Enantioselective syntheses of pachastrissamine and jaspine A via hydroxylactonization of a chiral epoxy ester

Article abstract of DOI:10.1271/bbb.90670

A new enantioselective total synthesis of pachastrissamine (jaspine B) was achieved from a known α,β-unsaturated aldehyde by utilizing Cordova's asymmetric epoxidation as the chirality-inducing step. The 2,3-cis stereochemistry of pachastrissamine was established via intramolecular epoxide ring opening of a γ,δ-epoxy-α,β-unsaturated ester intermediate coupled with oxy-Michael cyclization. Treatment of pachastrissamine with tetrahydro-2-furanol under acidic conditions led to smooth oxazolidine ring formation, furnishing jaspine A in a high yield.

Full text of DOI:10.1271/bbb.90670

Biosci. Biotechnol. Biochem., 74 (1), 152–157, 2010
Enantioselective Syntheses of Pachastrissamine and
Jaspine A via Hydroxylactonization of a Chiral Epoxy Ester
y
Hiroyuki URANO, Masaru ENOMOTO, and Shigefumi KUWAHARA
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University,
Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
Received September 15, 2009; Accepted October 6, 2009; Online Publication, January 7, 2010
[doi:10.1271/bbb.90670]
A new enantioselective total synthesis of pachastriss-
amine (jaspine B) was achieved from a known ꢀ,ꢁ-
Results and Discussion
´
unsaturated aldehyde by utilizing Cordova’s asymmetric
Our retrosynthetic analysis of 1 and 2 is shown in
Scheme 1. Heterobicyclic compound 2 would be readily
accessible from 1 through thermodynamically controlled
oxazolidine ring formation. We envisaged that the
ꢀ-oriented amino group at the C4 position of 1 could
be stereoselectively installed by reductive amination of
ketone intermediate 3. This dihydro-3(2H)-furanone
derivative 3 was considered to be obtainable from
bicyclic lactone 4 via reduction of the lactone moiety
and subsequent chain elongation and oxidation of the C4
alcoholic functionality. The tetrahydrofuran ring of 4
would be constructed by an intramolecular oxy-Michael
reaction of hydroxylactone 5, which in turn would
probably be prepared by the hydroxylactonization of
ꢂ,ꢃ-epoxy-ꢀ,ꢁ-unsaturated ester 6. To obtain 6, we
epoxidation as the chirality-inducing step. The 2,3-cis
stereochemistry of pachastrissamine was established via
intramolecular epoxide ring opening of a ꢂ,ꢃ-epoxy-
ꢀ,ꢁ-unsaturated ester intermediate coupled with oxy-
Michael cyclization. Treatment of pachastrissamine with
tetrahydro-2-furanol under acidic conditions led to
smooth oxazolidine ring formation, furnishing jaspine A
in a high yield.
Key words: pachastrissamine; jaspine; heterocycle;
phytosphingosine; cytotoxic
Pachastrissamine (1) was first discovered by Higa and
co-workers from the marine sponge Pachastrissa sp.
collected in Okinawa, Japan, and shown to exhibit
significant cytotoxicity against P388, A549, HT29, and
MEL28 cancer cell lines with an IC50 value of 10 ng/ml
(Fig. 1).1) Shortly after this discovery, Debitus et al. also
isolated the same compound together with another
anhydrophytosphingosine derivative from the marine
sponge Jaspis sp., and named them jaspine B (1) and
jaspine A (2); the hydrochloride of 1 was shown to
display marked cytotoxicity (IC50 ¼ 0:24 mM) against
the A549 human lung carcinoma cell line.2) Prompted by
the intriguing biological activity and unique molecular
architecture featuring an all-cis 2,3,4-trisubstituted tet-
rahydrofuran structural motif, many studies have been
made on the synthesis of 1 using various approaches.3)
As many as 17 syntheses of 1 have already been reported
which can be categorized into 5 groups according to the
source of chirality: i) chiral natural products (L-serine,
carbohydrates, and tartaric acids);4–12) ii) commercially
available D-ribo-phytosphingosine;13,14) iii) asymmetric
conjugate addition of a chiral amide;15) iv) Sharpless
asymmetric epoxidation/dihydroxylation;16–19) and v)
asymmetric aldol reaction.20) We describe here a new
enantioselective synthesis of 1 and the first synthesis
´
planned to utilize Cordova’s asymmetric epoxidation of
ꢀ,ꢁ-unsaturated aldehyde 7 and subsequent Z-selective
Wittig olefination
According to the synthetic plan, known unsaturated
aldehyde 821) was subjected to Cordova’s asymmetric
´
epoxidation conditions by using D-proline-derived orga-
nocatalyst 9 to give epoxy aldehyde 10 in an 80% yield
(Scheme 2).22) The Z-selective olefination of 10 using
Ando’s protocol proceeded smoothly,23) furnishing 11 in
an 89% yield with high geometric selectivity (Z=E ¼
18:1). The intramolecular epoxide ring opening of 11
could be induced with TFA in CH2Cl2,24) affording
hydroxylactone 12a in a 76% yield. The enantiomeric
excess of 12a was determined to be 95% by analyzing
the 1H-NMR spectra of corresponding (R)- and (S)-
MTPA esters 12b.25) The newly formed hydroxyl
group of 12a was protected as its PMB ether with
PMBOC(=NH)CCl3 and CSA to give 12c, the TBS
group of which was then removed under acidic
conditions to afford alcohol 13 in an 84% yield for the
two steps. The intramolecular oxy-Michael reaction of
13 to form the tetrahydrofuran ring was effected by
treating 13 with saturated aqueous NaHCO3 in EtOAc
according to Datta’s procedure,5) delivering desired
tetrahydrofuran derivative 14, albeit in a moderate yield
of 52% yield (69%, based on the recovered starting
material).
