Stereoselective synthesis of (2R,3S,4S)-3-hydroxy-4-methyl-2-tetradecyl-4- butanolide starting from 2,5-anhydro-D-mannitol

Article abstract of DOI:10.1016/j.tet.2005.04.059

A novel approach to natural β-hydroxy-γ-lactone 2 from 2,5-anhydro-d-mannitol (1) is described. The key reactions in this synthesis include stereoselective methylation of aldehyde 3 with lithium dimethylcuprate, an intramolecular radical cyclization of seleno carbonate 11 and an intermolecular cross-metathesis of 3-allyl-4-hydroxy-γ-lactone 16 with 1-tridecene.

Full text of DOI:10.1016/j.tet.2005.04.059

Tetrahedron 61 (2005) 6540–6545
Stereoselective synthesis of
(2R,3S,4S)-3-hydroxy-4-methyl-2-tetradecyl-4-butanolide
starting from 2,5-anhydro-D-mannitol
a
b
c
Shunya Takahashi,a, Narihito Ogawa, Nobuo Sakairi and Tadashi Nakata
*
aRIKEN (The Institute of Physical and Chemical Research), Wako-shi, 351-0198 Saitama, Japan
bGraduate School of Environmental Earth Science, Hokkaido University, Kita-ku 060-0810 Sapporo, Japan
cDepartment of Chemistry, Faculty of Science, Tokyo University of Science, 1-3, Kagurazaka, Shinjuku-Ku, 162-8601 Tokyo, Japan
Received 18 April 2005; revised 26 April 2005; accepted 26 April 2005
Available online 23 May 2005
Abstract—A novel approach to natural b-hydroxy-g-lactone 2 from 2,5-anhydro-D-mannitol (1) is described. The key reactions in this
synthesis include stereoselective methylation of aldehyde 3 with lithium dimethylcuprate, an intramolecular radical cyclization of seleno
carbonate 11 and an intermolecular cross-metathesis of 3-allyl-4-hydroxy-g-lactone 16 with 1-tridecene.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
congested compounds are prone to elimination of the
hydroxyl group during synthesis. Therefore, several syn-
thetic methods to overcome such a problem have been
devised, and total syntheses have been reported.7
Carbohydrates and their related compounds have been well
recognized as a chiral pool for the syntheses of optical
active natural products.1 2,5-Anhydro-D-mannitol (1),2
however, has not been employed as a starting material for
such syntheses† (Fig. 1). One of the reasons seems to stem
from the difficulties of desymmetrization of 1. For example,
mono acylation or alkylation of 1 under restricted conditions
is reported to result in a mixture of di- and mono protected
mannitol derivatives along with 1.3 In the course of our
synthetic studies on mucocin, we have developed a highly
efficient method for desymmetrization of 1.4 As part of our
continuing studies in this field, we describe herein the
stereocontrolled synthesis of (2R,3S,4S)-3-hydroxy-4-
methyl-2-tetradecyl-4-butanolide (2) starting from 1. The
lactone 2 was isolated from the methanol extract of fruits of
Trichila claussenii in admixture with its 70-dehydro form.5
Its biological activities, which remain unclear, are of
interest in connection with annonaceous acetogenins having
prominent biological properties such as cytotoxity and
antitumor activity.6 Structurally, the butanolide 2 has three
cis-substituents on the g-lactone ring, and such sterically
2. Results and discussion
Synthesis of 2 began from the preparation of 1. Although 1
had been prepared from D-glucosamine,10 we newly found
that 1 was also obtainable from a readily available
polysaccharide, chitosan. Thus, chitosan was treated with
sodium nitrite in aqueous acetic acid and subsequently
reduced with sodium borohydride to give 1 in 67% yield
(Scheme 1). The compound 1 was transformed into
aldehyde 3 in good overall yield according to the procedure
previously reported.4 Stereoselective methylation11 of 3 was
accomplished by the action of lithium dimethylcuprate in
Keywords: 2,5-Anhydro-D-mannitol; Intramolecular radical cyclization;
Intermolecular cross-metathesis.
*
Corresponding author. Tel: C81 48 467 9223; fax: C81 48 462 4627;
e-mail: shunyat@riken.go.jp
† Because of its unique C2-symmetrical structure, 1 served as a chiral
ligand of catalysts for asymmetric hydrogenation,8 and a central core of
chiral dendrimers.9
Figure 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.059

S. Takahashi et al. / Tetrahedron 61 (2005) 6540–6545
6541
Scheme 1. (a) NaNO2, 5% aqueous AcOH, 0 8C, and NaBH4, MeOH, 67%; (b) Ref.10; (c) Ref. 4; (d) Me2CuLi, Et2O, K78 8C, 70% (O92% de); (e) MOMCl,
i-Pr2NEt, CH2Cl2, rt,; (f) TBAF, THF, rt, 83% (two steps from 4); (g) MsCl, Et3N, CH2Cl2, rt, 74%; (h) Zn, NaI, DMF, 140 8C, 89%; (i) 10%HCl–MeOH,
CH2Cl2, rt, 97%; (j) TBDPSCl, imidazole, DMF, rt, 81%; (k) triphosgene, pyridine, CH2Cl2, 0 8Cwrt and then PhSeH, Et3N, 0 8Cwrt, 95%; (l) Bu3SnH,
AIBN, toluene, 100 8C, 93%.
