Asymmetric desymmetrization of a σ-symmetric erythritol derivative using C2-symmetric bis-sulfoxide: A total synthesis of (+)-aspicilin

Article abstract of DOI:10.1016/S0040-4020(00)00337-9

A total synthesis of (+)-aspicilin 1 was accomplished via an asymmetric desymmetrization of a meso-erythritol derivative using a C₂-symmetric bis- sulfoxide and a chelation-controlled Grignard reaction as the key steps. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00337-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4405±4413
Asymmetric Desymmetrization of a s-Symmetric Erythritol
Derivative Using C2-Symmetric Bis-sulfoxide:
a Total Synthesis of (+)-Aspicilin
Naoyoshi Maezaki, Ying-Xia Li, Kazumi Ohkubo, Satomi Goda, Chuzo Iwata
*
and Tetsuaki Tanaka
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
Received 24 March 2000; accepted 24 April 2000
AbstractÐA total synthesis of (1)-aspicilin 1 was accomplished via an asymmetric desymmetrization of a meso-erythritol derivative using
a C2-symmetric bis-sulfoxide and a chelation-controlled Grignard reaction as the key steps. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
commercially available cis-2-butene-1,4-diol via protection
of the diol followed by dihydroxylation of the double bond.
Furthermore, we applied our methodology to a synthesis of
(1)-aspicilin, which is an 18-membered ring macrolide
isolated from a lichen Aspicilia Gibbosa by Hesse in
1900.4 Construction of the contiguous stereogenic
centers at the C4±C6 positions has been a crucial part
of any previous synthesis of aspicilin.5 We planned
to construct these stereogenic centers by asymmetric
We have recently developed a novel chiral auxiliary, C2-
symmetric bis-sulfoxide 2,1 which ef®ciently differentiates
the enantiotopic hydroxy groups of cyclic meso-1,2-diols
via acetalization followed by base-promoted diastereo-
selective acetal ®ssion. Utilizing this methodology, various
carbocylic meso-1,2-diols were desymmetrized with very
high diastereoselectivity, and the resulting chiral alcohols
were successfully applied to a synthesis of natural products,
such as (2)-gala-quercitol2 and (2)-allosamizoline.3 Next,
we turned our attention to the asymmetric desymmetrization
of acyclic polyol derivatives, which are of interest as a part
of the structure of widespread polyol natural products and as
useful chiral building blocks. Among them, we focused on
protected erythritol derivatives, since these compounds are a
versatile C4-chiron and can be easily prepared from
desymmetrization of
a
meso-erythritol derivative
followed by a chelation-controlled alkylation of the
a-oxygenated aldehyde using a Grignard reagent as outlined
in Scheme 1.
In this paper, we describe an extension of our methodology
to the protected meso-erythritol derivative and an application
to a total synthesis of (1)-aspicilin.
Scheme 1.
Keywords: asymmetric synthesis; sulfoxides; natural products; macrolides.
* Corresponding author. Tel.: 181-6-6879-8210; fax: 181-6-6879-8214; e-mail: t-tanaka@phs.osaka-u.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00337-9

4406
N. Maezaki et al. / Tetrahedron 56 (2000) 4405±4413
A total synthesis of (1)-aspicilin
The remaining fragment involving the (17S)-hydroxy
moiety of (1)-aspicilin was prepared starting from known
bromide 14,10 which was converted into TBDPS ether 15
in 96% yield. Two fragments were assembled diastereo-
selectively in 88% yield by the addition of the Grignard
reagent generated from 15 to the aldehyde 16 prepared by
Swern oxidation of 13. The desired (4R)-isomer 17 was
mainly obtained (4R:4Sˆca. 5:1). As we expected, this reac-
tion was governed by chelation-controlled 1,2-asymmetric
induction.11 The absolute con®guration of the newly formed
hydroxy group of the major epimer was con®rmed by the
modi®ed Mosher method.9 Since the separation of the
epimers in 17 was dif®cult at this stage, the mixture was
used in the next step. Transposition of the acetonide was
carried out by sequential reactions: (1) selective hydrolysis
of the acetonide with 80% AcOH (95%); (2) protection of
the primary alcohol as a pivaloyl ester (91%); (3) acetoni-
zation of the 1,3-diol (91%); (4) deprotection of the pivaloyl
ester with DIBAL-H to give the desired alcohol 21a (77%)
and the C4-epimer 21b (19%), which were separable by
column chromatography. The E-enoate 22 having all the
functionalities of (1)-aspicilin was synthesized by Swern
oxidation of 21a followed by Horner±Wadsworth±Emmons
reaction in 91% yield in two steps. Conversion of the
E-enoate 22 into (1)-aspicilin was accomplished according
to Shinha's procedure.5g The E-enoate 22 was transformed
into seco acid 24 by hydrolysis of 22 with LiOH´H2O
followed by desilylation using TBAF in 94% yield in two
steps. Macrolactonization of 24 under high dilution condi-
tions by the Yamaguchi method12 afforded an 18-meme-
bered lactone in 54% yield. Finally, the MEM ether 25
was deprotected with BF3´OEt2 and 1,2-ethanedithiol at
08C to give (1)-aspicilin in 75% yield (Scheme 3). The
spectroscopic data (1H NMR, 13C NMR, and IR) was
identical to the reported data.5e,k The melting point and
the speci®c rotation [mp 153±1558C, [a]2D4ˆ136.9 (c
0.14, CHCl3)] were consistent with the reported value [mp
154±1568C, [a]Dˆ138.5 (c 1.05, CHCl3)].5g
Figure 1.
Results and Discussion
Asymmetric desymmetrization of meso-erythritol
derivative
At ®rst, we attempted the acetalization of acyclic meso-
erythritol derivatives, such as 1,4-dibenzyl ether 3a or 1,4-
dibenzoate 3b, by means of the C2-symmetric bis-sulfoxide
(S,S)-2 in the presence of TMSOTf and 2,6-lutidine in
CH2Cl2 at 08C (Terashima's procedure).6 Although these
were the best conditions for the acetalization of the carbo-
cyclic diols, the reactions were sluggish, presumably due to
the unsuitable orientation of the hydroxy group in the acetal
formation step as shown in Fig. 1.
This problem was overcome by protecting the diol as an
o-xylyl ether7 so as to ®x the orientation of two hydroxy
groups appropriately. According to the procedure reported
by Kleinperter,8 condensation of cis-2-butene-1,4-diol and
o-xylene dibromide was carried out in the presence of KOH
in THF to give the cyclic ether 5 but in poor yield (36%).
The yield was improved to 54% when this reaction was
carried out using NaH and n-Bu4NI in the presence of a
catalytic amount of KH in DMF. The cyclic meso-erythritol
derivative 6 was obtained in 78% yield by dihydroxylation
of 5 using a catalytic amount of OsO4 and NMO. In contrast
to the acyclic diols 3a and 3b, acetalization of 6 with the bis-
sulfoxide (S,S)-2 by Terashima's procedure proceeded
²
smoothly to give the acetal 8 in 56% yield. Furthermore,
a modi®ed procedure3 using the mono-TMS ether 7 fur-
nished 8 in 70% yield. Next, we examined the base-
promoted acetal ®ssion of 8 using KHMDS in the presence
of 18-crown-6 in THF at 2788C.1 The resulting alkoxide
was trapped with benzyl bromide to give the benzyl ether 9
in 81% yield with high diastereoselectivity (.98% de). The
absolute con®guration of 9 was assumed from the previous
results to be (4S,5R), which was unambiguously con®rmed
by the modi®ed Mosher method9 after removal of the chiral
auxiliary with 10% hydrochloric acid (91%) followed by
esteri®cation with (1)- or (2)-a-methoxy-a-tri¯uoro-
methyl-a-phenylacetic acid chloride (MTPACl). The opti-
cal purity of 10 was 95% ee and the chiral auxiliary (S,S)-2
was reproduced in 95% yield with no decrease of the optical
purity. Then, the alcohol 10 was transformed into the
precursor of the C3±C6 fragment as shown in Scheme 2.
After protection of 10 as an MEM ether (88%), the benzyl
and xylyl ethers were simultaneously deprotected to give
triol 12 in 88% yield. Selective protection of the 1,2-diol
was conducted on 12 in acetone in the presence of a catalytic
amount of PPTS to give the acetonide 13 in 92% yield.
Conclusion
We have demonstrated that the C2-symmetric bis-sulfoxide
2 effectively desymmetrizes the meso-erythritol derivative
6, which is an acyclic polyol equivalent, in good yield and
with high diastereoselectivity. The resulting chiral C4-unit
was successfully transformed into (1)-aspicilin via chelation-
controlled Grignard reaction.
Experimental
Melting points are uncorrected. Optical rotations were
measured using a JASCO DIP-360 digital polarimeter. IR
spectra were measured with a Horiba FT-210 IR spectro-
meter. 1H NMR spectra were measured with a JEOL JNM-
GX500 spectrometer (500 MHz). 13C NMR spectra were
measured with
a
JEOL JNM-EX270 spectrometer
(67.8 MHz) or a JEOL JMN-AL-300 (75 MHz). All signals
are expressed as ppm down®eld from tetramethylsilane used
as an internal standard (d value). The following abbreviations
²
In this case, partial loss of optical purity was observed (ca. 84% ee).

