The synthesis and applications of asymmetric phase-transfer catalysts derived from isomannide and isosorbide

Article abstract of DOI:10.1016/j.tet.2005.02.010

We report herein the synthesis of various derivatives of isomannide and isosorbide. Alkylation on N-(diphenylmethylene)glycine tert-butyl ester show the new catalysts to be effective phase-transfer catalysts with moderately good enantioselectivity. The ef

Full text of DOI:10.1016/j.tet.2005.02.010

Tetrahedron 61 (2005) 4141–4148
The synthesis and applications of asymmetric phase-transfer
catalysts derived from isomannide and isosorbide
*
Sanjeev Kumar and Uma Ramachandran
Department of Pharmaceutical Technology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, Mohali,
Punjab 160 062, India
Received 20 October 2004; revised 17 January 2005; accepted 3 February 2005
Abstract—We report herein the synthesis of various derivatives of isomannide and isosorbide. Alkylation on N-(diphenylmethylene)glycine
tert-butyl ester show the new catalysts to be effective phase-transfer catalysts with moderately good enantioselectivity. The effect of exo and
endo substituents on the enantioselectivity of alkylation reaction have also been studied.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
materials provide an easy and inexpensive access to
optically pure functionalized compounds. These have been
used as chiral auxiliaries and as chiral ligands in a number
of reactions like alkylations,6 Diels–Alder reaction7 and
asymmetric hydrogenation etc.8
Catalytic asymmetric phase-transfer reactions constitute an
important methodology in synthetic chemistry. Since the
pioneering work by O’Donnell et al., the enantioselective
alkylation of protected glycine derivative using chiral
quaternary ammonium salts has become a very attractive
method for the preparation of both natural and unnatural
a-amino acids.1 The phase-transfer catalysts (PTCs) that are
used effectively are mainly the derivatives of cinchona
alkaloids.2 Among the non-cinchona based PTCs, chiral
spiro ammonium salts derived from binapthol are very
promising.3
We focused our attention on designing new PTCs based on
structurally rigid bicyclic systems. Isomannide (1) and
isosorbide (2) also known as (3R,3aR,6R,6aR)-hexahydro-
furo[3,2-b]furan-3,6-diol and (6S,3R,3aR,6aR)-hexahydro-
furo[3,2-b]furan-3,6-diol, respectively, were selected as the
chiral templates for investigating the effect of substituents at
the exo and endo positions on asymmetric alkylation
reactions. In these dioxabicyclo systems, hydroxy group at
C3 and C6 are endo in case of isomannide, whereas C6 is exo
and C3 is endo in isosorbide. Isomannide and isosorbide are
important by-products of the starch industry, arising from
dehydration of D-sorbitol and D-mannitol that are produced
worldwide at a rate of 650,000 tons per annum.4 They are
widely used in the form of their nitrate esters in the
pharmaceutical industry.5 These commercial starting
2. Results and discussion
In the present study, we discuss the synthesis of various
derivatives of isomannide, isosorbide and their use as chiral
phase-transfer catalysts. In general, the strategy involves the
protection of one of the free hydroxy groups as ether while
the other is transformed to the amine function. This amine is
then quaternized with different aromatic and aliphatic
moieties. D-Mannitol was dehydrated to isomannide (1)9
and converted to its monotosyl derivative (3) using tosyl
chloride in pyridine. The crude product; which consisted
mainly of the mono-tosylate was purified by successive
recrystallizations from isopropanol and ethyl acetate.
Isomannide mono-tosylate (3) was then O-alkylated under
phase-transfer conditions in good yields with different
groups via Scheme 1. The resulting ethers (4a–c) were
reacted with excess of benzylamine in refluxing condition,
to give amino ethers (5a–c) in good yields (77–83%). As
expected, amination of tosylates occurs via the SN2
Keywords: Asymmetric alkylations; Chiral phase-transfer catalysts;
Isomannide; Isosorbide.
*
Corresponding author. Tel.: C91 172 2214682/87; fax: C91 172
2214692; e-mail: umaram54@yahoo.com
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.010

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S. Kumar, U. Ramachandran / Tetrahedron 61 (2005) 4141–4148
mechanism resulting in inversion of configuration giving
product 5a–c.10
The amino ether 5a–c were N-monomethylated with
dimethylsulfate under PTC conditions to give 6a–c, which
were quaternized with benzyl bromide in refluxing aceto-
nitrlie to afford the quaternary ammonium salts 7a–c in
75–84% yield.
Catalysts 7(a–c) were used for the asymmetric alkylation of
imine 16 using benzyl bromide as the alkylating agent in a
mixture of toluene/dichloromethane (7:3) at K20 8C (Table
1). In all these cases the benzylated product was formed
with a preference for the S-isomer as detected by chiral
HPLC.3
Similarly, the amino ether 5c was treated with an excess of
methyl iodide in acetonitrile and K2CO3 to afford the
quaternary ammonium salt 8 in 89% yield (Scheme 2).
Scheme 1. Reagents and conditions: (i) TsCl, pyridine, CH2Cl2, 10 h.
(ii) RX, TBAB, 50% aqueous KOH, CH2Cl2. (iii) BnNH2, 170 8C, 6 h.
(iv) Me2SO4, 50% aqueous KOH, TBAB, CH2Cl2. (v) BnBr, CH3CN, 15 h.
From the table it is evident that when the geometry of these
dioxabicyclo systems is 3-exo, 6-endo and the quaternary
nitrogen has aromatic benzyl groups, the enantioselectivity
for the benzylation reaction is 70:30 (entry 3, Table 1). The
nature of substituent at position C6 (methyl, allyl, benzyl)
has little effect on the enantioselectivity (entries 1–6).
However, when the quaternary nitrogen contains the alkyl
groups (dimethyl as in catalyst 8), in place of aromatic
moieties (N,N-dibenzyl as in catalyst 7), there is drop in
enantioselectivity (54:46, entry 7).
Scheme 2. Reagents and conditions: (i) MeI, K2CO3, CH3CN, 25 8C, 9 h.
Table 1. Benzylation of N-(diphenylmethylene)glycine tert-butyl ester
Entry
Catalyst
Base
Solvent
Temperature
(8C)
Time
(h)
Yielda
(%)
%Selectivityb
(S:R)
1
2
3
4
5
6
7
8
9
10
7a
7a
7a
7a
7b
7c
8
15
22
22
50% aqueous KOH
50% aqueous KOH
50% aqueous KOH
CsOH$H2O
50% aqueous KOH
50% aqueous KOH
50% aqueous KOH
50% aqueous KOH
50% aqueous KOH
CsOH$H2O
CH2Cl2
0
0
6
9
92
89
83
84
85
78
87
89
90
88
64:36
66:34
70:30
72:28
70:30
66:34
54:46
57:43
28:72
26:74
PhCH3:CH2Cl2 (7:3)
PhCH3:CH2Cl2 (7:3)
PhCH3:CH2Cl2 (7:3)
PhCH3:CH2Cl2 (7:3)
PhCH3:CH2Cl2 (7:3)
PhCH3:CH2Cl2 (7:3)
PhCH3:CH2Cl2 (7:3)
PhCH3:CH2Cl2 (7:3)
PhCH3:CH2Cl2 (7:3)
K20
K40
K20
K20
K20
K20
K20
K40
14
29
15
18
12
6
10
22
a Yield of isolated product.
b Based on chiral HPLC using Chiralcel OD-H column using hexane/2-propanol as eluent. Absolute configuration of 17 was determined by comparison of the
HPLC retention time with the authentic sample independently synthesized by the reported procedure.2
Scheme 3. Reagents and conditions: (i) TsCl, Pyr, CH2Cl2, 8 h. (ii) 2 M NaOH, TBAB, CH2Cl2, 5 h. (iii) BnBr, TBAB, 50% aqueous KOH. (iv) BnNH2,
170 8C. (v) Me2SO4, 50% aq. KOH, TBAB, CH2Cl2, 8 h. (vi) BnBr, CH3CN, 14 h.