ether at K78 8C to give 4 in high selectivity (O92% de, by
1H NMR analyses) while reaction with methylmagnesium
iodide–zinc chloride in dichloromethane–ether decreased
both yields and selectivities. The newly created stereo-
chemistry was determined by the modified Mosher’s
method12 of the corresponding MTPA esters. Furthermore,
this result was also confirmed by the chemical conversion of
4 into the final product 2. The stereoselectivity would be
explained by the formation of cyclic chelate13 involving the
aldehyde carbonyl and the ring oxygen. The free hydroxyl
group in 4 was temporarily protected as methoxymethyl
(MOM) ether with MOMCl and N,N-diisopropylethyl-
amine, and the resulting compound 5 was treated with
tetrabutylammonium fluoride, affording diol 6 in 83% yield
from 4. For deoxygenation of the tetrahydrofuran ring, 6
was mesylated to give dimesylate 7 in 74% yield. Upon
treatment with zinc powder–sodium iodide,14 7 led to olefin
8 in 89% yield. The compound 8 reacted with hydrogen
chloride in methanol–dichloromethane to provide diol 9,
which was silylated with tert-butylchlorodiphenylsilane to
give alcohol 10 in 79% yield (two steps). Successive
treatment of 10 with triphosgene15 and benzeneselenol16 in
a one-pot manner afforded seleno carbonate 11 in 95%
yield. Radical cyclization of 11 with tributyltin hydride
proceeded nicely to give g-lactone 12 as a single isomer in
93% yield. This complete stereoselection reflects the
stereochemical requirement of a 2,7-dioxabicyclo[3.3.0]
octane ring system.
Scheme 2. (a) TBAF, THF, rt, 89%; (b) p-TsCl, DMAP, Et3N, CH2Cl2,
0 8Cwrt, 94%; (c) NaI, acetone, 55 8C; (d) Zn, aqueous THF, 65 8C, 93%
(two steps form 14); (e) 1-tridecene, Grubbs catalyst 1st generation,
CH2Cl2, 40 8C, 45%; (f) (Ph3P)3RhCl, H2, benzene, rt, 95%.
7/1, by 1H NMR analysis) in 45% yield (52% yield based on
16 consumed). The production of dimers derived from 16
was traced judging by TLC analysis. Unexpectedly, the use
of Grubbs catalyst 2nd generation gave unsatisfactory
results arising from the yields (20–25%).‡ Finally, 17
underwent hydrogenation with Wilkinson’s catalyst to give
the g-lactone 2 in 95% yield. The spectroscopic and
physical properties of 2 were consistent with those of 2
previously reported.5,7
Having completed the construction of the g-lactone ring, we
next turned to the final C–C bond formation (Scheme 2).
Prior to the elaboration, the silyl group in 12 was removed to
afford alcohol 13 in 89% yield. As direct iodination of 13
with iodine, triphenylphosphine, and imidazole resulted in a
low yield (w50%) of iodide 15, the alcohol 13 was initially
transformed into the corresponding tosylate 14 with p-TsCl-
triethylamine in the presence of N,N-dimethylaminopyr-
idine, and then 15 (sodium iodide, acetone) in high yield.
Zinc-mediated elimination reaction of 15 furnished olefin
16 in 93% yield from 14. Intermolecular cross-metathesis17
of 16 with 1-tridecene was effected by treatment with a
catalytic amount of Grubbs catalyst 1st generation in
dichloromethane at 40 8C to give g-lactone 17 (E/ZZca.
In summary, we succeeded in the stereoselective synthesis
of 2 employing 2,5-anhydro-D-mannitol (1) as a starting
‡ A considerable amount of a b-hydroxy lactone carrying a 10-tridecenyl
group was isolated as a major side product. The compound was estimated
to be produced from an isomerization of the double bond in 16 followed
by the cross-metathesis with 1-tridecene.

6542
S. Takahashi et al. / Tetrahedron 61 (2005) 6540–6545
material. This study also shows one example of utilization
of a polysaccharide for fine chemicals. Now, bioassay of 2
and further application of 1 to natural product syntheses are
underway.
(t, JZ6.5 Hz, 1H), 4.07 (br s, 1H), 3.94 (br s, 1H), 3.90 (m,
1H), 3.68 (dd, JZ5.1, 1.7 Hz, 1H), 3.38 (dd, JZ9.4, 6.7 Hz,
1H), 3.08 (dd, JZ9.4, 6.7 Hz, 1H), 3.01 (d, JZ3.4 Hz, 1H),
1.23 (d, JZ6.3 Hz, 3H), 0.89 (s, 9H), 0.73 (s, 9H), 0.11 (s,
3H), 0.09 (s, 3H), K0.01 (s, 3H), K0.02 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 143.9, 128.6, 127.6, 126.8, 91.5, 86.7,
86.6, 80.8, 80.6, 67.2, 64.2, 25.8, 25.7, 19.8, 18.0, 17.8,
K4.5 (2C), K4.6, K4.7; HRMS calcd for C38H56O5Si2Na
[MCNa]C671.3564, found 671.3563. Anal. Found: C,
70.24; H, 8.75. Calcd for C38H56O5Si2: C, 70.32; H, 8.70.
