σ-Ferrier rearrangement of carbohydrate derived vinylcyclopropanes: a facile approach to oxepane analogs

Article abstract of DOI:10.1016/j.tet.2014.07.004

This article presents our work on the σ-Ferrier ring-expansion of carbohydrate derived vinylcyclopropanes (VCPs) under electrophilic conditions mediated by chloramine-T and a phase-transfer catalyst. The present work serves as the first example on the stu

Full text of DOI:10.1016/j.tet.2014.07.004

Accepted Manuscript
σ–Ferrier Rearrangement of Carbohydrate Derived Vinylcyclopropanes: A Facile
Approach to Oxepane Analogs
Venkataraman Ganesh, Taraknath Kundu, Srinivasan Chandrasekaran, Honorary
Professor
PII:
S0040-4020(14)01006-0
10.1016/j.tet.2014.07.004
TET 25798
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 April 2014
Revised Date: 23 June 2014
Accepted Date: 1 July 2014
Please cite this article as: Ganesh V, Kundu T, Chandrasekaran S, σ–Ferrier Rearrangement of
Carbohydrate Derived Vinylcyclopropanes: A Facile Approach to Oxepane Analogs, Tetrahedron (2014),
doi: 10.1016/j.tet.2014.07.004.
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σ–Ferrier Rearrangement of Carbohydrate
Derived Vinylcyclopropanes: A Facile
Approach to Oxepane Analogs
Venkataraman Ganesh,† Taraknath Kundu† and Srinivasan Chandrasekaran#*
Department of Organic Chemistry, Indian Institute of Science, Bangalore – 560 012, India.

1
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Tetrahedron
journal homepage: www.elsevier.com
σ–Ferrier Rearrangement of Carbohydrate Derived Vinylcyclopropanes: A Facile
Approach to Oxepane Analogs
Venkataraman Ganesh,† Taraknath Kundu† and Srinivasan Chandrasekaran#*
†Authors contributed equally
# Honorary Professor, Department of Organic Chemistry, Indian Institute of Science, Bangalore – 560 012, India. Hindustan Lever Professor, JNCASR, Jakkur,
Bangalore.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
This article presents our work on the σ–Ferrier ring-expansion of carbohydrate derived
vinylcyclopropanes (VCPs) under electrophilic conditions mediated by chloramine-T and a
phase-transfer catalyst. The present work serves as the first example on the studies of the
reactivity of carbohydrate VCPs towards the synthesis of densely functionalized oxepane
analogues. The work elaborates on a reasonable mechanism for the product formation and our
observations on the diastereoselectivity based on control experiments and gas-phase
calculations.
Available online
Keywords:
Carbohydrate
Vinylcyclopropane
σ–Ferrier Rearrangement
Oxepane
2009 Elsevier Ltd. All rights reserved
.
Septanoside; Heptanoside
1. Introduction
enol ethers as nucleophiles for ring expansion reactions of
cyclopropanones.14, 35 The chemistry involving ring expansion of
carbohydrate derived dihalocyclopropanes, mediated by bases
was demonstrated by Nagarajan et al.37 and Harvey et al.44
Jayaraman and coworkers38-41 further extended the methodology
towards a practical accessibility to septanosides and respective
polysaccharides.
Seven membered oxacycles have gained tremendous
significance due to their increasing prominence in numerous
naturally occurring biologically active compounds.1-6 The
increasing number of polyether natural products from marine
sources containing a seven membered oxacyclic core has
encouraged the development of new synthetic routes to achieve
highly functionalized oxepanes.7-17 Seven-membered ring
systems such as polyhydroxylated azepanes and septanosides
have received considerable attention as potential non-natural
surrogates for pyranoses in a number of biochemical processes.18-
21 Glycosylation of septanosides and the kinetics of hydrolysis of
such linkage have been carried out extensively to gain insight on
the stability and reactivity of these polysaccharides compared to
their pyranose counter-parts under physiological conditions.22-24
To the best of our knowledge, ring opening of carbohydrate
derived cyclopropanes mediated by electrophiles always led to a
ring-opening reaction through C1-C7 bond cleavage. Ring-
expansion by the cleavage of C1-C2 σ-bond has not been
observed so far (path-a, Scheme 1). Conversely, Lewis acid
catalysts are shown to be the best to effect ring-expansions
(path-b, Scheme 1).46-47 In the present study, we planned to install
an exocyclic methylene group, utilizing the electron-rich
character of the π-bond (in comparison to the cyclopropane σ-
bonds), to demonstrate an electrophile mediated ring-expansion
by the rupture of C1-C2 σ-bond, which is not a typical reactivity
pattern observed in the chemistry of carbohydrate-derived
cyclopropanes (Scheme 1).
Various routes like intramolecular epoxide ring-opening
12, 25-26
reaction,10,
nitrone-alkene cycloaddition reaction,27-28
skeletal rearrangements,29-31 cyclization reaction32-34 and ring-
expansion chemistry,14, 35-44 starting from both racemic and chiral
synthons have been developed. Pioneering efforts of Hoberg
towards the synthesis of optically active oxepane derivatives by
the ring expansion of carbohydrate derived cyclopropanes
For several years, our group has been actively involved in
exploring the reactivity of vinylcyclopropanes as masked donor–
acceptor systems, and synthetic methodologies on carbohydrate
systems in parallel. Our earlier reports on the electrophile
mediated ring–opening reaction of vinylcyclopropanes 48, 49 led us
to believe that the reaction of carbohydrate derived
vinylcyclopropane 6 in the presence of electrophiles would
possibly effect a σ-Ferrier type ring
promoted by Lewis acids in the presence of an external
nucleophile are noteworthy.42-43,
The reaction has been
45
proposed to proceed through a planar oxonium intermediate
following a Ferrier type rearrangement of C–C σ–bond.
Recently, Sridhar et al. extended this methodology to the
synthesis of septano-oligosaccharides from cyclopropanones with
glycans as nucleophiles.36 Earlier, Sugita et al. employed silyl