N. Maezaki et al. / Tetrahedron 56 (2000) 4405±4413
4407
Scheme 2. Reagents and Conditions: (a) (S,S)-2, TMSOTf, 2,6-lutidine, CH2Cl2, 08C; (b) o-xylene dibromide, NaH, cat. KH, n-Bu4Nl, DMF, 08C to rt (54%);
(c) cat. OsO4, NMO, acetone-H2O (6:1), rt (78%); (d) TMSCl, Et3N, CH2Cl2, rt [83% (95% based on consumed 6)]; (e) (S,S)-2, TMSOTf, CHCl3, 08C (70%);
(f) KHMDS, 18-crown-6, THF, 2788C then BnBr, 2788C (81%); (g) 10% HCl, acetone, rt (91%); (h) MEMCl, NaH, cat. n-Bu4Nl, DMF, rt (88%); (i) H2, 20%
Pd(OH)2-C, MeOH, rt (88%); (j) cat. PPTS, acetone, rt (92%).
Scheme 3. Reagents and Conditions: (a) TBDPSCl, imidazole, DMF (96%); (b) Swern oxidation, 2658C; (c) 15, Mg, THF, rt (88% in 2 steps); (d) 80% AcOH,
rt (95%); (e) PivCl, pyridine, CH2Cl2, rt (91%); (f) 2,2-dimethoxypropane, p-TsOH´H2O, rt (91%); (g) DIBAL-H, CH2Cl2, 2788C (21a; 77%, 21b; 19%); (h)
Swern oxidation then (EtO)2P(O)CH2CO2Et, n-BuLi, 08C (91%); (i) LiOH´H2O, MeOH±H2O (6:1), 408C; (j) TBAF, THF, rt (94% in 2 steps); (k) 2,4,6-
Cl3C6H2COCl, Et3N then DMAP, toluene, re¯ux (54%); l, HSCH2CH2SH, BF3´OEt2, 08C (75%).

4408
N. Maezaki et al. / Tetrahedron 56 (2000) 4405±4413
are used: singlet (s), doublet (d), triplet (t), quartet (q),
quintet (quint), multiplet (m). Mass spectra were taken
with a Shimadzu QP-1000 mass spectrometer and a JEOL
JMS-D300 mass spectrometer. High resolution mass spectra
were measured by a JEOL JMS-D300, a JEOL JMS-600H, a
JEOL JMS-700, or JEOL JMS-SX102A QQ. Unless stated,
all solvents were used after dryness and all extracts were
dried over MgSO4. Merck Kieselgel 60 was used as an
adsorbent for column chromatography.
8-H), 4.92 (d, 1H, Jˆ12.8 Hz, 1-H or 8-H), 7.21±7.29 (m,
4H, Ar-H). 13C NMR (CDCl3) d: 0.0 (3C), 68.4, 70.6, 70.8,
72.1, 72.9, 73.2, 128.3, 128.3, 130.0, 130.3, 137.3, 137.4. IR
(KBr) 3473, 2956, 2858, 1252, 1097 cm21. MS m/z (%): 296
(M1, 3.4), 104 (100). Anal. Calcd for C15H24O4Si: C, 60.78;
H, 8.16. Found: C, 60.62; H, 7.92.
(1S,5S)-Spiro[1,5-benzoditiepane-3,30-[meso-3a0,40,60,110,
130,13a0-hexahydro[1,3]dioxolo[4,5-d][2,7]benzodioxecin]]
1,5-dioxide (8). TMSOTf (0.20 ml, 1.03 mmol) was added
slowly to a solution of (S,S)-2 (236 mg, 1.03 mmol) and 7
(1.91 g, 5.17 mmol) in CHCl3 (5 ml) with stirring at 08C and
the stirring was continued at 08C for 1 d. The reaction was
quenched with saturated NH4Cl. The organic layer was
separated, washed with saturated NaHCO3 and brine, and
then dried. The solvent was evaporated and the residue was
chromatographed on silica gel (hexane±AcOEtˆ1:1!
AcOEt) to give 8 (314 mg, 70%) as colorless needles. Mp
218±219.58C (CHCl3±AcOEt). [a]2D7ˆ1154.4, (c 0.37,
CHCl3). 1H NMR (CDCl3) d:3.23 (d, 1H, Jˆ14.0 Hz,
CH2SO), 3.33 (d, 1H, Jˆ13.4 Hz, CH2SO), 3.51 (d, 1H,
Jˆ14.3 Hz, CH2SO), 3.58±3.61 (m, 2H, CH2SO,
OCH2CHO), 3.69 (dd, 1H, Jˆ9.8, 2.4 Hz, OCH2CHO),
3.80 (dd, 1H, Jˆ9.8, 6.7 Hz, OCH2CHO), 3.87 (dd, 1H,
Jˆ9.8, 7.3 Hz, OCH2CHO), 4.11±4.23 (m, 2H,
2£CH2CHO), 4.56 (d, 1H, Jˆ12.2 Hz, Ar-CH2), 4.60 (d,
1H, Jˆ11.6 Hz, Ar-CH2), 4.69 (d, 2H, Jˆ11.6 Hz, Ar-
CH2), 7.21±7.32 (m, 4H, Ar-H), 6.63 (td, 1H, Jˆ7.3,
1.2 Hz, Ar-H), 7.70 (td, 1H, Jˆ7.8, 1.2 Hz, Ar-H), 7.82
(dd, 1H, Jˆ7.3, 1.2 Hz, Ar-H), 7.99 (dd, 1H, Jˆ7.8,
1.2 Hz, Ar-H). 13C NMR (CDCl3) d: 61.4, 61.8, 66.6,
67.0, 73.5, 73.6, 75.8, 75.9, 104.3, 126.3, 128.6 (2C),
130.3, 130.3, 131.1, 131.9, 136.6, 141.5 (2C), 144.1 (2C).
IR (KBr) 3001, 2922, 2858, 1047 cm21. MS (FAB) m/z: 435
(MH1). Anal. Calcd for C21H22O6S2: C, 58.08; H, 5.10.
Found: C, 58.07; H, 5.15.
5,7,10,12-Tetrahydrobenzo[c][1,6]dioxecin (5). cis-2-
Butene-1,4-diol (1.64 ml, 20.0 mmol) was added to a
suspension of NaH (1.76 g, 44.0 mmol) in DMF (160 ml)
with stirring at 08C under N2. After 30 min, a solution of
o-xylenedibromide (37 mg, 0.10 mmol) in DMF (40 ml),
n-Bu4NI (37 mg, 0.10 mmol) and a catalytic KH (ca.
5 mg, 0.1 mmol) was added successively. The whole was
stirred at 08C for 10 min and room temperature for 19 h. The
reaction was quenched with water and the mixture was
extracted with ether. The extract was washed with brine
prior to drying and solvent evaporation. The residue was
chromatographed on silica gel (hexane±AcOEtˆ1:1) to
give 5 (2.05 g, 54%) as a pale yellow oil. The data were
in excellent agreement with that reported previously.8
meso-1,3,4,5,6,8-Hexahydro-2,7-benzodioxecin-4,5-diol
(6). OsO4 (55 mg, 0.22 mmol) and NMO (1.43 g, 11.9
mmol) were added successively to a solution of 5 (2.05 g,
10.8 mmol) in acetone±water (6:1) (70 ml) with stirring at
room temperature. After 2 h, the reaction was quenched
with saturated Na2S2O3. Celitew (15 g) was added to the
mixture and the stirring was continued for 30 min. After
Celitew was ®ltered off, the ®ltrate was concentrated under
the reduced pressure. The residue was dissolved with AcOEt
and the mixture was washed with brine prior to drying and
solvent evaporation. The residue was chromatographed on
silica gel (hexane±AcOEtˆ1:1) to give 6 (1.86 g 78%) as a
1
colorless powder. Mp 113.5±1158C (AcOEt±acetone). H
(1S,5S,40S,50R)-3-[(50-Benzyloxy-10,30,40,50,60,80-hexahy-
dro-20,70-benzodioxecin-40-yl)oxy]-4H-1,5-benzodithepine
1,5-dioxide (9). KHMDS (1.91 ml, 0.95 mmol) was added
dropwise to a solution of 8 (138 mg, 0.32 mmol) and 18-
crown-6 (252 mg, 0.95 mmol) in THF (12 ml) with stirring
at 2788C under N2. After 20 min, benzyl bromide (40 ml,
0.33 mmol) was added to the mixture and the whole was
stirred for 10 min. The reaction was quenched with satu-
rated NH4Cl aqueous solution and the mixture was extracted
with AcOEt. The extract was washed with water and brine
prior to drying and solvent evaporation. The residue was
chromatographed on silica gel (hexane±AcOEtˆ2:1) to
give 9 (136 mg, 81%, .98% de) as colorless needles. Mp
224±2258C (dec.) (AcOEt±acetone). [a]2D8168.2, (c 0.51,
CHCl3). 1H NMR (CDCl3) d: 3.57±3.62 (m, 2H, CH2CHO),
3.74±3.80 (m, 2H, CH2CHO), 3.88 (d, 1H, Jˆ 15.3 Hz,
CH2SO), 4.10±4.14 (m, 1H, CH2CHO), 4.19±4.22 (m,
1H, CH2CHO), 4.36 (d, 1H, Jˆ15.3 Hz, CH2SO), 4.53 (d,
1H, Jˆ12.5 Hz, ArCH2), 4.56 (d, 1H, Jˆ12.5 Hz, ArCH2),
4.65 (d, 1H, Jˆ12.2 Hz, ArCH2), 4.67±4.68 (m, 2H,
ArCH2), 4.71 (d, 1H, Jˆ11.6 Hz, PhCH2), 5.93 (s, 1H,
CˆCH), 7.05±7.30 (m, 9H, Ar-H), 7.62 (td, 1H, Jˆ 7.6,
1.2 Hz, S(O)Ar-H), 7.69 (td, 1H, Jˆ7.6, 1.2 Hz, S(O)Ar-H),
7.83 (dd, 1H, Jˆ7.3, 1.2 Hz, S(O)Ar-H), 7.90 (dd, 1H,
Jˆ7.3, 1.2 Hz, S(O)Ar-H). 13C NMR (CDCl3) d: 56.3,
67.6, 68.1, 71.9, 72.6, 72.8, 76.4, 79.3, 109.4, 125.4,
NMR (CDCl3) d: 2.67 (d, 2H, OH), 3.64±3.77 (m, 6H, 3-H,
4-H, 5-H, 6-H), 4.68 (q, 4H, Jˆ11.8 Hz, 1-H, 8-H), 7.22±
7.31 (m, 4H, Ar-H). 13C NMR (CDCl3) d: 68.9 (2C), 70.7
(2C), 73.3 (2C), 128.5 (2C), 130.1 (2C), 137.0 (2C). IR
(KBr) 3340, 3064, 2927, 2862, 1367, 1090 cm21. MS m/z
(%): 224 (M1, 4.3), 104 (100). Anal. Calcd for C12H16O4: C,
64.27; H, 7.19. Found: C, 64.22; H, 7.09.
