 1252, 1177, 1042,
(CHCl3): 3291, 2920, 1651, 1547, 1468, 1184, 1060 cm21
.
[lit.1 IR nmax (KBr): 3300, 2925, 1655, 1550, 1470, 1220,
1
1060 cm21.] H NMR (DMSO-d6/500 MHz) d: 0.841 (d,
12H, Jˆ6.7 Hz), 1.09±1.16 (m, 4H), 1.22 (brs, 36H),
1.36±1.53 (m, 4H), 2.02 (t, 2H, Jˆ7.3 Hz), 2.65 (dd, 1H,
Jˆ4.3, 14.0 Hz), 2.78 (dd, 1H, Jˆ6.1, 14.0 Hz), 3.51 (br,
1H), 3.84±3.87 (m, 1H), 4.83 (d, 1H, Jˆ5.5 Hz), 7.61 (d,
1H, Jˆ8.5 Hz). [lit.1 1H NMR (DMSO-d6/400 MHz) d: 0.84
(d, 12H, Jˆ6.8 Hz), 1.14 (m, 4H), 1.23 (brs, 36H), 1.40±
1.48 (m, 4H), 2.02 (t, 2H, Jˆ7.3 Hz), 2.62 (dd, 1H, Jˆ4.4,
14.2 Hz), 2.79 (dd, 1H, Jˆ5.9, 14.2 Hz), 3.51 (m, 1H), 3.84
(m, 1H), 4.83 (d, 1H, Jˆ5.4 Hz), 7.58 (d, 1H, Jˆ8.3 Hz).]
TLC (Rf value): 0.22 (solvent: the low layer of CHCl3±
MeOH±H2O (65:25:10) [lit.1 TLC (Rf value): 0.22 (solvent:
the lower layer of CHCl3±MeOH±H2O (65:25:10)]
1
837, 777 cm21. H NMR (CDCl3) d: 0.075 (s, 6H), 0.860
and 0.901 (d and s, 21H, Jˆ6.6 Hz), 1.25 and 1.16±1.26 (s
and m, 38H), 1.46±1.56 (m, 6H), 2.18 (t, 2H, Jˆ7.3 Hz),
3.02 (s, 3H), 3.82±3.84 (m, 1H), 4.29±4.40 (m, 3H), 5.68 (d,
1H, Jˆ8.6 Hz).
Method B:
To a stirred solution of the crude thiol 40 (50 mg,
0.078 mmol) in TFA (1 ml) was added dropwise 30%
aqueous H2O2 (0.1 ml). The reaction mixture was stirred
at room temperature of 0.5 h. Removal of the solvent
under reduced pressure afforded the residue, which was
puri®ed by silica gel column chromatography with
CHCl3±MeOH±H2O (65:10:1!65:25:3) to give sulfobacin
B (2) (19 mg, 42%) as a white solid.
The above material was dissolved in DMF (0.5 ml).
CH3COSK (50 mg, 0.438 mmol) was added at room
temperature. After stirring at room temperature for 4 h,
water (10 ml) was added, and the mixture was extracted
with AcOEt (30 ml). The extracts were washed with satu-
rated aqueous NaCl, and dried over Na2SO4. Concentration
in vacuo gave the residue, which was puri®ed by silica gel
column chromatography with hexane±Et2O (5:1) and then
AcOEt only to give the aziridine 39 (24 mg, 50%) as a
Ethyl (2R,3R)-3-hydroxy-2-[(R)-3-hydroxy-15-methyl-
hexadecanamido]-15-methylhexadecanoate (41). To a

T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
9139
solution of the crude 24 (1.20 mmol) and the carboxylic acid
22 (344 mg, 1.20 mmol) in DMF (5 ml) at 2108C was
added dropwise DEPC (0.20 ml, 1.32 mmol) and then
Et3N (0.42 ml, 3.01 mmol). The reaction mixture was stir-
red at 2108C for 1 h, and then at room temperature for 18 h.
After dilution with AcOEt±benzene (2:1, 75 ml), the whole
was washed with saturated aqueous NaHCO3, water, satu-
rated aqueous NaCl, dried over Na2SO4, and concentrated in
vacuo. The residue was puri®ed by silica gel column chro-
matography with hexane±AcOEt (2:1) to give 41 (598 mg,
83%) as a white solid, mp 64.5±668C. [a]2D3ˆ226.5 (c 1.0,
CHCl3). IR nmax (nujol): 3299, 2920, 1736, 1726, 1644,
1.58 (m, 6H), 2.28 (dd, 1H, Jˆ6.6, 14.2 Hz), 2.37 (dd, 1H,
Jˆ4.6, 14.5 Hz), 3.44 (br, 1H), 3.57 (br, 1H), 3.86±4.00 (m,
2H), 4.08±4.10 (m, 1H), 6.55 (d, 1H, Jˆ6.9 Hz) Anal.