S. Kumar, U. Ramachandran / Tetrahedron 61 (2005) 4141–4148
4143
To find the effect of substituent if the C6 is made exo,
catalyst 15 was synthesized according to Scheme 3, starting
from (3S,3aR,6R,6aR)-6-hydroxyhexahydrofuro [3,2-b]-
furan-3-yl acetate (9). The free hydroxy group of 9 was
activated as its tosylate (10) by treatment with p-toluene-
sulphonyl chloride in pyridine. Deacetylation of 10 was
achieved chemoselectively by treatment with 2 N NaOH at
25 8C in the presence of tertrabutylammonium bromide as
PTC in dichloromethane to afford the monotosylate 11 in
93% yield. The monotosylate 11 was O-benzylated in 88%
yield and then converted to amino ether 13 in 69% yield.
The amino ether was N-methylated and subsequently
quaternized with benzyl bromide to afford the quaternary
ammonium salt 15 in 87% yield. We found that the 3-exo,
6-exo combination as in catalyst 15 lowered the enantio-
selectivity for the benzylation reaction (57:43, entry 8,
Table 1).
does not have much effect on the enantioselectivity. Further,
the substituents at the C6 carbon atom when exo, lowers the
selectivity as compared to endo.
4. Experimental
4.1. General
1
Melting points are uncorrected. H and 13C spectra were
recorded at 300 MHz and 75 MHz Bruker Advance
Spectrometer respectively, with chemical shifts in ppm
and tetramethylsilane as the internal standard. Infra-red
absorption spectra were recorded on a Nicolet Impact 410
spectrometer, the frequencies in the IR spectra are indicated
in cmK1. Mass spectra data were recorded on a Finnigan-
MAT LCMS spectrometer. Elemental analyses were
recorded on a Elementa Vario EL. HPLC was performed
on a Shimadzu SPD-10A using chiral phase column
(DIACEL Chiralcel, OD-H). TLC was performed on plates
pre-coated (0.25 mm) with silica gel 60, Merck F-254. The
plates were visualized by the use of a combination of UV
(254 nm) and iodine. Column chromatography was carried
out with silica gel Merck 60 (80–230 mesh).
To study the effect of 3-endo,6-endo combination, quater-
nary ammonium salt 22 was obtained starting from
(3S,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl
acetate using different Scheme. This acetate was O-benzyl-
ated with benzyl bromide in tetrahydrofuran using sodium
hydride and the acetate was hydrolysed in situ with 25%
aqueous NaOH to afford the ether 18. This was converted to
the quaternary ammonium salt 22 according to Scheme 4.
4.2. General procedure for the benzylation of tert-butyl
N-(diphenylmethylene)glycinate
Benzyl bromide (8.4 mmol) was added to a mixture of
N-(diphenylmethylene)glycine tert-butyl ester12 (1.6 mmol)
and catalyst (0.16 mmol) in toluene/dichloromethane (7:3)
10 mL. The reaction mixture was cooled to the appropriate
temperatures given in Table 1, base (16.94 mmol) was
added and the resulting mixture stirred vigorously until the
starting material had been consumed (6–18 h). The suspen-
sion was diluted with diethyl ether (35 mL), washed with
water (2!10 mL), dried over Na2SO4, filtered and con-
centrated under reduced pressure to give crude product.
Purification of the residue by silica chromatography
afforded the desired product 17 in 78–92% yield as pale
yellow oil. 1H NMR (CDCl3, 300 MHz): 1.41 (s, 9H), 3.22–
3.09 (m, 2H), 4.08 (dd, JZ5.0, 9.1 Hz, 1H), 6.53–7.62
(m, 15H); Rt HPLC [99.5:0.5, hexane/isopropanol, 18.1 min
(R-isomer) 26.5 min (S-isomer)].
Scheme 4. Reagents and conditions: (i) (a) NaH, BnBr, THF, 5 h; (b) 25%
aqueous NaOH, TBAB, CH2Cl2, 5 h. (ii) TsCl, Pyr, 12 h. (iii) BnNH2,
170 8C. (iv) Me2SO4, 50% aqueous KOH, TBAB, CH2Cl2, 8 h. (v) BnBr,
CH3CN, 15 h.
When 22 was used as a chiral PTC for the benzylation of 16,
the product was obtained in moderately good enantioselec-
tivity (74%), with preference for the R-isomer.
4.2.1. Synthesis of (3R,3aS,6R,6aR)-6-hydroxy-3-(4-
methylphenyl)sulfonyloxyperhydrofuro[3,2-b]furan (3).
To a solution of 1 (50 g, 0.342 mol) and pyridine (55.2 mL,
0.682 mmol) in dichloromethane (150 mL) was added
p-toluenesulphonyl chloride (74.9 g, 0.393 mmol) at 0 8C.
After stirring the reaction mixture at rt for 10 h the solution
was diluted with dichloromethane (50 mL), washed with
1 N HCl (100 mL), water (50 mL), brine (50 mL) and dried
over anhydrous Na2SO4. The solvent was evaporated and
the residue was purified by successive recrystallizations
(ethyl acetate/isopropanol), to afford 3 as white crystalline
solid (69.8 g, 68%). Mp 104–105 8C. [a]3D0ZC77.98 (c,
0.95, MeOH). IR (KBr): n 3525, 2929, 2867, 1596, 1359,
1305, 1188, 1173, 1122, 1099, 1050, 1020, 923, 883, 843,
818 cmK1. 1H NMR (CDCl3): d 2.45 (s, 3H), 3.55 (dd, JZ
7.3, 1.7 Hz, 1H), 3.79 (t, JZ7.8 Hz, 1H), 3.93–4.05 (m,
2H), 4.29 (m, 1H), 4.42 (t, JZ5.1 Hz, 1H), 4.49 (t, JZ
4.8 Hz, 1H), 4.91 (dd, JZ6.6, 5.50 Hz, 1H), 7.35 (d, JZ
3. Conclusions
In conclusion, we found that rigid 1,4-dioxabicyclic systems
such as isomannide and isosorbide, when used as chiral
PTCs for the benzylation reaction, the stereochemistry at the
C3 carbon atom adjacent to the ring junction C3a–C6a plays a
crucial role in controlling the selectivity (R/S) of the
product. When quaternary nitrogen at C3 is exo (as in 7a–c)
it favors the (S)-isomer, whereas when it is endo (as in 22) it
favours the (R)-isomer. The aromatic moieties were found
to increase the selectivity as compared to the aliphatic
moieties at the quaternary nitrogen atom. Nature of
substituent, on the ether functions whether allyl or benzyl

4144
S. Kumar, U. Ramachandran / Tetrahedron 61 (2005) 4141–4148
8.0 Hz, 2H), 7.83 (d, JZ8.2 Hz, 2H). MS (MALDI): m/z
for C14H18O6S: C, 53.49; H, 5.77; S, 10.20. Found: C,
53.36; H, 5.81; S, 10.14.
