Highly regio- and diastereoselective, acidic clay supported intramolecular nitrile oxide-alkene cycloaddition on d-ribose derived nitriles: An efficient synthetic route to isoxazoline fused five and six membered carbocycles

Article abstract of DOI:10.1016/j.carres.2014.06.007

An efficient synthetic route to isoxazoline fused carbocycles from carbohydrate scaffolds that comprise of free hydroxyl group(s) is described with high regio- and stereoselectivity. Montmorillonite K-10/chloramine T oxidation and in situ intramolecular nitrile oxide-alkene cycloaddition (INOC) of d-ribose derived oximes have been developed for the diversity oriented synthesis of isoxazoline fused five and six membered carbocycles.

Full text of DOI:10.1016/j.carres.2014.06.007

Carbohydrate Research 398 (2014) 13–18
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Highly regio- and diastereoselective, acidic clay supported
intramolecular nitrile oxide–alkene cycloaddition on D-ribose
derived nitriles: an efficient synthetic route to isoxazoline fused
five and six membered carbocycles
⇑
Amarendra Panda, Sulagna Das, Shantanu Pal
School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar, Orissa 751007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic route to isoxazoline fused carbocycles from carbohydrate scaffolds that comprise
of free hydroxyl group(s) is described with high regio- and stereoselectivity. Montmorillonite
K-10/chloramine T oxidation and in situ intramolecular nitrile oxide–alkene cycloaddition (INOC) of
Received 22 April 2014
Received in revised form 2 June 2014
Accepted 6 June 2014
D-ribose derived oximes have been developed for the diversity oriented synthesis of isoxazoline fused five
Available online 19 June 2014
and six membered carbocycles.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Dipolar cycloadditions
Nitrile oxides
Isoxazoline fused carbocycles
Chloramin-T
Montmorillonite K-10
D-Ribose
Carbohydrates are one of the versatile staring materials for
analogues.5 While a number of methods have been established
for the synthesis of the isoxazoline ring or its derivatives, the
6
the synthesis of enantiomerically pure highly functionalized
1
carbocycles. Carbohydrate to carbocycle transformation plays an
1,3-dipolar cycloaddition of nitrile oxide to unsaturated systems
has emerged as one of the most familiar and efficient methods
important role for the synthesis of both natural and unnatural
biological potent compounds such as gabosines, pericosines, ariste-
romycin, conduritols, glycosidase inhibitors aminocyclopentitols
and modified carbocyclic nucleosides (Fig. 1).2 In particular,
isoxazoline fused carbocycles are imperative synthetic intermedi-
ates to a range of biologically active natural products and
pharmaceutical agents (e.g., N-octyl-4-epi-b-valienamine, tamiflu,
cortistatin A and neplanocin A).3
In addition, the manipulation of isoxazoline ring has been stim-
ulated interest for a long time due to their high synthetic potential.
Isoxazoline fused molecular frameworks interact with appropriate
sort of reagent/condition to cleave selectively either C@N bond or
NAO bond. The reductive cleavage of the C@N bond produces b-
7
for its fabrication. This is due to at least two reasons, that is, nitrile
oxides react with a great diversity of dipolarophiles by virtue of
their high reactivities and the reaction products. Among the
cycloadditions, intramolecular nitrile oxide–alkene cycloaddition
(INOC) on sugar frameworks has attracted much attention of
synthetic chemists as a useful and competent method for the
fabrication of highly functionalized carbocycles of different ring
8
sizes. In general, the intramolecular reactions are more viable
due to stereoelectronic factors, entropically more favourable and
close proximity which enable to give good yield. However, the
regio- and stereo chemistry of such cycloadditions are governed
by the functional groups present in the molecular frameworks9
and also most of these cycloadditions have been executed with
hydroxy ketone which further elaborates to
a,b unsaturated
1
0
ketones, allylic alcohols and 1,3 diols and similarly the selective
cleavage of NAO bond in the isoxazoline ring produces 1,3 amino
alcohols and b-hydroxy nitriles.4 The synthetic potential of selec-
tively cleaved products was elegantly demonstrated via their
transformations into various bio-active natural products and
protected hydroxyl groups. The protection/deprotection steps
lead to low over all yield, and lengthy steps. Recently, silica gel
mediated intramolecular nitrile oxide–alkene cycloaddition on
1
1a
11b
sugar derivatives
with synthetic applications
has been
reported, in such cycloadditions the use of acetonide protected
sugar derivatives has resulted in a mixture of diastereoisomers11
towards the fabrication of six membered rings. In addition, the
formation of nitrile oxides from oximes is commonly achieved
⇑
Corresponding author. Tel.: +91 674 2576054; fax: +91 674 2301983.
