A common synthetic approach for seven and eight-membered polyhydroxylated iminocyclitols

Article abstract of DOI:10.1016/j.tetasy.2012.04.017

A common strategy for making seven and eight-membered polyhydroxy iminoalditols has been developed from d-1,5-gluconolactone, using an RCM protocol as the key step.

Full text of DOI:10.1016/j.tetasy.2012.04.017

Tetrahedron: Asymmetry 23 (2012) 697–702
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A common synthetic approach for seven and eight-membered polyhydroxylated
iminocyclitols
⇑
Yerri Jagadeesh, Katakam Ramakrishna, Batchu Venkateswara Rao
Organic & Biomolecular Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
common strategy for making seven and eight-membered polyhydroxy iminoalditols has been
developed from -1,5-gluconolactone, using an RCM protocol as the key step.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 5 April 2012
Accepted 25 April 2012
Available online 8 June 2012
D
1. Introduction
while six new synthetic eight-membered ring compounds have re-
cently been reported by George et al.7b Generally the synthesis of
eight-membered rings is a challenging task because of unfavorable
entropic and enthalpic effects7a due to the strain and transannular
interactions.13
To the best of our knowledge, only one synthesis of 1, 2, 3, and 4
(Fig. 1) has been described. In a continuation of our efforts in the
synthesis of polyhydroxylated iminocyclitols,14 we herein report
the total synthesis of 1, 2, 3, and 4 and the new eight-membered
compound 5. As part of an ongoing program in our group to utilize
the ring closing metathesis reaction to construct functionalized
carbocycles15 and azasugars14e–g from diene precursors, we have
extended an RCM approach to the synthesis of the above polyhydr-
oxylated azepane derivatives starting from carbohydrates.
The diverse biological activities displayed by many naturally
occurring polyhydroxylated piperidine, pyrrolizidine, and indolizi-
dine alkaloids have stimulated considerable interest in the develop-
ment of synthetic approaches to these compounds and related
structures. Some of them have already been tested or approved in
the treatment of diabetes,1 cancer,2 Gaucher’s disease,3 and viral
infections including HIV4 and are now expected to find an increasing
number of therapeutic applications.5 In recent years, attention has
been increasingly focused on the structure–activity relationship of
iminosugars, particularly in seven-membered iminocyclitols, com-
monly known as azaseptanoses or polyhydroxy azepanes6 and
eight-membered iminoalditols.7 Some of these polyhydroxy aze-
pane derivatives show potent glycosidase8 and glycosyltransferase
inhibitory activities.9 In addition, azepanes are DNA minor
groove-binding ligands (MGBLs) due to their high water solubility
and flexibility (compared to a five- or six-membered ring), which al-
low the hydroxyl groups to adopt a variety of conformational posi-
tions, thus increasing the probability of them forming hydrogen
bonds with the purine and pyrimidine bases, thus making them
potentially useful as DNA MGBL’s.10 A number of synthetic ap-
proaches for trihydroxy, tetrahydroxy, and hydroxymethyl/acetam-
ido azepane analogues are reported in the literature.11 Among these
interesting class of azepane derivatives, Sinaÿ et al.12 reported for
the first time the preparation and biological evaluation of some imi-
noheptitols 1, 2, and 3, a novel family of polyhydroxylated azepanes
with a hydroxymethyl arm. These derivatives have shown potent
and specific glycosidase inhibition; for example, compound 2 is a
2. Results and discussion
Based on our retrosynthesis, the key intermediate 6 for the aze-
panes can be obtained from diene 7 through RCM. Diene com-
pound 7 can be prepared from compound 8, which in turn can be
obtained from D
-1,5-gluconolactone 10 (Scheme 1).14a The above
strategy can give the required key intermediate 6 with high enan-
tiomeric purity.
Accordingly,
D-1,5-gluconolactone 10 was transformed into
compound 11 using our earlier procedure.14a Compound 11 was
subjected to allylation with allyl chloride/NaH in DMF for 2 h to
give N-allyl derivative 8 in 85% yield. Selective deprotection of
the terminal acetonide of 8 with 80% AcOH in rt for 16 h afforded
the diol compound 12 in 95% yield. The diol functionality of 12
was converted into olefin 7 using Garegg’s protocol16 (TPP, I2,
imidazole) in 86% yield.
selective inhibitor of coffee bean a-galactosidase and compound 3
strongly inhibits bovine liver b-galactosidase. To date, no eight-
membered iminoalditol has been isolated. In 2004, Martin et al. syn-
thesized the first eight-membered iminoalditol, compound 4,7a
Initially, diene 7 was subjected to ring closing metathesis17
using Grubbs first generation catalyst in CH2Cl2 at reflux conditions
for 18 h to produce the key cyclic intermediate 6 in 88% yield. We
then tested Grubbs second generation catalyst in CH2Cl2 at reflux
to give compound 6 in 91% yield after 4 h (Scheme 2). Deprotection
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B. Venkateswara Rao).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.017

698
Y. Jagadeesh et al. / Tetrahedron: Asymmetry 23 (2012) 697–702
HO HO
OH
OH
OH
HO
HO
OH
OH
OH
OH
OH
OH
N
H
N
H
N
H
3
1
2
HO
HO
OH
OH
OH
OH
OH
OH
N
N
H
H
5
4
Figure 1. Some polyhydroxylated iminoalditols.