3. Experimental
3.1. General procedures
All reactions were carried out under an argon atmosphere,
unless otherwise noted. Melting points were determined
using a Yanaco MP-500 apparatus and are uncorrected.
Optical rotations were measured with a JASCO DIP-370
polarimeter. IR spectra were recorded with a JASCO
VALOR-III spectrophotometer. 1H NMR spectra were
recorded at 270 or 400 MHz with JEOL EX-270 or JNM-a
400 spectrometers, using tetramethylsilane as the internal
standard. Column chromatography was performed on Kanto
silica gel 60N (spherical, neutral; 40–100 mm). Merck
precoated silica gel 60 F254 plates, 0.25 mm thickness,
was used for analytical thin-layer chromatography. The
solvent extracts were dried with magnesium sulfate, and the
solutions were evaporated under diminished pressure at
40–42 8C.
3.1.3. (10S,2R,3R,4R,5R)-3,4-Bis(tert-butyldimethylsila-
nyloxy)-2-(10-methoxymethoxyethyl)-5-trityloxymethyl-
tetrahydrofuran (5). To a stirred solution of 4 (371 mg,
0.57 mmol) in CH2Cl2 (5.0 ml) was added chloromethyl
methyl ether (0.22 ml, 2.89 mmol) at 0 8C. The mixture was
stirred at 0 8Cwrt for two days, and then poured into ice-
water, extracted with ether. The extracts were washed
successively with water, cold aqueous HCl, water, saturated
aqueous NaHCO3, water, brine, dried, and concentrated to
give 5 (384 mg), which was employed to the next step
without further purification. An analytical sample was
prepared by preparative TLC {n-hexane/EtOAc (5:1)}. 5;
[a]2D4 K3.5 (c 0.95, CHCl3); IR (neat) 3060, 2954, 2930,
1252, 1115, 1090, 1035, 835, 775 cmK1 1H NMR
;
(400 MHz, CDCl3): d 7.45–7.42 (m, 6H), 7.26–7.24 (m,
9H), 4.73, 4.70 (each d, JZ6.8 Hz, 2H), 4.11 (t, JZ6.7 Hz,
1H), 4.09 (br s, 1H), 3.96 (br s, 1H), 3.92 (dt, JZ10.0,
6.5 Hz, 1H), 3.76 (dd, JZ7.0, 2.2 Hz, 1H), 3.38 (s, 3H),
3.30 (dd, JZ9.4, 6.1 Hz, 1H), 3.13 (dd, JZ9.4, 6.7 Hz, 1H),
1.19 (d, JZ6.3 Hz, 3H), 0.87 (s, 9H), 0.74 (s, 9H), 0.07 (s,
3H), 0.05 (s, 3H), 0.00 (s, 3H), K0.01 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 143.9, 128.6, 127.6, 126.8, 95.7, 90.2,
86.7, 86.6, 80.9, 80.5, 72.5, 64.2, 55.3, 25.8, 25.7, 17.9,
17.8, 17.3, K4.3, K4.4, K4.6 (2C); HRMS calcd for
C40H60O6Si2Na [MCNa]C715.3826, found 715.3843.
3.1.1. 2,5-Anhydro-D-mannitol (1). To an ice-cold solution
of chitosan (3.22 g, 0.02 mol of GlcNAc unit) in 5%
aqueous acetic acid (300 ml) was added sodium nitrite
(5.52 g, 0.08 mol) in several portions, and the mixture was
stirred at 0 8C for 6 h. Nitrogen gas was bubbled through the
mixture for 15 min. The resulting mixture was evaporated
and methanol (50 ml) was added to the residue, and the
insoluble solid was filtered off. Sodium borohydride (0.76 g,
0.02 mol) was added to the filtrate and the mixture was
stirred at 0 8C for 5 h. After treatment with Dowex 50W X4
(HC form), the mixture was evaporated and co-evaporated
with methanol several times. Methanol was added to the
residue and the solution was filtered through a Celite pad.
The filtrate was concentrated to ca. 20 ml and kept in a
refrigerator. The crystals were filtered and dried to give 1
(2.2 g, 67%); mp 100–102 8C (lit.10; mp 101–101.5 8C).
3.1.4. (10S,2S,3S,4S,5R)-2-(10-Methoxymethoxyethyl)-5-
trityloxymethyltetrahydrofuran-3,4-diol (6). To a stirred
solution of 5 (384 mg, 0.56 mmol) in tetrahydrofuran
(2.0 ml) was added a 1.0 M solution of n-tetrabutylammo-
nium fluoride (1.67 ml, 1.67 mmol) in tetrahydrofuran at rt.
