Exclusive ring opening of gem-dihalo-1,2-cyclopropanated oxyglycal to oxepines in AgOAc

Article abstract of DOI:10.1016/j.carres.2014.01.023

Treatment of gem-dihalo-1,2-cyclopropanated d-oxyglycal with primary, secondary, and unsaturated alcohols, in the presence of AgOAc, leads to the formation of chloro-oxepines exclusively. Reaction of the resulting 2-chloro-oxepines with excess alcohol in

Full text of DOI:10.1016/j.carres.2014.01.023

Carbohydrate Research 389 (2014) 66–71
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Exclusive ring opening of gem-dihalo-1,2-cyclopropanated oxyglycal
to oxepines in AgOAc
⇑
Supriya Dey, N. Jayaraman
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of gem-dihalo-1,2-cyclopropanated
D-oxyglycal with primary, secondary, and unsaturated
Received 10 October 2013
Received in revised form 27 January 2014
Accepted 30 January 2014
Available online 13 February 2014
alcohols, in the presence of AgOAc, leads to the formation of chloro-oxepines exclusively. Reaction of
the resulting 2-chloro-oxepines with excess alcohol in the presence of AgOAc, do not promote further
reactions. This result is in contrast to the reactions of D-glucal derived halo-oxepine with alcohols known
previously that lead to the formation of furanoses as the major product under similar reaction conditions.
Observation of this study consolidates the reactivity differences of gem-dihalo-1,2-cyclopropanated oxy-
glycals, as compared to gem-dihalo-1,2-cyclopropanated glycals.
Keywords:
Cyclopropanes
Glycals
Ó 2014 Elsevier Ltd. All rights reserved.
Oxepines
Oxyglycals
Ring expansion
Septanosides
1. Introduction
sugar-derived cyclopropylcarbinol for the synthesis of C-2 branched
pyranosides of type 8 were also demonstrated (Scheme 2).
Cyclopropanes undergo ring opening and rearrangement reac-
tions prominently.1 The ring opening reactions of the particular class
of cyclopropanated furanosides and pyranosides lead to various
products,2,3 depending on the nature of sugar derivatizations and
reaction conditions. Few illustrative examples are discussed herein.
HBr–AcOH was also used for the ring opening of ester contain-
ing 1,2-cyclopropane sugar derivatives to furnish C-2 branched
glycosyl bromide 9, as shown by Hoberg and co-workers.5d
1,2-Cyclopropanated sugars were used to synthesize 2-C branched
glycosides of the type as in 10, as shown by Zou and co-workers.9
In addition to cyclopropanated pyranoses, corresponding furanoses
were also studied, as for example, the synthesis of bicyclic ethers
upon reaction of ceric ammonium nitrate with cyclopropyl deriva-
tive of furanoses.10 The ring expansion of 1,2-dihalocyclopropanat-
ed sugars yielded chiral oxepines with K2CO3 in refluxing
methanol, whereas 2-halomethyl glycosides 7 resulted, in the pres-
ence of NBS, NIS, and IDCP (Scheme 1).11 Harvey and co-workers
Heathcock and co-workers reported ring opening of D-glucal derived
cyclopropane 1 using Hg(II)-salts to generate organomercury deriv-
ative, which upon reduction using Bu3SnH, afforded 2-C-branched
glycoside 2 (Scheme 1).4 1,2-Cyclopropanated sugars were utilized
by Hoberg and co-workers to synthesize oxepanes 3–5.5 A trimeth-
ylsilyl trifluoromethanesulfonate (TMSOTf)-promoted ring expan-
sion of a series of D-galactal derived cyclopropanes led to products
of the type 3, using azide, SPh, and CN as nucleophiles.5c The reaction
proceeded via a Lewis acid-induced removal of the allylic substitu-
ent to generate oxocarbenium ion, followed by an attack of nucleo-
phile at the anomeric center. It was observed that the protecting
group would play a major role to control the product formation
and its stereoselectivity. Pt-catalyzed ring opening reaction of
1,2-cyclopropanated sugars to C-2 branched glycosides of the type
as in 6,6 ring opening of cyclopropane derivative using NIS as an elec-
trophilic source,7 and Mitsunobu conditions8 for the ring opening of
demonstrated that ring opening of D-glycal derived gem-1,2-
dihalocyclopropane generated C-2 branched pyranoside 13, under
mild basic medium, whereas oxepine 11 formed in a Lewis acid
medium (Scheme 3).12a Furthermore, 1,2-dihalocyclopropane gly-
cal was reacted with AgOAc to furnish 2-chloro-pyran derivative,
which was used as an important intermediate for the synthesis
of natural product (ꢀ)-TAN-2483B.12b
D
-Oxyglycal derived gem-dihalocyclopropane derivatives were
found to be a useful precursor for the synthesis of a number of
septanoside derivatives of the type 12 (Scheme 3). An oxyglycal
route for the synthesis of alkyl,13 aryl, azide septanosides, septano-
side containing disaccharide,14 septanoside-containing trisaccha-
rides,15 and 2-deoxy aryl/alkyl septanoside16 were reported. The
⇑
Corresponding author. Tel.: +91 80 2293 2578; fax: +91 80 2360 0529.