O
O
HO
OH
HO
OH
OH
OH
OH
10
N
H
1
O
HO
OH
O
NCbz
O
NCbz
O
HO
OBn
OBn
OH
OH
O
HO
OBn
N
OH
OH
OH
O
O
O
N
H
CBz
8
7
6
2
HO
OH
N
H
4
HO
OH
OH
O
NCbz
N
H
HO
OBn
OH
OH
OH
3
O
OH
9
N
H
5
Scheme 1. Retrosynthetic pathway.
of the O-benzyl and N-Cbz groups under catalytic hydrogenation
conditions followed by acetonide deprotection with 6 M HCl in
ethanol gave the hydrochloride salt of azepane 1. Finally the com-
pound 1ꢀHCl was passed through a DOWEX W8–200 exchange re-
sin column with 30% NH3 solution to afford 1 as the free base in
71% yield. The spectroscopic and analytical data of synthetic com-
pound 1 were in excellent agreement with the reported values.12
In order to obtain the 1,6-dideoxy-1,6-iminoheptitols 2 and 3,
treatment of cyclized compound 6 with OsO4 for 8 h gave the de-
sired diol derivatives 13 and 14 (4:1) in 85% yield. The O-benzyl
and N-Cbz groups in compound 13 were deprotected by catalytic
hydrogenation followed by the acetonide group deprotection with
6 M HCl in ethanol to give the hydrochloride salt of azepane 2.
Finally, compound 2ꢀHCl was passed through a DOWEX W8–200
exchange resin column with 30% NH3 solution and afforded 2 in
72% yield as the free base, whose spectroscopic data were also iden-
tical with the reported values (Scheme 3).12 In a similar way, the
minor isomer 14 was transferred to compound 3 in 66% yield,
whose spectroscopic data were also in excellent agreement with
the reported values.12
In order to obtain the eight-membered iminocyclitols 4 and 5,
selective deprotection of the terminal acetonide of 8 and the
in situ oxidative cleavage13 of the resulting diol with periodic acid
in ether gave the aldehyde, which was treated with vinyl magne-
sium bromide to give a diastereomeric mixture 9 in 65% yield
(ꢁ2.5:1 ratio, as inseparable mixture). Compound 9 upon ring clos-
ing metathesis, afforded the cyclized compounds 15 and 16 as a sep-
arable mixture in 90% yield using column chromatography. Both
compounds 15 and 16 were transformed into 47a and 5 using the
procedure that was developed for compound 1 (Scheme 4). The
spectroscopic data of compound 4 were in excellent agreement with
the reported values.7a
3. Conclusion
In conclusion, we have developed a synthetic approach for
polyhydroxy iminoalditols 1, 2, 3, 4, and 5 from D-1,5-gluconolac-
tone using a RCM protocol as the key step.

Y. Jagadeesh et al. / Tetrahedron: Asymmetry 23 (2012) 697–702
699
O
NHCbz
OBn
O
NCbz
allyl chloride
O
O
NaH, DMF, DMAP
ref no: 12a
HO
OBn
O
O
0 °C-rt, 2h
85%
O
O
O
O
HO
OH
5 steps
OH
10
11
8
G-I, CH2Cl2
I2, TPP
imidazole
toluene
O
NCbz
O
NCbz
40 °C, 18h, 88%
80% AcOH
OBn
OBn
HO
or
110 °C, 3h
86%
0 °C-rt, 16h
95%
HO
O
O
G-II, CH2Cl2
40 °C, 4h, 91%
12
7
1. PdCl2/H2
methanol
rt, 12h
O
OH
2. 6M HCl, rt, 6h
O
OH
OH
DOWEX 5WX8-200
30% ammonia solution
71%
N
OBn
N
H
Cbz
6
1
Scheme 2.
OsO4
acetone:H2O
(1:5)
O
HO
HO
O
O
HO
HO
O
O
O
rt, 8h
85%
OBn
N
OBn
OBn
N
N
Cbz
Cbz
Cbz
(dr=3:1)
6
13
14
1. PdCl2/H2
methanol
rt, 12h
66%
OH
72%
2. 6M HCl, rt, 6h
3. DOWEX 5WX8-200
30% ammonia solution
HO
HO
OH
HO
HO
OH
OH
OH
N
H
OH
N
H
3
2
Scheme 3.
200 MHz) and 13C NMR (75 and 100 MHz) spectra were recorded
at the corresponding MHz. Chemical shifts are reported in ppm
with respect to TMS as the internal standard. Coupling constants
(J) are quoted in Hz. Optical rotations were measured with a
Horiba-SEPA-300 digital polarimeter. Accurate mass measurement
was performed on a Q STAR mass spectrometer (Applied Biosys-
tems, USA).
4. Experimental section
4.1. General
Moisture- and oxygen- sensitive reactions were carried out un-
der a nitrogen gas atmosphere. All solvents and reagents were
purified by standard techniques. TLC was performed on Merck
Kiesel gel 60, F254 plates (layer thickness 0.25 mm). Column chro-
matography was performed on silica gel (60–120 and 100–200
mesh) using ethyl acetate, hexane, chloroform, and methanol as
eluants. Melting points were determined on a Fisher John’s melting
point apparatus and are uncorrected. IR spectra were recorded on a
Perkin–Elmer RX-1 FT-IR system. 1H NMR (500, 400, 300 and
4.2. Benzyl allyl((R)-2-(benzyloxy)-1-((4S,40R,5R)-2,2,20,20-
tetramethyl-4,40-bi(1,3-dioxo-lan)-5-yl)ethyl)carbamate 8
To a stirred solution of compound 11 (7.5 g, 15.6 mmol) in dry
DMF (750 ml) were added NaH (1.12 g, 46.8 mmol) and allyl

700
Y. Jagadeesh et al. / Tetrahedron: Asymmetry 23 (2012) 697–702
HO
O
HO
O
1. HIO5, dry ether
0 °C-rt, 6h
O
NCbz
G-II, CH2Cl2
OBn
O
OBn
O
40 °C, 6h, 90%
2.