After 5 h, the reaction mixture was diluted with EtOAc,
washed with water, brine, dried, and concentrated. The
residue was chromatographed on silica gel (toluene/EtOAc
Z1:1) to give 6 (214 mg, 83% from 4) as a colorless liquid;
[a]2D6C48.2 (c 0.48, CHCl3); IR (neat) 3432, 2931, 1448,
1100, 1070, 1035, 708 cmK1; 1H NMR (400 MHz, CDCl3):
d 7.45–7.40 (m, 6H), 7.29–7.21 (m, 9H), 4.73, 4.63 (each d,
JZ6.8 Hz, 2H), 4.09–3.93 (m, 5H), 3.45–3.27 (m, 3H), 3.37
(s, 3H), 3.20 (dd, JZ10.1, 3.4 Hz, 1H), 1.30 (d, JZ6.3 Hz,
3H); 13C NMR (100 MHz, CDCl3): d 143.2, 128.6, 127.8,
127.1, 94.9, 87.9, 87.6, 84.2, 79.9, 79.1, 72.9, 64.9, 55.9,
16.1; HRMS calcd for C28H32O6Na [MCNa]C487.2077,
found 487.2097. Anal. Found: C, 72.33; H, 6.87. Calcd for
C28H32O6: C, 72.39; H, 6.94.
3.1.2. (1S,20R,30R,40R,50R)-1-[30,40-Bis(tert-butyldi-
methylsilanyloxy)-50-trityloxymethyltetrahydrofuran-
20-yl]ethanol (4). To a stirred suspension of CuI (302 mg,
1.58 mmol) in ether (3.0 ml) was added dropwise a 1.6 M
solution of methyllithium (2.7 ml, 3.16 mmol) in ether at
K78 8C, and the mixture was stirred at the same
temperature for 30 min. A solution of 3 (251 mg,
0.4 mmol) in ether (1.0 ml) was added dropwise at K78 8C,
and the resulting mixture was stirred at K78–K30 8C for
1 h. After addition of saturated aqueous NH4Cl, the
resulting mixture was allowed to warm to rt with stirring,
and extracted with ether. The extracts were washed with
water, brine, dried, and concentrated. The residue was
chromatographed on silica gel (n-hexane/EtOAcZ20:1) to
give a 24:1 mixture of 4 and its diastereomer (181 mg, 70%)
as a colorless liquid. The major isomer 4 was separated by
chromatography on silica gel (n-hexane/EtOAc Z15:1). 4;
[a]2D4 C5.6 (c 1.06, CHCl3); IR (neat) 3450, 3060, 2930,
3.1.5. (10S,2R,3R,4R,5R)-3,4-(Dimethanesulfonyloxy)-2-
(10-methoxymethoxyethyl)-5-trityloxymethyltetrahydro-
furan (7). To a stirred solution of 6 (214 mg, 0.46 mmol)
and triethylamine (0.52 ml, 3.70 mmol) in dichloromethane
(2.0 ml) was added methanesulfonyl chloride (0.11 ml,
1.38 mmol) at 0 8C, and the mixture was stirred at 0 8Cwrt
1
1258, 1089, 1069, 835, 775 cmK1; H NMR (400 MHz,
CDCl3): d 7.46–7.44 (m, 6H), 7.28–7.21 (m, 9H), 4.19

S. Takahashi et al. / Tetrahedron 61 (2005) 6540–6545
6543
for 12 h, poured into ice-water. The resulting mixture was
stirred for 2 h and extracted with ether. The extracts were
washed successively with cold aqueous HCl, water, satur-
ated aqueous NaHCO3, water, brine, dried and concentrated.
The residue was chromatographed on silica gel (n-hexane/
EtOAcZ2:1) to give 7 (211 mg, 74%) as amorphous solids;
mp 88–90 8C (ether); [a]2D4 C40.3 (c 1.05, CHCl3); IR
(KBr) 2937, 2873, 1448, 1359, 1179, 1100, 1035, 960,
3.1.8. (1S,20S,50S)-1-[50-(tert-Butyldiphenylsilanyloxy-
methyl)-20,50-dihydrofuran-20-yl]ethanol (10). To a stir-
red mixture of 9 (245 mg, 1.70 mmol) and imidazole
(289 mg, 4.3 mmol) in N,N-dimethylformamide (2.0 ml)
was tert-butylchlorodiphenylsilane (0.59 ml, 2.3 mmol) at
rt. After 6 h, the mixture was poured into ice-water, and
extracted with dichloromethane. The extracts were washed
successively with cold aqueous HCl, water, saturated
aqueous NaHCO3, water, brine, dried and concentrated.
The residue was chromatographed on silica gel (n-hexane/
EtOAcZ2:1) to give 10 (566 mg, 81%) as a colorless oil;
[a]2D1 K113.5 (c 1.02, CHCl3); IR (neat) 3438, 3072, 2931,
1
834 cmK1; H NMR (400 MHz, CDCl3): d 7.46–7.44 (m,
6H), 7.33–7.25 (m, 9H), 5.39 (dd, JZ5.4, 3.9 Hz, 1H), 5.32
(dd, JZ5.4, 3.4 Hz, 1H), 4.75, 4.71 (each d, JZ6.8 Hz, 2H),
4.33 (dd, JZ8.2, 3.8 Hz, 1H), 4.23 (dd, JZ5.8, 3.1 Hz, 1H),
4.00 (m, 1H), 3.46 (dd, JZ10.4, 4.1 Hz, 1H), 3.42 (s, 3H),
3.27 (dd, JZ10.4, 3.9 Hz, 1H), 3.12 (s, 3H), 2.97 (s, 3H),
1.34 (d, JZ6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
143.4, 128.6, 127.9, 127.2, 95.8, 87.2, 84.8, 83.5, 83.2, 81.4,
71.7, 62.8, 55.9, 38.5, 38.2, 16.5; HRMS calcd for
C30H36O10S2Na [MCNa]C643.1648, found 643.1646.