´
of 2 by using Cordova’s asymmetric epoxidation of an
ꢀ,ꢁ-unsaturated aldehyde as the chirality-inducing step
and hydroxylactonization of a chiral epoxy ester
intermediate coupled with oxy-Michael cyclization to
establish their 2,3-cis stereochemical relationship.
With bicyclic lactone 14 in hand, we moved on to its
elaboration into ketone intermediate 21, the substrate for
y
To whom correspondence should be addressed. Fax: +81-22-717-8783; E-mail: skuwahar@biochem.tohoku.ac.jp
Abbreviations: TBS, tert-butyldimethylsilyl; KHMDS, potassium hexamethyldisilazide; TFA, trifluoroacetic acid; CSA, 10-camphorsulfonic acid;
MTPA, ꢀ-methoxy-ꢀ-(trifluoromethyl)phenylacetyl; PMB, p-methoxybenzyl; DIBAL, diisobutylaluminum hydride; TBSOTf, tert-butyldimethylsilyl
trifluoromethanesulfonate; DDQ, 2,3-dichloro-5,6-dicyano-p-benzoquinone; DMP, Dess-Martin periodinane; TBAF, tetrabutylammonium fluoride

Syntheses of Pachastrissamine and Jaspine A
153
reductive amination (Scheme 3). Reduction of lactone
14 with DIBAL afforded lactol 15 which was then
subjected to the Wittig reaction to give 16 as a mixture
of geometrical isomers in a 70% yield from 14
(Z=E ¼ ca. 3:1). TBS protection of the hydroxyl group
of 16 gave 17 in an 82% yield which was then exposed
to H2 under two kinds of reaction condition (Pd/C in
MeOH and Pd(OH)2/C in EtOAc) to effect both
hydrogenation of the double bond and hydrogenolysis
of the PMB ether. This conversion aimed at obtaining 18
was, however, found to be very difficult; not only the
hydrogenolysis but also the hydrogenation did not
proceed at all, resulting only in the recovery of starting
material 17. Faced with unexpected difficulty in the
reduction of 17, we tried to first hydrogenate the double
bond of unprotected alcohol 16. Fortunately, this
reduction took place uneventfully to give 19 bearing
the saturated side chain in an almost quantitative yield.
After protecting the hydroxyl group of 19 as its TBS
ether, resulting product 20 was exposed to DDQ in THF
containing a phosphate buffer solution to give alcohol
intermediate 18 which was then oxidized with Dess-
Martin periodinane to furnish ketone 21 in an 84%
overall yield from 19.
The final stage of the syntheses of 1 and 2 is depicted
in Scheme 4. The stereoselective reductive amination of
21 to 22 was achieved by using Bhattacharyya’s
protocol (NH3/Ti(Oi-Pr)4 in EtOH, and then NaBH4),26)
furnishing desired reductive amination product 22 as a
single stereoisomer in a 60% yield; on the other hand,
exposure of 21 to conventional reductive amination
conditions (NaCNBH3/NH4OAc in MeOH) gave none
of the desired product, resulting only in reduction of the
ketone functionality to give alcohol 18. Finally, depro-
tection of the TBS group with TBAF gave pachastriss-
(CH2)3OH
H2N
3 OH
2
HN
O
4
O
O
(CH2)13CH3
(CH2)13CH3
1
1
Pachastrissamine
(jaspine B)
amine 1 in a 90% yield. The H- and 13C-NMR data, as
2
Jaspine A
well as the specific rotation value of 1, matched those
reported for the natural product.1,2) The conversion of 1
to jaspine A (2) proceeded uneventfully in an 89% yield
Fig. 1. Structures of Pachastrissamine (1) and Jaspine A (2).
(CH2)3OH
H2N
O
R2O
OR1
R
HN
O
OH
R
O
O
O
O
O
O
O
O
R
1
3
4
2
R = (CH2)13CH3
R2O
H
O
Ot-Bu
OR3
R3O
CHO
HO
7
O
6
5
Scheme 1. Retrosynthetic Analysis of 1 and 2.
aq. H2O2
KHMDS
CO2t-Bu
O P(OPh)2
18-crown-6
89%
TBSO
TBSO
HO
CHO
TBSO
CHO
O
Ph
Ph
8
10
N
H
OTMS
9
80%
O
O
Ot-Bu
O
TFA
76%
aq. TsOH
87%
TBSO
O
OR
12a: R = H
12b: R = MTPA
12c: R = PMB
11
CSA
NH
PMBO
CCl3
96%
O
PMBO
O
aq. NaHCO3
O
O
52%
O
OPMB
(69% brsm)
14
13
Scheme 2. Preparation of Intermediate 14.