Calcd for C49H97NO4Si2: C, 70.43; H, 12.46; N, 1.79.
Found: C, 70.29; H, 12.41; N, 1.95.
The corresponding diol was obtained as a white amorphous
solid. IR nmax (®lm): 3347, 2926, 1744, 1666, 1466, 1374,
1240, 1048, 837, 777 cm21. 1H NMR (CDCl3) d: 0.091 and
0.097 (s£2, 6H), 0.859 and 0.849±0.912 (d and m, 20H,
Jˆ6.6 Hz), 1.13±1.25 and 1.25 (m and brs, 38H), 1.44±
1.56 (m, 10H, 2H disappeared with D2O), 2.35 (dd, 1H,
Jˆ5.0, 14.9 Hz), 2.50 (dd, 1H, Jˆ4.3, 14.9 Hz), 3.71±
3.83 (m, 2H), 3.96±4.07 (m, 3H), 7.02 (d, 1H, Jˆ7.3 Hz).
1
1619, 1545, 1377, 1200, 1080, 1026, 720 cm21. H NMR
(CDCl3) d: 0.861 (d, 12H, Jˆ6.6 Hz), 1.16±1.33 and 1.25
(m and brs, 43H), 1.47±1.64 (m, 6H), 2.38 (dd, 1H, Jˆ8.9,
15.2 Hz), 2.46 (dd, 1H, Jˆ3.0, 15.2 Hz), 3.03 (brs, 1H,
disappeared with D2O), 3.38 (brs, 1H, disappeared with
D2O), 3.95±3.96 (m, 2H), 4.20±4.30 (m, 2H), 4.66 (dd,
1H, Jˆ3.3, 7.3 Hz), 6.82 (d, 1H, Jˆ7.3 Hz) Anal. Calcd
for C36H71NO5: C, 72.31; H, 11.97; N, 2.34. Found: C,
72.09; H, 11:87; N, 2.66.
Ethyl (2R,3R)-2-tert-butoxycarbonylamino-3-tert-butyl-
dimethylsiloxy-15-metylhexadecanoate (43). To a stirred
solution of the alcohol 31 (545 mg, 1.27 mmol) in DMF
(3 ml) was added imidazole (251 mg, 3.69 mmol) and
TBSCl (475 mg, 3.15 mmol). The mixture was stirred at
room temperature for 18 h. After dilution with Et2O
(100 ml), the whole was washed with 1N KHSO4, water,
saturated aqueous NaCl, and dried over Na2SO4. Concentra-
tion in vacuo gave the residue, which was puri®ed by silica
gel column chromatography with hexane±AcOEt (10:1) to
give 43 (663 mg, 96%) as a colorless oil, [a]1D6ˆ221.1 (c
1.02, CHCl3). IR nmax (®lm): 3447, 2928, 1744, 1717, 1497,
Ethyl (2R,3R)-3-tert-butyldimethylsiloxy-2-[(R)-3-hydroxy-
15-methylhexadecanamido]-15-methylhexadecanoate. To a
stirred solution of the diol 41 (200 mg, 0.335 mmol) in DMF
(1.5 ml) was added imidazole (194 mg, 2.85 mmol) and
TBSCl (303 mg, 2.01 mmol). The mixture was stirred at
room temperature for 43 h, and quenched with 1 M aqueous
KHSO4 (30 ml). After extraction with Et2O (50 ml), the
extracts were washed with saturated aqueous NaCl
(30 ml), dried over Na2SO4, and concentrated in vacuo.
The residue was puri®ed by silica gel column chromato-
graphy with hexane±AcOEt (10:1) to give the protected
compound of hydroxy group (257 mg, 93%) as a colorless
oil, [a]2D3ˆ219.0 (c 1.03, CHCl3). IR nmax (®lm): 3374,
2926, 1715, 1682, 1505, 1464, 1383, 1256, 1192, 1103,
1
1368, 1256, 1165, 1059, 1030, 837, 776 cm21. H NMR
(CDCl3) d: 0.047 and 0.075 (s£2, 6H), 0.861 and 0.872 (d
and s, 15H, Jˆ6.0 Hz), 1.26 (brs, 21H), 1.44 (s, 9H), 1.47±
2.04 (m, 5H), 3.90 (brs, 1H), 4.08±4.27 (m, 2H), 4.32 (d,
1H, Jˆ6.3 Hz), 5.28 (d, 1H, Jˆ7.3 Hz). Anal. Calcd for
C30H61NO5Si: C, 66.25; H, 11.30; N, 2.58. Found: C,
66.10; H, 11.43; N, 2.39.