MgBr
0 oC-rt, 2h
O
OH
N
OBn
N
Cbz
Cbz
16
9
15
1. PdCl2/H2
methanol
rt,12h
2. 6N HCl, rt, 6h
3. DOWEX 5WX8-200
30% ammonia solution
HO
HO
OH
OH
OH
OH
OH
OH
N
N
H
H
5
4
Scheme 4.
chloride (2.39 g, 31.2 mmol) at 0 °C. The reaction mixture was al-
lowed to return to room temperature, stirred it for 2 h, poured into
ice cold water (100 mL), and extracted with diethyl ether
(5 ꢂ 60 mL). The combined organic extracts were washed with
brine (80 mL), dried over anhydrous Na2SO4 and concentrated un-
der reduced pressure. Purification by silica gel column chromatog-
raphy using ethyl acetate/hexane (1:15) as an eluant afforded
4.4. Benzyl allyl((R)-2-(benzyloxy)-1-((4R,5R)-2,2-dimethyl-5-
vinyl-1,3-dioxolan-4-yl)eth-yl)carbamate 7
To a stirred solution of diol 12 (3.50 g, 7.22 mmol) in dry tolu-
ene (50 mL) were added triphenylphosphine (7.57 g, 28.87 mmol)
and imidazole (1.96 g, 28.87 mmol) at room temperature and then
heated at reflux after which iodine (5.50 g, 21.65 mmol) was
added in small portions. The reaction was then refluxed for 3 h.
After completion, the reaction mixture was quenched with aq.
sodium thiosulphate solution and extracted into ethyl acetate
(3 ꢂ 75 mL). The combined organic extracts were washed with a
saturated NaHCO3 solution (2 ꢂ 50 mL), dried over anhydrous
Na2SO4, and concentrated to give the crude product, which was
purified by column chromatography using ethyl acetate/hexane
(1:19) as an eluant to afford diene 7 (2.8 g, 86%) as a pale yellow
compound 8 (7.0 g, 85%) as a thick syrup. ½a D25
¼ þ21:3ðc6:38;
ꢃ
CHCl3Þ; IR (neat) mmax 2987, 2935, 2879, 1700, 1454, 1374, 1243,
1067, 698 cmꢄ1 1H NMR (500 MHz, CDCl3) d 1.19–1.41 (m, 12H),
;
3.49–4.25 (m, 9H), 4.38–4.63 (m, 3H), 5.0–5.35 (m, 4H), 5.91 (m,
1H), 7.18–7.38 (m, 10H) (because of the rotameric nature of the
compound, the NMR is not resolved clearly); 13C NMR (75 MHz,
CDCl3) d ⁄25.12, 25.26, ⁄26.22, 26.35, 27.11, 27.21, ⁄27.28, 47.68,
⁄56.96, 57.34, ⁄67.06, 67.13, 67.33, 72.61, 76.84, ⁄76.90, ⁄79.18,
79.23, 79.45, 80.32, ⁄109.53, 109.55, 109.70, 115.77, ⁄116.0,
⁄127.28, 127.33, 127.39, 127.58, ⁄127.73, 127.75, 1217.9, ⁄128.0,
⁄128.13, 128.25, 135.25, 135.57, 136.50, ⁄138.02, 138.05, ⁄155.83,
156.45 (⁄rotamer); ESI/MS (m/z) 526 (M++H); HRMS calcd for
thick syrup. ½a 2D5
¼ þ18:9 (c 3.09, CHCl3); IR (KBr) mmax 2986,
ꢃ
2933, 2868, 1704, 1698, 1455, 1410, 1244, 1109, 1057, 698 cmꢄ1
;
1H NMR (300 MHz, CDCl3) d 1.31–1.53 (m, 6H), 3.48–4.05 (m,
5H), 4.18–4.62 (m, 4H), 4.97–5.38 (m, 6H), 5.50–5.95 (m, 2H),
7.20–7.47 (m, 10H) (Because of the rotameric nature of compound,
NMR is not resolved clearly); 13C NMR (75 MHz, CDCl3) d 26.85,
26.91, 48.24, 57.60, 67.14, ⁄67.22, 67.98, 72.79, ⁄78.92, 79.54,
80.73, 80.85, 109.15, ⁄109.32, 116.08, ⁄116.44, 118.99, 127.46,
127.82, ⁄128.0, 128.08, 128.20, 128.30, ⁄134.76, 134.93, 135.05,
135.32, ⁄136.25, 136.53, ⁄137.92, 138.07, ⁄155.65, 156.27 (⁄rot-
amer); ESI/MS (m/z) 474 (M++Na); HRMS calcd for C27H33NO5Na
474.2256, found 474.2241.
C30H39O7NNa 548.2618, found 548.2599.