300 (MC).
4.2.2. Synthesis of (3R,3aS,6R,6aR)-6-(benzyloxy)-3-[(4-
methylphenyl)sulfonyloxy]hexahydrofuro[3,2-b]furan
(4a). To a solution of 3 (10 g, 33.3 mmol), 50% aqueous
KOH (5.59 mL) and TBAB (0.322 g, 1 mmol) in dichloro-
methane (80 mL) was added benzyl bromide (6.54 g,
38.2 mmol). After stirring the contents at rt for 5 h, the
reaction mixture was diluted with water (10 mL), organic
layer separated and the aqueous layer was extracted with
CH2Cl2 (3!40 mL). The combined organic extract was
dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (SiO2,
hexane/EtOAc, 85:15) to afford 4a as oil (11.6 g, 89%).
[a]3D0ZC82.35 (c, 0.79, MeOH). IR (film): n 3057, 3032,
2976, 2944, 2874, 1599, 1494, 1454, 1361, 1326, 1306,
4.3. General procedure for the synthesis of 5a–c
A solution of 4a–c and benzylamine was heated at 170 8C
for 8 h under argon atmosphere. The contents were cooled
to rt benzylamine was removed under reduced pressure
and the residue was purified by chromatography (SiO2,
hexane/ethyl acetate, 50:50) to afford 5a–c as colourless oil
(83–77%).
4.3.1. Synthesis of N-benzyl-N-[(3S,3aR,6R,6aS)-6-(ben-
zyloxy)hexahydrofuro[3,2-b]furan-3-yl]amine (5a). The
procedure discussed in Section 4.3 was followed; 5a was
obtained as oil (2.76 g, 83%) from 4a (4.0 g, 10.2 mmol)
and benzylamine (20 mL). [a]3D0ZC78.89 (c 1, MeOH).
IR (film): n 3324, 3025, 2945, 2864, 1532, 1489, 1444,
1332 cmK1. 1H NMR (CDCl3): d 3.33 (bs, 1H), 3.66 (t, JZ
8.1 Hz, 1H), 3.80 (s, 3H), 3.80–3.85 (m, 2H), 3.97–4.05 (m,
2H), 4.40 (d, JZ4.3 Hz, 1H), 4.54 (d, JZ11.8 Hz, 1H), 4.60
(t, JZ4.5 Hz, 1H), 4.74 (d, JZ11.9 Hz, 1H) 7.21–7.34 (m,
10H). 13C NMR (CDCl3): d 51.9, 64.8, 72.2, 74.0, 78.9,
80.0, 87.6, 127.0, 127.7, 127.7, 127.9, 128.2, 128.3, 128.7,
137.6, 139.5. MS (APCI): m/z 327 (MCC2), 326. Anal.
Calcd for C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C,
73.69; H, 7.18; N, 4.25.
1191, 1175, 1143, 1097, 1014, 977, 951, 887, 825, 758 cmK1
.
1H NMR (CDCl3): d 2.43 (s, 3H), 3.63 (t, JZ8.6 Hz, 1H),
3.84 (t, JZ7.6 Hz, 1H), 3.83–4.06 (m, 3H), 4.74 (t, JZ
2.3 Hz, 2H), 4.52 (d, JZ11.9 Hz, 1H), 4.69 (d, JZ11.8 Hz,
1H), 4.86 (dd, JZ4.8, 6.9 Hz, 1H), 7.26–7.34 (m, 7H), 7.81
(d, JZ8.2 Hz, 2H). MS (MALDI): m/z 391 (MCC1), 390.
Anal. Calcd for C20H22O6S: C, 61.52; H, 5.68; S, 8.21
Found: C, 61.42; H, 5.74; S, 8.16.
4.2.3. Synthesis of (3R,3aS,6R,6aR)-6-(allyloxy)-3-[(4-
methylphenyl)sulfonyloxy]hexahydrofuro[3,2-b]furan
(4b). To a solution of 3 (5.0 g, 16.6 mmol), 50% aqueous
KOH (2.79 mL, 24.9 mmol) and TBAB (0.161 g,
0.49 mmol) in dichloromethane (50 mL) was added allyl
bromide (2.4 g, 19.8 mmol). After stirring the contents at rt
for 6 h, the reaction mixture was diluted with water
(10 mL), organic layer separated and the aqueous layer
was extracted with CH2Cl2 (3!30 mL). The combined
organic extracts were dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by column
chromatography (SiO2, hexane/ethyl acetate, 85:15) to
afford 4b as oil (4.81 g, 85%). [a]3D0ZC163.65 (c 0.5,
MeOH). IR (film): n 2979, 2950, 2925, 2879, 1645, 1597,
4.3.2. Synthesis of N-[(3S,3aR,6R,6aS)-6-(allyloxy)hexa-
hydrofuro[3,2-b]furan-3-yl]-N-benzylamine (5b). The
procedure discussed in Section 4.3 was followed; 5b was
obtained as oil (3.23, 80%) from 4b (5.0 g, 14.7 mmol) and
benzylamine (30 mL). [a]3D0ZC157.70 (c 1, 0.5 MeOH).
IR (film): n 3027, 2940, 2874, 1645, 1494, 1454, 1360,
1
1327 cmK1. H NMR (CDCl3): d 1.72 (bs, 1H), 3.32 (bs,
1H), 3.61 (t, JZ8.1 Hz, 1H), 3.75–3.86 (m, 1H), 3.86 (s,
2H), 3.90 (dd, JZ7.0, 1.37 Hz, 1H), 3.95–4.05 (m, 3H),
4.10 (dd, JZ7.0, 5.5 Hz, 1H), 4.42 (d, JZ4.3 Hz, 1H), 4.57
(t, JZ4.4 Hz, 1H), 5.18 (d, JZ10.3 Hz, 1H), 5.31 (dd, JZ
1.4, 15.8 Hz, 1H), 5.91 (m, 1H), 7.20–7.37 (m, 5H). 13C
NMR (CDCl3): d 51.8, 61.8, 64.7, 69.6, 70.8, 71.3, 72.4,
73.8, 79.1, 79.8, 80.8, 87.4, 117.3, 126.8, 127.8, 128.2,
134.3, 139.4. MS (MALDI): m/z 276 (MCC1). Anal. Calcd
for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.64;
H, 7.75; N, 4.92.
1
1365, 1190, 1177, 1141, 1026 cmK1. H NMR (CDCl3): d
2.44 (s, 3H), 3.62 (t, JZ7.5 Hz, 1H), 3.82 (t, JZ7.5 Hz,
1H), 3.96–4.0 (m, 6H), 4.14 (dd, JZ5.6, 5.9 Hz, 1H), 4.46–
4.52 (m, 2H), 4.87 (dd, JZ5.4, 5.3 Hz, 1H), 5.91 (m, 1H),
7.34 (d, JZ8.3 Hz, 2H), 7.82 (d, JZ8.2 Hz, 2H). 13C NMR
(CDCl3): d 21.5, 70.0, 70.7, 71.5, 78.4, 78.9, 80.0, 80.0,
117.7, 127.7, 129.7, 133.0, 134.1, 145.0. MS (APCI): m/z
340 (MC), 316, 272. Anal. Calcd for C16H20O6S: C, 56.46;
H, 5.92; S, 9.42. Found: C, 53.36; H, 5.81; S, 10.14.