cis-5-[(Trimethylsilyl)oxy]-1,3,4,5,6,8-hexahydro-2,7-benzo-
dioxecin-4-ol (7). A solution of TMSCl (0.12 ml, 0.96
mmol) in CH2Cl2 (1 ml) was added slowly to a mixture of
6 (195 mg, 0.87 mmol) and Et3N (0.18 ml, 1.30 mmol) in
CH2Cl2 (10 ml) with stirring at 08C under N2. The stirring
was continued at 08C for 1 h and at room temperature for
1 d. The reaction was quenched with saturated NaHCO3
aqueous solution. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2. The combined
organic layers were washed with brine prior to drying and
solvent evaporation. The residue was chromatographed on
silica gel (hexane±AcOEtˆ1:1!AcOEt) to give 7 (213 mg,
83%) as a pale yellow oil along with the recovered 6 (31 mg,
12%). 1H NMR (CDCl3) d: 0.12 (s, 9H, SiCH3), 2.68 (d, 1H,
Jˆ3.7 Hz, OH), 3.50±3.91 (m, 6H, 3-H, 4-H, 5-H, 6-H),
4.54 (d, 1H, Jˆ12.8 Hz, 1-H or 8-H), 4.62 (d, 1H,
Jˆ11.0 Hz, 1-H or 8-H), 4.69 (d, 1H, Jˆ11.0 Hz, 1-H or

N. Maezaki et al. / Tetrahedron 56 (2000) 4405±4413
4409
127.8, 127.9 (2C), 128.3, 128.4 (2C), 128.5, 128.7, 129.1,
130.5, 131.0, 131.5, 131.9, 136.8, 136.9, 137.8, 141.7,
152.9. IR (KBr) 2870, 1605, 1059 cm21. MS (FAB) m/z:
525 (MH1). Anal. Calcd for C28H28O6S2: C, 64.10; H,
5.38. Found: C, 64,09; H, 5.46.
(d, 1H, Jˆ11.6 Hz, ArCH2), 4.72 (d, 1H, Jˆ11.6 Hz,
ArCH2), 4.75 (d, 1H, Jˆ11.0 Hz, ArCH2), 5.55±5.56 (m,
1H, 4-H), 7.20±7.55 (m, 12H, Ar-H), 7.54 (d, 2H, Jˆ
7.3 Hz, Ar-H). 13C NMR (CDCl3) d: 55.4, 66.7, 68.5,
71.9, 72.4, 72.6, 74.1, 76.5, 84.6, 121.2, 125.4, 127.5,
127.6 (2C), 127.7, 128.2 (2C), 128.3 (2C), 128.4 (2C),
129.5, 130.2, 130.3, 132.1, 136.8, 136.9, 137.8, 166.1. IR
(KBr) 2949, 2870, 1749, 1273, 1107 cm21 MS m/z (%): 530
(M1, 34.2),189 (100). Anal. Calcd for C29H29F3O6: C,
65.65; H, 5.51. Found: C, 65.91; H, 5.67.
(4S,5R)-5-Benzyloxy-1,3,4,5,6,8-hexahydro-2,7-benzo-
dioxecin-4-ol (10). A mixture of 9 (290 mg, 0.55 mmol) and
10% HCl (0.3 ml) in acetone (12 ml) was stirred at room
temperature for 10 h. Saturated NaHCO3 aqueous solution
was added to the mixture. After almost all of the solvent was
evaporated, the residue was chromatographed on silica gel
(hexane±AcOEtˆ1:1) to give 10 (157 mg, 91%) as a pale
yellow oil along with (S,S)-2 (120 mg, 95%). [a]2D8132.9 (c
(4R,5S)-4-Benzyloxy-5-[(2-methoxyethoxy)methoxy]-1,3,
4,5,6,8-hexahydro-2,7-benzodioxecin (11). NaH (7.2 mg,
0.18 mmol) was added to a solution of 10 (47 mg,
0.15 mmol) in DMF (2 ml) with stirring at 08C under N2
and the stirring was continued for 30 min. n-Bu4NI
(2.8 mg, 5.4 mmol) and MEMCl (68 ml, 0.60 mmol) were
added to the mixture and the whole was stirred at 08C for
10 min. Then, the ice-bath was removed and the stirring was
continued for 5 h. The mixture was partitioned between
AcOEt and saturated NaHCO3 aqueous solution. The
organic layer was separated and the aqueous layer was
extracted with AcOEt. The combined organic layers were
washed with brine and dried. The solvent was evaporated
and the residue was chromatographed on silica gel (hexane±
AcOEtˆ1:1) to give the acetal 11 (53 mg, 88%) as a color-
1
1.14, CHCl3). H NMR (CDCl3) d: 2.63 (d, 1H, OH), 3.55
(dt, 1H, Jˆ8.5, 2.5 Hz, 5-H), 3.62 (dd, 1H, Jˆ9.8, 1.8 Hz, 3-
H), 3.72 (dd, 1H, Jˆ9.8, 1.8 Hz, 6-H), 3.81 (dd, 1H, Jˆ9.8,
6.7 Hz, 3-H), 3.93 (dd, 1H, Jˆ9.8, 8.5 Hz, 6-H), 3.96 (m,
1H, 4-H), 4.56 (d, 1H, Jˆ11.6 Hz, ArCH2), 4.57 (d, 1H,
Jˆ11.6 Hz, ArCH2), 4.66 (d, 1H, Jˆ11.6 Hz, ArCH2),
4.67 (d, 1H, Jˆ11.6 Hz, ArCH2), 4.70 (d, 1H, Jˆ11.6 Hz,
ArCH2), 4.87 (d, 1H, Jˆ11.6 Hz, ArCH2), 7.18±7.37 (m,
9H, Ar-H). 13C NMR (CDCl3) d: 67.5, 68.8, 69.4, 71.4,
72.8, 73.0, 78.3, 127.8 (2C), 127.8, 128.3 (2C), 128.4 (2C),
130.0, 130.2, 137.2 (2C), 138.0. IR (KBr) 3448, 2922, 2852,
1097 cm21. MS m/z (%): 314 (M1, 4), 105 (100). Anal. Calcd
for C19H22O4: C, 72.59; H, 7.05. Found: C, 72.24; H, 7.02.