(2R,3R)-2-tert-Butoxycarbonylamino-3-tert-butyldimethyl-
siloxy-15-metylhexadecanol (44). To a stirred solution of
the ester 43 (563 mg, 1.04 mmol) in THF (1 ml) at 2108C
was added LiCl (275 mg, 6.46 mmol) and NaBH4 (237 mg,
6.27 mmol), followed by the dropwise addition of EtOH
(3 ml). The reaction mixture was stirred at 2108C for 1 h,
and then at room temperature for 19 h. Citric acid (10%,
30 ml) was added at 08C, and the mixture was extracted with
CHCl3 (100 ml). The extracts were dried over Na2SO4.
Concentration in vacuo gave the residue, which was puri®ed
by silica gel column chromatography with hexane±AcOEt
(5:1) to give the alcohol 44 (543 mg, quant.) as a colorless
oil, [a]1D6ˆ213.7 (c 1.02, CHCl3). IR nmax (®lm): 3451,
2928, 1700, 1499, 1464, 1366, 1255, 1173, 1055, 837,
1
839, 777 cm21. H NMR (CDCl3) d: 0.048 and 0.055 and
0.064 and 0.076 (s£4, 12H), 0.858 and 0.867 and 0.884 (d
and s£2, 30H, Jˆ6.3 Hz), 1.16±1.30 and 1.25 (m and brs,
43H), 1.46±1.59 (m, 6H), 2.32 (dd, 1H, Jˆ5.6, 14.9 Hz),
2.46 (dd, 1H, Jˆ4.6, 14.9 Hz), 3.95±4.05 (m, 1H), 4.11±
4.13 (m, 1H), 4.18 (q, 2H, Jˆ7.3 Hz), 4.69 (dd, 1H, Jˆ3.3,
7.9 Hz), 6.80 (d, 1H, Jˆ7.3 Hz) Anal. Calcd for
C48H99NO5Si2: C, 69.76; H, 12.07; N, 1.69. Found: C,
69.73; H, 11.81; N, 1.72.
N-[(10R,20R)-10-Hydroxymethyl-20-tert-butyldimethyl-
siloxy-14-methylpentadecanyl]-(R)-3-hydroxy-15-methyl-
hexadecanamide (42). To a stirred solution of the above
compound (250 mg, 0.303 mmol) in THF (1 ml) at 2108C
was added LiCl (65 mg, 1.53 mmol) and NaBH4 (58 mg,
1.53 mmol), followed by the dropwise addition of EtOH
(2 ml). The reaction mixture was stirred at 2108C for 1 h,
and then at room temperature for 64 h. Citric acid (10%,
10 ml) was added, and the mixture was extracted with
AcOEt (40 ml). The extracts were dried over Na2SO4.
Concentration in vacuo gave the residue, which was puri®ed
by silica gel column chromatography with hexane±AcOEt
(5:1) to give the alcohol 42 (85 mg, 37%) as a colorless oil,
[a]2D3ˆ211.5 (c 0.501, CHCl3). IR nmax (®lm): 3362, 2926,
1
776 cm21. H NMR (CDCl3) d: 0.078 and 0.102 (s£2,
6H), 0.859 and 0.894 (d and s, 15H, Jˆ6.6 Hz), 1.25 (brs,
18H), 1.45 (s, 9H), 1.45±1.59 (m, 5H), 3.10 (d, 1H,
Jˆ10.2 Hz, disappeared with D2O), 3.56±3.59 (m, 1H),
3.63±3.64 (m, 1H), 3.95±3.99 (m, 1H), 4.04±4.08 (m,
1H), 5.34 (d, 1H, Jˆ8.6 Hz). Anal. Calcd for
C28H59NO4Si: C, 67.01; H, 11.85; N, 2.79. Found: C,
66.68; H, 11.79; N, 2.54.