E-mail address: spal@iitbbs.ac.in (S. Pal).
http://dx.doi.org/10.1016/j.carres.2014.06.007
008-6215/Ó 2014 Elsevier Ltd. All rights reserved.
0

1
4
A. Panda et al. / Carbohydrate Research 398 (2014) 13–18
NH2
N
N
N
HO
OH
H CS
3
HO
N
N
HO
HO
NH2
NHR
OH
O
HO
OH
3
HO
O
HO 1 OH
2
R=a-1-Glucose
OMe
OH
HO
HO
CO Me HO
2
O
O
O
R
O
O
N
HO
N
R
O
4
OH
5
OH
6
7
Figure 1. Aristeromycin 1, mannostatin A 2, trehazoline 3, (+) pericosine B 4,
ꢁ) gabosine O 5 and synthetic intermediates (6 and 7).
(
Figure 2. ORTEP diagram of 10 (30% ellipsoid probability).
under basic conditions for instance NaOCl, NaOCl with Et
with Et
3
N, NCS
N, t-BuOI with 2,6 lutidine, etc.1 Under such conditions,
3
2
MK-10
OH
the free hydroxyl groups get deprotonated leading to the deterio-
ration of the desired cycloaddition due to the enhancement of
nucleophilicity. Hence search for new and efficient methods is
continuing. In view of the above and our interest in the chemistry
of carbocyclic nucleosides, we considered developing a versatile
and general methodology to isoxazoline fused highly functional-
ized carbocycles and examined the intra molecular nitrile oxide–
alkene cycloaddition on different carbohydrate frameworks having
free hydroxyl group(s) under mild acidic support and wish to
report our exploratory results here in.
O
O
N
O
Figure 3. Co-ordination with MK-10.
OH
Initially, lactol 8 was converted to its oxime 9 by treating with
O
a, b
NH
2
OHꢀHCl and NaHCO
3
in MeOH and the oxidation of the result-
1
2
HO
HO
O
ing oxime 9 was achieved by using chloramin-T, which is known
for the generation of nitrile oxide from oxime.1 But under such
condition, the desired isoxazoline 10 was isolated in a poor yield
O
O
N
O
(81%)
3
O
O
1
1a
OH
OH
11
(
17%). This may be due to the basic nature of chloramin-T which
enhances the nucleophilicity of the free hydroxyl group of oxime
leading to the impedance of the desired cycloaddition. The ease
OH
O
a, b
a, b
HO
O
9
OH
(71%)
O
O
N
O
and efficiency of the preferred cycloaddition increased remarkably
when the oxidation of oxime 9 was carried out under mild acidic
clay (Montmorillonite K-10) support with chloramin-T. The isoxaz-
oline fused carbocycle 10 was isolated as a sole product with good
yield (84%) (Scheme 1).
The spectral features of isoxazoline 10 clearly suggested its
gross structure. However, it was difficult to assign the accurate
stereochemistry on the basis of spectral data alone. Hence a single
crystal X-ray structure of isoxazoline 10 was determined which
evidently established the structure of the cycloadduct (Fig. 2).
Several reaction conditions were employed like varying the
solvent, temperature and time, however the reaction was best
carried out in ethanol at room temperature with chloramin-T
and Montmorillonite K-10. It is presumed that under this clay
mediated transformation the free hydroxyl group of the substrate
coordinates to the clay surface (Fig. 3) which deactivates the
nucleophilicity to enhance the favoured cycloaddition.
1
2a
12
OH
O
3
4
HO
O
N
OO
(81%)
O
O
13a
1
3
OH
O
a, b
HO
O
(83%)
N
OO
O
O
14a
1
4
HO
O
a, b
a, b
5
6
OH
HO
O
(
69%)
N
OO
HO
15a
O
O
15
OH
HO
The generality and the scope of the aforesaid cycloadditions
were examined on various ribose derivatives with unmasked
O
HO
HO
O
(77%)
O
O
N
O
O
16a
1
6
OH
OH
O
Scheme 2. INOC on various D ribose derived oximes. Reagents and conditions: (a)
NH , MeOH; (b) chloramin-T hydrate, EtOH, Montmorillonite K-10.