1
less oil. [a]2D9115.3 (c 1.27, CHCl3). H NMR (CDCl3) d:
3.37 (s, 3H, OCH3), 3.50 (t, 2H, Jˆ4.6 Hz,
OCH2CH2OCH3), 3.62 (m, 4H, 3-H 6-H, OCH2CH2OCH3),
3.77 (m, 1H, 4-H), 3.90 (dd, 1H, Jˆ11.0, 6.7 Hz, 3-H or 6-
H), 3.97 (dd, 1H, Jˆ11.0, 7.3 Hz, 3-H or 6-H), 4.12 (m, 1H,
5-H), 4.60 (s, 2H, OCH2O), 4.66 (d, 1H, Jˆ11.6 Hz,
ArCH2), 4.71 (d, 1H, Jˆ11.6 Hz, ArCH2), 4.74 (d, 1H, Jˆ
11.6 Hz, ArCH2), 4.75 (d, 1H, Jˆ11.6 Hz, ArCH2), 4.77 (d,
1H, Jˆ11.6 Hz, ArCH2), 4.83 (d, 1H, Jˆ11.6 Hz, ArCH2),
7.20±7.40 (m, 9H, Ar-H). 13C NMR (CDCl3) d: 58.9, 66.9,
68.6 (2C), 71.7, 71.8, 72.2, 72.4, 75.5, 78.1, 95.2, 127.48,
127.53 (2C), 128.2, 128.3 (3C), 130.1, 130.5, 137.0, 137.2,
138.4. IR (KBr) 2924, 2872, 1103, 1041 cm21. MS (FAB)
m/z: 403 (MH1). Anal. Calcd for C23H30O6: C, 68.64; H,
7.51. Found C, 68.53; H, 7.68.
(1)-MTPA ester of 10. (1)-MTPACl (33 ml, 0.18 mmol)
was added to a mixture of 10 (50 mg, 0.16 mmol) and
DMAP (29 mg, 0.24 mmol) in CH2Cl2 (1.2 ml) with stirring
at 08C under N2. After 15 min, the reaction was quenched
with saturated NaHCO3 aqueous solution. The mixture was
extracted with CH2Cl2 and the extract washed with brine
prior to drying and solvent evaporation. The residue was
chromatographed on silica gel (hexane±AcOEtˆ1:1) to
give the (1)-MTPA ester of 10 (80 mg, 95%) as a pale
yellow oil. [a]2D9127.5 (c 1.00, CHCl3). H NMR (CDCl3)
1
d: 3.53 (s, 3H, OCH3), 3.65 (dd, 1H, Jˆ10.4, 3.7 Hz, 6-H),
3.73±3.76 (m, 2H, 3-H, 5-H), 3.81 (dd, 1H, Jˆ10.4, 7.3 Hz,
6-H), 4.08 (dd, 1H, Jˆ11.0, 7.3 Hz, 3-H), 4.34 (d, 1H,
Jˆ11.6 Hz, CH2Ph), 4.47 (d, 1H, Jˆ11.6 Hz, CH2Ph),
4.64 (d, 1H, Jˆ11.0 Hz, ArCH2), 4.70 (d, 1H, Jˆ11.6 Hz,
ArCH2), 4.76 (d, 1H, Jˆ11.6 Hz, ArCH2), 4.79 (d, 1H,
Jˆ11.6 Hz, ArCH2), 5.57±5.60 (m, 1H, 4-H), 7.16 (d, 2H,
Jˆ6.1 Hz), 7.17±7.38 (m, 12H, Ar-H), 7.55 (d, 2H,
Jˆ7.9 Hz, Ar-H). 13C NMR (CDCl3) d: 55.5, 66.7, 68.6,
72.1, 72.2, 72.7, 74.0, 77.1, 85.0, 121.2, 125.4, 127.4,
127.5 (2C), 127.6, 128.3 (4C), 128.4 (2C), 129.5, 130.3,
130.4, 132.2, 136.7, 136.9, 137.9, 165.9. IR (KBr) 2922,
2869, 1747, 1271, 1107 cm21. MS m/z (%): 530 (M1,
19.6), 91 (100). Anal. Calcd for C29H29F3O6: C, 65.65; H,
5.51. Found: C, 65.86; H, 5.67.
(2R,3S)-3-[(2-Methoxyethoxy)methoxy]-1,2,4-butanetriol
(12). A solution of 11 (38 mg, 0.094 mmol) in MeOH
(1.5 ml) was hydrogenated over 20% Pd(OH)2-C with
stirring at room temperature for 5 h. The Pd(OH)2-C was
®ltered off and the ®ltrate was concentrated under the
reduced pressure. The residue was puri®ed by a short
column chromatography (AcOEt) to give 12 (17 mg, 88%)
1
as a colorless oil. [a]2D7ˆ15.7 (c 0.90, CHCl3). H NMR
(CDCl3) d: 2.83 (t, 1H, Jˆ5.8 Hz, OH), 3.18 (d, 1H,
Jˆ6.7 Hz, OH), 3.27 (t, 1H, Jˆ6.4 Hz, OH), 3.39 (s, 3H,
OCH3), 3.57 (t, 2H, Jˆ 4.6 Hz, OCH2CH2OCH3), 3.65±
3.68 (m, 1H, 2-H), 3.66 (dt, 1H, Jˆ9.7, 4.3 Hz, 3-H),
3.81±3.86 (m, 6H, 1-H, 4-H, OCH2CH2OCH3), 4.78 (d,
1H, Jˆ7.3 Hz, OCH2O), 4.84 (d, 1H, Jˆ7.3 Hz, OCH2O).
13C NMR (CDCl3) d: 58.7, 61.6, 63.1, 67.3, 71.4, 71.5, 80.0,
95.4. IR (KBr) 3473, 3442, 1456, 1041 cm21. MS m/z (%)
210 (M1, 0.5), 89 (100). Anal. Calcd for C8H18O6: C, 45.71;
H, 8.63. Found: C, 45.51; H, 8.35.
(2)-MTPA ester of 10. By the same procedure as that
described for the preparation of (1)-MTPA ester of 10, 10
(40 mg, 0.13 mmol) was converted into the (2)-MTPA
ester (64 mg, 96%). Pale yellow oil. [a]2D9112.2 (c 0.72,
1
CHCl3). H NMR (CDCl3) d: 3.51 (s, 3H, OCH3), 3.70±
3.73 (m, 2H, 3-H, 6-H), 3.82±3.85 (m, 1H, 5-H), 3.91 (dd,
1H, Jˆ10.7, 7.6 Hz, 6-H), 3.98 (dd, 1H, Jˆ11.0, 7.3 Hz, 3-
H), 4.50 (d, 1H, Jˆ11.6 Hz, CH2Ph), 4.57 (d, 1H,
Jˆ11.6 Hz, CH2Ph), 4.64 (d, 1H, Jˆ11.0, ArCH2), 4.65
(2S,3R)-3,4-Isopropylidenedioxy-2-[(2-methoxyethoxy)-
methoxy]-1-butanol (13). A mixture of 12 (110 mg, 0.52

4410
N. Maezaki et al. / Tetrahedron 56 (2000) 4405±4413
mmol) and PPTS (4.0 mg, 0.016 mmol) in acetone (3 ml)
was stirred at room temperature for 1 d. The reaction was
quenched with saturated NaHCO3 aqueous solution and the
mixture was extracted with AcOEt. The extract was washed
with brine prior to drying and solvent evaporation. The
residue was chromatographed on silica gel (AcOEt) to
give 13 (120 mg, 92%) as a colorless oil. [a]2D8127.2 (c
of iodine (2 mg, 8 mmol), the mixture was heated at 55±
608C for 2 h. Then, the mixture was cooled to room
temperature. A solution of 16 (360 mg, 1.45 mmol) in
THF (1 ml) was added to the mixture with stirring at
room temperature and the stirring was continued for 1.5 h.
Then, the reaction mixture was quenched with saturated
NH4Cl aqueous solution and the mixture was extracted
with AcOEt. The extract was washed with brine prior to
drying end solvent evaporation. The residue was chromato-
graphed on silica gel (hexane±AcOEtˆ2:1!1:1) to give 17
(910 mg, 88% in 2 steps) as a colorless oil (5: 1 diastereo-
meric mixture). Separation of diastereomeric isomers was
dif®cult at this stage and the mixture was used in the next
step without further puri®cation. [a]2D8ˆ127.2 (c 2.29,
1
2.29, CHCl3). H NMR (CDCl3) d: 1.32 (s, 3H, C(CH3)2),
1.38 (s, 3H, C(CH3)2), 3.28 (t, 1H, Jˆ6.7 Hz, OH), 3.37 (s,
3H, OCH3), 3.52±3.58 (m, 2H, OCH2CH2O), 3.67±3.68 (m,
2H, OCH2CH2O), 3.81±3.85 (m, 2H, 1-H), 3.83 (td, 1H,
Jˆ6.1, 5.5 Hz, 2-H), 3.87 (dd, 1H, Jˆ8.5, 6.1 Hz, 4-H),
4.04 (dd, 1H, Jˆ8.5, 6.1 Hz, 4-H), 4.10 (dd, 1H, Jˆ6.3,
6.1 Hz, 3-H), 4.77 (d, 1H, Jˆ7.3 Hz, OCH2O), 4.83 (d,
1H, Jˆ7.3 Hz, OCH2O). 13C NMR (CDCl3) d: 25.2, 26.6,
59.0, 62.6, 66.7, 67.6, 71.6, 75.2, 82.2, 96.1, 109.3. IR (KBr)
3464, 1381, 1095 cm21. MS m/z (%): 249 (M121, 0.6), 89
(100). Anal. Calcd for C11H22O6: C, 52.79; H, 8.86. Found:
C, 52.67; H, 8.63.