S-(2R,3R)-2-tert-Butoxycarbonylamino-3-tert-butyldi-
methylsiloxy-15-metylhexadecanyl thioacetate (45). To a
solution of the alcohol 44 (100 mg, 0.199 mmol) in benzo-
tri¯uoride (0.5 ml) at 08C was added Et3N (0.06 ml,
0.43 mmol), followed by the dropwise addition of MsCl
1
1650, 1464, 1366, 1256, 1055, 837, 777 cm21. H NMR
(CDCl3) d: 0.051 and 0.076 and 0.097 (s£3, 12H), 0.848±
0.912 (m, 30H), 1.16±1.28 and 1.25 (m and brs, 43H), 1.46±

9140
T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
(0.03 ml, 0.388 mmol). The mixture was stirred at 08C for
1 h. After dilution with AcOEt (60 ml), the whole was
washed with water, 5% aqueous NaHCO3, and dried over
Na2SO4. Concentration in vacuo gave the residue, which
was puri®ed by silica gel column chromatography with hex-
ane±Et2O (10:1) to give the mesylate (116 mg, 100%) as a
colorless oil which was unstable, and used for the next
reaction immediately, IR nmax (®lm): 3389, 2928, 1713,
0.171 mmol) in Et2O (1 ml) was added LiAlH4 (15 mg,
0.316 mmol) at 08C. The reaction mixture was stirred at
08C for 0.5 h. HCl (3N, 10 ml) was added, and the mixture
was extracted with AcOEt (30 ml). The extracts were dried
over Na2SO4. Concentration in vacuo gave the thiol 47
(92 mg, 94%) as a pale yellow oil which was directly used
for the next reaction. IR nmax (®lm): 3304, 2923, 1647, 1541,
1377, 1080, 722 cm21. 1H NMR (CDCl3) d: 0.859 (d, 12H,
Jˆ6.6 Hz), 1.16±1.25 and 1.25 (m and brs, 40H), 1.43±1.59
(m, 6H), 2.04±2.08 (m, 1H), 2.32 (dd, 1H, Jˆ9.2, 15.0 Hz),
2.45 (d, 1H, Jˆ14.8 Hz), 2.76±2.82 (m, 2H), 3.72 (brs, 1H),
4.01 (br, 2H), 6.41 (d, 1H, Jˆ8.6 Hz).
1
1366, 1254, 1177, 1053, 837, 777 cm21. H NMR (CDCl3)
d: 0.067 and 0.082 (s£2, 6H), 0.861 and 0.893 (d and s,
15H, Jˆ6.6 Hz), 0.949±1.23 and 1.25 (m and brs, 18H),
1.44 (s, 9H), 1.45±1.55 (m, 5H), 3.03 (s, 3H), 3.80±3.82
(m, 1H), 3.91±3.93 (m, 1H), 4.25 (dd, 1H, Jˆ10.2, 6.6 Hz),
4.37 (dd, 1H, Jˆ4.3, 10.6 Hz), 4.76 (d, 1H, Jˆ9.6 Hz).
Sulfobacin A (1). Method A:
To a stirred solution of the thiol 47 (68 mg, 0.119 mmol) in
TFA (0.5 ml) was added dropwise 30% aqueous H2O2
(0.05 ml). The reaction mixture was stirred at room
temperature for 0.5 h. Removal of the solvent under reduced
pressure afforded the residue, which was puri®ed by silica
gel column chromatography with CHCl3±MeOH±H2O
(65:10:1!65:25:3) to give sulfobacin A (1) (34 mg, 46%)
as a white solid, mp 220±2228C, [a]1D8ˆ231.6 (c 0.14,
MeOH). [lit.1 [a]D24ˆ235 (c 0.14, MeOH)] IR nmax
The above material was dissolved in DMF (1 ml).
CH3COSK (130 mg, 1.14 mmol) was added at room
temperature. After the mixture was stirred at room tempera-
ture for 20 h, water (20 ml) was added, and the mixture was
extracted with AcOEt (60 ml). The extracts were washed
with saturated aqueous NaCl (20 ml), and dried over
Na2SO4. Concentration in vacuo gave the crude thioacetate
45 (119 mg, quantitative) as a yellow oil which was directly
used for the next reaction. IR nmax (®lm): 3374, 2906, 1716,
(CHCl3): 3291, 2922, 1647, 1553, 1466, 1168, 1059 cm21
.