4.3. Benzyl allyl((R)-2-(benzyloxy)-1-((4R,5R)-5-((R)-1,2-
dihydroxyethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)ethyl)carbamate 12
A solution of compound 8 (6.6 g, 12.57 mmol) in 60% aq. AcOH
(70 mL) was stirred at room temperature for 16 h. The reaction
mixture was neutralized to pH 7 by adding dropwise a saturated
30% ammonia solution at 0 °C. The resulting reaction mixture
was concentrated under reduced pressure and the residue was
purified by column chromatography on silica gel using ethyl ace-
tate/hexane (1:4) as the eluant to give the diol compound 12
4.5. (3aR,4R,8aR)-Benzyl 4-(benzyloxymethyl)-2,2-dimethyl-
6,8a-dihydro-3aH-[1,3]diox-olo[4,5-c]azepine-5(4H)-
carboxylate 6
(5.8 g, 95%) as a thick syrup. ½a D25
¼ þ26:2 (c 4.65, CHCl3); IR
ꢃ
4.5.1. Method 1
(KBr) mmax 3441, 2986, 2934, 2877, 1680, 1454, 1370, 1248, 1079,
To a solution of diene 7 (1 g, 2.22 mmol) in CH2Cl2 (60 mL), was
added Grubbs’ first-generation catalyst (0.18 g, 0.22 mmol) and the
reaction mixture was refluxed for 18 h. After completion of the
reaction, CH2Cl2 was removed under vacuum, and purified by col-
umn chromatography using ethyl acetate/hexane (1:9) to provide
cyclic compound 6 as a light yellowish thick syrup (0.83 g, 88%).
698 cmꢄ1 1H NMR (500 MHz, CDCl3) d 1.31 (s, 3H), 1.33 (s, 3H),
;
2.25 (br s, 1H), 3.45–4.02 (m, 9H), 4.12 (br s, 1H), 4.32–4.55 (m,
3H), 5.01–5.19 (m, 4H), 5.84 (m, 1H), 7.20–7.36 (m, 10H) (because
of the rotameric nature of the compound, the NMR is not resolved
clearly); 13C NMR (75 MHz, CDCl3) d 27.06, 47.28, 57.03, ⁄57.55,
63.72, 66.28, 67.42, ⁄67.56, 72.74, 73.08, 78.48, ⁄78.81, ⁄79.25,
80.79, 109.72, 116.21, ⁄126.73, ⁄127.06, 127.50, 127.57, 127.68,
127.87, ⁄128.11, 128.23, 128.33, 135.02, 136.27, 137.76, ⁄156.21,
157.10 (⁄rotamer); ESI/MS (m/z) 486 (M++H); HRMS calcd for
4.5.2. Method 2
To a solution of diene 7 (1 g, 2.22 mmol) in CH2Cl2 (60 mL), was
added Grubbs’ second-generation catalyst (0.09 g, 0.11 mmol) and
C27H35O7NNa 508.2306, found 508.2309.

Y. Jagadeesh et al. / Tetrahedron: Asymmetry 23 (2012) 697–702
701
the reaction mixture refluxed for 4 h. After completion of the reac-
tion, CH2Cl2 was removed under vacuum, the crude product was
purified by column chromatography using ethyl acetate/hexane
(1:9) to provide cyclic compound 6 as a light yellowish thick syrup
Further elution with ethyl acetate/hexane (1: 3.5) afforded 13 as
a thick syrup (0.76 g, 64%). ½a D26
ꢃ
¼ ꢄ43:1 (c 2.83, CHCl3); IR (KBr))
m
max: 3438, 2985, 2931, 1692, 1454, 1422, 1250, 1219, 1077,
1053, 774, 698 cmꢄ1
;
1H NMR (300 MHz, CDCl3): d 1.36–144 (m,
(0.86 g, 91%). ½a D25
ꢃ
¼ ꢄ84:8 (c 2.80, CHCl3); IR (KBr) mmax 2985,
6H), 2.69–3.08 (m, 1H), 3.15 (dd, J= 3.46, 15.82 Hz, 1H), 3.43–
3.56 (m, 2H), 3.61–3.80 (m, 2H), 3.86 (d, 1H), 3.91–4.09 (m, 3H),
4.28 (m, 1H), 4.41–4.52 (m, 2H), 5.07 (2d, J= 11.86 Hz, 1H), 5.16
(2d, J= 12.86 Hz, 1H), 7.16–7.40 (m, 10H) (because of the rotameric
2934, 1703, 1453, 1418, 1235, 1112,1072, 698 cmꢄ1
;
1H NMR
(300 MHz, CDCl3) d 1.32–143 (m, 6H), 3.62–3.94 (m, 3H), 3.96–
4.23 (m, 2H), 4.26–4.62 (m, 4H), 5.08–5.20 (m, 2H), 5.60–5.91
(m, 2H), 7.17–7.38 (m, 10H) (because of the rotameric nature of
the compound, the NMR is not resolved clearly); 13C NMR
nature of the compound, the NMR showed doubling of peaks); 13
C
⁄
⁄
⁄
NMR (75 MHz, CDCl3): d 26.82, 27.27, 44.20, 44.82, 57.0, 57.10,
⁄67.60, 68.07, ⁄68.58, 69.44, ⁄69.63, 69.94, ⁄73.27, 73.30, 74.04,
⁄74.94, 75.0, ⁄78.58, 79.14, 110.14, ⁄110.20, 127.29, ⁄127.53,
⁄127.66, 127.78, ⁄127.86, 128.10, 128.17, ⁄128.30, 128.38, 128.52,
135.92, ⁄136.29, 137.93, ⁄138.21, ⁄156.23, 158.32 (⁄rotamer);
ESI/MS (m/z): 480 (M++Na); HRMS (ESI): calcd for C25H31NO7Na
480.1993, found 480.1988.