Anal. Found: C, 56.07; H, 5.76. Calcd for C30H36O10S2$
H2O: C, 56.41; H, 6.00.
1
2858, 1589, 1428, 1136, 1113, 1083, 702 cmK1; H NMR
(400 MHz, CDCl3): d 7.69–7.66 (m, 4H), 7.42–7.36 (m,
6H), 5.94 (br d, JZ6.0 Hz, 1H), 5.81 (br d, JZ6.0 Hz, 1H),
4.92 (m, 1H), 4.59 (br t, JZ3.8 Hz, 1H), 3.71 (dd, JZ
10.6 Hz, 4.6 Hz, 1H), 3.68 (dd, JZ10.6, 5.1 Hz, 1H), 3.63
(m, 1H), 2.24 (m, 1H), 1.18 (d, JZ6.5 Hz, 3H), 1.05 (s, 9H);
13C NMR (100 MHz, CDCl3): d 135.5, 135.4, 133.5, 129.8,
129.5, 127.8, 127.5, 90.8, 86.7, 70.4, 66.4, 26.9, 19.4, 18.7;
HRMS calcd for C23H30O3SiNa [MCNa]C405.1862, found
405.1846.
3.1.6. (10S,2S,5S)-2-(10-Methoxymethoxyethyl)-5-trityl-
oxymethyl-2,5-dihydrofuran (8). A mixture of 7 (211 mg,
0.34 mmol), zinc powder (334 mg, 5.12 mmol) and sodium
iodide (409 mg, 2.73 mmol) in N,N-dimethylformamide
(2.5 ml) was stirred at 140 8C for 27 h. More zinc powder
(334 mg, 5.12 mmol) and sodium iodide (409 mg,
2.73 mmol) were added, and stirring was continued for
7 h. The resulting mixture was cooled to rt, diluted with
water, and then extracted with dichloromethane. The
extracts were washed successively with water, brine,
dried, and concentrated. The residue was chromatographed
on silica gel (n-hexane/EtOAcZ10:1) to give 8 (130 mg,
89%) as a colorless oil; [a]2D4 K110.3 (c 1.04, CHCl3); IR
(neat) 2930, 2882, 1491, 1448, 1216, 1153, 1104, 1086,
1038, 788, 762 cmK1; 1H NMR (400 MHz, CDCl3): d 7.43–
7.40 (m, 6H), 7.28–7.19 (m, 9H), 5.96 (dt, JZ6.3, 2.0 Hz,
1H), 5.83 (dt, JZ6.3, 1.9 Hz, 1H), 4.97 (m, 1H), 4.87 (m,
1H), 4.69 (s, 2H), 3.77 (qd, JZ6.5, 6.3 Hz, 1H), 3.36 (s,
3H), 3.17 (dd, JZ9.2, 4.8 Hz, 1H), 3.06 (dd, JZ9.2, 4.3 Hz,
1H), 1.12 (d, JZ6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 143.9, 129.9, 128.6, 127.7, 127.6, 126.8, 95.6, 88.8, 86.4,
85.3, 74.9, 55.4, 15.9; HRMS calcd for C28H30O4Na [MC
Na]C 453.2042, found 453.2029.
3.1.9. (1S,20S,50S)-1-[50-(tert-Butyldiphenylsilanyloxy-
methyl)-20,50-dihydrofuran-20-yl]ethyl phenylselenocar-
bonate (11). To a stirred mixture of 10 (566 mg,
1.48 mmol) and triphosgene (161 mg, 0.54 mmol) in
dichloromethane (3.0 ml) was added pyridine (0.14 ml,
1.78 mmol) at 0 8C. After 30 min, the reaction mixture was
allowed to warm to rt with stirring for 2 h. Then
benzeneselenol (0.31 ml, 2.96 mmol) and triethylamine
(0.83 ml, 5.92 mmol) were added sequentially at 0 8C with
stirring. The resulting mixture was stirred at 0 8C for 30 min
and rt for 1 h, and then diluted with hexane, poured into a
column of silica gel. Elution with toluene/hexane (1/2/1/0)
gave 11 (794 mg, 95%) as a light-yellow oil; [a]2D2 K123.3
(c 1.15, CHCl3); IR (neat) 2931, 2857, 1728, 1428, 1131,
1044, 703 cmK1; 1H NMR (400 MHz, CDCl3): d 7.69–7.63
(m, 4H), 7.62–7.61 (m, 2H), 7.42–7.35 (m, 9H), 5.98 (br d,
JZ6.3 Hz, 1H), 5.75 (br d, JZ6.3 Hz, 1H), 5.10 (qd, JZ
6.5, 3.6 Hz, 1H), 4.85–4.84 (m, 2H), 3.72 (dd, JZ10.4,
3.8 Hz, 1H), 3.68 (dd, JZ10.4, 4.8 Hz, 1H), 1.30 (d, JZ
6.5 Hz, 3H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3): d
166.2, 135.6, 135.5, 135.4, 133.5, 133.4, 130.7, 129.5,
129.4, 129.1, 128.9, 127.5, 126.8, 87.4, 86.9, 76.0, 66.3,
26.9, 19.4, 15.9; HRMS calcd for C30H34O4SiNaSe [MC
Na]C589.1292, found 589.1290.