1
CHCl3). H NMR (500 MHz, CDCl3) d: 1.04±1.05 (m,
12H, 15-CH3, SiC(CH3)3), 1.07±1.58 (m, 20H, (CH2)10),
1.36 (s, 3H, C(CH3)2), 1.41 (s, 3H, C(CH3)2), 2.54 (d, 5/
6H, Jˆ7.3 Hz, OH), 2.95 (d, 1/6H, Jˆ7.3 Hz, OH), 3.39
(s, 3H, OCH3), 3.55 (t, 2H, Jˆ4.3 Hz, OCH2CH2O), 3.56±
3.63 (m, 4H, 4-H), 3.65 (t, 1H, Jˆ4.3 Hz, OCH2CH2O),
3.69±3.77 (m, 2H, 3-H, OCH2CH2O), 3.82 (sextet, 1H,
Jˆ6.1 Hz, 17-H), 3.93 (d, 1H, Jˆ6.1 Hz, 1-H), 4.05 (d,
1H, Jˆ6.1 Hz, 1-H), 4.14 (td, 1/6H, Jˆ6.7, 6.1 Hz, 2-H),
4.21 (td, 5/6H, Jˆ6.7, 6.1 Hz, 2-H), 4.82 (d, 1H, Jˆ7.3 Hz,
OCH2O), 4.86 (d, 1H, Jˆ7.3 Hz, OCH2O), 7.36 (t, 4H,
Jˆ7.3 Hz, Ar-H), 7.41 (td, 2H, Jˆ7.3, 2.4 Hz, Ar-H), 7.68
(ddd, 4H, Jˆ7.3, 2.4, 1.2 Hz, Ar-H). 13C NMR (300 MHz,
CDCl3) (major) d: 19.2, 23.2, 25.2, 25.3, 25.8, 26.4, 27.0
(3C), 29.5 (2C), 29.6 (2C), 29.7, 33.6, 39.4, 59.0, 66.1, 67.9,
69.6, 71.5, 71.6, 76.3, 77.2, 80.7, 96.9, 108.8, 127.3 (2C),
127.4 (2C), 129.3, 129.4, 134.5, 134.9, 135.8 (4C). IR (KBr)
3491, 2981, 2856, 1111 cm21. MS (FAB) m/z: 695 (MNa1).
Anal. Calcd for C39H64O7Si: C, 69.60; H, 9.58. Found: C,
69.58; H, 9.39.
(2S)-12-Bromo-2-[[tert-butyl(diphenyl)silyl]oxy]dodecane
(15). TBDPSCl (1.23 g, 4.56 mmol) was slowly added to a
mixture of the alcohol 14 (1.00 g, 3.80 mmol) and imidazole
(620 mg, 9.12 mmol) in DMF (4 ml) with stirring at room
temperature under N2. The stirring was continued for 2 h.
The reaction was quenched with saturated NH4Cl aqueous
solution and the mixture was extracted with AcOEt. The
extract was washed with brine prior to drying and solvent
evaporation. The residue was chromatographed on silica gel
(hexane±AcOEtˆ2:1) to give 15 (1.83 g, 96%) as a color-
less oil. [a]2D4ˆ213.5 (c 0.93, CHCl3). 1H NMR (CDCl3) d:
1.05 (s, 9H, SiC(CH3)3), 1.05 (d, 3H, Jˆ5.8 Hz, 1-H), 1.10±
1.56 (m, 16H, 3-H,10-H), 1.86 (quint, 2H, Jˆ7.2 Hz,
11-H), 3.41 (t, 2H, Jˆ7.0 Hz, 12-H), 3.83 (sextet, 1H, Jˆ
5.8 Hz, 2-H), 7.36 (d, 4H, t, Jˆ7.0 Hz, Ar-H), 7.42 (td, 2H,
Jˆ7.3, 2.1 Hz, Ar-H), 7.68 (ddd, 4H, Jˆ7.0, 2.1, 1.2 Hz,
Ar-H). 13C NMR (CDCl3) d: 19.3, 23.2, 25.2, 27.0 (3C),
28.2, 28.8, 29.4 (2C), 29.5, 29.6, 32.8, 34,0, 39.4, 69.6,
127.3 (2C), 127.4 (2C), 129.3, 129.4, 134.7, 135.0, 135.9
(4C). IR (KBr) 2929, 2856, 702 cm21. MS (FAB) m/z: 527
(MNa1). HRMS (FAB) Calcd for C28H43BrNaOSi (MNa1):
527.2143. Found: 527.2162.
(1)-MTPA ester of 17 By the same procedure as that
described for the preparation of (1)-MTPA ester of 10, 17
(diastereomeric mixture, 30 mg, 0.045 mmol) was
converted into the (1)-MTPA ester (diastereomeric mixture,
30 mg, 75%). Colorless oil. [a]2D5ˆ114.5 (c 0.32, CHCl3). 1H
NMR (500 MHz, CDCl3) (major) d: 1.04±1.05 (m, 12H, 15-
CH3, SiC(CH3)3), 1.17±1.67 (m, 20H, (CH2)10), 1.31 (s, 3H,
C(CH3)2), 1.55 (s, 3H, C(CH3)2), 3.37 (s, 3H, OCH3), 3.52±
3.57 (m, 5H, PhC(OCH3), OCH2CH2O), 3.65±3.71 (m, 2H,
OCH2CH2O), 3.80±3.86 (m, 2H, 15-H, 4-H), 3.91 (dd, 1H,
Jˆ8.5, 6.1 Hz, 1-H), 3.98 (dd, 1H, Jˆ8.5, 6.1 Hz, 1-H), 4.07
(q, 1H, Jˆ6.1 Hz, 2-H), 4.77 (d, 1H, Jˆ7.3 Hz, OCH2O),
4.79 (d, 1H, Jˆ7.3 Hz, OCH2O), 5.20±5.30 (m, 1H, 4-H),
7.34±7.42 (m, 8H, Ar-H), 7.55 (td, 2H, Jˆ7.3, 1.2 Hz,
Ar-H), 7.68 (ddd, 4H, Jˆ7.3, 2.4, 1.2 Hz, Ar-H). 13C
NMR (300 MHz, CDCl3) (major) d: 19.3, 23.2, 25.2, 25.3,
25.6, 26.5, 27.0 (4C), 29.3, 29.4, 29.5 (2C), 29.6, 30.0, 39.4,
55.5, 59.0, 66.4, 67.7, 69.6, 71.6, 75.1, 76.3, 77.2, 77.9,
96.9, 108.8, 121.2, 125.4, 127.3 (2C), 127.4 (3C), 127.7,
128.4, 129.3, 129.4, 129.6, 132.2, 134.6, 135.0, 135.9
(4C), 165.9. IR (KBr) 1749, 1260, 1170, 1110 cm21. MS
(FAB) m/z: 911 (MNa1). HRMS (FAB) Calcd for
C49H71F3NaO9Si (MNa1): 911.4717. Found: 911.4711.
(2R,3S,4RS,15S)-15-[[tert-Butyl(diphenyl)silyl]oxy]-1,2-
isopropylidenedioxy-3-[(2-methoxyethoxy)methoxy]-4-
hexadecanol (17). DMSO (1.00 ml, 14.1 mmol) was added
to a solution of oxalyl chloride (0.61 ml, 7.03 mmol) in
CH2Cl2 (15 ml) with stirring at 2788C under Ar. After
15 min, a solution of 13 (0.80 g, 3.20 mmol) in CH2Cl2
(10 ml) was added to the mixture and the stirring was
continued for 20 min. Then, Et3N (2.23 ml, 16.0 mmol)
was added to the mixture and the temperature was raised
to room temperature. The stirring was continued for 1 h. The
reaction was quenched with water and the mixture was
extracted with AcOEt. The extract was washed with brine
prior to drying and solvent evaporation. The residue was
chromatographed on silica gel (hexane±AcOEtˆ1:1) to
give the aldehyde 16 (667 mg) as a colorless oil. The alde-
hyde 16 was unstable and used immediately in the next step
without further puri®cation. A solution of the bromide 15
(1.39 g, 2.75 mmol) in THF (4 ml) was added to magnesium
turnings (74 mg, 3.03 mmol), whose surfaces was mechanic-
ally activated for 3 h under Ar in advance. After the addition
(2)-MTPA ester of 17. By the same procedure as that
described for the preparation of (1)-MTPA ester of 10, 17
(diastereomeric mixture, 30 mg, 0.045 mmol) was con-
verted into the (2)-MTPA ester (diastereomeric mixture,

N. Maezaki et al. / Tetrahedron 56 (2000) 4405±4413
4411
36 mg, 91%). Colorless oil. [a]2D4 216.9 (c 0.45, CHCl3). 1H
NMR (500 MHz, CDCl3) (major) d: 1.04±1.05 (m, 12H, 15-
CH3, SiC(CH3)3), 1.17±1.67 (m, 20H, (CH2)10), 1.25 (s, 3H,
C(CH3)2), 1.35 (s, 3H, C(CH3)2), 3.37 (s, 3H, OCH3),
3.52±3.57 (m, 5H, PhC(OCH3), OCH2CH2O), 3.65 (t, 1H,
Jˆ4.3 Hz, OCH2CH2O), 3.66 (t, 1H, Jˆ4.3 Hz,
OCH2CH2O), 3.76±3.80 (m, 1H, 1-H), 3.81±3.91 (m, 4H,
1-H, 2-H, 4-H, 15-H), 4.71 (d, 1H, Jˆ6.7 Hz, OCH2O), 4.73
(d, 1H, Jˆ6.7 Hz, OCH2O), 5.21 (m, 1H, 4-H), 7.34±7.45
(m, 9H, Ar-H), 7.56 (td, 2H, Jˆ7.3, 1.2 Hz, Ar-H), 7.68
(ddd, 4H, Jˆ7.3, 2.4, 1.2 Hz, Ar-H). 13C NMR (300 MHz,
CDCl3) (major) d: 19.3, 23.2, 25.2, 25.5, 25.6, 26.4, 27.0
(4C), 29.4, 29.5 (2C), 29.6 (2C), 33.9, 39.4, 55.5, 59.0, 66.3,
67.7, 69.6, 71.6, 75.0, 76.4, 77.2, 77.9, 96.9, 108.7, 121.2,
125.4, 127.3 (2C), 127.4 (3C), 128.3 (2C), 129.3, 129.4,
129.5, 132.2, 134.6, 135.0, 135.9 (4C), 165.9. IR (KBr)
1749, 1255, 1170, 1110 cm21. MS (FAB) m/z: 911
(MNa1). HRMS (FAB) Calcd for C49H71F3NaO9Si
(MNa1): 911.4717. Found: 911.4726.