154
H. URANO et al.
PMBO
PMBO
n-C12H25PPh3Br
n-BuLi
O
O
DIBAL
O
OH
70% from 14
O
O
14
16
15
PMBO
PMBO
HO
H2
TBSOTf
OH
OTBS
OTBS
R
2,6-lutidine
Pd/C
or Pd(OH)2
82%
O
O
O
18
17
(CH2)10CH3
(CH2)10CH3
R = (CH2)13CH3
H2, Pd/C
99%
TBSOTf
PMBO
PMBO
O
1) DDQ
2,6-lutidine
OH
R
OTBS
R
OTBS
98%
2) DMP
86%
O
O
O
(CH2)13CH3
19
20
21
Scheme 3. Preparation of Intermediate 21.
Experimental
O
O
H2N
OTBS
NH3, Ti(Oi-Pr)4
OTBS
IR spectra were recorded by a Jasco FT/IR-4100 spectrometer
using an ATR (ZnSe) attachment and are reported in cmꢀ1. NMR
spectra were recorded with TMS as an internal standard in CDCl3 by a
Varian Unity plus-500 spectrometer (500 MHz for 1H and 125 MHz for
13C) unless otherwise stated. Optical rotation values were measured
with a Jasco DIP-371 polarimeter, and the mass spectra were obtained
with Jeol JMS-700 spectrometer operated in the EI or FAB mode.
Melting point (mp) data were determined with a Yanaco MP-J3
apparatus and are uncorrected. Merck silica gel 60 (7–230 mesh) was
used for column chromatography unless otherwise stated. The solvents
used for the reactions were distilled prior to use: THF from Na and
benzophenone; MeOH from Mg and I2; and CH2Cl2 from CaH2. All
air- or moisture-sensitive reactions were conducted in a nitrogen
atmosphere.
NaBH4
60%
O
(CH2)13CH3
21
(CH2)13CH3
22
TBAF
90%
(CH2)3OH
O
O
HO
HN
O
H2N
OH
TsOH·H2O
89%
O
(CH2)13CH3
(CH2)13CH3
2
1
Scheme 4. Completion of the Syntheses of 1 and 2.
(2R,3S)-3-[(tert-Butyldimethylsilyloxy)methyl]-2-oxiranecarbalde-
hyde (10). To a stirred solution of 8 (1.59 g, 7.94 mmol) in CHCl3
(60.0 ml) was added catalyst 9 (355 mg, 1.09 mmol) at room temper-
ature. After 10 min, 30% aqueous H2O2 (1.08 g, 9.55 mmol) was
added, and the resulting mixture was stirred vigorously for 3 h at room
temperature. The mixture was quenched with solid Na2S2O3, dried
(Na2SO4), filtered through a pad of Celite, and concentrated in vacuo.
by treating 1 with tetrahydro-2-furanol in the presence of
p-toluenesulfonic acid.27) The 1H- and 13C-NMR spectral
data and specific rotation value of 2 were in good
agreement with those reported for natural jaspine A.2) It
1
is worth mentioning that, unlike its H-NMR spectrum,
the 13C-NMR spectrum of 2 in CDCl3, which required a
The residue was chromatographed over SiO2 (hexane/EtOAc ¼ 10:1)
24
þ43:8ꢂ (c 1.33,
1
to give 1.38 g (80%) of 10 as a colorless oil. ½ꢀꢁ
D
prolonged measurement time as compared to H-NMR,
CHCl3); IR ꢄmax: 2955 (m), 1731 (s), 1131 (m), 836 (m); 1H-NMR ꢃ:
0.075 (3H, s), 0.085 (3H, s), 0.90 (9H, s), 3.37 (1H, dd, J ¼ 2:0,
6.5 Hz), 3.37–3.42 (1H, m), 3.79 (1H, dd, J ¼ 4:0, 12 Hz), 4.00 (1H,
dd, J ¼ 2:5, 12 Hz), 9.08 (1H, d, J ¼ 6:5 Hz); 13C-NMR ꢃ: ꢀ5:5 (2C),
18.2, 25.7 (3C), 56.1, 56.7, 61.2, 198.1; HRMS (FAB) m=z
(½M þ Hꢁþ): calcd. for C10H21O3Si, 217.1260; found, 217.1264.
indicated gradual transformation of 2 into another
compound. Although we could not identify the newly
formed compound, this phenomenon seems to be
ascribable to the slightly acidic nature of CDCl3, since
this transformation was substantially suppressed by
recording the 13C-NMR in C5D5N.