(75 MHz, CDCl3)
d
26.86, 27.13, 42.95, 56.30, ⁄56.79, 67.34,
⁄67.50, 69.73, ⁄69.76, 73.11, ⁄73.20, 77.15, 78.43, ⁄78.59, ⁄109.89,
109.98, ⁄127.27, 127.36, 127.48, ⁄127.52, 127.72, 127.92, ⁄127.96,
128.30, 128.41, ⁄129.11, ⁄136.42, 136.50, ⁄138.01, 138.12,
⁄155.68, 156.0 (⁄rotamer); ESI/MS (m/z) 446 (M++Na); HRMS calcd
for C25H29NO5Na 446.1938, found 446.1922.
4.8. (2R,3R,4S,5S,6S)-2-(Hydroxymethyl)azepane-3,4,5,6-tetraol
2
4.6. (2R,3R,4R)-2-(Hydroxymethyl)-2,3,4,7-tetrahydro-1H-azepine-
3,4-diol 1
Compound 13 (0.3 g, 0.43 mmol) was transformed into final
product 2 (0.09 g, 72%) as colorless oil by following the procedure
A solution of 6 (0.2 g, 0.47 mmol) in methanol (5 mL) was stirred
at room temperature in the presence of PdCl2 (catalytic amount) un-
der a hydrogen atmosphere for 12 h. To this solution, aqueous 6 M
HCl (1.5 ml) was added, and the mixture was stirred for 6 h. The cat-
alyst was removed by filtration and the reaction mixture was con-
centrated. Further evaporation under reduced pressure gave a salt
of compound 1, which was passed through the Dowex 50WX400 re-
sin using 30% NH3 solution, to give 1 (0.065 g) as a colorless oil in
used in the synthesis of azepane 1. ½a D26
ꢃ
¼ þ37:2 (c 1.3, MeOH)
max: 3312, 2943,
;
1H NMR (500 MHz, D2O): d
{lit.12
½
a 2D5
ꢃ
¼ þ32 (c 1.13, MeOH)}; IR (neat)
m
2834, 1450, 1416, 1018, 771 cmꢄ1
3.28 (dd, J = 2.0, 14.4 Hz, 1H), d 3.36 (dd, J = 6.4, 14.4 Hz, 1H), 3.48
(ddd, 1H, J = 3.5, 6.5, 9.4 Hz), 3.61–3.68 (m, 2H), 3.73 (t, J = 8.4 Hz,
1H), 3.85 (dd, J = 6.5, 12.4 Hz, 1H), 3.94 (dd, J = 3.5, 12.4 Hz, 1H),
4.23 (m, 1H); 13C NMR (75 MHz, D2O) d 44.48, 59.16, 59.19, 66.31,
68.50, 73.35, 74.28; ESI/MS (m/z): 194 (M++H); HRMS (ESI): calcd
for C7H16NO3 194.1023, found 194.1024.
71% yield. ½a 2D6
ꢃ
¼ þ5:5 (c 1.84, MeOH) {lit.12
½
a 2D5
ꢃ
¼ þ6 (c 0.1,
MeOH)}; IR (neat) mmax: 3321, 2945, 2832, 1644, 1450, 1414, 1017,
771 cmꢄ1 1H NMR (500 MHz, D2O): d 1.74–2.12 (m, 4H) 3.18 (m,
;
1H), 3.26–3.42 (m, 2H), 3.67 (t, J = 8.4 Hz, 1H), 3.78 (m, 1H), 3.86
(dd, J = 6.9, 12.4 Hz, 1H), 3.97 (m, 1H); 13C NMR (75 MHz, D2O) d
19.15, 28.51, 46.11, 59.75, 60.45, 72.18, 73.94; ESI/MS (m/z): 162
(M++H); HRMS (ESI): calcd for C7H16NO3 162.1125, found 162.1124.
4.9. (2R,3R,4S,5R,6R)-2-(Hydroxymethyl)azepane-3,4,5,6-tetraol
3
Compound 14 (0.20 g, 0.43 mmol) was transformed into final
product 3 (0.055 g, 66%) as a colorless oil by following the procedure
used in the synthesis of azepane 1. ½a D26
ꢃ
¼ ꢄ9:4 (c 1.28, MeOH) {lit.12
4.7. (3aR,4R,7S/R,8S/R,8aR)-Benzyl 4-(benzyloxymethyl)-7,8-dihy-
droxy-2,2-dimethyltet-rahydro-3aH-[1,3]dioxolo[4,5-c]azepine-
5(4H)-carboxylates 13/14
½
a 2D5
ꢃ
¼ ꢄ9:0 (c 1.07, MeOH)}; IR (neat)
m
max: 3317, 2945, 2833, 1451,
1416, 1017, 771 cmꢄ1 1H NMR (500 MHz, D2O): d 3.21–3.32 (m,
;
2H), 3.40 (dd, J = 5.7, 13.7 Hz, 1H), 3.72–3.79 (m, 2H), 3.85 (t,
J = 9.1 Hz, 1H), 3.96 (m, 1H), 4.15 (m, 1H), 4.22 (m, 1H); 13C NMR
(75 MHz, D2O) d 47.20, 59.84, 61.20, 66.30, 68.65, 74.54, 75.24;
ESI/MS (m/z): (m/z): 194 (M++H); HRMS (ESI): calcd for C7H16NO3
194.1023, found 194.1023.