2
Tetrahedron
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Scheme 1. General strategy of reactivity of carbohydrate derived VCPs.
expansion through a tight-carbocation intermediate to densely
functionalized oxepanes. We convincingly showed that the
overlap between the π–orbital of vinyl group and the
cyclopropane C–C σ*–orbital facilitates the ring–opening to a
great extent.48-50 In the present case, a minimum overlap is
expected between the π–bond and the C–C σ–bond due to their
orthogonality and restricted conformational freedom. The
reactivity of VCP 6 could be interesting due to the orthogonal
orientation of the π–bond and the cyclopropane C–C σ–bond of
interest.
The galacto-VCP 7 was also prepared following a similar
reaction sequence used for 6. To introduce rigidity and to study
the effect of steric bulk on the reaction, we planned to protect the
C-4 and C-6 hydroxyl groups of both D-glucal and D-galactal
with cyclic protecting groups so as to have the C-3 hydroxyl
group for guided cyclopropanation under Simmon–Smith
conditions. Accordingly the glucal 1a
was converted to
acetonide protected derivative 2c52 and the galactal 1b was
protected as the silyl derivative 2d.53,54 The protected glycals 2c
and 2d were converted to the corresponding VCPs 8 and 9
following a similar reaction sequence used for the synthesis of 6
and 7 (Scheme 3).
2. Results and Discussion
To study these aspects we planned the synthesis of the
carbohydrate derived vinylcyclopropane 6, starting from D-
glucal. Glucal 1a was first converted to C–4 O–benzylated glucal
2a using known procedure from the literature,51 followed by
regioselective protection of the C–6 hydroxyl group as its TBS
ether 3a using a standard protocol. The C–3 hydroxyl group was
used as a handle to carry out Simmons–Smith cyclopropanation
at the β–face with high stereoselectivity to get 4a exclusively.
The C–3 hydroxyl in 4a was later oxidized to the corresponding
1,2–cyclopropylketone 5a using the Dess–Martin reagent, which
was then subjected to Wittig reaction to furnish the desired
gluco–VCP 6 in good yield (Scheme 2).
VCP 6 was subjected to a ring–expansion reaction using
chloramine–T trihydrate 10 and phenyltrimethylammonium
tribromide (PTAB, 11) as catalyst in MeOH (rt, 4 h). After 4 h,
VCP 6 successfully underwent ring–opening to furnish a highly
functionalized oxepane 12a in excellent yield as a mixture of
anomers (3:2) (Scheme 4). The configuration at the anomeric
position was established with help of 2D-NMR (NOESY
spectrum shown in Scheme 4) and by comparing the reported
resonance frequency of the anomeric carbon.38-41
Reagents and Conditions: (a) TBSCl (1.05 equiv), Imidazole (2 equiv), DMF, 0 °C to rt, 3 h; (b) Et2Zn (1.5 equiv), CH2I2 (2 equiv), DCM, 0 °C, 4 h; (c) DMP
(1.1 equiv), DCM, 0 °C, 2 h; (d) [Ph3PCH3]+I-, n-BuLi, THF, 0 °C, 5 h
Scheme 2. Synthesis of gluco- and galacto-VCPs 6 and 7.