OHꢀHCI, NaHCO
HO
a
b
O
O
O
2
3
N
O
HON
O
O
O
10
9
8
hydroxyl group(s) to obtain highly functionalized isoxazoline fused
carbocycles. The different synthesized lactols 11 to 16 were first
converted to their corresponding oximes by treating with
Scheme 1. Reagents and conditions: (a) NH
amin-T hydrate, EtOH, Montmorillonite K-10.
2
OHꢀHCI, NaHCO
3
, MeOH; (b) chlor-

A. Panda et al. / Carbohydrate Research 398 (2014) 13–18
15
NH
2 3
OHꢀHCl and NaHCO in MeOH then the resulting oximes were
oxidized to nitrile oxides and then in situ [3+2] intra molecular
cycloaddition with alkene afforded the isoxazolines 11a–16a,
respectively, in good yields as shown in Scheme 2. However
compounds 13 and 14 yielded a mixture of diastereoisomers under
silica gel condition as reported.1 Conversely, acidic medium by
MK-10 plays an undefined role by resulting exclusively one
diastereomer in each case.
1a
All the synthesized compounds 11a–16a were characterized
thoroughly by their spectral analysis and the single crystal X-ray
structures of compounds 14a (Fig. 4) and 15a (Fig. 5) were further
confirmed to portray the exact stereochemistry of the compounds.
The high degree of regio- and diastereoselectivity observed in
the above cycloaddition may be explained as follows. There are
two modes of INOC reactions, that is, exo mode and endo mode
which leads to either fused or bridged isoxazoline, respectively.
In the above INOC reactions the addition of nitrile oxides to alkenes
occurs through exo mode only because, the endo mode leads to the
formation of bridged isoxazoline ring containing double bond at
bridge head position. Hence such mode of INOC is unfavourable
Figure 5. ORTEP diagram of compound 15a (30% ellipsoid probability).
(
Fig. 6).
In case of isoxazoline fused five membered carbocycles, the
nitrile oxide approaches to the face of alkene in order to achieve
a
O
O
O
O
the more stable conformation cis/anti/cis. It is interesting to note
that acetonide protected diol creates a five membered ring which
N
N
N
N
Endo
mode
Exo
mode
governs the cycloaddition at
a face through exo attack to obtain
n
n
n
a cis/anti/cis conformation which resembles the structure of
various triquinane natural products14 such as hirsutic acid and
connatusin B. On the other hand, for isoxazoline fused six
membered carbocycles, the nitrile oxide comes up to the b face
of alkene with an anticipation to attain the less hindered stable
conformation.
Figure 6. exo and endo modes of INOC.
HO
OH
O
O
HO
HO
HO
c
d
OH
All the substrates employed above for the cycloaddition were
b
synthesized from the versatile starting material
-Ribose was protected as its 2,3 acetonide 18 by catalytic amount
of concd SO in acetone which was treated with vinyl
D-ribose 17.
O
O
HO
O
O
O
O
O
19
8
11
D
OH
H
2
4
HO
magnesium bromide in THF under Grignard condition to give the
stereoselective ring opened triol 19. Oxidative cleavage of vicinal
diol in triol 19 with sodium m-periodate afforded lactol 8 in very
good yield (Scheme 3).15 The stereoselective introduction of a
hydroxymethyl group into lactols 8 and 18 was successfully
O
O
O
HO
b
O
d
OH
OH
OH
HO
18
c
OH
a
OH
O
O
O
O
OH
O
O
D-Ribose
20
12
2
1
17
accomplished by using K
anol to give hydroxymethylated lactols 11 and 20, respectively.
Further the hydroxymethylated lactol 20 was subjected to
2 3
CO and formaldehyde solution in meth-
1
6
Scheme 3. Synthesis of precursors (for five membered fused carbocycles). Reagents
and conditions: (a) acetone, concd SO 92%; (b) vinylmagnesium bromide
solution, THF, ꢁ78 °C to RT, 88%; (c) NaIO , H O, MC, 85% for 8 and 82% for 12; (d)
CO , HCHO soln, MeOH, reflux, 90% for 11 and 86% for 20.
H
2
4
,
4
2
K
2
3
Grignard reaction with vinyl magnesium bromide in THF followed
by oxidative cleavage with NaIO to obtain lactol 12.
4
Towards lactols 13–16, 2,3 acetonide 18 was treated with allyl
magnesium bromide solution in ether under Grignard condition
to give an inseparable mixture of diastereomers 22 and 23 which
were separated further as their mono-TBDPS protected diols 24
and 25. The deprotection of silylether by tetrabutyl ammonium
fluoride solution followed by oxidative cleavage exhibited lactols
1
7
1
3 and 14, respectively (Scheme 4). The stereoselective insertion
of hydroxymethyl group to the respective lactols afforded the
hydroxymethylated lactols 15 and 16 as mentioned earlier.