To an ice cooled, stirred solution of compound 6 (1.1 g, 2.60
mmol) in acetone/water (5:1, 15 mL) were added NMO (0.46 g,
3.9 mmol) and OsO4 (0.013 g, 0.052 mmol, in toluene). The reaction
was allowed to return to room temperature and stirred for 8 h. The
reaction mixture was quenched with solid sodium sulfite. The sol-
vent was removed under reduced pressure and extracted with
ethyl acetate (3 ꢂ 50 mL). The combined organic extracts were
washed with water and brine, and dried over Na2SO4. The solvent
was concentrated under reduced pressure to afford diastereomeric
mixture of diols 13 and 14. Purification by column chromatogra-
phy, by eluting first with ethyl acetate/hexane (1: 4) gave 14 as a
4.10. Benzyl allyl((1R)-2-(benzyloxy)-1-((4R,5R)-5-(1-hydroxy-
allyl) -2,2-dimethyl-1,3-diox-olan-4-yl)ethyl)carbamate 9
To a solution of 8 (1.8 g, 3.43 mmol) in dry ether (25 mL) was
added periodic acid (1.17 mg, 5.13 mmol) portion wise at 0 °C un-
der a nitrogen atmosphere. After being stirred for 6 h at room tem-
perature, the reaction mixture was neutralized with NaHCO3,
filtered through a pad of Celite, and the filtrate was concentrated
under reduced pressure to give a crude aldehyde derivative, which
was used in the next step without any purification. To a stirred
solution of aldehyde (1.35 g, 2.98 mmol) in dry THF (15 mL) at -
15 °C, was added vinyl magnesium bromide (12 mL) dropwise over
a period of 5 min. The solution was then gradually warmed to room
temperature. After completion of the reaction, the reaction mixture
was cooled to 0 °C and a saturated aq. NH4Cl solution was added.
The mixture was extracted with ethyl acetate (3 ꢂ 50 mL) and
the combined organic extracts were washed with water and brine,
and dried over anhydrous Na2SO4. The solvent was removed on a
rotary evaporator and the residue was purified by column
chromatography on silica gel using ethyl acetate/hexane (1:8) as
thick syrup (0.25 g, 21%). ½a D26
ꢃ
¼ ꢄ21:3 (c 3.57, CHCl3); IR (KBr))
m
max: 3444, 2986, 2931, 2868, 1695, 1682, 1417, 1245, 1218,
1058, 736, 698 cmꢄ1
;
1H NMR (400 MHz, CDCl3): d 1.32–1.50 (m,
6H), 1.74 (br s, 1H), 2.84 (br s, 1H), 3.27 (m, 1H), 3.53–3.83 (m,
5H), 3.85–4.05 (2d, 1H), 4.21 (br s, 1H), 4.44–4.60 (m, 3H), 4.97–
5.19 (s and 2d, 2H), 7.11–7.42 (m, 10H) (because of the rotameric
nature of the compound, the NMR is not resolved clearly); 13C NMR
(75 MHz, CDCl3): d ⁄26.74, ⁄26.86, 27.04, 44.53, 57.34, ⁄57.61,
67.41, ⁄67.64, 68.33, ⁄68.53, ⁄68.75, 69.43, 69.63, ⁄69.85, 70.29,
⁄70.33, 73.09, 79.09, ⁄79.14, ⁄109.79, 109.85, ⁄127.23, 127.27,
⁄127.44, 127.50, ⁄127.74, 127.79, 128.05, 128.27, ⁄128.32,
⁄
⁄128.46, 128.53, ⁄136.14, 136.36, ⁄138.08, 138.23, 155.78, 155.84
(⁄rotamer); ESI/MS (m/z): 458 (M++H); HRMS (ESI): calcd for
C25H31NO7Na 480.1993, found 480.1993.

702
Y. Jagadeesh et al. / Tetrahedron: Asymmetry 23 (2012) 697–702
the eluant to give a 2.5:1 mixture of 9 (1.2 g, 73%) as a light yellow-
ish oil. IR (neat) max: 3446, 2985, 1693, 1244, 1101, 752,
698 cmꢄ1 1H NMR (400 MHz, CDCl3): d 1.34 (s, 3H), 1.37 (s, 3H),
4.13. (2R,3R,4R,5R)-2-(Hydroxymethyl)azocane-3,4,5-triol 5
m
;
Compound 16 (0.15 g, 0.33 mmol) was transformed into final
product 5 (0.046 g, 73%) as colorless oil by following the procedure
3.62–4.23 (m, 7H), 4.37–4.52 (m, 3H), 5.02–5.33 (m, 6H), 5.65–
5.95 (m, 2H), 7.2–7.33 (m, 10H); 13C NMR (75 MHz, CDCl3) d
27.09, ⁄27.17, 27.19, 48.00, ⁄57.76, 57.99, 67.33, ⁄67.46, 71.56,
⁄71.83, ⁄72.56, 72.76, 72.83, ⁄73.15, 76.23, 78.36, ⁄81.34, 81.63,
109.58, ⁄109.66, ⁄116.24, 116.42, ⁄116.82, 117.09, 127.51, 127.95,
128.27, 128.40, 129.55, ⁄130.03, 133.02, ⁄134.88, 135.10, ⁄135.17,
135.96, ⁄136.46, ⁄136.89, 137.15, 137.97, ⁄155.91, 156.58 (⁄rotamer
and minor isomer); ESI/MS (m/z): 504 (M++Na); HRMS calcd for
used in the synthesis of azepane 1. ½a D26
ꢃ
¼ ꢄ4:3 (c 0.43, MeOH); IR
(neat)
m
max: 3327, 2944, 2832, 1449, 1413, 1019, 651 cmꢄ1 1H
;
NMR (500 MHz, D2O): d 1.68 (m, 1H), 1.81–1.93 (m, 2H), 2.0 (m,
1H), 3.02–3.19 (m, 3H), 3.75–3.86 (m, 3H), 3.94 (dd, J = 2.9, 11.7,
1H), 4.18 (t, J = 4.4 Hz, 1H); 13C NMR (75 MHz, D2O) d 19.12,
30.07, 46.22, 57.47, 59.63, 68.24, 71.79, 75.8; ESI/MS (m/z): 192
(M++H); HRMS calcd for C8H18NO4 192.1230, found 192.1233.