E-mail address: jayaraman@orgchem.iisc.ernet.in (N. Jayaraman).
http://dx.doi.org/10.1016/j.carres.2014.01.023
0008-6215/Ó 2014 Elsevier Ltd. All rights reserved.

S. Dey, N. Jayaraman / Carbohydrate Research 389 (2014) 66–71
67
O
R1O
R2O
OR3
1
a.Hg(CF3COO)2
TMSNu, TMSOTf TMSCN,TMSOTfa
[Pt(C2H4)Cl2]2
BnOH, rt
NBSb or NISc
or IDCPd,ROH
THF, H2O
b. Bu3SnH
CH3CN
CH3CN
AIBN (cat)
OR
OH
O
O
OBn
CH3
O
O
O
Nu
H3C
R2O
R1O
R2O
CN
R1O
R1O
O
O
O
R
X
R2O
CH3
R2O
O
R2O
OR3
OR3
OR3
2
3
4
5
6
7
R = R1= R2 = SitBu2
R1= R2 = R3= Bn
R2 = Ac
R2 = Ac
R1 = R2= R3= Bn
R1 = R2= R3= Bn; R = Me
4
a: for , 10 mol % TMSOTf
b: NBS = N-bromosuccinimide ; c: NIS = N-iodosuccinimide
Nu = N3, SPh, CN, Allyl
5
for , 40 mol % TMSOTf
d: IDCP = iodonium di(s-collidine) perchlorate
Scheme 1.
O
OR1
R4
OR2
OR3
1a
K2CO3 or TFA
PPh3, DEAD,
30 % HBr/AcOH
NuH, rt or reflux
ArCOOH, THF, rt
R1O
OCOAr
O
Br
OCOAr
R1O
O
O
O
R1O
R2O
R3O
R1O
Nu
+
R4
R2O
R2O
R2O
O
OR3
OR3
Br
R
8
9
10
R1 = R2 = R3 = Bn, R = H, Me
NuH = ROH, RSH, NaN3
R1 = R2 = TBSO, R3 = TBS, R4= CH2OH
R1= R2 = Ac, R4 = COOEt
Scheme 2.
O
R1O
R2O
X
X
R4
OR3
1b
K2CO3, ROH
PhCH3, reflux
NaOR, ROH
THF, reflux
AgOAc, ROH
reflux
OR
OR
X
R1O
O
R1O
O
OR
O
R1O
R2O
X
X
R2O
R3O
R2O
R3O
OR3
R4
R4
11
12
13
R1 = R2 = R3 = Bn; R4 = OBn; R =
alkyl, aryl, azide, sugar
X =Br, Cl
R1 = R2 = R3
Bn;
=
R1 = R2 = R3 = Bn; R4 = H;
R = methyl, allyl, acetyl
X =Br
R = Me, Bn, allyl ;
X = Br
Scheme 3.

68
S. Dey, N. Jayaraman / Carbohydrate Research 389 (2014) 66–71
CHCl3, aq.
NaOH (50%)
TEBAC, rt, 6 h
81 %
OAc
Cl
O
O
O
R
BnO
BnO
BnO
O
Cl
Cl
O
BnO
BnO
BnO
HO
R
+
BnO
BnO
Cl
BnO
BnO
OBn
AgOAc, PhCH3
reflux, 48-72 h
OBn
OBn
OBn
OBn
OBn
16a-h
14
15
17
O
O
O
O
O
O
BnO
6
O
O
BnO
BnO
BnO
Cl
Cl
BnO
BnO
BnO
BnO
Cl
Cl
BnO
BnO
BnO
BnO
OBn
OBn
OBn
OBn
16a
16b
16c
16d
(72 %)
(70 %)
(88 %)
(66 %)
Ph
O
O
O
O
O
Ph
O
O
O
O
BnO
BnO
OH
BnO
BnO
Cl
Cl
Cl
BnO
BnO
BnO
BnO
BnO
BnO
Cl
BnO
BnO
OBn
OBn
OBn
OBn
16e (75 %)
16f (68 %)
16g (76 %)
16h (65 %)
Scheme 4.