3
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Reagents and Conditions: (a) 2,2-DMP (5 equiv), p-TsOH (pH ~ 3), DMF, rt, 4 h; (b) Et2Zn (1.5 equiv), CH2I2 (2 equiv), DCM, 0 °C, 4 h; (c) DMP (1.1 equiv),
DCM, 0 °C, 2 h; (d) [Ph3PCH3]+I-, n-BuLi, THF, 0 °C, 5 h; (e) tBu2Si(OTf)2 (1.2 equiv), pyridine, DCM, 0 °C, 6 h.
Scheme 3. Synthesis of gluco- and galacto-VCPs 8 and 9.
From the literature, it is known that the β–anomer resonates (13C)
generally at a higher frequency compared to the α-anomer. 38-41
Unlike in the case of furanosides and pyranosides, the resonance
frequencies of the anomeric carbon of α– and β–anomer are
indistinct. For 12a, the carbon-13 of the α–anomer resonates at
100.2 ppm and β–anomer at 100.6 ppm. Quantum chemical
predictions of the chemical shift of anomeric carbon using GIAO
method (at M06-2x/6-31+G* level) suggested that the β–anomer
resonates at higher frequency when compared with α-anomer (α-
anomer: 104.0 ppm, β-anomer: 106.0 ppm).
reaction of galacto–VCP 7 under standard reaction conditions in
the presence of different alcohol nucleophiles was promising
which led to successful ring–opening to the corresponding
oxepane derivatives 13a-c. We envisaged that the introduction of
cyclic bifunctional protecting groups (like acetonide and di–t–
butylsilyl protection) will impart more rigidity to the skeleton
and steric crowding, which in-turn will help in improving the
selectivity at the anomeric center. However, in both the VCPs (8
and 9), no appreciable improvement in the selectivity was
observed in the product (14a-c and 15a-c, Table 1). This
observation suggested the intermediacy of a planar oxonium
intermediate as proposed by Hoberg.45
Our present observation does not corroborate with our earlier
results with vinylcyclopropanes in support of the existence of an
intimate carbocation. Hence, we undertook an exercise to explore
the possible intermediate through which the ring expansion can
occur. Geometry optimization of the bromenium intermediate at
M06-2x/6-31+G* level showed the existence of
a tight
carbocation as observed by us earlier but purely as a transient
intermediate (A), which spontaneously undergoes complete ring-
opening to the more
T.S.
Transient
Intermediate
Reactive
Intermediate
O
O
G
O
Br
O
O
A
O
Br
B
Reaction Coordinate
Scheme 4. Ring-expansion of gluco-VCP 6 to oxepane 12a.
H
H
OMe
We further studied the generality of the reaction, by exploring
O
TBSO
BnO
the reactivity of VCPs 6-9 with various alcohols as nucleophiles
TsHN
(Table 1). Very little improvement in the ratio of anomers was
observed with sterically demanding alcohols as nucleophiles. The
Figure 1. Energy profile for the ring-expansion reaction (Color only in Web
version)

4
Tetrahedron
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Table 1. Ring-expansion of carbohydrate derived VCPs
stable (~4 kcal) planar oxonium ion B (Figure 1). Since, the
conversion of the transient intermediate A to the oxonium ion B
is a barrierless transition, trapping of A via an SN2 pathway
occurs to a negligible extent compared to the ring-expansion
process. Hence, the reaction proceeds typically through a planar
oxonium ion intermediate, resulting in poor diastereoselectivity.
OMe
O
RO
RO
O
RO
RO
Br-X
TsHN
Based on our earlier studies on the reactivity of VCPs with
halogen electrophiles and DFT calculations a plausible catalytic
cycle for ring expansion of carbohydrate derived VCPs has been
proposed (Scheme 5). In the first step, the reaction of
chloramine-T with PTAB (catalyst, 10 mol%) enables the
formation of interhalogen compounds in situ in catalytic
amounts. These interhalogen compounds undergo addition across
the VCP’s double bond inducing the ring expansion through a
transient tight carbocation intermediate. This transient
intermediate spontaneously undergoes complete ring opening to
give a planar oxonium intermediate. Subsequent attack of alcohol
(MeOH) nucleophiles and displacement of bromo group by NTs-
results in the formation of the desired oxepane analogoues.
X = Cl, Br, Nu
OMe
O
RO
RO
O
RO
RO
Br-X
Br
Na
N
Ts
Cl
+
-
PhMe3N+Br3
MeOH
Transient
Intermediate
Stable
Intermediate
O
RO
RO
O
RO
RO
Further, we were interested in functionalizing the methylene
carbon of the cyclopropane ring anticipating that the reaction will
lead to a densely functionalized oxepane. Hence, we synthesized
the corresponding carboxylate derived cyclopropane 16a using
Rh2(OAc)4 catalyzed cyclopropanation of the fully protected
glucal with methyl diazoacetate. The resulting cyclopropane
Br
X
Fast
Extremely Slow
Br
Scheme 5. Plausible mechanism for ring expansion of VCPs