In conclusion, we have described an efficient, versatile and
readily adaptable methodology by using Montmorillonite K-10
supported intramolecular 1,3 dipolar nitrile oxide–alkene cycload-
dition of carbohydrate derivatives with unmasked hydroxyl groups
for the synthesis of potential isoxazoline fused five and six
membered carbocycles. The advantage of the methodology con-
voys highly regio- and stereoselective synthesis of isoxazoline
fused carbocycles and the alleviation of protection/deprotection
Figure 4. ORTEP diagram of compound 14a (30% ellipsoid probability).

1
6
A. Panda et al. / Carbohydrate Research 398 (2014) 13–18
per million (d) relative to the solvent peak. IR spectra were
HO
O
HO
obtained on NaCl plates (film) with a Bruker Tensor 27 FT-IR and
HO
OH
OH
OH
ꢁ1
a
selected absorbance is reported in cm . High-resolution (HR)
OH
OH
OH
mass spectrometry data were acquired by a Bruker Daltonics
MicroTOF-Q-II Mass Spectrometer using MeOH/CH CN as solvent.
3
Single crystal X-ray structures were determined by a Bruker D8
Venture diffractometer equipped with CMOS detector.
O
O
O
2
O
O
O
b
23
2
18
TBDPSO
TBDPSO
OH
OH
1
.2. General procedure for oxime formation
OH
O
O
O
25
c, d
O
4
O
To a stirred solution of lactol (1 mmol) in MeOH, hydroxylamine
hydrochloride (1.5 mmol) and NaHCO (2 mmol) were added. The
3
reaction mixture was stirred at room temperature until the
disappearance of the starting material as shown on TLC. Then it
was partitioned between EtOAc and water. The aqueous layer
was extracted with EtOAc. The combined organic extracts were
2
c, d
O
O
HO
HO
2 4
washed with brine, dried over anhydrous Na SO , filtered and
O
O
O
O
evaporated. The residue was purified by silica gel column
chromatography (hexane/EtOAc) to give oxime which was used
for cycloaddition reaction.
1
4
1
3
e
e
1
.3. General procedure for the intramolecular nitrile oxide–
alkene cycloaddition reaction
O
O
HO
HO
HO
HO
O
O
O
To a stirred suspension of oxime (1 mmol) and Montmorillonite
K-10 (2ꢂ weight of oxime) in EtOH was added drop wise a milky
solution of chloramine-T hydrate (1.3 mmol) in EtOH. The reaction
mixture was stirred at room temperature until the disappearance
of oxime as shown on TLC and the clay was filtered off. Concentra-
tion of the filtrate followed by silica gel column chromatography
1
5
16
Scheme 4. Synthesis of precursors (for six membered fused carbocycles). Reagents
and conditions: (a) allyl magnesium bromide solution, ether, ꢁ78 °C to RT, 91%; (b)
TBDPSCI, Et
3
N, MC, DMAP, 23% for 24 and 66% for 25; (c) TBAF, THF; (d) NalO
4
, H
2
O,
MC 74% for 13 and 71% for 14 (two steps); (e) K
for both 15 and 16.
2 3
CO , HCHO soln, MeOH, reflux 85%
(
hexane/EtOAc) of the residue afforded the isoxazoline derivative.
1
.4. (3aS,4S,4aS,7aR)-6,6-Dimethyl-3a,4,4a,7a-tetrahydro-3H-
steps leading to the synthetic avenues shorter and efficient. The
achievement of high degree of regio- and stereo selectivity is,
therefore, of paramount importance for further expanding the
scope and exploiting the potential of this elegant synthetic
methodology.
0
0
[1,3]dioxolo[4 ,5 :4,5]cyclopenta[1,2-c]isoxazol-4-ol (10)
23
Yield: 84%; colourless solid; mp 94–95 °C; [
CHCl ); R
a]
D
+86.4 (c 0.25,
ꢁ1
3
f
0.3 (hexane/EtOAc, 1:1); IR (film) vmax/cm : 3382,
1
2
989, 2939, 1644, 1456, 1380; H NMR (400 MHz, CDCl
3 H
): d
1
.41 (3H, s), 1.56 (3H, s), 2.63 (1H, d, J = 8 Hz), 3.75 (1H, br m),
1
1
. Experimental
3.90 (1H, dd, J = 8, 12 Hz), 4.23 (1H, t, J = 8 Hz), 4.66 (1H, dd, J = 8,
13
8
Hz), 4.87 (1H, t, J = 4 Hz), 5.05 (1H, d, J = 4 Hz);
C NMR
.1. General
(100 MHz, CDCl ): d 23.99, 25.92, 56.53, 71.96, 73.98, 74.18,
3
C
8
9 13 4
2.95, 112.98, 160.62; HRMS (ESI)(m/z): calcd for C H O N
+
Reactions were performed under ambient atmosphere unless
[M+Na] 222.0737; found 222.0734.