tert-Butyl (Z)-3-[(2S,3S)-3-(tert-butyldimethylsilyloxy)methyl-2-oxy-
ranyl]-2-propenoate (11). To a stirred solution of 18-crown-6 (438 mg,
1.66 mmol) and (PhO)2P(O)CH2CO2t-Bu (578 mg, 1.66 mmol) in THF
(14.5 ml) was added KHMDS (0.5 M in THF, 3.3 ml, 1.66 mmol) at
ꢀ78 ꢂC. After 35 min, a solution of 10 (276 mg, 1.28 mmol) in THF
(14.5 ml) was added at ꢀ78 ꢂC, and the mixture was gradually warmed
to room temperature. After being stirred overnight at room temper-
ature, the reaction mixture was quenched with saturated aqueous
NH4Cl and extracted with Et2O. The extract was successively washed
with water and brine, dried (Na2SO4), and concentrated in vacuo. The
residue was chromatographed over SiO2 (hexane/EtOAc ¼ 10:1) to
In conclusion, a new enantioselective total synthesis of
pachastrissamine (1) was achieved in a 7.5% overall
yield from known unsaturated aldehyde 8 via 14 steps.
´
The new synthetic route utilized Cordova’s asymmetric
epoxidation as the chirality-inducing step and established
the 2,3-cis stereochemistry of 1 by intramolecular
epoxide ring opening of epoxy ester intermediate 11
coupled with oxy-Michael cyclization of "-hydroxy-ꢀ,ꢁ-
unsaturated ꢂ-lactone intermediate 13. The C4 amino
group was stereoselectively installed by reductive ami-
nation of ketone intermediate 21 under Bhattacharyya’s
conditions. Jaspine A (2) was also synthesized for the
first time by treating 1 with tetrahydro-2-furanol under
acidic conditions.
give 358 mg (89%) of an 18:1 mixture of 11 and its E-isomer as a
28
colorless oil. ½ꢀꢁ
þ31:5ꢂ (c 1.2, CHCl3); IR ꢄmax: 2958 (m), 2858
D
(m), 1716 (s), 1159 (m), 839 (m); 1H-NMR ꢃ: 0.08 (3H, s), 0.09 (3H,
s), 0.91 (9H, s), 1.50 (9H, s), 3.06 (1H, m), 3.66 (1H, dd, J ¼ 5:5,
12 Hz), 3.99 (1H, dd, J ¼ 2:5, 12 Hz), 4.43 (1H, d, J ¼ 8:5 Hz), 5.69

Syntheses of Pachastrissamine and Jaspine A
155
(1H, dd, J ¼ 8:5, 11.5 Hz), 5.89 (1H, d, J ¼ 11:5 Hz); 13C-NMR ꢃ:
ꢀ5:3 (2C), 18.3, 25.8 (3C), 28.1 (3C), 51.7, 60.0, 63.4, 80.9, 125.8,
144.4, 165.1; HRMS (FAB) m=z (½M þ Hꢁþ): calcd. for C16H31O4Si,
315.1992; found, 315.1998.
(13 ml) was added saturated aqueous NaHCO3 (50 ml) at room
temperature. After 15 h, the reaction mixture was extracted with
EtOAc, and the extract was dried (Na2SO4) and concentrated in vacuo.
The residue was chromatographed over SiO2 (hexane/EtOAc ¼
5:1{4:1) to give 215 mg (52%) of 14 as a colorless oil together with
27
102 mg of recovered 13. ½ꢀꢁ
ꢀ119ꢂ (c 1.00, CHCl3); IR ꢄmax: 1780
(R)-5-[(S)-2-(tert-Butyldimethylsilyloxy)-1-hydroxyethyl]-5H-furan-
2-one (12a). To a stirred solution of 11 (697 mg, 2.22 mmol) in CH2Cl2
(22 ml) was added CF3CO2H (160 ml, 2.09 mmol) at room temperature.
After being stirred overnight, the reaction mixture was quenched with
saturated aqueous NaHCO3 at 0 ꢂC and extracted with CH2Cl2. The
extract was successively washed with water and brine, dried (MgSO4),
and concentrated in vacuo. The residue was chromatographed over
D
(s), 1613 (m), 1513 (m), 1249 (m); 1H-NMR ꢃ: 2.67 (1H, dd, J ¼ 2:0,
18.5 Hz), 2.78 (1H, dd, J ¼ 7:0, 18.5 Hz), 3.77 (1H, dd, J ¼ 7:0,
9.0 Hz), 3.81 (3H, s), 3.92 (1H, dd, J ¼ 6:0, 9.0 Hz), 4.11–4.15 (1H,
m), 4.51 (1H, d, J ¼ 11:5 Hz), 4.69 (1H, d, J ¼ 11:5 Hz), 4.75 (1H,
ddd, J ¼ 2:0, 5.0, 7.0 Hz), 4.94 (1H, dd, J ¼ 5:0, 5.0 Hz), 6.89 (2H, d,
J ¼ 8:8 Hz), 7.30 (2H, d, J ¼ 8:8 Hz); 13C-NMR ꢃ: 36.2, 55.2, 69.3,
72.2, 76.8, 77.4, 80.9, 113.8 (2C), 129.1, 129.6 (2C), 159.4, 175.4;
HRMS (EI) m=z ([M]þ): calcd. for C14H16O5, 264.0998; found,
264.0998.