4.3.3. Synthesis of N-benzyl-N-[(3S,3aR,6R,6aS)-6-meth-
oxyhexahydrofuro[3,2-b]furan-3-yl]amine (5c). The pro-
cedure discussed in Section 4.3 was followed; 5c was
obtained as oil (3.05 g, 77%) from 4c (5.0 g, 15.9 mmol)
and benzyl amine (30 mL). [a]3D0ZC108.48 (c 1.26,
CHCl3). IR (film): n 3316, 3027, 2927, 1666, 1603, 1537,
4.2.4. Synthesis of (3R,3aS,6R,6aR)-6-(methoxy)-3-[(4-
methylphenyl)sulfonyloxy]hexahydrofuro[3,2-b]furan
(4c). The procedure described in Section 4.2.2 was
followed; 4c was obtained as oil (4.81 g, 92%) from 3
(5.0 g, 16.6 mmol). [a]3D0ZC103.14 (c, 1, MeOH). IR
(film): n 3436, 2948, 2880, 1597, 1456, 1364, 1190, 1174,
1494, 1454, 1380, 1218, 1067, 1019 cmK1 1H NMR
.
(CDCl3): d 1.67 (bs, 1H), 3.36 (m, 1H), 3.45 (s, 3H),
3.58–3.64 (m, 1H), 3.84 (s, 2H), 3.80–3.84 (m, 1H), 3.95–
3.86 (m, 2H), 3.99 (dd, JZ4.8, 4.5 Hz, 1H), 4.45 (d, JZ
4.2 Hz, 1H), 4.64 (t, JZ4.2 Hz, 1H), 7.22–7.34 (m, 5H). 13C
NMR (CDCl3): d 51.9, 58.1, 64.8, 69.6, 74.1, 79.7, 81.6,
87.2, 127.1, 127.4, 127.7, 128.0, 128.4, 139.5. MS (APCI):
m/z 251 (MCC2), 249. Anal. Calcd for C14H19NO3: C,
67.45; H, 7.68; N, 5.62. Found: C, 67.32; H, 7.74; N, 5.52.
1
1146, 1098, 1084, 1030, 916, 853, 817 cmK1. H NMR
(CDCl3): d 2.45 (s, 3H), 3.58 (s, 3H), 3.61 (t, JZ8.3 Hz,
1H), 3.79 (t, JZ7.7 Hz, 1H), 3.93 (d, JZ6.4 Hz, 1H), 3.99
(dd, JZ7.2, 7.8 Hz, 2H), 4.50–4.53 (m, 2H), 4.8 (dd, JZ
5.0, 6.3 Hz, 1H), 7.34 (d, JZ8.1 Hz, 2H), 7.82 (d, JZ
7.9 Hz, 2H). MS (APCI): m/z 314 (MC), 241. Anal. Calcd

S. Kumar, U. Ramachandran / Tetrahedron 61 (2005) 4141–4148
4145
4.4. General procedure for the N-methylation of 5a–c
Calcd for C15H21NO3: C, 68.42; H, 8.04; N, 5.32 Found: C,
68.34; H, 8.12; N, 5.22.
To a solution of 5a–c (9.21 mmol), 50% aqueous KOH
(2.0 mL) and TBAB (0.089 g, 0.27 mmol) in CH2Cl2
(50 mL), was added dimethyl sulfate (1.27 g, 10.0 mmol).
After stirring for 5 h at rt, the reaction mixture was diluted
with water (15 mL), organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3!30 mL). The
combined organic extract was washed with brine, dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, hexane/
ethyl acetate, 80:20) to afford 6a–c as oil (88–79%).
4.4.3.1. Synthesis of (3S,6aS,3aR,6R)-dibenzyl-(6-ben-
zyloxy-hexahydrofuro[3,2-b]furan-3-yl)methyl ammo-
nium bromide (7a). A solution of compound 6a (1.0 g,
2.94 mmol) and benzyl bromide (1.0 g, 5.84 mmol) in
acetonitrile (10 mL) was stirred at 80 8C under argon for
15 h. The contents were cooled to rt and evaporated to
dryness in vacuo. The residue was diluted with hexane
(15 mL), stirred at rt for 15 min and filtered to afford 7a as
white solid (1.20 g, 80%). Analytical sample was prepared
by purification with preparative TLC. Mp 94–95 8C.
[a]3D0ZC27.86 (c 1.1, MeOH). IR (KBr): n 3034, 2925,
2879, 1630, 1455, 1373, 1214, 1135, 1110, 1080 cmK1. 1H
NMR (CDCl3): d 3.08 (s, 3H), 3.75–3.80 (m, 3H), 4.01 (dd,
JZ4.5, 4.4 Hz, 1H), 4.27 (dd, JZ6.1, 6.2 Hz, 1H), 4.38 (d,
JZ11.6 Hz, 1H), 4.58 (d, JZ11.6 Hz, 1H), 4.65 (d, JZ
12.1 Hz, 1H), 4.88 (d, JZ12.8 Hz, 1H), 5.05 (d, JZ5.2 Hz,
1H), 5.10 (d, JZ6.2 Hz, 1H), 5.19 (t, JZ5.1 Hz, 1H), 5.43
(d, JZ12.9 Hz, 1H), 6.13 (d, JZ5.4 Hz, 1H), 7.24–7.42 (m,
11H), 7.67 (d, JZ6.7 Hz, 2H), 7.74 (d, JZ6.3 Hz, 2H). 13C
NMR (CDCl3): d 29.6, 46.9, 64.2, 64.7, 68.6, 72.1, 72.7,
78.6, 82.1, 83.1, 126.5, 126.5, 127.7, 128.4, 129.1, 129.3,
130.7, 130.7, 133.8, 137.7. MS (APCI): m/z 430 (MCK80),
356. Anal. Calcd for C28H32BrNO3: C, 65.88; H, 6.32; N,
2.74. Found: C, 65.02; H, 6.85; N, 2.54.
4.4.1. Synthesis of N-benzyl-N-[(3S,3aR,6R,6aS)-6-(ben-
zyloxy)hexahydrofuro[3,2-b]furan-3-yl]-N-methylamine
(6a). The procedure discussed in Section 4.4 was followed;
6a was obtained as yellowish oil (88%) from 5a. [a]3D0Z
C89.73, (c 1 MeOH). IR (film): n 3316, 3027, 2927, 1666,
1603, 1537, 1494, 1454, 1380, 1218, 1067, 1019 cmK1. 1H
NMR (CDCl3): d 2.14 (s, 3H), 3.11 (td, JZ2.2, 4.3 Hz, 1H),
3.40 (d, JZ13.3 Hz, 1H), 3.70 (t, JZ7.9 Hz, 2H), 3.83 (m,
JZ1.9, 4.6 Hz, 2H), 3.90 (m, 1H), 4.20 (dd, JZ6.7, 4.2 Hz,
1H), 4.55 (d, JZ8.7 Hz, 2H), 4.61 (dd, JZ2.3, 2.9 Hz, 1H),
4.75 (d, JZ11.8 Hz, 1H), 7.21–7.37 (m, 10H). 13C NMR
(CDCl3): d 39.5, 60.0, 68.8, 72.0, 72.3, 78.5, 80.5, 86.4,
126.9, 127.7, 127.8, 128.1, 128.3, 128.7, 137.6, 138.3. MS
(APCI): m/z 341 (MCC2), 340. Anal. Calcd for
C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C, 74.26;
H, 7.49; N, 4.04.