otherwise noted. All reagents and solvents were general reagent
grade unless otherwise stated. Tetrahydrofuran and diethyl ether
were freshly distilled from Na to benzophenone under nitrogen.
1.5. (3aS,4S,4aS,7aS)-7a-(Hydroxymethyl)-6,6-dimethyl-3a,4,4a,
7a-tetrahydro-3H[1,3]dioxolo[4 ,5 :4,5]cyclopenta[1,2-c]isoxazol-
0
0
Dichloromethane was freshly distilled from P
2
O
5
under nitrogen.
4-ol (11a)
HPLC grade ethanol was used for the cycloaddition reaction. All
other reagents and solvents were used as supplied commercially
without further purification. Chloramin-T hydrate and Montmoril-
lonite K-10 were purchased from Sigma Aldrich and used as
supplied. All reactions were monitored by analytical thin-layer
chromatography (TLC) on aluminium-pre coated plates of silica
gel (EM 60-F254) purchased from Merck, Germany. Visualization
was accomplished with UV light (254 nm) and exposure to
2
3
Yield: 80%; colourless solid; mp 103–104 °C; [
a]
D
+84.0 (c 0.25,
ꢁ1
CHCl ); R 0.35 (hexane/EtOAc, 1:1.5); IR (film) vmax/cm : 3381,
2990, 2936, 1640, 1456, 1379; H NMR (400 MHz, CDCl ): dH
1.48 (3H, s), 1.56 (3H, s), 2.21 (1H, t, J = 8 Hz), 2.48 (1H, d,
J = 12 Hz), 3.81 (1H, dt, J = 4, 8 Hz), 3.93 (1H, dd, J = 8, 12 Hz),
4.02 (2H, m), 4.19 (1H, dd, J = 8, 12 Hz), 4.70 (1H, dd, J = 8,
3
f
1
3
1
3
12 Hz), 4.83 (1H, d, J = 4 Hz); C NMR (100 MHz, CDCl ): d
3
C
p-anisaldehyde or KMnO
Column chromatography was generally performed on silica gel
100–200 mesh). Melting points are uncorrected. Nuclear magnetic
resonance (NMR) spectra were acquired on a Bruker 400 at
4
stain solutions followed by heating.
26.24, 27.16, 57.42, 62.91, 73.92, 74.11, 83.64, 87.53, 113.52,
+
162.73; HRMS (ESI)(m/z): calcd for C10H15O N [M+Na] 252.0842;
5
(
found 252.0847.
1
13
4
00 MHz ( H) or at 100 MHz ( C) in CDCl
3
solutions, unless stated
1.6. (3aS,4S,4aS,7aR)-4a-(Hydroxymethyl)-6,6-dimethyl-3a,4,4a,
0
0
otherwise. The NMR data are reported as peak multiplicities: s for
singlet, d for doublet, dd for doublet of doublets, t for triplet, q for
quartet, br s for broad singlet and m for multiplet. Coupling
constants (J value) were measured directly from the spectra and
are reported in hertz and chemical shifts are reported as parts
7a-tetrahydro-3H[1,3]dioxolo[4 ,5 :4,5]cyclopenta[1,2-c]isoxazol-
4-ol (12a)
2
3
Yield 71%; colourless viscous liquid; [
a]
D 3
+94.8 (c 0.25, CHCl );
ꢁ1
Rf 0.2 (hexane/EtOAc, 1:1); IR (film) vmax/cm : 3423, 2990, 2939,

A. Panda et al. / Carbohydrate Research 398 (2014) 13–18
17
1
1
(
3
(
(
9
[
640, 1457, 1379; H NMR (400 MHz, CDCl
3H, s), 1.96 (1H, br s), 2.86 (1H, d, J = 12 Hz), 3.63 (1H, t, J = 8 Hz),
.71 (1H, dd, J = 4, 12 Hz), 3.77 (1H, d, J = 8 Hz), 3.91 (1H, m), 4.22
3
): d
H
1.53 (3H, s), 1.59
Acknowledgment
This work was supported by the Department of Science and
Technology (DST), India FAST track Project Grant No: SERB/F/0287.