SiO2 (hexane/EtOAc ¼ 3:1) to give 437 mg (76%) of 12a as a
27
colorless oil. ½ꢀꢁ
þ78:2ꢂ (c 1.00, CHCl3); IR ꢄmax: 3449 (m), 1752
D
(s), 1255 (m), 835 (m); 1H-NMR ꢃ: 0.115 (3H, s), 0.120 (3H, s), 0.92
(9H, s), 2.68 (1H, d, J ¼ 7:5 Hz, OH), 3.55 (1H, m), 3.83 (1H, dd,
J ¼ 3:5, 10.5 Hz), 3.89 (1H, dd, J ¼ 3:5, 10.5 Hz), 4.97 (1H, ddd,
J ¼ 1:5, 2.0, 8.0 Hz), 6.18 (1H, dd, J ¼ 2:0, 6.0 Hz), 7.73 (1H, dd,
J ¼ 1:5, 6.0 Hz); 13C-NMR ꢃ: ꢀ5:5 (2C), 18.2, 25.8 (3C), 63.4, 72.3,
82.3, 121.8, 155.7, 172.9; HRMS (FAB) m=z (½M þ Hꢁþ): calcd. for
C12H23O4Si, 259.1366; found, 259.1366.
(2S,3R,4S)-4-(4-Methoxybenzyloxy)-2-[(E/Z)-2-tetradecenyl]tetra-
hydrofuran-3-ol (16). To a stirred solution of 14 (385 mg, 1.46 mmol) in
CH2Cl2 (13 ml) was added DIBAL (1.03 M in hexane, 1.84 ml,
1.89 mmol) at ꢀ78 ꢂC. After 1 h, the reaction mixture was quenched
with saturated aqueous Rochelle’s salt and extracted with a mixture of
CH2Cl2 and EtOAc. The extract was dried (Na2SO4) and concentrated
in vacuo to give crude 15 (366 mg) which was then dissolved in THF
(8 ml) and added at ꢀ78 ꢂC to a solution of n-C11H23CH=PPh3
[prepared by treating a solution of n-C12H25PPh3Br (3.16 g, 6.18 mmol)
in THF (31 ml) with n-BuLi (1.6 M in hexane, 3.4 ml, 5.5 mmol) at
ꢀ78 ꢂC]. The mixture was gradually warmed to room temperature over
18 h and quenched with saturated aqueous NH4Cl. The mixture was
then extracted with EtOAc, and the extract was successively washed
with water and brine, dried (MgSO4), and concentrated in vacuo. The
residue was chromatographed over SiO2 (hexane/EtOAc ¼ 10:1) to
Determination of the enantiomeric excess of 12a. According to the
literature,25) compound 12a was treated with (R)- and (S)-MTPA
chloride in pyridine to respectively give MTPA esters (S)-12b and (R)-
12b which were analyzed as CDCl3 solutions by 1H-NMR. The signals
for the two protons on the TBSO-bearing methylene carbon of (R)-12b
were observed at ꢃ 3.98 (1H, dd, J ¼ 3:9, 11.7 Hz) and ꢃ 4.02 (1H, dd,
J ¼ 3:4, 11.7 Hz), while those of (S)-12b appeared at ꢃ 3.86 (1H, dd,
J ¼ 4:6, 11.5 Hz) and ꢃ 3.94 (1H, dd, J ¼ 3:7, 11.5 Hz). A comparison
of the two 1H-NMR spectra clearly showed the enantiomeric excess of
12a to be ca. 95%.
give 423 mg (70% from 14) of 16 (E=Z ¼ ca. 1:3) as a white waxy
25
solid. ½ꢀꢁ
þ8:2ꢂ (c 1.40, CHCl3); IR ꢄmax: 3366 (m), 2918 (s), 1614
D
(m), 1515 (m), 1251 (m); 1H-NMR (3:1 mixture of Z/E isomer) ꢃ: 0.88
(3H, t, J ¼ 6:5 Hz), 1.20–1.36 (18H, m), 1.99 (0:25 ꢃ 2H, dt, J ¼ 7:0,
7.0 Hz, 40-H2), 2.07 (0:75 ꢃ 2H, dt, J ¼ 7:0, 7.0 Hz, 40-H2), 2.36
(0:25 ꢃ 1H, dt, J ¼ 14:2, 7.0 Hz, 10-H), 2.44 (0:25 ꢃ 1H, dt, J ¼ 14:2,
7.0 Hz, 10-H), 2.46 (0:75 ꢃ 2H, dd, J ¼ 7:1, 7.1 Hz, 10-H2) 2.61 (1H, br
s, OH), 3.65–3.70 (1H, m), 3.79–3.88 (2H, m), 3.81 (3H, s), 4.07–4.15
(1H, m), 4.14–4.19 (1H, m), 4.50 (1H, d, J ¼ 11:2 Hz), 4.54 (1H, d,
J ¼ 11:2 Hz), 5.38–5.53 (0:75 ꢃ 2H þ 0:25 ꢃ 1H, m, 20-H þ 30-H),
5.56 (0:25 ꢃ 1H, dt, J ¼ 15:1, 6.8 Hz, 20-H), 6.89 (2H, d, J ¼ 8:3 Hz),
7.27 (2H, d, J ¼ 8:3 Hz); 13C-NMR ꢃ: 14.4, 22.9, 27.4/27.6, 29.5,
29.60/29.61, 29.67, 29.77, 29.82, 29.90, 29.93, 32.2, 32.6/32.9, 55.5,
69.87/69.89, 70.4, 72.56/72.58, 79.13/79.14, 82.34/82.58, 114.2 (2C),
125.2/125.9, 129.5 (2C), 129.8, 132.7/133.6, 159.8; HRMS (EI) m=z
([M]þ): calcd. for C26H42O4, 418.3083; found, 418.3084.