1
1698, 1499, 1366, 1252, 1171, 1113, 837, 776 cm21. H
[lit.1 IR nmax (KBr): 3350, 2945, 2860, 1660, 1560, 1480,
1200, 1070 cm21.] 1H NMR (DMSO-d6/500 MHz) d: 0.841
(d, 12H, Jˆ6.7 Hz), 1.04±1.14 (m, 4H), 1.23 and 1.234±
1.47 (s and m, 40H), 1.48±1.53 (m, 2H), 2.08±2.17 (m, 2H),
2.74 (d, 2H, Jˆ5.5 Hz), 3.35±3.43 (m, 1H), 3.63±3.75 (m,
1H), 3.90±3.96 (m, 1H), 4.67 (d, 1H, Jˆ4.3 Hz), 4.80 (d,
1H, Jˆ5.5 Hz), 7.70 (d, 1H, Jˆ8.9 Hz). [lit.1 1H NMR
(DMSO-d6/400 MHz) d: 0.84 (d, 12H, Jˆ6.8 Hz), 1.14
(m, 4H), 1.22 (m, 38H), 1.37 (m, 2H), 1.49 (m, 2H), 2.11
and 2.13 (dd and dd, 2H, Jˆ5.9, 10.8 Hz and Jˆ5.4,
10.8 Hz), 2.73 (d, 2H, Jˆ8.3 Hz), 3.46 (m, 1H), 3.76 (m,
1H), 3.92 (m, 1H), 4.66 (d, 1H, Jˆ4.4 Hz), 4.80 (d, 1H,
Jˆ5.4 Hz), 7.68 (d, 1H, Jˆ8.3 Hz).] 13C NMR (DMSO-
d6) d: 22.4 (q), 25.1 (t), 25.3 (t), 26.7 (t), 27.3 (d), 28.9±
29.3 (m), 33.2 (t), 36.5 (t), 38.4 (t), 44.6 (t), 51.0 (d), 51.7 (t),
67.4 (t), 71.8 (d), 170.2 (s). [lit.1 13C NMR (DMSO-d6) d:
22.6 (q£2), 25.2 (t), 25.5 (t), 26.9 (t), 27.4 (d), 29.2±29.4
(t£4), 33.4 (t), 36.6 (t), 38.5 (t), 44.8 (t), 51.1 (d), 51.8 (t),
67.6 (d), 72.0 (d), 170.2 (s).] TLC (Rf value): 0.26 (solvent:
the low layer of CHCl3±MeOH±H2O (65:25:10) [lit.1 TLC
(Rf value): 0.26 (solvent: the low layer of CHCl3±MeOH±
H2O (65:25:10)]
NMR (CDCl3) d: 0.059 and 0.081 (s£2, 6H), 0.861 and
0.914 (d and s, 15H, Jˆ6.6 Hz), 1.16±1.26 and 1.256 (m
and s, 18H), 1.42±1.55 and 1.43 (m and s, 14H), 2.34 (s,
3H), 2.98±2.99 (m, 1H), 3.11 (dd, 1H, Jˆ3.3, 14.0 Hz),
3.60±3.85 (m, 2H), 4.70 (d, 1H, Jˆ8.6 Hz).
S-(2R,3R)-3-Hydroxy-2-[(R)-3-hydroxy-15-methylhexa-
decanamido]-15-methylhexadecanyl thioacetate (46).
The thioacetate 45 (77 mg, 0.128 mmol) was treated with
4N HCl±dioxane at room temperature for 3 h. Removal of
the solvent under reduced pressure afforded the crude hy-
drochloride salt as a pale yellow solid. To a solution of the
above crude solid and b-hydroxycarboxylic acid 22 (30 mg,
0.106 mmol) in DMF (1 ml) at 2108C was added dropwise
DEPC (0.02 ml, 0.132 mmol) and then Et3N (0.055 ml,
0.395 mmol). The reaction mixture was stirred at 2108C
for 1 h, and then at room temperature for 20 h. After dilution
with AcOEt±benzene (2:1, 60 ml), the whole was washed
with saturated aqueous NaHCO3, water, saturated aqueous
NaCl, dried over Na2SO4, and concentrated in vacuo. The
residue was puri®ed by silica gel column chromatography
with hexane±AcOEt (1:1) to give 46 (53 mg, 82%) as a
white solid, mp 85±878C, [a]1D7ˆ21.61 (c 0.3, CHCl3). IR
nmax (nujol): 3291, 2922, 1694, 1643, 1539, 1377, 1134,
Method B:
To a stirred solution of the thioacetate 46 (25 mg,
0.041 mmol) in TFA (0.1 ml) was added dropwise 30%
aqueous H2O2 (0.025 ml). After being stirred at room
temperature for 1 h, removal of the solvent under reduced
pressure afforded the residue, which was puri®ed by silica
gel column chromatography with CHCl3±MeOH±H2O
(65:10:1!65:25;3) to given sulfobacin A (1) (8 mg, 32%)
as a white solid.
.
1036 cm21 1H NMR (CDCl3) d: 0.860 (d, 12H,
Jˆ6.6 Hz), 1.16±1.25 and 1.253 (m and brs, 40H), 1.43±
1.57 (m, 6H), 2.21 (dd, 1H, Jˆ8.9, 15.2 Hz), 2.366 and
2.370 (dd and s, 4H, Jˆ2.6, 14.9 Hz), 2.57 (brs, 1H, disap-
peared with D2O), 3.05 (dd, 1H, Jˆ3.6, 14.5 Hz), 3.19 (dd,
1H, Jˆ9.2, 14.5 Hz), 3.32 (brs, 1H, disappeared with D2O),
3.64 (br, 1H), 3.96±4.07 (m, 2H), 6.21 (d, 1H, Jˆ8.9 Hz).