1
3
1H, t, J = 8 Hz), 4.70 (1H, t, J = 8 Hz), 5.01 (1H, s); C NMR
100 MHz, CDCl ): d 26.76, 27.38, 57.85, 63.27, 74.27, 74.54,
3.16, 114.04, 160.3; HRMS (ESI)(m/z): calcd for C10
3
C
15 5
H O N
Supplementary data
+
M+Na] 252.0842; found 252.0843.
Supplementary data (characterisation data of compounds, CCDC
numbers for compounds 10, 14a and 15a are 978899, 978900 and
1
.7. (3aR,5S,5aS,8aR)-7,7-Dimethyl-3,3a,4,5,5a,8a-hexahydro[1,3]
9
78901, respectively, and refinement data in Table 1) associated
0
0
dioxolo[4 ,5 :5,6]benzo[1,2-c]isoxazol-5-ol (13a)
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.carres.2014.06.007.
2
3
Yield: 81%; colourless liquid; [
.25 (hexane/EtOAc, 1:2); IR (film) vmax/cm : 3423, 2986, 2935,
249, 1635, 1453, 1379; 1H NMR (400 MHz, CDCl
): d 1.37 (3H,
a
]
D
ꢁ61.37 (c 0.28, CHCl
3 f
); R
ꢁ1
0
2
References
3
H
s), 1.49 (3H, s), 1.82 (1H, q, J = 12 Hz), 2.07(1H, t, J = 8 Hz), 2.72
1H, br s), 3.24 (1H, m), 3.92 (1H, t, J = 8 Hz), 4.01 (1H, d, 8 Hz),
4
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(
6
(
.40–4.55 (2H, m), 4.85 (1H, d, J = 4 Hz); 1 C NMR (100 MHz,
3
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CDCl ): d 26.09, 27.31, 32.42, 45.29, 67.61, 70.92, 73.44, 76.68,
3
C
+
1
15 4
11.05, 158.46; HRMS (ESI)(m/z): calcd for C10H O N [M+Na]
(
2
36.0899; found 236.0898.
5
1
.8. (3aR,5R,5aS,8aR)-7,7-Dimethyl-3,3a,4,5,5a,8a-hexahydro-[1,3]
2
0
0
dioxolo[4 ,5 :5,6]benzo[1,2-c]isoxazol-5-ol (14a)
4230; (g) Mathe, C.; Perigaud, C. Eur. J. Org. Chem. 2008, 1489–1505; (h) Romeo,
G.; Chiacchio, U.; Corsaro, A.; Merino, P. Chem. Rev. 2010, 110, 3337–3370; (i)
Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779–2831.
2
3
Yield: 83%, colourless solid; mp 145–146 °C; [
a]
D
ꢁ81.6 (c 0.25,
ꢁ1
3.
(a) Matsuda, J.; Suzuki, O.; Oshima, A.; Yamamoto, Y.; Noguchi, A.; Takimoto,
K.; Itoh, M.; Matsuzaki, Y.; Yasuda, Y.; Ogawa, S.; Sakata, Y.; Nanba, E.; Higaki,
K.; Ogawa, Y.; Tominaga, L.; Ohno, K.; Iwasaki, H.; Watanabe, H.; Brady, R. O.;
Suzuki, Y. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 15912–15917; (b) Magano, J.
Chem. Rev. 2009, 109, 4398–4438; (c) Magano, J. Tetrahedron 2011, 67, 7875–
7899; (d) Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku, N.;
Kobayashi, M. J. Am. Chem. Soc. 2006, 128, 3148–3149; (e) Kobayashi, Y.;
Miyazaki, H.; Shiozaki, M. J. Org. Chem. 1994, 59, 813–822; (f) Lygo, B.; Swiatyj,
M.; Trabsa, H.; Voyle, M. Tetrahedron Lett. 1994, 35, 4197–4200; (g) Najera, C.;
Sansano, J. M. Org. Biomol. Chem. 2009, 7, 4567–4581; (h) Hashimato, Y.;
Takada, A. T.; Takikawa, H.; Suzuki, K. Org. Biomol. Chem. 2012, 10, 6003–6009.