(R)-5-[(S)-2-(tert-Butyldimethylsilyloxy)-1-(4-methoxybenzyloxy)eth-
yl]-5H-furan-2-one (12c). To a stirred solution of 12a (100 mg, 0.39
mmol) and camphorsulfonic acid (13 mg, 0.06 mmol) in CH2Cl2
(1.0 ml) was added a solution of PMBOC(=NH)CCl3 in CH2Cl2
(0.6 ml) at room temperature. After 20 h, the reaction mixture was
quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2.
The extract was successively washed with water and brine, dried
(Na2SO4), and concentrated in vacuo. The residue was triturated with
hexane and then filtered. The filtrate was concentrated in vacuo and the
residue was chromatographed over SiO2 (hexane/EtOAc ¼ 20:1{2:1)
25
to give 142 mg (96%) of 12c as a colorless oil. ½ꢀꢁ
þ99:3ꢂ (c 1.36,
D
CHCl3); IR ꢄmax: 1756 (s), 1613 (m), 1513 (m), 1249 (m), 833 (m);
1H-NMR ꢃ: 0.07 (6H, s), 0.90 (9H, s), 3.68 (1H, dt, J ¼ 5:5, 4.8 Hz),
3.78 (2H, d, J ¼ 4:8 Hz) 3.80 (3H, s), 4.50 (1H, d, J ¼ 11:2 Hz), 4.58
(1H, d, J ¼ 11:2 Hz), 5.20 (1H, ddd, J ¼ 1:5, 1.5, 5.5 Hz), 6.14 (1H,
dd, J ¼ 1:5, 6.0 Hz), 6.87 (2H, d, J ¼ 8:5 Hz), 7.21 (2H, d,
J ¼ 8:5 Hz), 7.57 (1H, dd, J ¼ 1:5, 6.0 Hz); 13C-NMR ꢃ: ꢀ5:5 (2C),
18.2, 25.8 (3C), 55.2, 62.4, 73.0, 78.7, 82.9, 113.8 (2C), 122.2, 129.6
(3C), 154.4, 159.4, 173.0; HRMS (EI) m=z ([M]þ): calcd. for
C20H30O5Si, 378.1863; found, 378.1863.
(2S,3R,4S)-4-(4-Methoxybenzyloxy)-2-tetradecyltetrahydrofuran-3-
ol (19). A mixture of 16 (264 mg, 0.63 mmol) and 10% Pd/C (50 mg)
in EtOAc (25 ml) was stirred at room temperature under a hydrogen
atmosphere. After 2.5 h, the mixture was filtered through a pad of
Celite and the filtrate was concentrated in vacuo. The residue was
chromatographed over SiO2 (hexane/EtOAc ¼ 4:1) to give 261 mg
26
(99%) of 19 as a white crystalline solid. Mp 80–81 ꢂC; ½ꢀꢁ
þ3:5ꢂ
(R)-5-[(S)-2-Hydroxy-1-(4-methoxybenzyloxy)ethyl]-5H-furan-2-one
(13). To a stirred solution of 12c (1.21 g, 3.20 mol) and water (0.6 ml)
D
(c 1.64, CHCl3); IR ꢄmax 3378 (m), 2916 (s), 1613 (m), 1515 (m), 1251
(m), 907 (m); 1H-NMR ꢃ: 0.88 (3H, t, J ¼ 6:5 Hz), 1.20–1.44 (24H,
m), 1.62–1.71 (2H, m), 2.59 (1H, d, J ¼ 4:5 Hz, OH), 3.62–3.67 (1H,
m), 3.81 (3H, s), 3.77–3.85 (2H, m), 4.04–4.09 (1H, m), 4.17 (1H, dd,
J ¼ 6:0, 12.0 Hz), 4.50 (1H, d, J ¼ 11:2 Hz), 4.54 (1H, d, J ¼ 11:2
Hz), 6.89 (2H, d, J ¼ 8:8 Hz), 7.27 (2H, d, J ¼ 8:8 Hz); 13C-NMR ꢃ:
14.1, 22.7, 26.1, 28.8, 29.3, 29.54, 29.56, 29.63 (2C), 29.64, 29.65,
29.72, 31.9, 55.2, 69.4, 70.3, 72.3, 79.0, 82.3, 82.4, 113.9 (2C), 129.2,
129.5 (2C), 159.5; HRMS (EI) m=z ([M]þ): calcd. for C26H44O4,
420.3240; found, 420.3244.