Table 1
1H NMR chemical shifts, multiplicities, and coupling constants of 16a–h and 17 in CDCl3
Compound H-1
H-4 & H-6
H-5
3.88 (dd) 3.75 (dd), 3.58 (dd), 7.32–7.06 (m), 4.74 (d), (11.2), 4.70 (d), (12.8), 4.56 (dd), (12.0, 5.6), 4.46 (d), (11.2), 4.31
(9.6, 6.4) (8.4, 1.6) (10.4, 6.4) (d), (11.6), 3.50–3.44 (band), 1.61–1.50 (m), 1.33–1.26 (m), 0.88 (t), (6.8)
5.31 (s) 4.23–4.17 (band) 3.75 (dd), 3.56 (dd), 3.51–3.47 7.36–7.07 (m), 4.74 (d), (11.2), 4.72 (d), (12.8), 4.55 (dd), (12.0, 6.4), 4.46 (dd), (12.4, 2.4),
(8.4, 1.6) (10.8, 6.0) (m) 4.31 (d), (11.2), 3.64 (t), (6.4), 1.57–1.53 (m), 1.28–1.25 (m), 0.88 (t), (7.2)
H-7a
H-7b
Other signals
16a
16b
16c
16d
16e
16f
16g
16h
17
5.29 (s) 4.23–4.17 (m)
5.36 (s) 4.22–4.18 (band) 3.71 (dd), 3.57 (dd), 3.49 (dd), 7.33–7.07 (m), 5.95–5.85 (m), 5.29 (app d), (17.2), 5.16 (app d), (10.4), 4.74 (d), (11.2),
(8.8, 6.4) (10.4, 6.4) (10.8, 2.8) 4.71 (d), (12.8), 4.59–4.54 (m), 4.46 (dd), (12.0, 1.6), 4.36–4.28 (m), 4.10 (dd), (13.2, 6.4)
5.55 (s) 4.21–4.17 (m)
5.42 (s) 4.22–4.18 (m)
5.38 (s) 4.31–4.20 (m)
5.36 (s) 4.23–4.19 (m)
5.40 (s) 4.31–4.25 (m)
6.65 (s) 4.26–4.16 (m)
3.62 (dd), 3.56 (dd), 3.46 (dd), 7.33–7.07 (m), 4.76 (d), (11.2), 4.72 (d), (12.4), 4.56 (dd), (12.4, 4.0), 4.47–4.44 (m), 4.35–
(8.4, 1.6) (10.4, 3.6) (10.4, 2.4) 4.29 (m), 2.42 (t), (2.4)
3.70 (dd), 3.62 (dd), 3.51 (dd), 7.30–7.06 (m), 6.58 (d), (16.4), 6.26 (td), (16.0, 6.0), 4.76–4.69 (m), 4.60–4.55 (m), 4.53–
(8.4, 2.0) (10.4, 6.0) (10.4, 3.2) 4.44 (m), 4.31–4.23 (m)
3.80 (dd), 3.57 (dd), 3.49 (dd), 7.32–7.22 (m), 7.07 (d), (4.0), 4.73 (d), (11.2), 4.56 (app d), (11.2), 4.48 (dd), (12.4, 3.6),
(8.0, 1.6) (10.4, 5.2) (10.0, 4.0) 4.29 (d), (11.2), 4.13–4.03 (m), 1.19 (qt), (6.0)
3.75 (dd), 3.60 (dd), 3.49 (dd), 7.30–7.06 (m), 4.74 (d), (11.2), 4.69 (d), (12.4), 4.57 (dd), (12.0, 4.4), 4.45 (dd), (12.4, 3.2),
(9.2, 4.4) (9.2, 6.4)
(10.4, 2.8) 4.31 (app d), (12.0), 3.67 (dd), (8.8, 4.0), 3.56–3.54 (m),
3.70 (dd), 3.59 (dd), 3.48 (dd), 7.32–7.05 (m), 4.90 (d), (12.4), 4.74 (d), (11.2), 4.70 (d), (12.4), 4.66 (d), (12.0), 4.56 (dd),
(8.4, 2.0) (10.4, 6.4) (10.8, 2.4) (12.0, 2.4), 4.46 (dd), (12.0, 4.8), 4.20 (aap d), (11.6)
3.66 (br) 3.54–3.47 3.54–3.47 7.33–7.10 (m), 4.74 (d), (11.6), 4.70 (d), (12.0), 4.61 (d), (11.2), 4.52–4.43 (m), 4.36 (d),
(band)
(band)
(11.6), 1.90 (s)
Table 2
13C NMR chemical shifts for 16a–h and 17 in CDCl3
Compound
C-1
C-2
C-3
C-4
C-5
C-6
C-7
Other signals
16a
16b
16c
16d
16e
16f
16g
16h
17
99.3
99.3
98.3
97.3
98.3
97.1
99.4
98.6
92.4
122.7
122.6
122.3
121.6
122.4
122.8
122.0
122.4
119.9
152.5
152.3
152.9
153.3
153.0
152.5
152.8
152.9
153.9
77.7
77.5
77.1
77.2
76.9
77.2
77.1
77.2
77.4
80.5
80.4
80.5
80.5
80.5
80.5
80.3
80.6
80.2
71.1
71.1
71.2
71.2
71.2
71.1
71.1
71.1
71.1
70.8
70.7
70.7
70.7
70.9
70.7
70.8
70.9
70.5