HRMS Calcd for C36H67NO2S (M1-2H2O): 577.4892.
Found: 577.4900. HRMS Calcd for C34H68NO3S (M1-
SCOCH3): 570.4920. Found: 570.4933.
Ethyl (2R,3R)-2-tert-butoxycarbonylamino-3-tert-butyl-
dimethylsiloxy-15-metyl-4-hexadecenoate (48). Prepared
from 34 in a similar manner as 43. [a]2D4ˆ225.8 (c 1.09,
CHCl3). IR nmax (®lm): 3447, 2927, 1725, 1497, 1471, 1368,
N-[(10R,20R)-10-Mercaptomethyl-20-hydroxy-14-methyl-
pentadecanyl]-(R)-3-hydroxy-15-methylhexadecanamide
(47). To a suspension of the thioacetate 46 (105 mg,
1
1252, 1169, 837 cm21. H NMR (CDCl3) d: 0.0099 and
0.0429 (s£2, 6H), 0.857 and 0.867 (d and s, 15H,

T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
9141
Jˆ6.0 Hz), 1.25 and 1.25±1.30 (brs and m, 21H), 1.44 (s,
9H), 1.49±1.55 (m, 1H), 2.00±2.03 (m, 2H), 4.18 and 4.21±
4.27 and 4.30±4.37 (dd, Jˆ3.0, 7.0 Hz, and m and m, 4H),
5.14 (brs, 1H), 5.43 (dd, 1H, Jˆ15.5, 6.6 Hz), 5.62±5.70 (m,
1H). Anal. Calcd for C30H59NO5Si: C, 66.50; H, 10.97; N,
2.58. Found: C, 66.60; H, 11.31; N, 2.50.
1028, 965 cm21
.
1H NMR (CDCl3) d: 0.861 (d, 12H,
Jˆ6.6 Hz), 1.25 and 1.16±1.36 (brs and m, 40H), 1.39±
1.62 (m, 4H), 2.05±2.11 and 2.07 and 2.09 (m and s, 8H),
2.35 and 2.41 (s and d, 5H, Jˆ6.3 Hz), 2.99±3.15 (m, 2H),
4.29±4.31 (m, 1H), 5.06±5.11 (m, 1H), 5.28±5.29 (m, 1H),
5.40 (dd, 1H, Jˆ7.3, 15.5 Hz), 5.76±5.82 (m, 1H), 5.94 (d,
1H, Jˆ8.9 Hz). Anal. Calcd for 1.5 C40H73NO6S´CH3-
COOC2H5: C, 67.89; H, 10.46; N, 1.86. Found: C, 68.06;
H, 10.38; N, 1.79.
(2R,3R)-2-tert-Butoxycarbonylamino-3-tert-butyldimethyl-
siloxy-15-metyl-4-hexadecenol (49). Prepared from 48 in a
similar manner as 44. [a]2D4ˆ214.5 (c 1.13, CHCl3). IR nmax
(®lm): 3451, 2927, 1698, 1501, 1366, 1252, 1173,
Flavocristamide A (3). To a solution of 52 (82 mg,
0.118 mmol) in AcOH (3 ml) was added AcOK
(375 mg, 3.82 mmol) and then OXONEw (160 mg,
0.260 mmol). The reaction mixture was stirred at room
temperature for 23 h. Removal of the solvent under
reduced pressure afforded the residue, to which was
added water (50 ml). The mixture was extracted with
AcOEt (4£50 ml). The extracts were washed saturated
aqueous NaHCO3 (50 ml), and dried over Na2SO4.
Concentration in vacuo gave a colorless oil (93 mg)
which was directly used for the next reaction. The
above material was dissolved in methanol (4 ml) and
H2O (1 ml). K2CO3 (199 mg, 1.43 mmol) was added at
room temperature. After being stirred for 19 h at room
temperature, 1N aqueous HCl was added. The mixture
was extracted with AcOEt (2£100 ml). The extracts
were dried over Na2SO4. Concentration in vacuo gave
the residue, which was puri®ed by silica gel column
chromatography with CHCl3±MeOH±H2O (65:25:10
low layer) to give ¯avocristamide A (3) (73 mg, quant.)