.
in THF (12 ml) was added TsOH H2O (183 mg, 0.96 mmol) at room
temperature. After 12 h, the reaction mixture was quenched with solid
NaHCO3, dried (Na2SO4), filtered through a pad of Celite, and
concentrated in vacuo. The residue was chromatographed over SiO2
(hexane/EtOAc ¼ 1:1{0:1) to give 735 mg (87%) of 13 as a colorless
23
oil. ½ꢀꢁ
þ113ꢂ (c 1.06, CHCl3); IR ꢄmax: 3474 (m), 1752 (s), 1613
D
(m), 1513 (m), 1250 (m); 1H-NMR ꢃ: 1.95 (1H, s, OH), 3.63 (1H, dt,
J ¼ 6:0, 3.5 Hz), 3.75 (1H, dd, J ¼ 3:5, 11.0 Hz), 3.81 (3H, s), 3.87
(1H, dd, J ¼ 3:5, 11.0 Hz), 4.55 (2H, s), 5.15 (1H, ddd, J ¼ 1:5, 1.8,
6.0 Hz), 6.16 (1H, dd, J ¼ 1:8, 5.8 Hz), 6.89 (2H, d, J ¼ 8:8 Hz), 7.23
(2H, d, J ¼ 8:8 Hz), 7.61 (1H, dd, J ¼ 1:5, 5.8 Hz); 13C-NMR ꢃ: 55.2,
61.3, 72.9, 78.7, 82.6, 113.9 (2C), 122.1, 129.1, 129.6 (2C), 154.7,
159.5, 172.7; HRMS (EI) m=z ([M]þ): calcd. for C14H16O5, 264.0998;
found, 264.1001.
(2S,3R,4S)-3-(tert-Butyldimethylsilyloxy)-4-(4-methoxybenzyloxy)-
2-tetradecyltetrahydrofuran (20). To a stirred solution of 19 (238 mg,
0.566 mmol) in CH2Cl2 (8 ml) were added 2,6-lutidine (395 ml, 3.40
mmol) and TBSOTf (519 ml, 2.26 mmol) at 0 ꢂC. After 15 min, the
reaction mixture was quenched with saturated aqueous NH4Cl and
extracted with CH2Cl2. The extract was successively washed with
water and brine, dried (Na2SO4), and concentrated in vacuo. The
(3aS,6S,6aR)-6-(4-Methoxybenzyloxy)tetrahydrofuro[3,2-b]furan-2-
one (14). To a stirred solution of 13 (414 mg, 1.57 mmol) in EtOAc

156
H. URANO et al.
residue was chromatographed over SiO2 (hexane/EtOAc ¼ 30:1) to
J ¼ 4:9, 6.8, 7.8 Hz), 3.71–3.76 (1H, m), 3.87 (1H, dd, J ¼ 3:4,
4.9 Hz), 3.93 (1H, dd, J ¼ 7:8, 8.3 Hz); 13C-NMR ꢃ: 14.1, 22.7, 26.3,
29.35, 29.39, 29.57, 29.60, 29.64, 29.66, 29.68, 29.69, 29.8, 31.9, 54.2,
71.7, 72.3 (2C), 83.2; HRMS (FAB) m=z (½M þ Hꢁþ): calcd. for
C18H38NO2, 300.2903; found, 300.2911.
25
give 296 mg (98%) of 20 as a colorless oil. ½ꢀꢁ
ꢀ5:6ꢂ (c 1.18,
D
CHCl3); IR ꢄmax: 2926 (s), 1614 (m), 1514 (m), 1250 (m); 1H-NMR ꢃ:
0.072 (3H, s), 0.082 (3H, s), 0.88 (3H, t, J ¼ 7:0 Hz), 0.91 (9H, s),
1.20–1.34 (22H, m), 1.34–1.42 (2H, m), 1.51–1.59 (1H, m), 1.59–1.68
(1H, m), 3.73–3.78 (2H, m), 3.81 (3H, s), 3.85 (1H, dd, J ¼ 7:5,
7.5 Hz), 3.94–3.99 (1H, m), 4.12 (1H, dd, J ¼ 4:0, 4.0 Hz), 4.43 (1H, d,
J ¼ 11:7 Hz), 4.55 (1H, d, J ¼ 11:7 Hz), 6.87 (2H, d, J ¼ 8:3 Hz), 7.24
(2H, d, J ¼ 8:3 Hz); 13C-NMR ꢃ: ꢀ4:9, ꢀ4:2, 14.1, 18.5, 22.7, 25.9
(3C), 26.2, 29.4, 29.59, 29.62, 29.64 (2C), 29.67 (2C), 29.69, 29.73,
29.76, 31.9, 55.2, 68.5, 72.0, 73.0, 79.1, 81.3, 113.7 (2C), 129.3 (2C),
130.3, 159.2; HRMS (FAB) m=z (½M þ Naꢁþ): calcd. for
C32H58O4SiNa, 557.4002; found, 557.4004.