4.4.3.2. Synthesis of (3S,6aS,3aR,6R)-dibenzyl-(6-
allyloxy-hexahydrofuro[3,2-b]furan-3-yl)methylammo-
nium bromide (7b). The procedure discussed in Section
4.4.3.1 was followed; 7b was obtained from 6b (1.0 g,
3.4 mmol) as white solid (1.19 g, 75%). Analytical sample
was prepared by purification with preparative TLC. Mp
147–148 8C. [a]2D5ZC60.68 (c 0.82, MeOH). IR (KBr): n
3420, 2938, 2944, 2856, 1635, 1457, 1421, 1213, 1129,
4.4.2.
N-[(3S,3aR,6R,6aS)-6-(Allyloxy)hexahydro-
furo[3,2-b]furan-3-yl]-N-benzyl-N-methylamine (6b).
The procedure discussed in Section 4.4 was followed; 6b
was obtained as yellowish oil (92%) from 5b. [a]3D0Z
C93.33, (c 0.5, MeOH). IR (film): n 3459, 3027, 2942, 2853,
1644, 1494, 1454, 1366, 1317, 1139, 1104, 1039 cmK1. 1H
NMR (CDCl3): d 2.14 (s, 3H), 3.12 (dd, JZ2.5, 4.1 Hz, 1H),
3.41 (d, JZ13.7 Hz, 1H), 3.64–3.71 (m, 2H), 3.94 (dd, JZ
5.2, 3.7 Hz, 1H), 3.93–3.96 (m, 2H), 4.01 (dd, JZ5.2,
4.6 Hz, 1H), 4.16–4.21 (m, 2H), 4.52 (d, JZ4.7 Hz, 1H),
4.65 (dd, JZ2.4, 2.7 Hz, 1H), 5.20 (d, JZ10.3 Hz, 1H),
5.32 (dd, JZ1.4, 15.7 Hz, 1H), 5.93 (m, 1H), 7.23–7.30 (m,
5H). 13C NMR (CDCl3): d 39.5, 60.1, 68.6, 71.5, 72.1, 72.3,
78.8, 80.4, 86.5, 117.6, 127.0, 128.1, 134.3, 138.3. MS
(APCI): m/z 291 (MCC2), 290. Anal. Calcd for
C17H23NO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.44;
H, 4.93; N, 4.73.
1113, 1059, 1034, 992, 913, 884, 749 cmK1 1H NMR
.
(CDCl3): d 3.11 (s, 3H), 3.72–3.83 (m, 3H), 3.91–4.04 (m,
3H), 4.24 (dd, JZ5.3, 4.4 Hz, 1H), 4.60 (d, JZ12.8 Hz,
1H), 4.81 (d, JZ12.8 Hz, 1H), 5.10–5.18 (m, 5H), 5.24 (d,
JZ12.8 Hz, 1H), 5.81 (m, 1H), 6.16 (d, JZ5.0 Hz, 1H),
7.30–7.41 (m, 6H), 7.70 (d, JZ6.7 Hz, 2H), 7.76 (d, JZ
6.7 Hz, 2H). 13C NMR (CDCl3): d 47.0, 64.1, 64.4, 68.6,
71.5, 71.9, 78.5, 80.5, 82.0, 82.9, 117.2, 126.4, 126.5, 128.3,
129.1, 129.2, 130.6, 130.7, 133.5, 133.7, 134.1. MS (APCI):
m/z 379 (MCK81), 306. Anal. Calcd for C24H30BrNO3: C,
62.61; H, 6.57; N, 3.04. Found: C, 63.47; H, 6.89; N, 2.83.
4.4.3.3. Synthesis of (3S,6aS,3aR,6R)-dibenzyl-(6-
methoxy-hexahydrofuro[3,2-b]furan-3-yl)methyl ammo-
nium bromide (7c). The procedure discussed in Section
4.4.3.1 was followed; 7c was obtained from 6c (1.0 g,
3.79 mmol) as white solid (1.38 g, 84%). Analytical sample
was prepared by purification with preparative TLC. Mp
143–144 8C. [a]3D0ZC56.78 (c 0.98, MeOH). IR (KBr): n
2931, 2894, 1455, 1421, 1376, 1288, 1212, 1137, 1107,
1067, 1037, 999, 883, 757 cmK1. 1H NMR (CDCl3): d 2.66
(s, 3H), 3.32 (s, 3H), 3.80–3.83 (m, 5H), 4.18 (t, JZ6.3 Hz,
2H), 4.55 (d, JZ12.5 Hz, 1H), 4.74 (d, JZ12.4 Hz, 1H),
5.14 (d, JZ10.5 Hz, 1H), 5.24 (d, JZ12.5 Hz, 1H), 5.36 (d,
JZ12.5 Hz, 1H), 7.32–7.40 (m, 6H), 7.75 (t, JZ7.4 Hz,
4H). 13C NMR (CDCl3): d 45.2, 54.4, 65.6, 66.0, 71.1, 71.4,
84.4, 87.9, 89.3, 89.9, 133.5, 133.7, 136.2, 136.3, 137.8,
4.4.3. Synthesis of N-benzyl-N-[(3S,3aR,6R,6aS)-6-meth-
oxyhexahydrofuro[3,2-b]furan-3-yl]-N-methylamine
(6c). The procedure discussed in Section 4.4 was followed;
6c was obtained as yellowish oil (79%) from 5c. [a]3D0Z
C118.23 (c 0.5, MeOH). IR (film): n 2975, 2940, 2870,
2796, 1644, 1668, 1602, 1494, 1454, 1139, 1128, 1063,
1084, 1040, 1027 cmK1. 1H NMR (CDCl3): d 2.15 (s, 3H),
3.11 (td, JZ2.3, 2.3 Hz, 1H), 3.42 (d, JZ13.3 Hz, 1H), 3.47
(s, 3H), 3.63 (d, JZ8.1 Hz, 1H), 3.69 (d, JZ12.9 Hz, 1H),
3.79–3.85 (m, 2H), 3.93 (dd, JZ6.3, 1.70 Hz, 1H), 4.17 (dd,
JZ6.6, 2.5 Hz, 1H), 4.56 (t, JZ5.0 Hz, 1H), 4.67 (dd, JZ
2.4, 2.8 Hz, 1H), 7.22–7.31 (m, 5H). 13C NMR (CDCl3): d
39.5, 58.2, 60.1, 72.1, 72.4, 80.2, 81.1, 86.6, 127.0, 128.2,
128.8, 138.3. MS (APCI): m/z 264 (MCC1), 263. Anal.