as a white solid, mp 216±2188C, [a]2D6ˆ218.7 (c 0.27,
MeOH). [lit.2 [a]D20ˆ217 (c 0.27, MeOH)] IR nmax
(nujol): 3308, 2922, 1634, 1553, 1202, 1051, 965, 826,
722 cm21. [lit.2 IR nmax (KBr): 3450, 1640, 1560, 1200,
1060 cm21.] 1H NMR (CD3OD/500 MHz) d: 0.876 (d,
12H, Jˆ6.6 Hz), 1.15±1.29 and 1.29 (m and br, 36H),
1.37±1.45 (m, 2H), 1.48±1.55 (m, 2H), 2.01±2.07 (m,
2H), 2.28±2.31 (m, 2H), 2.97 (dd, 1H, Jˆ9.1,
14.3 Hz), 3.13 (dd, 1H, Jˆ3.2, 14.3 Hz), 3.96 (br, 1H),
4.14 (t, 1H, Jˆ6.6 Hz), 4.32±4.36 (m, 1H), 5.47 (dd, 1H,
Jˆ15.4, 6.9 Hz), 5.70±5.76 (m, 1H). [lit.2 1H NMR
(CD3OD/500 MHz) d: 0.92 (d, 12H, Jˆ6.7 Hz), 1.1±1.4
(m, 32H), 1.21 (m, 4H), 1.50 (m, 2H), 1.55 (m, 2H),
2.09 (m, 2H), 2.35 (m, 2H), 3.05 (dd, 1H, Jˆ8.8,
14.4 Hz), 3.16 (dd, 1H, Jˆ3.2, 14.4 Hz), 4.00 (m, 1H),
4.23 (m, 1H), 4.37 (m, 1H), 5.52 (dd, 1H, Jˆ15.5,
7.1 Hz), 5.78 (dt, 1H, Jˆ15.5, 6.8 Hz).] 13C NMR
(CD3OD) d: 23.10 (q), 26.74 (t), 28.59 (t), 28.62 (t),
29.20 (d), 30.45, 30.50, 30.78, 30.85, 30.87, 30.93,
31.10, 31.13, 33.54 (t), 38.16 (t), 40.29 (t), 40.31 (t),
45.43 (t), 51.84 (t), 52.60 (d), 69.81 (d), 75.15 (d),
130.57 (d), 134.98 (d), 173.99 (CvO). [lit.2 13C NMR
(CD3OD) d: 23.1 (q), 26.7 (t), 28.6 (t), 29.2 (d), 30.4,
30.5, 30.7, 30.8 (t), 30.9, 31.1, 33.5 (t), 38.1 (t), 40.3 (t),
45.6 (t), 51.7 (t), 52.7 (d), 69.8 (d), 75.0 (d), 130.5 (d),
134.9 (d).]
1
837 cm21. H NMR (CDCl3) d: 0.0331 and 0.0746 (s£2,
6H), 0.861 and 0.900 (d and s, 15H, Jˆ6.6 Hz), 1.26 (brs,
16H), 1.45 and 1.49±1.60 (s and m, 11H, 1H disappeared
with D2O), 2.00±2.04 (m, 2H), 3.40±3.50 (m, 1H), 3.57 (dd,
1H, Jˆ3.3, 11.2 Hz), 4.03 (d, 1H, Jˆ9.3 Hz), 4.48 (br, 1H),
5.53 (br, 1H), 5.54 (dd, 1H, Jˆ6.3, 15.5 Hz), 5.49±5.77 (m,
1H). Anal. Calcd for C28H57NO4Si: C, 67.28; H, 11.49; N,
2.80. Found: C, 67.43; H, 11.78; N, 2.79.
S-(2R,3R)-2-tert-Butoxycarbonylamino-3-tert-butyldi-
methylsiloxy-15-metyl-4-hexadecenyl thioacetate (50).
Prepared from 49 in a similar manner as 45. [a]1D8ˆ214.9
(c 1.01, CHCl3). IR nmax (®lm): 3368, 2926, 1721, 1698,
1
1505, 1470, 1366, 1254, 1173, 1113, 967, 837 cm21. H
NMR (CDCl3) d: 0.011 and 0.055 (s£2, 6H), 0.859 and
0.916 (d and s, 15H, Jˆ6.6 Hz), 1.25 and 1.42 and 1.46±
1.54 (brs and s and m, 26H), 2.01±2.33 (m, 1H), 2.52 (s,
3H), 3.04±3.12 (m, 2H), 3.65 (br, 1H), 4.23 (br, 1H), 4.17
(d, 1H, Jˆ8.2 Hz), 5.39 (dd, 1H, Jˆ6.3, 15.5 Hz), 5.62±
5.73 (m, 1H). Anal. Calcd for C30H59NO4SSi: C, 64.58; H,
10.66; N, 2.51. Found: C, 64.67; H, 10.72; N, 2.21.