(a) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826–5833; (b) Annunziata, R.;
Cinquini, M.; Cozzi, F.; Gilardi, A.; Restelli, A. J. Chem. Soc., Perkin Trans. 1 1985,
CHCl
056, 2988, 2934, 1631, 1429, 1378, 1328; H NMR (400 MHz,
CDCl ): d 1.41 (3H, s), 1.53 (3H, s), 1.84–1.92 (1H, m), 2.07–2.14
1H, m), 2.31 (1H, br s), 3.62–3.73 (1H, m), 3.93 (1H, dd, J = 8,
3 f
); R 0.35 (hexane/EtOAc, 1:2); IR (film) vmax/cm : 3404,
1
3
3
H
(
1
2 Hz), 4.30 (1H, ddd, J = 4.8, 4.2, 2.4 Hz), 4.40 (1H, s), 4.56 (1H,
13
dd, J = 8, 12 Hz), 5.03 (1H, d, J = 4 Hz); C NMR (100 MHz, CDCl
24.19, 25.81, 30.66, 39.73, 65.81, 68.96, 75.39, 76.68, 111.16,
3
):
d
C
+
1
57.01; HRMS (ESI)(m/z): calcd for C10
15 4
H O N [M+Na] 236.0899;
4.
found 236.0899.
2289–2292; (c) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410–416; (d) Nair, V.;
Suja, T. D. Tetrahedron 2007, 63, 12247–12275; (e) Rajawinslin, R. R.; Raihan, M.
J.; Janreddy, D.; Kavala, V.; Kuo, C. W.; Kuo, T. S.; Chen, M. L.; He, C. H.; Yao, C. F.
Eur. J. Org. Chem. 2013, 5743–5749; (f) Kociolek, M. G.; Kalbarczyk, K. P. Synth.
Commun. 2004, 34, 4387–4394; (g) Nonn, M.; Kiss, L.; Sillanpaa, R.; Fulop, F.
Beilstein J. Org. Chem. 2012, 8, 100–106; (h) Tam, W.; Tranmer, G. K. Org. Lett.
1
5
5
.9. (3aR,5S,5aS,8aS)-8a-(Hydroxymethyl)-7,7-dimethyl-3,3a,4,
,5a,8a-hexahydro-[1,3]dioxolo[4 ,5 :5,6]benzo[1,2-c]isoxazol-
-ol (15a)
0
0
2
002, 4, 4101–4104; (i) Jiang, D.; Chen, Y. J. Org. Chem. 2008, 73, 9181–9183.
2
3
Yield: 69%; colourless solid; mp 142–143 °C; [
.47, CHCl ); R 0.14 (hexane/EtOAc, 1:2); IR (film) vmax/cm
410, 2988, 2938, 2882, 1623, 1454, 1379; H NMR (400 MHz,
): d 1.45 (3H, s), 1.53 (3H, s), 1.87 (2H, q, J = 12 Hz), 2.18
1H, td, J = 4, 8 Hz), 3.27–3.37 (1H, m), 3.75 (1H, d of part of an
a
]
D
ꢁ54.62 (c
5. (a) Fuller, A. A.; Chen, B.; Minter, A. R.; Mapp, A. K. J. Am. Chem. Soc. 2005, 127,
5376–5383; (b) Bode, J. W.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 3611–
ꢁ
1
0
3
CDCl
3
f
:
3612; (c) Jiang, S.; McCullough, K. J.; Mekki, B.; Gingh, G.; Wightman, R. H. J.
1
Chem. Soc., Perkin Trans. 1 1997, 1805–1814.
3
H
6. (a) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203–5205; (b) Tang, S.; He, J.;
Sun, Y.; He, L.; She, X. Org. Lett. 2009, 11, 3982–3985; (c) Kumar, A.; Maruya, R.
A.; Sharma, S.; Ahmad, P.; Singh, A. B.; Tamrakar, A. K.; Srivastava, A. K. Bioorg.
Med. Chem. 2009, 17, 5285–5292; (d) Wang, Y. G.; Xu, W. M.; Huang, X.
Synthesis 2007, 28–32; (e) Praveen, C.; Kalyanasundaram, A.; Perumal, P. T.
Synlett 2010, 777–781; (f) Mazzei, M.; Balbi, A.; Sottofattori, E.; Garzoglio, R.;
Montis, A. D.; Corrias, S.; Colla, P. L. Eur. J. Med. Chem. 1993, 28, 669–674; (g)
Yoshimura, A.; Zhu, C.; Middleton, K. R.; Todora, A. D.; Kastern, B. J.; Maskaev, A.
V.; Zhdankin, V. V. Chem. Commun. 2013, 4800–4802.