3.1.7. (1S,20S,50S)-1-[50-(Hydroxymethyl)-20,50-dihydro-
furan-20-yl]ethanol (9). To a stirred solution of 8 (1.03 g,
2.39 mmol) in dichloromethane (8.0 ml) was added a 10%
solution of hydrogen chloride (2.0 ml) in methanol at 0 8C,
and the mixture was stirred at 0 8Cwrt for two days. After
being neutralized by NaHCO3 powder, the resulting mixture
was filtered, and then concentrated. The residue was
chromatographed on silica gel (EtOAc/chloroform/
methanolZ20:1) to give 9 (334 mg, 97%) as a colorless
oil; [a]2D4 K173.9 (c 1.08, CHCl3); IR (neat) 3369, 2873,
3.1.10. (2S,3aR,6S,6aS)-2-(tert-Butyldiphenylsilanyloxy-
methyl)-6-methyltetrahydrofuro[3,4-b]furan-4-one (12).
To a stirred solution of 11 (669 mg, 1.18 mmol) in toluene
(35 ml) was added dropwise a mixture of n-tributyltin
hydride (0.64 ml, 2.37 mmol) and a trace amount of AIBN
in toluene (5.0 ml) at 100 8C over 30 min. The mixture was
stirred at the same temperature for 40 min and concentrated.
The residue was chromatographed on silica gel (n-hexane/
EtOAc Z10:1/4:1) to give 12 (450 mg, 93%) as a white
solid; [a]2D2 K24.3 (c 1.09, CHCl3); IR (KBr) 2932, 2860,
1
1366, 1071, 1039 cmK1; H NMR (400 MHz, CDCl3): d
5.86 (br d, JZ5.8 Hz, 1H), 5.84 (br d, JZ5.8 Hz, 1H), 4.95
(m, 1H), 4.66 (t, JZ6.8 Hz, 1H), 3.71 (br d, JZ11.6 Hz,
1H), 3.64 (qd, JZ6.8, 6.3 Hz, 1H), 3.54 (br dd, JZ11.6,
4.8 Hz, 1H), 2.83 (s, 1H), 2.60 (s, 1H), 1.16 (d, JZ6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): d 128.5, 128.4, 91.2,
87.1, 70.4, 64.9, 18.5; HRMS calcd for C7H12O3Na [MC
Na]C167.0684, found 167.0679.
1
1772, 1348, 1178, 1132, 1113, 1005, 702 cmK1; H NMR
(400 MHz, CDCl3): d 7.68–7.64 (m, 4H), 7.45–7.38 (m,
6H), 4.59–4.54 (m, 2H), 4.12 (qd, JZ6.3, 4.1 Hz, 1H), 3.77
(dd, JZ11.1, 3.9 Hz, 1H), 3.66 (dd, JZ11.1, 4.1 Hz, 1H),
3.32 (dd, JZ8.2, 5.3 Hz, 1H), 2.43 (ddd, JZ12.8, 6.3,

6544
S. Takahashi et al. / Tetrahedron 61 (2005) 6540–6545
1.2 Hz, 1H), 2.20 (ddd, JZ12.8, 9.0, 8.7 Hz, 1H), 1.45 (d,
JZ6.5 Hz, 3H), 1.06 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 178.0, 135.5, 135.4, 133.3, 133.1, 129.7, 129.6, 127.6,
127.5, 80.4, 80.1, 79.5, 65.8, 47.5, 31.5, 26.9, 19.4, 14.4;
HRMS calcd for C24H30O4SiNa [MCNa]C433.1811, found
433.1841. Anal. Found: C, 70.27; H, 7.39. Calcd for
C24H30O4Si: C, 70.21; H, 7.36.
JZ13.0, 5.5 Hz, 1H), 2.01 (ddd, JZ13.0, 9.5, 8.7 Hz, 1H),
1.46 (d, JZ6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
177.2, 80.7, 79.8, 78.3, 47.6, 36.3, 14.4, 9.1; HRMS calcd
for C8H11IO3Na [MCNa]C304.9651, found 304.9642.
3.1.14. (2R,3S,4S)-2-Allyl-3-hydroxy-4-methyl-4-butano-
lide (16). A mixture of the above iodide 15 (199 mg, ca.
0.63 mmol) and zinc powder (824 mg, 12.6 mmol) in
tetrahydrofuran–water (20:1, 16.6 ml) was stirred at 65 8C
for 3 h, cooled to rt, and then filtered through a pad of Celite.
The filtrate was extracted with dichloromethane. The
extracts were washed with brine, dried, and concentrated.