138.2–136.9,128.3–127.5, 73.0–71.2, 68.9, 29.0, 28.2, 22.4, 14.0
138.2–136.9,128.3–127.5, 72.9–71.2, 68.9, 63.0, 31.8, 29.5, 29.4, 29.3, 25.7, 22.6, 14.0
138.2–136.8,133.9,128.3–127.5,117.5, 72.9–71.4, 68.8
138.0–136.7, 128.3–127.5, 78.9, 74.9, 72.9–71.8, 54.8
138.2–136.0, 133.0, 128.3–127.5, 126.6, 73.0–71.5, 68.6
138.2–136.9, 128.3–127.5, 73.1–71.2, 69.7, 23.0, 20.9
138.0–136.7, 128.7–126.7, 73.0–72.0, 71.4, 69.8, 67.6, 61.7
138.1–136.9, 128.5–127.1, 73.0–71.6, 70.0
169.5, 138.0–136.5, 128.4–127.6, 74.2–72.2, 20.8
ring expansion strategies involving glycals lead to C-2 deoxy sept-
anoside, which demands additional synthetic manipulations at C-2
in order to generate fully functionalized septanosides. This limita-
tion could be overcome by the oxyglycal route, having an addi-
tional oxy-substituent at C-2. We anticipated that the presence of
oxygen functionality at C-2 in oxyglycal might alter the reactivity
when compared to D-glycal. A difference in the reactivity would,
in principle, be verified in reactions as in ring expansion of cyclo-
propanated sugar derivative with an external nucleophile. For
example, a gem-dihalo-1,2-cyclopropanated glycal derivative and
an oxyglycal derivative lead to a pyranoside with exocyclic double
bond12a and an oxepine,13–16 respectively, even when the reactions

S. Dey, N. Jayaraman / Carbohydrate Research 389 (2014) 66–71
69
opening reaction of 15, using tert-butanol, furnished C-1 acetylated
chloro-oxepine, 17 only. This observation confirmed that tertiary
alcohol did not participate in the ring opening reaction.
OAc
Cl
O
BnO
O
AgOAc:NaOAc (1:1)
Cl
Cl
BnO
BnO
BnO
BnO
The formation of oxepine was confirmed by 1H as well as 13C
NMR spectral characterization. Signals at 5.36–5.29 ppm and
99.5–97.0 ppm in 1H and 13C NMR spectra, respectively, confirmed
the formation of seven-membered chloro-oxepine. Mass spectral
data further confirmed the formation of chloro-oxepines 16a–h.
Characterization data for 16a–h and 17 are given in Tables 1 and 2.
The course of the reaction in the absence of any external alcohol
PhCH3, reflux, 48 h, 78 %
OBn
OBn
OBn
17
15
Scheme 5.
were performed under mild basic condition with both the sub-
strates, illustrating a sufficient reactivity difference between a gly-
cal and an oxyglycal. The behavior of D-glycal derived cyclopropane
was also verified.
D-Oxyglycal derived cyclopropane 15 was
refluxed in toluene with 1:1 molar equivalent of AgOAc/NaOAc
for 48 h, which led to formation of only O-acetyl chloro-oxepine
17, in a good yield (Scheme 5).
The presence of O-acetyl group at C-1 of 17 led to H-1 appearing
at 6.65 ppm, almost 1.40 ppm downfield shift than that of 16a–h in
the 1H NMR spectrum, whereas in 13C NMR spectrum of 17, the
anomeric carbon appeared at 92.4 ppm. The resonances at 153.9,
119.9 ppm indicated C-3 and C-2 nuclei, respectively.