S-(2R,3R)-3-Hydroxy-2-[(R)-3-hydroxy-15-methylhexa-
decanamido]-15-methyl-4-hexadecenyl thioacetate (51).
Prepared from 50 and 22 in a similar manner as 46. A
white solid: mp 89±908C, [a]2D5ˆ213.1 (c 0.52, CHCl3).
IR nmax (nujol): 3293, 1694, 1644, 1539, 1134, 1034,
1
961 cm21. H NMR (CDCl3) d: 0.861 (d, 12H, Jˆ6.6 Hz),
1.16±1.25 and 1.26 and 1.38±1.54 (m and brs and m, 40H),
2.02±2.12 (m, 2H), 2.20 (dd, 1H, Jˆ8.9, 15.2 Hz), 2.35 and
2.36 (dd and s, 4H, Jˆ2.6, 15.2 Hz), 2.68 (brs, 1H, disap-
peared with D2O), 3.02 (dd, 1H, Jˆ3.6, 14.2 Hz). 3.16 (dd,
1H, Jˆ9.2, 14.2 Hz), 3.33 (brs, 1H, disappeared with D2O),
3.92±3.94 (m, 1H), 4.08±4.15 (m, 2H), 5.48 (dd, 1H, Jˆ6.3,
15.5 Hz), 5.71±5.82 (m, 1H), 6.16 (d, 1H, Jˆ7.3 Hz). Anal.
Calcd for C36H69NO4S: C, 70.65; H, 11.36; N, 2.29. Found:
C, 70.56; H, 11.30; N, 2.11.
S-(2R,3R)-3-Acetoxy-2-[(R)-3-acetoxy-15-methylhexa-
decanamido]-15-methyl-4-hexadecenyl thioacetate (52).
To a solution of 51 (40 mg, 0.065 mmol) in pyridine
(0.5 ml) at room temperature was added Ac2O (0.025 ml).
After stirring for 15.5 h at room temperature, ice water
(20 ml) was added, and the mixture was extracted with
Et2O (30 ml). The organic extracts were washed with 1N
aqueous KHSO4 (20 ml), water (20 ml), and saturated
aqueous NaHCO3 (20 ml), and dried over Na2SO4. Concen-
tration in vacuo gave the residue, which was puri®ed by
silica gel column chromatography with hexane±AcOEt
(2:1) to give 52 (36 mg, 79%) as a white solid, mp 45±
468C, [a]2D4ˆ27.95 (c 0.35, CHCl3). IR nmax (nujol):
3314, 2926, 1738, 1700, 1651, 1545, 1468, 1372, 1235,
Acknowledgements
We are grateful to Dr T. Kamiyama (Nippon Roche
Research Center) for the gifts of natural sulfobacins A (1)
and B (2) as well as the copies of their spectra. We are also

9142
T. Shioiri, N. Irako / Tetrahedron 56 (2000) 9129±9142
5. (a) Shioiri, T.; Yokoyama, Y.; Kasai, Y.; Yamada, S.
Tetrahedron 1976, 32, 2211 and 2854. (b) Takuma, S.; Hamada,
Y.; Shioiri, T. Chem. Pharm. Bull. 1982, 30, 3147.
Â
6. Solladie-Cavallo, A.; Koessler, J. L. J. Org. Chem. 1994, 59,
3240.
grateful to Professor J. Kobayashi (Hokkaido University)
for the gifts of natural ¯avocristamide A (3) and the copies
of its spectra. This research was supported by the Grants-in-
Aid from the Ministry of Education, Science, Sports and
Culture, Japan.
7. (a) Oguri, T.; Kawai, N.; Shioiri, T.; Yamada, S. Chem. Pharm.
Bull. 1978, 26, 803. (b) Irako, N.; Hamada, Y.; Shioiri, T.
Tetrahedron 1995, 51, 12731 and references therin.
(c) Matsumoto, T.; Shioiri, T.; Osawa, F. Tetrahedron 1996, 52,
5961 and 5971. (d) Sugiyama, H.; Yokokawa, F.; Shioiri, T.;
Katagiri, N.; Oda, O.; Ogawa, H. Tetrahedron Lett. 1999, 40,
2569. (e) Sasaki, S.; Hamada, Y.; Shioiri, T. Synlett 1999, 453.
8. Shioiri, T.; Terao, Y.; Irako, N.; Aoyama, T. Tetrahedron 1998,
54, 15701.
References
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