The residue was chromatographed on silica gel (n-pentane/
etherZ2:1/0:1) to give 16 (92 mg, 93%) as a colorless
liquid; [a]2D1 K81.1 (c 1.00, CHCl3); IR (neat) 3447, 3083,
2982, 2937, 1755, 1644, 1386, 1359, 1188, 1042, 1005, 980,
3.1.11. (2S,3aR,6S,6aS)-2-Hydroxymethyl-6-methylte-
trahydrofuro[3,4-b]furan-4-one (13). Treatment of 12
(1.56 g, 3.80 mmol) as described for preparation of 6 from
5 gave 13 (581 mg, 89%) as a colorless oil; [a]2D2 K60.0 (c
1.09, CHCl3); IR (neat) 3448, 2939, 1767, 1449, 1356,
1194, 1140, 1056, 1031 cmK1 1H NMR (400 MHz,
;
CDCl3): d 4.63–4.58 (m, 2H), 4.06 (m, 1H), 3.80 (br d,
JZ11.8 Hz, 1H), 3.53 (dd, JZ11.8, 4.1 Hz, 1H), 3.35 (dd,
JZ8.2, 5.3 Hz, 1H), 2.39 (dd, JZ12.8, 5.3 Hz, 1H), 2.13
(dddd, JZ12.8, 9.8, 9.6, 0.9 Hz, 1H), 1.90 (br s, 1H), 1.45
(d, JZ6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 177.7,
80.2, 80.0, 79.8, 63.5, 47.5, 30.9, 14.4; HRMS calcd for
C8H13O4 [MCH]C173.0814, found 173.0812.
1
923 cmK1; H NMR (400 MHz, CDCl3): d 5.90 (m, 1H),
5.20 (ddd, JZ17.2, 2.9, 1.5 Hz, 1H), 5.11 (ddd, JZ13.2,
2.4, 1.5 Hz, 1H), 4.47 (qd, JZ6.5, 3.1 Hz, 1H), 4.33 (dd,
JZ8.0, 4.8 Hz, 1H), 2.71 (ddd, JZ10.6, 4.8, 4.6 Hz, 1H),
2.62 (ddd, JZ14.9, 5.8, 4.6 Hz, 1H), 2.44 (m, 1H), 2.06 (m,
1H), 1.43 (d, JZ6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 176.8, 135.1, 116.9, 79.0, 70.9, 47.1, 27.9, 13.8; HRMS
calcd for C8H13O3 [MCH]C157.0865, found 157.0863.
3.1.12. (2S,3aR,6S,6aS)-6-Methyl-2-tosyloxymethyltetra-
hydrofuro[3,4-b]furan-4-one (14). To a stirred mixture of
13 (462 mg, 1.02 mmol), N,N-dimethylaminopyridine
(8.2 mg, 0.07 mmol) and triethylamine (0.37 ml, 2.68 mmol)
in dichloromethane (8.0 ml) was added p-toluenesulfonyl
chloride (256 mg, 1.34 mmol) at 0 8C. The mixture was
stirred at 0 8C for 30 min and at rt for 1.5 h, and then poured
into ice-water. The resulting mixture was extracted with
dichloromethane. The extracts were washed successively
with cold aqueous HCl, water, saturated aqueous NaHCO3,
water, brine, dried and concentrated. The residue was
chromatographed on silica gel (dichloromethane/methanolZ
20:1) to give 14 (206 mg, 94%) as a colorless oil; [a]D24
K32.2 (c 1.02, CHCl3); IR (neat) 2939, 1770, 1600, 1451,
3.1.15. (2R,3S,4S)-3-Hydroxy-4-methyl-2-(20-tetradecen-
yl)-4-butanolide (17). A mixture of 16 (4.8 mg, 31 mmol),
1-tridecene (22 ml, 93 mmol) and Grubbs catalyst 1st
generation (0.8 mg, 0.8 mmol) in dichloromethane (1.0 ml)
was stirred at 40 8C for 3 h. More catalyst (0.8 mg,
0.8 mmol) was added and the mixture was stirred for an
additional 6 h, then cooled to rt. Florisil was added with
stirring, and the resulting mixture was allowed to stand
overnight, then filtered through a pad of Celite. The filtrate
was concentrated to give a syrup, which was chromato-
graphed on silica gel (n-hexane/EtOAcZ4:1) to give 17
(4.3 mg, 45%) as an amorphous solid. In addition, starting
lactone 16 (0.6 mg) was also recovered.
1359, 1190, 1176, 1139, 1096, 976 cmK1 1H NMR
;
(400 MHz, CDCl3): d 7.77 (dd, JZ8.2, 1.7 Hz, 2H), 7.34
(d, JZ7.8 Hz, 1H), 4.56–4.51 (m, 2H), 4.15 (m, 1H), 4.13
(dt, JZ10.9, 2.2 Hz, 1H), 3.99 (ddd, JZ10.9, 4.2, 1.5 Hz,
1H), 3.31 (dd, JZ9.0, 5.3 Hz, 1H), 2.44 (s, 3H), 2.43 (br dd,
JZ13.0, 6.2 Hz, 1H), 2.07 (m, 1H), 1.38 (d, JZ6.3 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 177.1, 144.9, 132.6, 129.8,
127.8, 80.7, 79.3, 76.7, 70.5, 47.2, 31.2, 21.7, 14.3; HRMS
calcd for C15H18O6SNa [MCNa]C349.0722, found
349.0714.