Further, chloro-oxepines 16a, 16b, 16d, and 16g were reacted
with respective alcohol nucleophile in the presence of AgOAc
under reflux for a prolonged time, separately. In the event, it was
found that chloro-oxepines did not undergo further reaction,
which confirmed that the oxepines remain intact even after
prolonged heating.
derivatives in Lewis acid medium was tested by several groups and
the general observation was the formation of seven-membered
oxepine derivatives and also a number of pyranoside derivatives,
depending on the nature of sugar derivatives.4–9 In the present
work, the ring opening of oxyglycal derived gem-dichloro-1,2-
cyclopropane adduct in the presence of Lewis acid, hitherto
unknown, was investigated. Results of the study are presented
herein.
2. Results and discussion
Hydroxy glycal ether or oxyglycal 14 was prepared through a
dehydration of an appropriately protected pyranosyl bromide.13
Cyclopropanation of oxyglycal, using dichlorocarbene, led to
Harvey and Hewitt reported synthesis of C-furanosides from a
1,2-C-(dichloromethylene)-
a-
D
-glycero-hexitol 15, in a good yield
D
-glucal-derived gem-dihalo cyclopropane.17 The reaction led to a
(Scheme 4). The ring opening reaction was examined in the
presence of different Lewis acids, namely, BF3–Et2O, TMSOTf, and
Tf2O. Early attempt was to use BF3–Et2O/CH3CN at ꢀ20 °C,
however, under the reaction conditions, only decomposition was
observed. Use of Tf2O or TMSOTf as Lewis acids also did not
promote the reaction. Interestingly, silver salts, such as, AgOTf,
AgNO3, and AgOAc mediated the reaction, and among these, AgOAc
was found to be more effective. The reaction of 15 with an alcohol,
in the presence of AgOAc (1 molar equiv) in refluxing toluene,
afforded a product, which was identified to be 16 (Scheme 4).
The counter anion also reacted as a nucleophile in the reaction,
to furnish O-acetyl chloro-oxepine derivative 17, along with
chloro-oxepines 16. The ratio of formation of 16:17, after purifica-
tion, varied with the changing nucleophile. The nucleophiles
included primary, secondary, and unsaturated alcohols. The ring
sequence of ring-opening, formation of oxepine intermediate, yet
another ring-expansion and a ring closure, leading to the formation
of C-furanosides. In contrast, oxyglycal derived gem-dihalo cyclo-
propane studied herein led only to chloro-oxepine formation, with-
out subsequent reactions, in contrast to that observed by Harvey
and Hewitt. The ring opening of gem-dihalocyclopropane ethers
of glycals to chloro-oxepine was susceptible to further rearrange-
ment, which led to the formation of furanoside,17 which was
related closely to the acid-catalyzed rearrangement as proposed
by Skattebøl in less substituted oxepine systems.18 The sequence
of reactions involved protonation of the endocyclic oxygen initially,
followed by a ring opening to generate resonance stabilized allylic
carbocation, which rearranged further to a C-furanoside. Ring-
opening followed by cyclization to C-furanoside is likely to have
occurred due to isomerization of less-substituted endocyclic double
OR
OR
Cl
CHO
O
Cl RO-, ROH
Cl
O
OH
+
H+
O
reflux, 24 h
Cl
Cl
Ring expansion
Ring-opening
Ring-closure
18
Skattebøl observation
Br
OR
Br
OR
Br
O
O
O
BnO
O
Br
BnO
BnO
OR
Ag(I), ROH
BnO
BnO
BnO
+
OR
BnO
BnO
Br
27 h-5 d
BnO
OBn
OBn
OBn
H
Ring-opening-ring-closure
17
Ring expansion
Harvey observation
OR
Cl
O
BnO
O
Cl
Cl
AgOAc, ROH, PhCH3
reflux, 48-72 h
BnO
BnO
BnO
BnO
OBn
OBn
OBn
Present study
Ring expansion
Exclusive product
Scheme 6.