4.17 (dd, 1H, Jˆ11.6, 7.3 Hz, 1-H), 4.28 (dd, 1H, Jˆ11.6,
4.3 Hz, 1-H), 4.79 (d, 1H, Jˆ7.3 Hz, OCH2O), 4.89 (d, 1H,
Jˆ7.3 Hz, OCH2O), 7.36 (t, 4H, Jˆ7.3 Hz, Ar-H), 7.41 (td,
2H, Jˆ7.3, 1.2 Hz, Ar-H), 7.68 (ddd, 4H, Jˆ7.3, 2.4,
1.2 Hz, Ar-H). 13C NMR (CDCl3) (major) d: 14.1, 19.2,
23.2, 25.2, 27.0 (3C), 27.1 (3C), 29.5 (3C), 29.5 (2C), 29.6,
33.3, 38.8, 39.4, 58.9, 65.5, 67.8, 69.5, 70.6, 71.3, 71.5, 82.7,
96.9, 127.3 (2C), 127.4 (2C), 129.2, 129.3, 134.6, 134.9,
135.8 (4C), 178.7. IR (KBr) 3070, 2931, 1427,1105,
1039 cm21. MS (FAB) m/z: 739 (MNa1). Anal. Calcd for
C41H68O8Si: C, 68.68, H, 9.56. Found: C, 68.57; H, 9.30.
(2R,3S,4RS,15S)-15-[[tert-Butyl(diphenyl)silyl]oxy]-2,4-
isopropylidenedioxy-3-[(2-methoxyethoxy)methoxy]hexa-
decyl pivalate (20). A mixture of 19 (0.41 g, 0.58 mmol)
and p-toluenesulfonic acid monohydrate (6.6 mg, 0.035
mmol) in 2,2-dimethoxypropane (1 ml) was stirred at
room temperature for 3 h. Solvent was evaporated and the
residue was chromatographed on silica gel (hexane±
AcOEtˆ4:1) to give 20 (diastereomeric mixture, 400 mg
1
(2R,3S,4RS,15S)-15-[[tert-Butyl(diphenyl)silyl]oxy]-3-[(2-
methoxyethoxy)methoxy]-1,2,4-hexadecanetriol (18). A
solution of 17 (1.04 g, 1.55 mmol) in 80% AcOH (5 ml)
was stirred at room temperature for 1 d. The solvent was
evaporated and the residue was chromatographed on silica
gel (AcOEt) to give 18 (diastereomeric mixture, 929 mg,
91%) as a colorless oil. [a]2D7123.7 (c 0.98, CHCl3). H
NMR (CDCl3) d: 1.05 (m, 12H, 15-CH3, SiC(CH3)3),
1.06±1.45 (m, 20H, (CH2)10), 1.38 (s, 9H, COC(CH3)3),
1.44 (s, 3H, C(CH3)2), 1.56 (s, 3H, C(CH3)2), 3.78 (s, 3H,
OCH3), 3.53±3.60 (m, 3H, OCH2CH2OCH3, H-3), 3.61±
3.98 (m, 5H, OCH2CH2OCH3, 2-H, 4-H, 17-H), 4.12 (dd,
1H, Jˆ11.6, 7.0 Hz, H-1), 4.42 (dd, 1H, Jˆ11.6, 2.4 Hz,
1-H), 4.68 (d, 1H, Jˆ7.3 Hz, OCH2O), 4.78 (d, 1H,
Jˆ7.3 Hz, OCH2O), 7.36 (t, 4H, Jˆ7.3 Hz, Ar-H), 7.41
(td, 2H, Jˆ7.3, 1.2 Hz, Ar-H), 7.68 (ddd, 4H, Jˆ7.3, 2.4,
1.2 Hz, 4H, Ar-H). 13C MNR (CDCl3) (major) d: 19.2, 23.2,
23.7, 24.7, 25.2, 25.7, 26.9 (4C), 27.1 (3C), 29.1, 29.5 (3C),
29.6 (2C), 38.8, 39.4, 59.0, 64.2, 67.6, 69.6, 70.7, 71.5, 72.1,
78.0, 96.4, 100.8, 127.3 (2C), 127.4 (2C), 129.3, 129.4,
134.6, 134.9, 135.8 (4C), 178.1. IR (KBr) 3447, 2931,
1462, 1427 1375, 1105, 1039 cm21. MS (FAB) m/z: 695
(MNa1). Anal. Calcd for C44H72O8Si: C, 69.80; H, 9.58.
Found: C, 69.95; H, 9.40.
1
95%) as a colorless oil. [a]2D514.7 (c 0.97, CHCl3). H
NMR (CDCl3) d: 1.04 (d, 3H, Jˆ6.1Hz, 15-CH3), 1.05 (s,
9H, SiC(CH3)3), 1.07±1.52 (m, 20H, (CH2)10), 2.98 (d, 1H,
Jˆ7.9 Hz, OH), 3.40 (s, 3H, OCH3), 3.53 (d, 1H, Jˆ7.9 Hz,
OH), 3.56±3.58 (m, 3H, OCH2CH2OCH3, 3-H), 3.68±3.72
(m, 2H, OCH2CH2OCH3, OH), 3.75±3.78 (m, 3H, 1-H, 2-H,
4-H), 3.80±3.87 (m, 3H, OCH2CH2OCH3, 1-H, 17-H), 4.78
(d, 1H, Jˆ7.3 Hz, OCH2O), 4.87 (d, 1H, Jˆ7.3 Hz,
OCH2O), 7.36 (t, 4H, Jˆ7.30 Hz, Ar-H), 7.41 (td, 2H,
Ar-H, Jˆ7.3, 1.2 Hz), 7.68 (ddd, 4H, Jˆ7.3, 2.4, 1.2 Hz,
Ar-H). 13C NMR (CDCl3) (major) d: 19.3, 23.2, 25.2, 25.8,
27.0 (5C), 29.6 (4C), 33.6, 39.4, 59.0, 62.8, 67.9, 69.6, 71.5,
72.3, 76.5, 95.1, 97.0, 127.3, 127.4, 128.3 (2C), 129.3,
129.4, 134.6, 135.0, 135.9 (4C). IR (KBr) 3397, 2913,
2854, 1105, 1039 cm21. MS (FAB) m/z: 633 (MH1).
Anal. Calcd for C36H60O7Si: C, 68.30; H, 9.55. Found: C,
68.14; H, 9.42.