Compound 17. [a]2D1 K48.3 (c 1.04, CHCl3); IR (neat) 3449,
1
2922, 2851, 1733, 1468, 1194, 1135, 1044, 972 cmK1; H
NMR of major isomer (400 MHz, CDCl3): d 5.62 (ddd, JZ
15.2, 7.0, 6.5 Hz, 1H), 5.48 (ddd, JZ15.2, 7.7, 6.7 Hz, 1H),
4.47 (qd, JZ6.3, 3.1 Hz, 1H), 4.33 (dd, JZ8.0, 4.1 Hz, 1H),
2.59 (ddd, JZ14.7, 5.6, 5.3 Hz, 1H), 2.37 (ddd, JZ14.9,
10.7, 7.8 Hz, 1H), 2.00 (m, 2H), 1.44 (d, JZ6.6 Hz, 3H),
1.38–1.20 (m, 18H), 0.88 (t, JZ6.3 Hz, 3H); 13C NMR of
major isomer (100 MHz, CDCl3): d 176.8, 133.5, 126.2,
78.9, 71.0, 47.5, 32.6, 31.9, 29.7 (3C), 29.6, 29.4 (2C), 29.3,
26.9, 22.7, 14.2, 13.8; HRMS calcd for C19H34O3Na [MC
Na]C333.2406, found 333.2413.
3.1.13. (2S,3aR,6S,6aS)-2-Iodomethyl-6-methyltetra-
hydrofuro[3,4-b]furan-4-one (15). A mixture of 14
(207 mg, 0.63 mmol) and sodium iodide (1.89 g,
12.6 mmol) in acetone (10 ml) was heated under reflux
with stirring for 20 h, cooled to rt, and concentrated. The
residue was diluted with EtOAc, filtered through a pad of
Celite, and the filtrate was concentrated to give 15 (199 mg)
as a yellow liquid, which was employed to the next step
without further purification. An analytical sample was
prepared by preparative TLC {chloroform/methanol (20:1),
two developments}. 15; [a]2D1 K60.9 (c 0.35, CHCl3); IR
3.1.16. (2R,3S,4S)-3-Hydroxy-4-methyl-2-tetradecyl-4-
butanolide (2). A mixture of 17 (10.4 mg, 34 mmol) and
Wilkinson catalyst (7.1 mg, 7.7 mmol) in benzene (0.6 ml)
was stirred at rt under hydrogen for 6.5 h, and then
concentrated. The residue was chromatographed on silica
gel (n-hexane/EtOAcZ4:1) to give 2 (9.9 mg, 95%) as
colorless crystals; mp 93–94 8C (n-hexane/ether) {lit.7a, 86–
88 8C for (C)-form}; [a]2D2 K43.6 (c 0.67, CHCl3) {lit.7a;
[a]2D5 C37.2 for (C)-form, lit.7b; [a]D K36.7}; IR (KBr)
(neat) 2936, 1770, 1353, 1185, 1158, 1139, 1001, 910 cmK1
;
1H NMR (400 MHz, CDCl3): d 4.72 (dd, JZ5.5, 3.9 Hz,
1H), 4.59 (qd, JZ6.5, 3.8 Hz, 1H), 3.93 (ddd, JZ11.4, 9.9,
5.5 Hz, 1H), 3.37 (dd, JZ8.2, 6.0 Hz, 1H), 3.32 (dd, JZ
10.4, 5.6 Hz, 1H), 3.28 (dd, JZ10.4, 4.3 Hz, 1H), 2.61 (dd,
3423, 2930, 2851, 1735, 1457, 1225, 1203, 1160, 1122 cmK1
1H NMR (400 MHz, CDCl3): d 4.45 (qd, JZ6.5, 3.1 Hz,
;

S. Takahashi et al. / Tetrahedron 61 (2005) 6540–6545
6545
G. M.; Christina, A. E.; Buizert, A. E. M.; van der Marel,
G. A.; Overkleeft, H. S.; Overhand, M. J. Org. Chem. 2004,
69, 8331–8339.
1H), 4.32 (dd, JZ4.8, 3.2 Hz, 1H), 2.58 (dt, JZ10.1,
4.8 Hz, 1H), 1.83 (m, 1H), 1.63 (m, 1H), 1.56 (m, 1H), 1.44
(d, JZ6.5 Hz, 3H), 1.40–1.19 (m, 24H), 0.88 (t, JZ6.3 Hz,
3H); 13C NMR (100 MHz, CDCl3): d 177.4, 78.8, 71.2,
47.6, 32.0, 29.8 (3C), 29.7 (3C), 29.6, 29.5, 29.4, 27.7, 23.4,
22.8, 14.2, 13.8; HRMS calcd for C19H36O3Na [MCNa]C
335.2562, found 335.2562.
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Acknowledgements
This work was supported by the Chemical Biology Project
(RIKEN). We thank Ms. K. Harata (RIKEN) for mass
spectral measurements, and Dr. T. Chihara and his
collaborators in RIKEN for the elemental analyses.
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