70
S. Dey, N. Jayaraman / Carbohydrate Research 389 (2014) 66–71
OC5H11
1.RuCl3, NaIO4, H2O,CH3CN, EtOAc, 8 h
O
O
O
BnO
O
O
BnO
HO
HO
H2, Pd/C, rt
Cl
BnO
BnO
oC - rt,
CH3OH/EtOAc (1:1)
12 h, 92 %
BnO
BnO
OH
OH
0
OBn
OH
HO
OH
16a
2. NaBH4, CH3OH 0 oC, 3 h
72 %
18
19
Scheme 7.
bond at C2-C3 of oxepine to C1-C2 unsaturated vinyl ether. On the
other hand, gem-dichloro-1,2-cyclopropanated oxyglycal derived
chloro-oxepine did not undergo such an isomerization, possibly
due to unsaturation being present at highly substituted C2-C3 car-
bons. Further, it may be noted that the electronic nature of enol
ether oxepine disfavours rearrangement to a C-furanoside.19 The
course of the reaction is depicted in Scheme 6.
(Na2SO4), and concentrated in vacuo. The resulting residue was
purified (hexane/EtOAc = 9:1) to afford 16a (0.039 g, 72%) as an
oil, and 17 (0.010 g, 20%). Rf 0.6 (hexane/EtOAc 9:1); ½a D25
ꢀ11.24
ꢂ
(c 0.5, CHCl3); HRMS m/z C40H45O6ClNa calcd 679.2802; found
679.2803.
4.1.2. n-Nonayl 2-chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-
a-D-
The observation that D-oxyglycal derived cyclopropane afforded
arabino-hept-2-enoseptanoside (16b)
only halo-oxepines, without undergoing further reactions, was
confirmed further by the following reactions. (i) RuCl3–NaIO4 med-
iated oxidation reaction; (ii) NaBH4-reduction and (iii) Pd/C-medi-
ated hydrogenolysis (Scheme 7). Septanoside 19 was confirmed by
NMR spectroscopies and mass spectral analysis and by comparison
with such products reported by us previously.13–16
A solution of 15 (0.08 g, 0.13 mmol) in toluene (3 mL) was treated
with AgOAc (0.022 g, 0.13 mmol) and 1-nonanol (0.023 mL,
0.13 mmol) and the mixture refluxed for 48 h. The solution was
diluted with EtOAc (20 mL), washed with water (2 ꢁ 20 mL), dried
(Na2SO4), and concentrated in vacuo. The resulting residue was puri-
fied (hexane/EtOAc = 9:1) to afford 16b (0.067 g, 70%) as an oil, along
with 17 (0.010 g, 19%) Rf 0.65 (hexane/EtOAc 9:1); ½a D25
ꢀ21.7 (c 0.5,
ꢂ
CHCl3); HRMS m/z C44H53O6ClNa calcd 735.3428; found 735.3430.
3. Conclusion
4.1.3. Allyl 2-chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-
arabino-hept-2-enoseptanoside (16c)
A solution of 15 (0.05 g, 0.08 mmol) in toluene (1 mL) was trea-
ted with AgOAc (0.013 g, 0.07 mmol) and allyl alcohol (5 L,
a-D-
In conclusion, D-oxyglycal derived gem-dichloro 1,2-cycloprop-
anated sugar derivative undergoes AgOAc catalyzed ring expansion
reaction, using alcohol as nucleophile to provide ring expanded
chloro-oxepines, exclusively. The presence of an additional oxy-
l
0.06 mmol) and the mixture refluxed for 48 h. The solution was
diluted with EtOAc (20 mL), washed with water (2 ꢁ 20 mL), dried
(Na2SO4), and concentrated in vacuo. The resulting residue was
purified (hexane/EtOAc = 9:1) to afford 16c (0.045 g, 88%) as an
substituent at C-2 in
D-oxyglycal derived cyclopropane derivative
plays a major role to control the reactivity, as compared to
D-glycal
derived cyclopropane derivative. Further, the presence of oxygen
functionality at C-3 also controls the stability of chloro-oxepine.
The present study demonstrates an advantage of the oxyglycal pre-
cursor in order to prepare the reactive halo-oxepine intermediate
exclusively in the presence of AgOAc.
oil, along with 17 (0.005 g, 10%). Rf 0.60 (hexane/EtOAc 9:1); ½a D25
ꢂ
ꢀ16.23 (c 0.5, CHCl3); HRMS m/z C38H39O6ClNa calcd 649.2333;
found 649.2333.