3-[(2R,3aS,6S,6aS)-6-Tetradecylhexahydrofuro[3,4-d]oxazol-2-yl]-
1-propanol (2). To a stirred solution of 1 (24 mg, 0.081 mmol) and
tetrahydro-2-furanol (21 mg, 0.24 mmol) in MeOH (1.5 ml) was added
TsOHꢄH2O (4.6 mg, 0.024 mmol) at room temperature. After 17 h, the
reaction mixture was concentrated in vacuo and the residue was
chromatographed over SiO2 (Kanto Kagaku silica gel 60N,
CHCl3=MeOH ¼ 30:1) to give 27 mg (89%) of 2 as a colorless
22
20
powder. Mp 82–83 ꢂC; ½ꢀꢁ
þ26ꢂ (c 0.27, CHCl3) (lit.2 ½ꢀꢁ
þ25ꢂ
D
D
(4R,5S)-4-(tert-Butyldimethylsilyloxy)-5-tetradecyldihydrofuran-3-
one (21). To a stirred solution of 20 (296 mg, 0.550 mmol) in CH2Cl2
(9.4 ml) containing a phosphate buffer (pH 7.0, 0.1 M, 0.47 ml) was
added DDQ (151 mg, 0.660 mmol) at room temperature. After 4.5 h,
the reaction mixture was quenched with saturated aqueous NaHCO3
and extracted with CH2Cl2. The extract was successively washed with
water and brine, dried (Na2SO4), and concentrated in vacuo to give
224 mg of crude 18 which was then dissolved in CH2Cl2 (12 ml). The
solution was added to a suspension of Dess-Martin periodinane
(687 mg, 1.62 mmol) and NaHCO3 (136 mg, 1.62 mmol) in CH2Cl2
(6 ml) at room temperature. After 2 h, the reaction mixture was
quenched with saturated aqueous Na2S2O3 and extracted with CH2Cl2.
The extract was successively washed with water and brine, dried
(Na2SO4), and concentrated in vacuo. The residue was chromato-
(c 1, CHCl3)); IR ꢄmax: 3303 (w), 2921 (s), 2850 (s), 1468 (w), 1054
(w); 1H-NMR ꢃ: 0.88 (3H, t, J ¼ 6:8 Hz), 1.24–1.37 (22H, m), 1.37–
1.46 (2H, m), 1.56 (2H, br s, OH, NH), 1.66–1.79 (6H, m), 3.39 (1H,
dt, J ¼ 3:5, 7.0 Hz), 3.63–3.72 (3H, m), 3.90 (1H, d, J ¼ 10:3 Hz),
4.05 (1H, dd, J ¼ 6:0, 6.0 Hz), 4.34 (1H, dd, J ¼ 3:5, 5.6 Hz), 4.51
(1H, m); 13C-NMR (pyridine-d5) ꢃ: 14.2, 22.9, 26.6, 29.5, 29.8–29.9
(8C), 30.0, 30.1, 31.3, 32.0, 61.8, 64.1, 74.4, 80.9, 84.1, 94.4;
13C-NMR (CDCl3) ꢃ: 14.1, 22.7, 26.3, 28.6, 28.8, 29.2, 29.4, 29.6–29.8
(7C), 31.4, 31.9, 62.7, 63.4, 73.7, 80.8, 83.9, 93.7; HRMS (FAB) m=z
(½M þ Hꢁþ): calcd. for C22H44NO3, 370.3321; found, 370.3326.
Acknowledgments
This work was supported, in part, by grant-aid for
scientific research (B) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan
(no. 19380065). We also thank Ms. Yamada (Tohoku
University) for measuring the NMR and MS data.
graphed over SiO2 (hexane/EtOAc ¼ 100:1) to give 196 mg (86%
25
from 20) of 21 as a colorless oil. ½ꢀꢁ
ꢀ22:1ꢂ (c 1.42, CHCl3); IR
D
ꢄ
max: 2926 (s), 1773 (m), 1468 (m), 1254 (m); 1H-NMR ꢃ: 0.11 (3H, s),
0.14 (3H, s), 0.88 (3H, t, J ¼ 7:0 Hz), 0.91 (9H, s), 1.23–1.40 (22H,
m), 1.44–1.54 (2H, m), 1.52–1.65 (2H, m), 3.94 (1H, d, J ¼ 17:8 Hz),
3.98 (1H, d, J ¼ 17:8 Hz), 4.16–4.20 (1H, m), 4.24 (1H, d,
J ¼ 6:5 Hz); 13C-NMR ꢃ: ꢀ5:3, ꢀ4:6, 14.1, 18.3, 22.7, 25.4, 25.65,
25.67 (3C), 27.8, 29.3, 29.5 (2C), 29.64 (2C), 29.66, 29.68 (2C), 31.9,
67.6, 74.1, 80.6, 213.7; HRMS (FAB) m=z (½M þ Hꢁþ): calcd. for
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25
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23
25
EtOH), lit.15 ½ꢀꢁ
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