(2R,3S,4R,15S)- and (2R,3S,4S,15S)-15-[[tert-Butyl(di-
phenyl)silyl]oxy]-2,4-isopropylidenedioxy-3-[(2-methoxy-
ethoxy)methoxy]-1-hexadecanol (21a and 21b). DIBAL-
H (1.0 M in toluene) (0.30 ml, 0.30 mmol) was added
slowly to a solution of 20 (90 mg, 0.12 mmol) in CH2Cl2
(0.6 ml) with stirring at 2788C and the stirring was con-
tinued at 2788C for 15 min. The reaction was quenched
with saturated NaHCO3 aqueous solution and the whole
was stirred at room temperature for 1 h. After ®ltration
through Celitew, the ®ltrate was concentrated under the
reduced pressure. The residue was chromatographed on
silica gel (hexane±AcOEtˆ3:1) to give 21a (more polar)
(62 mg, 77%) and 21b (less polar) (15 mg, 19%) each as a
(2R,3S,4RS,15S)-15-[[tert-Butyl(diphenyl)silyl]oxy]-2,4-
dihydroxy-3-[(2-methoxyethoxy)methoxy]hexadecyl
pivalate (19). Pivaloyl chloride (0.11 ml, 0.87 mmol) was
added to a mixture of 18 (500 mg, 0.79 mmol) and pyridine
(0.79 ml) in CH2Cl2 (1.2 ml) with stirring at 08C. The whole
was stirred at room temperature for 3 h. The mixture was
partitioned between AcOEt and water. The organic layer
was separated and washed with brine prior to drying and
solvent evaporation. The residue was chromatographed on
silica gel (hexane±AcOEtˆ1:1) to give 19 (diastereomeric
mixture, 520 mg, 91%) as a colorless oil. Separation of dia-
stereomeric isomers was dif®cult at this stage and performed
later. [a]2D614.6 (c 0.94, CHCl3). 1H NMR (CDCl3) d: 1.05
(m, 12H, 15-CH3, SiC(CH3)3), 1.08±1.55 (m, 29H, (CH2)10,
COC(CH3)3), 2.86 (d, 1H, Jˆ4.9 Hz, OH), 3.39 (s, 3H,
OCH3), 3.50 (t, 1H, Jˆ4.3 Hz, 3-H), 3.57 (t, 2H,
Jˆ4.9 Hz, OCH2CH2OCH3), 3.62 (d, 1H, Jˆ6.1Hz, OH),
3.71±3.75 (m, 1H, OCH2CH2OCH3), 3.78±3.87 (m, 3H,
OCH2CH2OCH3, 4-H, 17-H), 4.07±4.11 (m, 1H, 2-H),
1
colorless oil. 21a: [a]2D7118.4 (c 1.01, CHCl3). H NMR
(CDCl3) d: 1.04 (d, 3H, Jˆ6.1 Hz, 15-CH3), 1.05 (s, 9H,
SiC(CH3)3), 1.06±1.49 (m, 20H, (CH2)10), 1.33 (s, 3H,
C(CH3)2), 1.42 (s, 3H, C(CH3)2), 2.24 (t, 1H, Jˆ6.1 Hz,
OH), 3.55 (t, 2H, Jˆ3.7 Hz, OCH2CH2O), 3.39 (s, 3H,
OCH3), 3.60±3.62 (m, 1H, OCH2CH2O), 3.68±3.78 (m,
3H, 1-H, 3-H, 4-H), 3.80±3.84 (m, 4H, OCH2CH2O, 1-H,
2-H, 17-H), 4.68 (d, 1H, Jˆ7.3 Hz, OCH2O), 4.78 (d, 1H,
Jˆ7.3Hz, OCH2O), 7.38 (t, 4H, Jˆ7.3 Hz, Ar-H), 7.41 (td,
2H, Jˆ7.3, 1.2 Hz, Ar-H), 7.67 (ddd, 4H, Jˆ7.3, 2.4,
1.2 Hz, Ar-H). 13C NMR (CDCl3) d: 19.2, 23.2, 24.0,

4412
N. Maezaki et al. / Tetrahedron 56 (2000) 4405±4413
24.9, 25.2, 25.7, 27.0 (4C), 29.1, 29.5 (5C), 39.4, 59.0, 63.5,
67.4, 69.6, 70.7, 71.6, 74.4, 78.2, 96.5, 100.8, 127.3 (2C),
127.4 (2C), 129.3, 129.4, 135.0 (2C), 135.8 (4C). IR (KBr)
3493, 2933, 2856, 1110, 1051, 1008 cm21. MS (FAB) m/z:
695 (MNa1). Anal. Calcd for C39H64O7Si: C, 69.60; H, 9.58.
Found C, 69.73, H, 9.44. 21b: [a]2D5 24.9 (c 0.30, CHCl3).
1H NMR (CDCl3) d: 1.04 (d, 3H, Jˆ6.1 Hz, 17-CH3), 1.05
(s, 9H, SiC(CH3)3), 1.07±1.57 (m, 20H, (CH2)10), 1.40 (s,
3H, C(CH3)2), 1.46 (s, 3H, C(CH3)2), 2.40 (t, 1H, Jˆ6.7 Hz,
OH), 3.28 (t, 1H, Jˆ9.8 Hz, 3-H), 3.39 (s, 3H, OCH3), 3.56
(t, 2H, Jˆ4.3 Hz, OCH2CH2O), 3.60±3.72 (m, 4H,
OCH2CH2O, 2-H, 4-H), 3.73±3.77 (m, 2H, 1-H, 2-H),
3.98 (sextet, 1H, Jˆ6.1 Hz, 17-H), 4.76 (d, 1H, Jˆ6.7 Hz,
OCH2O), 4.78 (d, 1H, Jˆ6.7 Hz, OCH2O), 7.36 (t, 4H,
Jˆ7.3 Hz, Ar-H), 7.41 (td, 2H, Jˆ7.3, 1.2 Hz, Ar-H), 7.68
(ddd, 4H, Jˆ7.3, 2.4, 1.2 Hz, Ar-H). 13C NMR (CDCl3) d:
19.2, 19.4, 23.2, 25.0, 25.2, 27.0 (5C), 29.4, 29.6 (4C), 32.0,
39.4, 59.1, 62.2, 68.0, 69.6, 71.6, 73.4, 74.3, 77.2, 97.3,
98.4, 127.3 (2C), 127.4 (2C), 129.3, 129.4, 134.6, 135.0,
(2E,4R,5S,6R,17S)-17-[[tert-Butyl(diphenyl)silyl]oxy]-4,6-
isopropylidenedioxy-5-[(2-methoxyethoxy)methoxy]-2-
octadecenoic acid (23). LiOH´H2O (21 mg, 0.51 mmol)
was added to a solution of 22 (51 mg, 0.067 mmol) in a
mixture of MeOH and water (6:1) (2.1 ml) with stirring at
room temperature. The stirring was continued at 408C for
4 h. The mixture was acidi®ed to pH 4±5 with oxalic acid
(48 mg, 0.53 mmol) at 08C and extracted with ether. The
extract was washed with water and brine prior to drying
and solvent evaporation. The crude 23 (51 mg) was used
in the next step without further puri®cation. Analytical
sample of 23 was puri®ed by column chromatography on
1
silica gel (AcOEt). [a]2D917.2 (c 0.51, CHCl3). H NMR
(CDCl3) d: 1.04±1.05 (m, 12H, 17-CH3, SiC(CH3)3),
1.07±1.62 (m, 20H, (CH2)10), 1.35 (s, 3H, C(CH3)2), 1.41
(s, 3H, C(CH3)2), 3.39 (s, 3H, OCH3), 3.56±3.62 (m, 3H,
OCH2CH2O, 5-H), 3.64±3.84 (m, 3H, OCH2CH2O, 4-H, 17-
H), 4.32±4.35 (m, 2H, OCH2CH2O, 6-H), 4.71 (d, 1H,
Jˆ7.3 Hz, OCH2O), 4.79 (d, 1H, Jˆ7.3 Hz, OCH2O), 6.14
(d, 1H, Jˆ15.9 Hz, 2-H), 7.27±7.42 (m, 7H, Ar-H, 3-H),
7.67 (ddd, 4H, Jˆ7.3, 2.4, 1.2 Hz, Ar-H). 13C NMR (CDCl3)
d: 19.2, 23.2, 24.0, 24.5, 25.2, 25.7, 27.0 (4C), 29.1, 29.6
(5C), 39,4, 59.0, 67.7, 69.6, 70.5, 71.5, 72.2, 80.8, 96.4,
101.2, 119.6, 127.3 (2C), 127.4 (2C), 129.3, 129.4, 134.6,
135.0, 135.9 (4C), 147.9, 170.7. IR (KBr) 3133, 2929, 2856,
1701, 1111, 1047 cm21. MS (FAB) m/z: 735 (MNa1). Anal.
Calcd for C41H64O8Si: C, 69.06; H, 9.05. Found: C, 69.00,
H, 8.94.
135.9 (4C). IR (KBr) 3654, 2927, 2856, 1111, 1045 cm21
.
MS (FAB) m/z: 695 (MNa1). Anal. Calcd for C39H64O7Si:
C, 69.60; H, 9.58. Found C, 69.72, H, 9.43.
Ethyl (2E,4R,5S,6R,17S)-17-[[tert-butyl(diphenyl)silyl]-
oxy]-4,6-isopropylidenedioxy-5-[(2-methoxyethoxy)meth-
oxy]-2-octadecenoate (22). DMSO (90 ml, 1.27 mmol) was
added to a solution of oxalyl chloride (56 ml, 0.64 mmol) in
CH2Cl2 (1.4 ml) with stirring at 2508C under Ar. After
15 min, a solution of 21a (214 mg, 0.32 mmol) in CH2Cl2
(5 ml) was added to the mixture and the stirring was con-
tinued for 1 h. Then, Et3N (0.18 ml, 1.27 mmol) was added
to the mixture and the stirring was continued at room
temperature for 1.5 h. Horner±Wadsworth±Emmons reagent
[prepared by the addition of n-BuLi (1.57 M in hexane)
(7.00 ml, 10.5 mmol) to a solution of diethyl phosphono-
acetic acid ethyl ester (1.91 ml, 9.53 mmol) in CH2Cl2
(6.4 ml) at 08C and the stirring of the mixture at 08C for
20 min] was added to the mixture and the stirring was
continued at 08C for 20 min. The reaction mixture was
poured into brine. The organic layer was separated and
the aqueous layer was extracted with CH2Cl2. The combined
organic layers were dried. The solvent was evaporated and
the residue was chromatographed on silica gel (hexane±
AcOEtˆ1:1) to give 22 (214 mg, 91%) as colorless oil.
(2E,4R,5S,6R,17S)-17-Hydroxy-4,6-isopropylidenedioxy-
5-[(2-methoxyethoxy)methoxy]-2-octadecenoic acid (24).