4.1.4. Propargyl 2-chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-
arabino-hept-2-enoseptanoside (16d)
a-D-
4. Experimental
A solution of 15 (0.05 g, 0.08 mmol) in toluene (1 mL) was trea-
ted with AgOAc (0.013 g, 0.08 mmol) and propargyl alcohol
(0.004 mL, 0.08 mmol) and the mixture refluxed for 72 h. The solu-
tion was diluted with EtOAc (20 mL), washed with water
(2 ꢁ 20 mL), dried (Na2SO4), and concentrated in vacuo. The result-
ing residue was purified (hexane/EtOAc = 9:1) to afford 16d
(0.034 g, 66%) as an oil, and 17 (0.015 g, 30%). Rf 0.70 (hexane/
4.1. General methods
Chemicals were purchased from commercial sources and were
used without further purification. Solvents were dried and distilled
according to literature procedures. Analytical TLC was performed
on commercial Merck plates coated with silica gel GF254
(0.25 mm) with detection by U.V and/or charring following immer-
sion in 5% H2SO4–EtOH. Silica gel (230–400 mesh) was used for col-
EtOAc 8:2); ½a 2D5
ꢂ
+18.96 (c 0.5, CHCl3); HRMS m/z C38H37O6ClNa
calcd 647.2176; found 647.2174.
umn chromatography. Optical rotations were recorded on
a
polarimeter at the sodium D line at 25 °C. High-resolution mass
spectra were obtained from Q-TOF instrument by electron spray
ionization (ESI) technique. NMR spectral analyses were performed
on a spectrometer operating at 400 MHz for 1H nucleus and
100 MHz spectrometer for 13C nucleus, with residual solvent signal
acting as the internal standard. Standard abbreviations s, d, t, dd, br,
app, m, and band refer to singlet, doublet, triplet, doublet of dou-
blet, broad, apparent, multiplet, and set of resonances, respectively.
4.1.5. Phenyl allyl 2-chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-
arabino-hept-2-enoseptanoside (16e)
a-D-
A solution of 15 (0.05 g, 0.08 mmol) in toluene (1 mL) was trea-
ted with AgOAc (0.013 g, 0.08 mmol) and cinnamyl alcohol
(0.010 g, 0.08 mmol) and the mixture refluxed for 48 h. The solution
was diluted with EtOAc (20 mL), washed with water (2 ꢁ 20 mL),
dried (Na2SO4), and concentrated in vacuo. The resulting residue
was purified (hexane/EtOAc = 9:1) to afford 16e (0.043 g, 75%) as
an oil. Rf 0.66 (hexane/EtOAc 8:2) ½a D25
ꢀ22.20 (c 1, CHCl3); HRMS
ꢂ
4.1.1. n-Pentyl 2-chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-
a
-D
-
m/z C44H43O6ClNa calcd 725.2646; found 725.2643.
arabino-hept-2-enoseptanoside (16a)
A solution of 15 (0.05 g, 0.08 mmol) in toluene (1 mL) was trea-
ted with AgOAc (0.012 g, 0.08 mmol) and 1-pentanol (0.008 mL,
0.08 mmol) and the mixture refluxed for 48 h. The solution was
diluted with EtOAc (20 mL), washed with water (2 ꢁ 20 mL), dried
4.1.6. Isopropyl 2-chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-
arabino-hept-2-enoseptanoside (16f)
A solution of 15 (0.05 g, 0.08 mmol) in toluene (1 mL) was trea-
ted with AgOAc (0.013 g, 0.07 mmol) and iso-propyl alcohol
a-D-

S. Dey, N. Jayaraman / Carbohydrate Research 389 (2014) 66–71
71
(0.010 mL, 0.13 mmol) and the mixture refluxed for 72 h. The solu-
tion was diluted with EtOAc (20 mL), washed with water
(2 ꢁ 20 mL), dried (Na2SO4), and concentrated in vacuo. The result-
ing residue was purified (hexane/EtOAc = 9:1) to afford 16f
(0.035 g, 68%) as an oil and 17 (0.011 g, 21%). Rf 0.62 (hexane/EtOAc
4.80 (d, J = 12.0 Hz, 1H), 4.73 (d, J = 12.0 Hz, 1H), 4.52 (d,
J = 12.0 Hz, 1H), 4.46–4.41 (m, 2 H), 4.18–4.12 (m, 2H), 4.05–3.99
(m, 3H), 3.90 (ddd, J = 9.6, 6.8, 4.0 Hz, 1H), 3.55–3.52 (m, 3H),
3.40 (ddd, J = 9.6, 6.8, 4.4 Hz, 1H), 1.58–1.50 (m, 2H), 1.32–1.18
(m, 4H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
138.6–137.8, 128.4–127.6, 97.6, 80.2, 78.5, 73.5, 73.3, 72.7, 71.5,
71.3, 70.5, 69.9, 68.9, 29.1, 28.2, 22.6, 14.1; HRMS: m/z C33H42O7Na
calcd for 573.2828; found: 573.2828.