4146
S. Kumar, U. Ramachandran / Tetrahedron 61 (2005) 4141–4148
138.4, 140.7, 140.9. MS (APCI): m/z 353 (MCK81), 281.
Anal. Calcd for C22H28BrNO3: C, 60.83; H, 6.50; N, 3.22.
Found: C, 59.94; H, 6.94; N, 2.94.
1H), 7.83 (d, JZ7.9 Hz, 2H). MS (ESI) m/z (%): 300
(MC,100), 218 (64).
4.4.7. Synthesis of (3R,3aS,6S,6aR)-6-(benzyloxy)hexa-
hydrofuro[3,2-b]furan-3-yl-4-methylbenzenesulfonate
(12). The procedure discussed in Section 4.2.2 was
followed; 12 was obtained from 11 (5.0, 16.6 mmol) as
white solid (5.72 g, 88%). Mp 52–53 8C. [a]3D0ZC57.914
(c 1.7, CHCl3). IR (KBr): n 3030, 2912, 2873, 1598, 1454,
4.4.4. Synthesis of (3S,6aS,3aR,6R)-benzyl-(6-methoxy-
hexahydro-furo[3,2-b]furan-3-yl)-dimethyl-ammonium
iodide (8). To a solution of 5c (1.0 g, 4.0 mmol), K2CO3
(0.554 g, 4.0 mmol) in acetonitrile (10 mL) was added
methyl iodide (2.27 g, 15.9 mmol) under argon. After
stirring at rt, for 9 h, the solvent was evaporated and the
residue was diluted with water (10 mL). The organic layer
was separated and the aqueous layer extracted with CH2Cl2
(3!40 mL), dried over anhydrous Na2SO4 and concen-
trated in vacuo, to afford white solid, recrystallization from
acetone afforded 8 as crystalline solid (1.44 g, 89%). Mp
165–166 8C. [a]3D0ZC48.62, (c 1.02, MeOH). IR (KBr): n
2969, 2856, 1616, 1465, 1379, 1288, 1215, 1141, 1109,
1031 cmK1. 1H NMR (CDCl3): d 3.11 (s, 3H), 3.16 (s, 3H),
3.45 (s, 3H), 3.79–3.98 (m, 2H), 4.00 (q, JZ5.2 Hz, 1H),
4.11 (t, JZ4.0 Hz, 1H), 4.29 (m, 1H), 4.59 (dd, JZ3.2,
8.6 Hz, 1H), 4.76 (d, JZ16.2 Hz, 2H), 4.96 (t, JZ5.6 Hz,
1H), 5.41 (d, JZ5.7 Hz, 1H), 7.50–7.59 (m, 3H), 7.69 (d,
JZ6.3 Hz, 2H). 13C NMR (CDCl3): d 49.5, 49.7, 58.9, 68.5,
69.1, 72.3, 80.1, 81.9, 83.0, 83.5, 128.2,130.3, 132.1, 134.6.
MS (APCI): m/z 277 (MCK128), 207. Anal. Calcd for
C16H24INO3: C, 47.42; H, 5.97; N, 3.46. Found: C, 47.20;
H, 5.68; N, 3.29.
1
1360, 1189, 1170, 1103, 1044, 1005, 973 cmK1. H NMR
(CDCl3): d 2.42 (s, 3H), 3.71 (t, JZ7.1 Hz, 1H), 3.82–3.89
(m, 2H), 3.97 (d, JZ10.2 Hz, 1H), 4.03 (bs, 1H), 4.47 (d,
JZ4.2 Hz, 1H), 4.52 (s, 2H), 4.58 (t, JZ4.4 Hz, 1H), 4.85
(dd, JZ5.8, 5.71 Hz, 1H), 7.27–7.34 (m, 7H), 7.82 (d, JZ
7.9 Hz, 2H). 13C NMR (CDCl3): d 21.5, 69.2, 71.3, 73.3,
78.6, 80.1, 83.1, 85.8, 127.6, 127.8 (2C), 128.4, 129.8,
133.1, 137.3. MS (APCI): m/z (%) 390 (MC, 100), 298 (85).
Anal. Calcd for C20H22O6S: C, 61.52; H, 5.68; S, 8.21.
Found: C, 61.45; H, 5.76; S, 8.16.
4.4.8. Synthesis of N-benzyl-N-[(3S,3aR,6S,6aS)-6-(ben-
zyloxy)hexahydrofuro[3,2-b]furan-3-yl]amine (13). The
procedure discussed in Section 4.3 was followed; 13 was
obtained from 12 (5.0 g, 12.8 mmol) as white solid (2.87 g,
69%). Mp 54–55 8C. [a]D30ZC24.06, (c 1.25, MeOH). IR
(KBr): n 3309, 3029, 2950, 2882, 1493, 1464, 1342, 1216,
1190, 1085 cmK1. 1H NMR (CDCl3): d 3.33 (bs, 1H), 3.68
(d, JZ9.2 Hz, 1H), 3.76–3.91 (m, 6H), 4.04 (s, 1H),
4.51–4.65 (m, 4H), 7.22–7.31 (m, 10H). 13C NMR: d 51.9,
63.9, 71.4, 72.1, 72.8, 83.0, 85.6, 87.0, 127.1, 127.6, 127.7,
128.0, 128.4, 137.5, 139.6. MS (APCI): m/z 326 (MCC1),
325. Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12; N, 4.30.
Found: C, 73.71; H, 7.23; N, 4.19.
4.4.5. Synthesis of (3S,3aR,6R,6aS)-6-{[(4-methylphenyl)
sulfonyl]oxy}hexahydrofuro[3,2-b]furan-3-yl-acetate
(10). To a solution of (3S,3aR,6R,6aR)-6-hydroxyhexa-
hydrofuro[3,2-b]furan-3-yl acetate11 (5.0 g, 26.5 mmol) in
pyridine (30 mL) was added p-toluenesulphonyl chloride
(5.57 g, 29.2 mmol) at 0 8C. After stirring the reaction
mixture for 8 h at rt, pyridine was removed under reduced
pressure. The residue was dissolved in CH2Cl2 (60 mL) and
washed successively with 1 N HCl, water, brine, dried over
anhydrous Na2SO4 and concentrated in vacuo to afford 10 as
white solid (7.8 g, 86%). Mp 56–58 8C. [a]3D0ZC72.50 (c 1,
ethanol). IR (KBr): n 3052, 2980, 2874, 1740, 1596, 1451,
4.4.9. Synthesis of N-benzyl-N-[(3S,3aR,6S,6aS)-6-(ben-
zyloxy)hexahydrofuro[3,2-b]furan-3-yl]-N-methylamine
(14). The procedure discussed in Section 4.4 was followed;
14 was obtained from 13 (2.0 g, 6.14 mmol) as white solid
(1.77 g, 85%). Mp 60–61 8C. [a]3D0ZC23.26 (c 0.85,
MeOH). IR (KBr): n 3031, 2989, 2911, 2853, 2796, 1498,
1454, 1362, 1340, 1215, 1106, 1078, 1054, 1032, 970, 920,
1379, 1345, 1287, 1242, 1174, 1112, 1081, 1011, 973 cmK1
.