TBAF (1.0 M in aqueous THF, 0.34 ml, 0.34 mmol) was
added to a solution of crude 23 (51 mg) in THF (1.2 ml)
with stirring at 08C. The stirring was continued at room
temperature for 2 d. The mixture was acidi®ed with 10%
HCl and the solvent was evaporated under the reduced
pressure. The residue was partitioned between ether and
water. The organic layer was separated and the aqueous
layer was extracted with ether. The combined organic layers
were washed with brine prior to drying and solvent evapo-
ration. The residue was chromatographed on silica gel
(CH3Cl±MeOHˆ95:5) to give 24 (30 mg, 94% in 2 steps)
1
as a colorless oil. [a]2D4131.6 (c 0.25, CHCl3). H NMR
(CDCl3) d: 1.18 (d, 3H, Jˆ6.1 Hz, 17-CH3), 1.36 (s, 3H,
C(CH3)2), 1.41 (s, 3H, C(CH3)2), 1.07±1.61 (m, 21H,
(CH2)10, OH), 3.39 (s, 3H, OCH3), 3.57±3.62 (m, 3H,
OCH2CH2O, 5-H), 3.65±3.69 (m, 1H, OCH2CH2O), 3.77±
3.84 (m, 3H, OCH2CH2O, 6-H), 4.32±4.35 (m, 1H, 4-H),
4.71 (d, 1H, Jˆ7.3 Hz, OCH2O), 4.79 (d, 1H, Jˆ7.3 Hz,
OCH2O), 6.14 (d, 1H, Jˆ15.9 Hz, 2-H), 7.25 (dd, 1H,
Jˆ15.9, 3.7 Hz, 3-H). 13C NMR (CDCl3) d: 23.4, 24.0,
24.6, 25.6, 25.7, 27.0, 29.0, 29.6 (5C), 39.3, 59.0, 67.7,
68.2, 70.5, 71.5, 72.2, 80.7, 96.5, 101.1, 119.6, 147.9,
170.7. IR (KBr) 3429, 1701, 1460, 1379, 1223, 1173,
1136, 1111, 1043 cm21. MS (FAB) m/z: 497 (MNa1).
HRMS (FAB) Calcd for C25H46NaO8 (MNa1): 497.3103.
Found: 497.3077.
1
[a]2D519.5 (c 1.20, CHCl3). H NMR (CDCl3) d: 1.03±
1.04 (m, 12H, 17-CH3, SiC(CH3)3), 1.07±1.48 (m, 20H,
(CH2)10), 1.29 (t, 3H, Jˆ7.3, CH2CH3), 1.35 (s, 3H,
C(CH3)2), 1.40 (s, 3H, C(CH3)2), 3.39 (s, 3H, OCH3),
3.41±3.60 (m, 3H, OCH2CH2O, 5-H), 3.66±3.70 (t, 1H,
Jˆ3.7 Hz, OCH2CH2O), 3.77±3.84 (m, 3H, OCH2CH2O,
6-H, 17-H), 4.20 (t, 2H, Jˆ7.2 Hz, CH2CH3), 4.29±4.32
(m, 1H, 4-H), 4.71 (d, 1H, Jˆ7.3 Hz, OCH2O), 4.79 (d,
1H, Jˆ7.3 Hz, OCH2O), 6.12 (dd, 1H, Jˆ15.9, 1.8 Hz,
2-H), 7.11 (dd, 1H, Jˆ15.9, 4.3 Hz, 3-H), 7.36 (t, 4H,
Jˆ7.3 Hz, Ar-H), 7.41 (td, 2H, Jˆ7.3, 1.2 Hz, Ar-H), 7.68
(ddd, 4H, Jˆ7.3, 2.4, 1.2 Hz, Ar-H). 13C NMR (CDCl3) d:
14.3, 19.2, 23.2, 24.0, 24.6, 25.2, 25.7, 27.0 (4C), 29.1, 29.6
(5C), 39,4, 59.0, 60.3, 67.6, 69.6, 70.4, 71.5, 72.4, 80.5,
96.4, 101.0, 120.8, 127.3 (2C), 127.4 (2C), 129.3, 129.4,
134.6, 135.0, 135.8 (4C), 145.1, 166.3. IR (KBr) 2929,
2856, 1722, 1304, 1171, 1111, 1045 cm21. MS (FAB) m/z:
763 (MNa1). Anal. Calcd for C43H68O8Si: C, 69.69; H, 9.25.
Found: C, 69.66, H, 9.26.
(2E,4R,5S,6R,17S)-4,6-Isopropylidenedioxy-5-[(2-meth-
oxyethoxy)methoxy]-17-methyl-2-heptadecen-17-olide
(25). Et3N (48 ml, 0.35 mmol) was added to a solution of the
seco acid 24 (35 mg, 0.074 mmol) in THF (1.3 ml) with
stirring at room temperature and the stirring was continued

N. Maezaki et al. / Tetrahedron 56 (2000) 4405±4413
4413
for 15 min. Then, 2,4,6-trichlorobenzoyl chloride (17 ml,
0.11 mmol) was added to the mixture and the whole was
stirred at room temperature for 4 h. Toluene (40 ml) was
added to a mixture and the mixture was ®ltrated. The
mixture was added to a re¯uxing solution of DMAP
(44 mg, 0.36 mmol) in toluene (10 ml) over 2.5 h by a
syringe pump. After cooling to room temperature, the
mixture was diluted with ether and washed with water and
brine prior to drying and solvent evaporation. The residue
was roughly chromatographed on silica gel (hexane±
AcOEtˆ3:1) to give 25 (18 mg, 54%) as a colorless oil.
for Encouragement of Young Scientists from the Ministry of
Education, Science, Sports and Culture, Japan.
References
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1
[a]2D4ˆ129.6 (c 0.70, CHCl3). H NMR (CDCl3) d: 1.26
(d, 3H, Jˆ6.1 Hz, 17-CH3), 1.10±1.66 (m, 18H, (CH2)9),
1.42 (s, 3H, C(CH3)2), 1.46 (s, 3H, C(CH3)2), 1.68±1.78
(m, 2H, 7-H), 3.39 (s, 3H, OCH3), 3.47±3.63 (m, 3H,
OCH2CH2O, 5-H), 3.73±3.86 (m, 2H, OCH2CH2O), 3.92±
3.95 (m, 1H, 6-H), 4.47±4.72 (m, 1H, 4-H), 4.82 (d, 1H,
Jˆ7.3 Hz, OCH2O), 4.92 (d, 1H, Jˆ7.3 Hz, OCH2O), 5.04
(sextet, 1H, Jˆ6.1 Hz, 17-H), 6.04 (dd, 1H, Jˆ16.2, 2.1 Hz,
2-H), 7.11 (dd, 1H, Jˆ16.2, 3.1 Hz, 3-H). 13C NMR
(CDCl3) d: 20.0, 23.3, 23.5, 25.5, 25.9, 27.1, 27.2, 27.8
(2C), 27.9, 28.2, 28.3, 34.9, 58.6, 65.6, 67.2, 70.7, 71.1,
72.8, 73.8, 95.0, 99.4, 102.8, 146.3, 165.2. IR (KBr) 3043,
2927, 2856, 1720, 1612, 1126, 1109 cm21. MS (FAB) m/z:
457 (MH1). HRMS (FAB) Calcd for C25H45O7 (MH1):
457.3165. Found: 457.3167.
3. Maezaki, N.; Sakamoto, A.; Tanaka, T.; Iwata, C. Tetrahedron:
Asymmetry 1998, 9, 179±182.
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Solladie, G.; Fernandez, I.; Maestro, C. Tetrahedron: Asymmetry
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(1)-Aspicilin (1). BF3´OEt2 (3.9 ml, 0.028 mmol) was
added to a mixture of the lactone 25 (6.0 mg, 0.014
mmol) and 1,2-ethanedithiol (5.1 ml, 0.055 mmol) in
CH2Cl2 (20 ml) with stirring at 08C under Ar. After
45 min, the reaction was quenched with saturated
NaHCO3 and extracted with AcOEt. The extract was
washed with brine prior to drying and solvent evaporation.
The residue was chromatographed on silica gel (hexane±
AcOEtˆ1:1) to give (1)-aspicilin (1) (3.2 mg, 75%) as a
colorless powder. Mp 153±1558C (ether). [a]2D4136.9 (c
È
1753±1786. (k) Quinkert, G.; Heim, N.; Glenneberg, J.; Doller, U.;
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1
0.14, CHCl3). H NMR (CDCl3) d: 1.18±1.50 (m, 17H,
(CH2)8, OH), 1.25 (d, 3H, Jˆ6.1 Hz, 17-CH3), 1.49 (q,
4H, Jˆ5.5 Hz, 7-H, 16-H), 2.98 (m, 1H, OH), 3.56±3.59
(m, 2H, 5-H, OH), 3.78 (td, 1H, Jˆ9.1, 6.7 Hz, 6-H), 4.58
(m, 1H, 4-H), 5.06 (sextet, 1H, Jˆ6.1 Hz, 5-H), 6.12 (dd,
1H, Jˆ15.9, 1.2 Hz, 2-H), 6.90 (dd, 1H, Jˆ15.9, 4.9 Hz, 3-
H). 13C NMR (CDCl3) d: 20.5, 23.6, 24.3, 26.3, 27.1, 27.2,
27.5, 27.7, 28.3, 32.0, 35.7, 69.9, 71.1, 73.2, 74.8, 123.0,
144.6, 165.5. IR (KBr) 3288, 2927, 2856, 1716 cm21. MS
(FAB) m/z: 329 (MH1). HRMS (FAB) Calcd for C18H33O5
(MH1): 329.2328. Found: 329.2324.
8. Kleinperter, E.; Hartmann, J.; Schroth, W. Magn. Reson. Chem.
1990, 28, 628±634.
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Acknowledgements
12. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
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This work was supported by a Grant-in-Aid (No. 10771318)