7. (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley:
New York, 1984; Vol. 1, pp 1–176; (b) Jawalekar, A.; Reubsaet, E.; Rutjes, F. P. J.
T.; Van Delft, F. L. Chem. Commun. 2011, 3198–3200; (c) Namboothiri, I. N. N.;
Rastogi, N.; Ganguly, B.; Mobin, S. M.; Cojocaru, M. Tetrahedron 2004, 60, 1453–
(
AB system, J = 12 Hz), 3.85 (1H, d of part of an AB system,
J = 12 Hz), 3.96 (1H, t, J = 8 Hz), 4.05 (1H, td, J = 4, 12 Hz), 4.47
(
1H, d, J = 4 Hz), 4.58 (1H, dd, J = 8, 12 Hz); 13C NMR (100 MHz,
3 C
CDCl ): d 26.74, 27.49, 32.84, 46.362, 63.89, 68.14, 73.86, 78.93,
0.76, 110.77, 159.72; HRMS (ESI)(m/z): calcd for C11H O N
17 5
8
+
[
M+Na] 266.1004; found 266.1003.
1
5
.10. (3aR,5R,5aS,8aS)-8a-(Hydroxymethyl)-7,7-dimethyl-3,3a,4,
,5a,8a-hexahydro[1,3]dioxolo[4 ,5 :5,6]benzo[1,2-c]isoxazol-5-
1462; (d) Yoshimura, A.; Middleton, K. R.; Todora, A. D.; Kastern, B. J.; Koski, S.
0
0
R.; Maskaev, A. V.; Zhdankin, V. V. Org. Lett. 2013, 15, 4010–4013; (e) Jen, T.;
Mendelsohn, B. A.; Ciufolini, M. A. J. Org. Chem. 2011, 76, 728–731; (f)
Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.; Ciufolini, M. A. Org.
Lett. 2009, 11, 1539–1542; (g) Dadiboyena, S.; Xu, J.; Hamme, A. T., II.
Tetrahedron Lett. 2007, 48, 1295–1298; (h) Beha, S.; Giguere, D.; Patnam, R.;
Roy, R. Synlett 2006, 1739–1743; (i) Maugein, N.; Wagner, A.; Mioskowski, C.
Tetrahedron Lett. 1997, 38, 1547–1550; (j) Mukaiyama, T.; Hoshino, T. J. Am.
Chem. Soc. 1960, 82, 5339–5342.
(a) Gallos, J. K.; Koumbis, A. E. Curr. Org. Chem. 2003, 7, 397–426; (b) Ferrier, R.
J.; Furneaux, R. H.; Prasit, P.; Tyler, P. C.; Brown, K. L.; Gainsford, G. J.; Diehl, J.
W. J. Chem. Soc., Perkin Trans. 1 1983, 1621–1628; (c) Osborn, H. M. I.; Gemmell,
N.; Harwood, L. M. J. Chem. Soc., Perkin Trans. 1 2002, 2419–2438.
ol (16a)
23
Yield: 77%; colourless viscous liquid; [
D 3
a] +60.8 (c 0.25, CHCl );
0.21 (hexane/EtOAc, 1:2); IR (film) vmax/cm : 3422, 2985, 2933,
631, 1454, 1383; H NMR (400 MHz, CDCl ): d 1.49 (3H, s), 1.54
3 H
3H, s), 1.80 (1H, ddd, J = 4, 8, 16 Hz), 1.95 (1H, br s), 2.32–2.40 (2H,
m), 3.76 (1H, dq, J = 4, 12 Hz), 3.87–3.93 (3H, m), 4.08 (1H, dd, J = 4,
Hz), 4.54 (1H, s), 4.69 (1H, dd, J = 8, 12 Hz); 13C NMR (100 MHz,
CDCl ): d 26.10, 27.20, 30.79, 40.82, 63.69, 66.77, 76.55, 78.67,
1.72, 111.22, 158.00; HRMS (ESI)(m/z): calcd for C11
ꢁ1
R
1
f
1
(
8
9
.
.
8
3
C
Litvinovskaya, R. P.; Khripach, V. A. Russ. Chem. Rev. 2001, 70, 405–424.
0. Gallos, J. K.; Koumbis, A. E.; Xiraphaki, V. P.; Dellios, C. C.; Argyropoulou, E. C.
8
17 5
H O N
1
+
[
M+Na] 266.1004, found 266.1004.
Tetrahedron 2000, 55, 15167–15180.

1
8
A. Panda et al. / Carbohydrate Research 398 (2014) 13–18
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1
1
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