1H NMR (CDCl3): d 2.05 (s, 3H), 2.45 (s, 3H), 3.74 (dd, JZ
6.7, 2.9 Hz, 1H), 3.87 (dd, JZ6.2, 3.3 Hz, 1H), 3.9 (m, 2H),
4.46 (d, JZ4.3 Hz, 1H), 4.68 (t, JZ4.6 Hz, 1H), 4.9 (q, JZ
5.5 Hz, 1H), 5.1 (s, 1H), 7.3 (d, JZ7.9 Hz, 2H), 7.8 (d, JZ
8.0 Hz, 2H). MS (ESI): m/z 342 (MC).
885 cmK1. H NMR (CDCl3): d 2.12 (s, 3H), 3.07 (t, JZ
1
13.2 Hz, 1H), 3.41 (d, JZ12.5 Hz, 1H), 3.72 (d, JZ
12.5 Hz, 1H), 3.75 (d, JZ6.1 Hz, 1H), 3.86 (dd, JZ3.7,
6.3 Hz, 1H), 3.88 (t, JZ9.9 Hz, 1H), 4.01–4.05 (m, 2H),
4.58 (dd, JZ11.8, 5.0 Hz, 3H), 4.78 (d, JZ3.2 Hz, 1H),
7.23–7.33 (m, 10H). 13C NMR (CDCl3): d 39.5, 60.0, 71.2,
71.3, 71.7, 83.0, 85.8, 86.6, 127.1, 127.7, 128.2, 128.4,
128.9, 137.5, 138.4. MS (APCI): m/z 340 (MCC1), 339.
Anal. Calcd for C21H25NO3: C, 74.31; H, 7.42; N, 4.13.
Found: C, 74.19; H, 7.53; N, 4.06.
4.4.6. Synthesis of (3R,3aS,6S,6aR)-6-hydroxyhexa-
hydrofuro[3,2-b]furan-3-yl-4-methylbenzenesulfonate
(11). To a solution of 10 (7.0 g, 20.4 mmol) and TBAB
(0.197 g, 0.61 mmol) in CH2Cl2 (50 mL) was added 2 M
NaOH (12 mL, 24.5 mmol). After stirring for 5 h at rt, the
reaction mixture was cooled to 0 8C and neutralized with
1 N HCl. The organic layer was separated and the aqueous
layer extracted with CH2Cl2 (2!50 mL). The combined
organic extract was dried over Na2SO4 and concentrated in
vacuo to afford 11 as white solid (5.7 g, 93%). Mp 48–
49 8C. [a]3D0ZC57.58 (c 1, ethanol). IR (KBr): n 3564,
2929, 2875, 1598, 1455, 1364, 1190, 1170, 1098, 1010,
4.4.9.1. Synthesis of (3S,6S,6aS,3aR)-dibenzyl-(6-ben-
zyloxy-hexahydro-furo[3,2-b]furan-3-yl)methyl ammo-
nium bromide (15). The procedure discussed in Section
4.4.3.1 was followed; 15 was obtained from 14 (1.0 g,
2.94 mmol) as white solid (1.30 g, 87%). Analytical sample
was prepared by purification with preparative TLC. Mp
106–107 8C. [a]3D0ZK2.73 (c, 0.62, MeOH). IR (KBr): n
3025, 2922, 2863, 1491, 1469, 1454, 1369, 1340, 1211,
1
972 cmK1. H NMR (CDCl3): d 2.41 (s, 1H), 2.45 (s, 3H),
3.70 (t, JZ9.2 Hz, 1H), 3.83 (d, JZ6.2 Hz, 1H), 3.88 (s,
2H), 4.29 (s, 1H), 4.38 (d, JZ4.1 Hz, 1H), 4.65 (t, JZ
4.6 Hz, 1H), 4.86 (t, JZ5.7 Hz, 1H), 7.35 (d, JZ7.9 Hz,
1163, 1084, 1023, 912, 875, 755, 703 cmK1 1H NMR
.
(CDCl3): d 3.14 (s, 3H), 3.81 (t, JZ5.2 Hz, 1H), 3.86–3.90
(m, 2H), 4.01 (bs, 1H), 4.09 (dd, JZ6.5, 5.4 Hz, 1H), 4.45

S. Kumar, U. Ramachandran / Tetrahedron 61 (2005) 4141–4148
4147
(d, JZ11.7 Hz, 1H), 4.60 (d, JZ11.7 Hz, 1H), 4.85–4.92
(m, 3H), 5.03 (dd, JZ4.2, 3.9 Hz, 1H), 5.18 (d, JZ12.8 Hz,
1H), 5.31 (d, JZ12.8 Hz, 1H), 5.63 (d, JZ4.5 Hz, 1H),
7.26–7.47 (m, 11H), 7.71 (t, JZ7.8 Hz, 4H). 13C NMR
(CDCl3): d 47.0, 64.4, 67.1, 71.5, 71.8, 76.6, 81.8, 82.4,
87.2, 126.5, 126.6, 127.8, 128.3, 129.1, 130.7, 133.5, 133.7,
137.2. MS (APCI): m/z 430 (MCK80), 356. Anal. Calcd for
C28H32BrNO3: C, 65.88; H, 6.32; N, 2.74. Found: C, 65.16;
H, 6.83; N, 2.58.
1136, 1083, 1027 cmK1. 1H NMR (CDCl3): d 2.09 (bs, 1H),
3.40 (dd, JZ4.1, 2.5 Hz, 1H), 3.46 (dd, JZ8.2, 2.0 Hz, 1H),
3.66 (t, JZ8.4 Hz, 1H), 3.78 (d, JZ12.8 Hz, 1H), 3.90 (d,
JZ7.8 Hz, 1H), 3.92 (d, JZ9.6 Hz, 1H), 4.08 (dd, JZ2.5,
4.9 Hz, 1H), 4.13 (t, JZ7.5 Hz, 1H), 4.45 (t, JZ4.1 Hz,
1H), 4.53–4.60 (m, 2H), 4.76 (d, JZ11.9 Hz, 1H), 7.26–
7.37 (m, 10H). 13C NMR (CDCl3): d 52.1, 61.8, 70.9, 72.2,
72.4, 79.6, 80.0, 80.9, 126.8, 127.6, 127.7, 127.9, 128.2,
137.6, 139.8. MS (APCI): m/z 327 (MCC2), 326. Anal.
Calcd for C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C,
73.72; H, 7.19; N, 4.23.
4.4.10. Synthesis of (3S,3aR,6R,6aR)-6-(benzyloxy)hexa-
hydrofuro[3,2-b]furan-3-ol (18). To an ice cooled (0 8C)
suspension of sodium hydride (1.27 g, 52.9 mmol) in dry
tetrahydrofuran (50 mL) under argon was added a solution
of (3S,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-
3-yl acetate (10.0 g, 53.14 mmol) in tetrahydrofuran
(40 mL) dropwise via an addition funnel over a period of
0.5 h. The reaction mixture was stirred at 25 8C for 3 h,
followed by heating at 60 8C for 2 h. The reaction mixture
was cooled to rt and 25% aqueous NaOH (8.5 mL) was
added and continued stirring for 4 h. The reaction mixture
was cooled externally by ice and the contents neutralized by
adding 1 N HCl solution. Tetrahydrofuran was removed
under reduced pressure and the residue diluted with water
(30 mL) and CH2Cl2 (50 mL). The organic layer was
separated and aqueous layer extracted with CH2Cl2 (3!