5
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Reagents and conditions: (a) N2CHCO2Me (2 equiv), Rh2(OAc)4 (10 mol%), DCM, rt, 4 h; (b) TBAF (1.2 equiv/TBS group), THF, 2 h; (c) DMP (1.1 equiv),
DCM, 0 °C, 2 h; (d) [Ph3PCH3]+I- (2 equiv), n-BuLi (1.5 equiv), THF, 0 °C, 5 h; (e) Chloramine-T, PTAB (10 mol%), MeOH, rt, 6 h.
Scheme 6. Reactivity of vinyl cyclopropane carboxylates 16 and 17.
Reagents and conditions: (a) (i) LiAlH4 (1 equiv), THF, 0 °C; (ii) BnBr (1.05 equiv), NaH (1.5 equiv), DMF, 0 °C; (b) TBAF (1.2 equiv/TBS group), THF, 2 h;
(c) DMP (1.1 equiv), DCM, 0 °C, 2 h; (d) [Ph3PCH3]+I- (2 equiv), n-BuLi (1.5 equiv), THF, 0 °C, 5 h; (e) chloramine-T, PTAB (10 mol%), MeOH, rt, 6 h; (f)
TBS-Cl (1.1 equiv), imidazole (2 equiv), DMF, 0 °C-rt, 3 h; (g).
Scheme 7. Ring expansion of 18 to a densely functionalized oxepane 19
ester 16a was converted to the desired VCP 16 using a standard
protocol. Reaction of 16 under ring–expansion conditions
(chloramine-T, PTAB) led to a complex mixture of products
(Scheme 6). This result was further confirmed by subjecting VCP
ester 17 to similar reaction conditions, which led to a mixture of
products as well. We speculate that the possible side reactions
could be due to the activation of the ester carbonyl under the
influence of an electrophile due to the inherent donor-acceptor
nature of the carbohydrate derived VCP esters. The ring–opening
of such cyclopropane carboxylate systems under the influence of
an electrophile have been explored extensively by our group.55, 56
To confirm our speculation, we decided to convert the
cyclopropane carboxylate 17a to the reduced derivative 18a. The
desired VCP 18 was obtained by the deprotection of the silyl
group followed by oxidation and the Wittig reaction sequence.
Reaction of 18 under standard reaction conditions (chloramine-T,
PTAB) in methanol led to the ring- expanded oxepane 19 in
good yield but with poor selectivity. (Scheme 7)
Reagents and Conditions: (a) 10 (1.1 equiv), 11 (0.1 equiv), Moist MeCN
(0.5 mL H2O/ 5mL MeCN).
Interestingly, with water as the nucleophile, the gluco-VCP 6
under similar conditions using moist acetonitrile, led to the ring-
opened product followed by elimination of bromide to yield an
Scheme 8. Reactivity of VCP 6 and 7 in the presence of water