C28H35NO6Na 504.2357, found 504.2348.
Acknowledgments
4.11. (5S/R,6R,7R,8R,Z)-Benzyl 8-((benzyloxy)methyl)-5,6,7-trihy-
droxy-5,6,7,8-tetrahyd-roazocine-1(2H)-carboxylates 15/16
Y.J. and K.R. thank the CSIR, New Delhi for the research fellow-
ship. The authors also thank Drs. J. S. Yadav and G. V. M. Sharma for
their support and encouragement.
To a solution of diene 9 (0.9 g, 1.87 mmol) in CH2Cl2 (60 mL), was
added Grubbs’ second-generation catalyst (0.08 g, 0.094 mmol)
after which the reaction mixture was heated at reflux for 6 h. After
completion of the reaction, CH2Cl2 was removed under vacuum, and
purified by column chromatography using ethyl acetate/hexane
(1:4.5) to provide the faster moving cyclic compound 15 as a light
References
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Krol, A. Diab. Care 1994, 17, 20; (b) Kleist, P.; Ehrlich, A.; Suzuki, Y.; Timmer, W.;
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yellowish thick syrup (0.50 g, 60%). ½a D26
¼ ꢄ83:2 (c 1.47, CHCl3);
ꢃ
IR (neat) mmax
: 3478, 2985, 1693, 1244, 1212, 1045, 735,
696 cmꢄ1 1H NMR (400 MHz, CDCl3): d 1.36–1.50 (4s, 6H), 2.73
;
(2s, 1H) 3.37–3.98 (m, 5H), ⁄4.05 (d, J = 9.75 Hz, 1H), 4.20 (d,
J = 10.14 Hz, 1H), 4.31–4.57 (m, 4H), 5.02–5.20 (m, 2H), 5.57–5.67
(m, 1H), 5.75–5.86 (m, 1H), ⁄5.95–6.05 (m, 1H), 7.16–7.39 (m,
10H) (because of the rotameric nature of the compound, the NMR
showed a doubling of peaks); 13C NMR (75 MHz, CDCl3) d ⁄26.53,
26.56, ⁄26.87, 26.96, 40.91, ⁄41.19, 58.01, ⁄58.28, 67.40, 69.85,
⁄69.96, 72.75, 73.17, 76.46, 82.31, ⁄82.53, ⁄109.34, 109.49, ⁄127.30,
127.33, 127.51, 127.59, 127.66, ⁄127.80, 127.96, ⁄127.99, 128.29,
128.33, 128.45, ⁄134.13, 134.31, 136.43, 138.21, ⁄155.39, 155.79
(⁄rotamer); ESI/MS (m/z): 454 (M++H); HRMS calcd for C26H31NO6-
Na 476.2044, found 476.2038.
3. (a) Alper, J. Science 2001, 291, 2338; (b) Stone, D. L.; Tayebi, N.; Orvisky, E. Hum.
Mutat. 2000, 15, 181.
4. (a) Robina, I.; Moreno-Vargas, A. J.; Carmona, A. T.; Vogel, P. Curr. Drug Metab.
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Wilson, F.; Witty, D. R.; Jacobs, G. S.; Rademacher, T. W. FEBS Lett. 1988, 237,
128.
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6. Paulsen, H.; Todt, K. Chem. Ber. 1967, 100, 512.
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Yang, Y.; Zhu, J.-Y.; Tash, J. S.; Schonbrunn, E.; George, G. I. J. Org. Chem. 2012,
77, 3082.
The slower moving cyclic compound 16 was eluted in the col-
umn (ethyl acetate/hexane = 1:4) as light yellowish thick syrup
8. (a) Simmott, M. L. Chem. Rev. 1990, 90, 1171; (b) Winchester, B.; Fleet, G. W. J.
Glycobiol. 1992, 2, 199; (c) Bols, M. Acc. Chem. Res. 1998, 31, 1; (d) Heightman, T.
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M. Chem. Rev. 2002, 102, 515; (g) Asano, N. Curr. Top. Med. Chem. 2003, 3, 471.
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Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2301; (c) Saotome, C.;
Wong, C.-H.; Kanie, O. Chem. Biol. 2001, 8, 1061; (d) Pandey, G.; Kapur, M. Org.
Lett. 2002, 4, 3883; (e) Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003, 3,
541.