30 mL). The combined organic extract was washed with
cold water (10 mL), dried over Na2SO4 and concentrated in
vacuo. The residue was chromatographed on silica gel
[hexane/ethyl acetate, 60:40 (v:v)] to afford 18 as white
solid (9.41 g, 75%). Mp 59–61 8C (lit. mp 60–62 8C).10
[a]2D5&C97.92 (c 2.7 MeOH) [lit. [a]2D5ZC121.2 (c 0.53,
CHCl3)].10 IR (KBr): n 3447, 2959, 2939, 2892, 2878, 1499,
1371, 1327, 1208, 1134, 1110, 1081, 1065, 1020, 981,
4.4.13. Synthesis of N-benzyl-N-[(3R,3aR,6R,6aS)-6-
(benzyloxy)hexahydrofuro[3,2-b]furan-3-yl]-N-methyl-
amine (21). The procedure discussed in Section 4.4 was
followed; 21 was obtained from 20 (0.700 g, 2.15 mmol) as
off-white solid (0.584 g, 80%). Mp 55–56 8C. [a]3D0Z
C135.45 (c 0.44, MeOH). IR (KBr): n 3065, 3025, 2979,
2948, 2879, 2792, 1497, 1452, 1402, 1342, 1296, 1223,
1
1132, 1085, 1064, 1022, 889 cmK1. H NMR (CDCl3): d
2.22 (s, 3H), 2.88 (d, JZ3.9 Hz, 1H), 3.48 (d, JZ13.1 Hz,
1H), 3.71–3.85 (m, 3H), 3.96 (t, JZ8.3 Hz, 1H), 4.05 (d,
JZ2.8 Hz, 1H), 4.13 (t, JZ5.9 Hz, 1H), 4.54 (d, JZ2.3 Hz,
1H), 4.59 (m, 2H), 4.72 (d, JZ11.9 Hz, 1H), 7.29–7.34 (m,
10H). 13C NMR (CDCl3): d 40.7, 60.8, 68.6, 71.1, 72.1,
72.2, 79.3, 81.0, 81.6, 127.0, 127.7, 128.0, 128.2, 129.3,
137.1, 137.6. MS (APCI): m/z (%) 341 (MCC2, 22), 340
(100). Anal. Calcd for C21H25NO3: C, 74.31; H, 7.42; N,
4.13. Found: C, 74.23; H, 7.36; N, 4.07.
4.4.13.1. Synthesis of (6aS,3R,3aR,6R)-dibenzyl-(6-
benzyloxy-hexahydrofuro[3,2-b]furan-3-yl)methyl
ammonium bromide (22). The procedure discussed in
Section 4.4.3.1 was followed; 22 was obtained from 21
(0.500 g, 1.47 mmol) as a white solid (0.624 g, 83%).
Analytical sample was prepared by purification with
preparative TLC. Mp 99–100 8C. [a]3D0ZC66.64 (c 0.70,
MeOH). IR (KBr): n 3033, 2952, 2634, 1641, 1456, 1369,
1214, 1137, 1093, 1024, 919, 879 cmK1. 1H NMR (CDCl3):
d 2.95 (t, JZ7.8 Hz, 1H), 3.14 (s, 3H), 3.49 (t, JZ9.2 Hz,
1H), 3.79–4.01 (m, 3H), 4.16 (d, JZ5.2 Hz, 1H), 4.44 (d,
JZ5.2 Hz, 1H), 4.55–4.76 (m, 2H), 5.02 (d, JZ12.2 Hz,
1H), 5.14 (s, 1H), 5.50 (bs, 1H), 5.80 (d, JZ12.5 Hz, 1H),
6.14 (d, JZ12.2 Hz, 1H), 7.28–7.51 (m, 11H), 7.65 (d, JZ
6.8 Hz, 2H), 7.78 (d, JZ6.2 Hz, 2H). 13C NMR (CDCl3): d
44.3, 60.9, 65.2, 67.2, 68.3, 71.2, 72.4, 72.7, 78.5, 80.2,
81.5, 127.4, 127.9, 128.0, 128.1, 128.4, 128.9, 129.3, 129.6,
130.9, 131.1, 132.8, 133.8, 137.1. MS (APCI): m/z 430
(MC-80), 356. Anal. Calcd for C28H32BrNO3: C, 65.88; H,
6.32; N, 2.74. Found: C, 65.27; H, 6.93; N, 2.36.
1
890 cmK1. H NMR (CDCl3): d 2.71 (bs, 1H), 3.58 (t, JZ
8.1 Hz, 1H), 3.83 (t, JZ7.8 Hz, 1H), 3.89–4.05 (m, 3H),
4.26 (s, 1H), 4.38 (s, 1H), 4.54 (d, JZ11.8 Hz, 1H), 4.67
(bs, 1H), 4.74 (d, JZ11.8 Hz, 1H), 7.31 (m, 5H). MS
(APCI): m/z (%) 236 (MC, 40), 180 (100).
4.4.11. Synthesis of (3S,3aS,6R,6aR)-6-(benzyloxy)hexa-
hydrofuro[3,2-b]furan-3-yl-4-methylbenzenesulfonate
(19). The procedure discussed in Section 4.2.1 was
followed; 19 was obtained from 18 (8.0 g, 33.8 mmol) as
white solid (11.10 g, 84%). Mp 84–85 8C (lit. mp 85 8C).
[a]2D5ZC89.2 (c 1, EtOH) [lit. [a]2D5ZC95.1 (c 0.51,
CHCl3)].10 IR (KBr): n 3050, 2974, 2872, 1598, 1455, 1362,
1173, 1142, 1094, 980, 951 cmK1. 1H NMR (CDCl3): d 2.44
(s, 3H), 3.57 (t, JZ7.9 Hz, 1H), 3.81 (dd, JZ6.7, 2.1 Hz,
1H), 3.95–4.06 (m, 3H), 4.50–4.53 (m, 2H), 4.66 (t, JZ
4.3 Hz, 1H), 4.72 (d, JZ11.8 Hz, 1H), 4.87 (bs, 1H), 7.32
(m, 7H), 7.78 (d, JZ8.1 Hz, 2H). 13C NMR (CDCl3): d
21.5, 70.4, 72.4, 73.1, 78.8, 80.4, 83.91 85.7, 127.7, 127.8,
127.8, 128.4, 129.9, 133.1, 137.4, 145.22. MS (APCI) m/z
(%): 390 (MC,100), 298 (90). Anal. Calcd for C20H22O6S:
C, 61.52; H, 5.68; S, 8.21 Found: C, 61.44; H, 7.19; S, 8.13.
Acknowledgements
This work was funded by grant from National Institute of
Pharmaceutical Education & Research (NIPER).
4.4.12. Synthesis of N-benzyl-N-[(3R,3aR,6R,6aS)-6-
(benzyloxy)hexahydrofuro[3,2-b]furan-3-yl]amine (20).
The procedure discussed in Section 4.3 was followed; 20
was obtained from 19 (1.5 g, 3.84 mmol) as white solid
(0.812 g, 65%). Mp 59–60 8C. [a]3D0ZC128.79 (c 0.95). IR
(KBr): n 3325, 3029, 2941, 2871, 1495, 1454, 1367, 1309,
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