8:2); ½a 2D5
ꢂ
+6.83 (c 0.9, CHCl3); HRMS m/z C38H41O6ClNa calcd
651.2489; found 651.2493.
4.1.7. ((2-Hydroxyethoxy)ethyl)-2-chloro-2-deoxy-3,4,5,7-tetra-
O-benzyl-a-D-arabino-hept-2-enoseptanoside (16g)
4.1.11. n-Pentyl-a-D-glycero-D-galacto-septanoside (19)
A solution of 15 (0.07 g, 0.11 mmol) in toluene (2 mL) was trea-
ted with AgOAc (0.019 g, 0.13 mmol) and diethylene glycol
(0.010 mL, 0.11 mmol) and the mixture refluxed for 72 h. The solu-
tion was diluted with EtOAc (20 mL), washed with water
(2 ꢁ 20 mL), dried (Na2SO4), and concentrated in vacuo. The result-
ing residue was purified (hexane/EtOAc = 8:2) to afford 16g
A solution of diol 18 (0.023 g, 0.0418 mmol) in MeOH/EtOAc
(1:1, 7 mL) was added with Pd/C (10%, 0.06 g) and the mixture
was stirred under a positive pressure of H2 gas for 12 h. The reac-
tion mixture was filtered over a celite pad and washed with MeOH
(2 ꢁ 10 mL), and solvents were removed in vacuo to afford 19
(0.010 g, 92%) as a colorless oil. ½a D25
ꢂ
+33.60 (c 0.5, MeOH); 1H
(0.059 g, 76%) as an oil. Rf 0.28 (hexane/EtOAc 9:1); ½a D25
ꢂ
+2.14 (c
NMR (400 MHz, D2O) d 4.91 (d, J = 3.2 Hz, 1H), 4.10 (dd, J = 6.8,
2.0 Hz, 1H), 4.00 (dd, J = 6.8, 3.2 Hz, 1H), 3.96 (dd, J = 7.6, 2.0 Hz,
1H), 3.89 (m, 3H), 3.76 (dd, J = 12.0, 6.8 Hz, 1H), 3.70–3.66 (m,
1H), 3.58 (dd, J = 16.0, 6.8 Hz, 1H), 1.64–1.60 (m, 3H), 1.33–1.30
(m, 5H), 0.90 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, D2O) d 96.7,
73.3, 73.3, 71.4, 71.0, 69.6, 68.8, 62.1, 28.2, 27.5, 21.8, 13.3; HRMS:
m/z C12H24O7Na calcd for 303.1420; found: 303.1419.
0.3, CHCl3); HRMS m/z C39H43O8ClNa calcd 697.2544; found
697.2545.
4.1.8. Benzyl 2-chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-
arabino-hept-2-enoseptanoside (16h)
a-D-
A solution of 15 (0.05 g, 0.08 mmol) in toluene (1 mL) was trea-
ted with AgOAc (0.013 g, 0.07 mmol) and benzyl alcohol (0.010 mL,
0.10 mmol) and the mixture refluxed for 72 h. The solution was
diluted with EtOAc (20 mL), washed with water (2 ꢁ 20 mL), dried
(Na2SO4), and concentrated in vacuo. The resulting residue was
purified (hexane/EtOAc = 9:1) to afford 16h (0.036 g, 65%) as an
Acknowledgements
We thank the Department of Science and Technology, New Del-
hi, for a financial support. S.D. thanks Council of Scientific and
Industrial Research, New Delhi, for a senior research fellowship.
oil and 17 (0.008 g, 17%). Rf 0.59 (hexane/EtOAc 8:2);
½ ꢂ
a 2D5
ꢀ19.03 (c 1.1, CHCl3); HRMS m/z C42H41O6ClNa calcd 699.2489;
found 699.2488.
Supplementary data
4.1.9. Acetyl 2-chloro-2-deoxy-3,4,5,7-tetra-O-benzyl-
a-D-
arabino-hept-2-enoseptanoside (17)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2014.01.
023.
A solution of 15 (0.05 g, 0.08 mmol) in toluene (1 mL) was
treated with AgOAc (0.013 g, 0.08 mmol) and NaOAc (0.007 g,
0.08 mmol) and the mixture refluxed for 48 h. The solution was
diluted with EtOAc (20 mL), washed with water (2 ꢁ 20 mL), dried
(Na2SO4), and concentrated in vacuo. The resulting residue was
purified (hexane/EtOAc = 9:1) to afford 17 (0.040 g, 78%) as an
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½
a 2D5
ꢂ
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19. We thank a referee for this suggestion.
2