10. Johnson, H. A.; Thomas, N. R. Bioorg. Med. Chem. Lett. 2002, 12, 237.
11. Kalamkar, N. B.; Kasture, V. M.; Chavan, S. T.; Sabharwal, S. G.; Dhavale, D. D.
Tetrahedron: Asymmetry 2010, 66, 8522. and references cited therein.
12. Li, H.; Bleriot, Y.; Chantereau, C.; Mallet, J.-M.; Sollogoub, M.; Zhang, Y.;
Rodriguez-Garcia, E.; Vogel, P.; Jimenez-Barbero, J.; Sinay, P. Org. Biomol. Chem.
2004, 2, 1492.
(0.22 g, 26%). ½a D26
ꢃ
¼ ꢄ44:4 (c 1.28, CHCl3); IR (neat)
mmax: 3317,
2925, 1640, 1213, 753, 667 cmꢄ1
;
1H NMR (300 MHz, CDCl3): d
1.21–1.49 (4s, 6H), 2.27 (m, 1H), 3.53–3.80 (m, 3H), 3.86–4.07 (m,
⁄
2H), 4.19 (m, 1H), 4.30 (m, 1H), 4.39–4.61 (m, 4H), 5.03–5.21 (m,
2H), 5.71–5.93 (m,. 2H), ⁄5.99 (m, 1H), 7.15–7.42 (m, 10H) (because
of the rotameric nature of the compound, the NMR showed a dou-
bling of peaks); 13C NMR (75 MHz, CDCl3) d ⁄26.36, 26.55, ⁄26.96,
27.02, 40.89, ⁄41.13, 57.32, ⁄57.78, 66.76, 67.42, ⁄67.49, ⁄69.26,
69.36, 72.52, ⁄72.80, 73.06, 81.64, ⁄81.75, 85.30, 109.04, ⁄127.33,
127.39, 127.46, ⁄127.53, 127.69, 127.82, 127.98, 128.27, 128.31,
128.45, 129.48, ⁄132.15, 132.41, ⁄136.45, 136.50, ⁄138.08, 138.24,
⁄155.75, 156.11 (⁄rotamer); ESI/MS (m/z): 476 (M++Na); HRMS calcd
for C26H31NO6Na 476.2044, found 476.2047.
13. (a) Michaut, A.; Rodriguez, J. Angew. Chem., Int. Ed. 2006, 45, 5740; (b) Kotha, S.;
Dipak, M. K. Tetrahedron 2012, 68, 397.
14. (a) Jagadeesh, Y.; Reddy, J. S.; Rao, B. V.; Swarnalatha, J. L. Tetrahedron 2010, 66,
1202; (b) Jagadeesh, Y.; Chandrasekhar, B.; Rao, B. V. Tetrahedron: Asymmetry
2010, 21, 2314; (c) Jagadeesh, Y.; Rao, B. V. Tetrahedron Lett. 2011, 52, 6366; (d)
Jagadeesh, Y.; Reddy, K. S.; Rao, B. V. Tetrahedron: Asymmetry 2011, 22, 1485;
(e) Chandrasekhar, B.; Rao, B. V. Tetrahedron: Asymmetry 2009, 20, 1217; (f)
Chandrasekhar, B.; Madhan, A.; Rao, B. V. Tetrahedron 2007, 63, 8746; (g)
Madhan, A.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5641.
15. (a) Rao, J. P.; Rao, B. V.; Swarnalatha, J. L. Tetrahedron Lett. 2010, 51, 3083; (b)
Rao, J. P.; Rao, B. V. Tetrahedron: Asymmetry 2010, 21, 930; (c) Ramana, G. V.;
Rao, B. V. Tetrahedron Lett. 2006, 47, 4441; (d) Ramana, G. V.; Rao, B. V.
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2003, 44, 5103.
4.12. (2R,3R,4R,5S)-2-(Hydroxymethyl)azocane-3,4,5-triol 4
Compound 15 (0.25 g, 0.55 mmol) was transformed into final
product 4 (0.075 g, 71%) as a colorless oil by following the proce-
dure used in the synthesis of azepane 1. ½a D26
ꢃ
¼ þ9:61 (c 0.85,
MeOH), ½a 2D6
ꢃ
¼ þ8:7 (c 0.80, H2O) {lit.7a
½ ꢃ ¼ þ10:5 (c 0.2,
a 2D5
H2O)}; IR (neat)
mmax: 3327, 2944, 2833, 1449, 1412, 1018,
659 cmꢄ1 1H NMR (500 MHz, D2O): d 1.58 (m, 1H), 1.72–1.81
;
(m, 2H), 1.9 (m, 1H), 2.74 (m, 1H), 2.82–2.98 (m, 2H), 3.58 (dd,
J = 3.4, 8.8, 1H), 3.64–3.72 (m, 2H), 3.88 (dd, J = 3.4, 11.8 Hz, 1H),
3.98 (dd, J = 3.4, 8.7 Hz, 1H); 13C NMR (75 MHz, D2O) d 22.15,
25.89, 41.38, 58.66, 59.21, 69.54, 70.32, 78.21; ESI/MS (m/z): 192
(M++H); HRMS calcd for C8H18NO4 192.1230, found 192.1232.
16. Garegg, P. J.; Samuelsson, B. Synthesis 1979, 469.
17. (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953; (b)
Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim, Germany, 2003;
(c) Grubbs, R. H.; Trnka, T. M. In Ruthenium in Organic Synthesis; Murahashi, S. I.,
Ed.; Wiley-VCH: Weinheim, Germany, 2004; p 153. chapter 6.