6
Tetrahedron
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open chain polyhydroxylated diene 20a in excellent yield
concentrated in vacuo. The residue was then washed with water
(Scheme 8). Similar reactivity was observed in the case of
galacto-VCP 7 which resulted in the formation of epimeric diene
20b. These polyhydroxylated dienes are potential synthons for
the synthesis of zaragozic acids and amphidinolides.
and extracted with CH2Cl2 (2X200 mL). The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product provided the title
compound in its pure form. Gummy; Rf = 0.58 (hexanes/EtOAc,
8 : 2); Yield: 14 g, 80%; [α]25D= +27.6 (CHCl3, c = 1.7) (lit.
[α]25D= +27.2 (CHCl3, c = 1.0):57 IR (neat): 3422, 2954, 2930,
2884, 2858, 1651, 1253, 1538, 1109, 837, 778 cm-1; H-NMR
1
(400 MHz, CDCl3): 7.37-7.30 (5H, m, Ph), 6.36 (1H, d, J = 6.0
Hz, O-CH=CH), 4.79 (2H, dd, J = 12.4 Hz, O-CH2-Ph), 4.71
(1H, dd, J = 2.8 Hz, 6.0 Hz, O-CH=CH), 4.29-4.28 (1H, m, CH-
O), 3.95 (2H, d, J = 2.0 Hz, CH2-OTBS), 3.87-3.85 (1H, m, CH-
O), 3.68 (1H, dd, J = 6.4 Hz, 7.2 Hz, CH-O), 2.33 (1H, s, -OH),
0.92 (9H, s, Si(tBu)), 0.09 (6H, s, Si(Me)2); 13C-NMR (100 MHz,
CDCl3): 144.5, 138.4, 128.5, 127.9, 102.1, 77.5, 77.0, 73.6, 67.9,
62.4, 25.8, 18.3, -5.2, -5.5; HRMS m/z: calcd for C19H30O4Si
[M+Na] +: 373.1811; found: 373.1811.
1,5-Anhydro-2-deoxy-4-O-benzyl-6-O-TBS-β-1,2-C-methylene-
D-arabino-hexitol (4a): To a stirred solution of diethyl zinc (1M
Scheme 9. Synthesis of 2-deoxyseptanoside derivatives 21,
22.
The oxepane β-12a (separated by flash column
chromatography) and 15a were further dihydroxylated in a
diastereoselective fashion using OsO4/NMMO in t-butanol under
reflux to the corresponding 2-deoxyseptanoside derivatives 21
(92%) and 22 (83%) respectively (Scheme 9).
solution in toluene, 15 mL,15.0 mmol, 1.5 equiv) in DCM (15
mL) at -15 °C was added a solution of CH2I2 (4.6 g, 17 mmol, 1.7
equiv) in DCM (30 mL) drop wise under nitrogen atmosphere.
The solution was stirred for 20 min to form iodozinc methyl
iodide as a yellowish white precipitate. To the reaction mixture a
solution of glycal 3a (3.5 g, 10 mmol, 1 equiv) in DCM (3X2
mL) was added at -15 °C. After the addition, the reaction mixture
was allowed to warm to room temperature .The progress of the
reaction was monitored by TLC. After complete consumption of
the starting material, the reaction mixture was poured into ice-
cold sat. NH4Cl solution and then washed with water and
extracted with CH2Cl2 (2X50 mL). The organic layer was dried
over anhydrous Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product provided 4a in its pure
form. Gummy, Rf = 0.51 (hexanes /EtOAc, 8 : 2); Yield: 3.1 g,
85%; [α]25D= +21.2 (CHCl3, c = 1.3) IR (neat): 3442, 2952,
2928, 2856, 1107, 1076, 1054, 949, 836, 774 cm-1; 1H-NMR (400
MHz, CDCl3): 7.35-7.25 (5H, m, Ph), 4.72 (2H, s, O-CH2-Ph),
4.26-4.25 (1H, m, CH-O), 3.81 (1H, d, J = 11.6 Hz, CH-O), 3.73
(1H, d, J = 11.6 Hz, CH-O), 3.71-3.67 (1H, m, CH-O), 3.29-3.27
(2H, m, CH2-O), 2.18 (1H, s, -OH), 1.40-1.32 (1H, m, CH-CH-
CH2), 0.90 (9H, s, Si(tBu)), 0.70-0.64 (2H, m, CH-CH2-CH), 0.08
(s, 3H), 0.07 (s, 3H); 13C-NMR (100 MHz, CDCl3): 138.6, 128.5,
127.8, 127.8, 79.3, 78.8, 74.0, 70.7, 62.4, 53.3, 25.9, 18.3, 17.9,
3. Conclusion
In summary, we have developed a novel route to access
densely functionalized oxepanes and 2-deoxyseptanosides
through a σ-Ferrier type ring-expansion of carbohydrate derived
VCPs. Attempts were made to improve the diastereoselectivity
at the anomeric position. Since the reaction proceeds through a
planar oxonium intermediate, controlling the diastereoselectivity
at the anomeric position is challenging. Our efforts are being
continued to access the transient, tight-carbocation intermediate.
4. Experimental section
4.1 General Information
All solvents for routine isolation of products and
chromatography were laboratory grade and redistilled.
Acetonitrile and DCM used for the reaction were dried under
reflux over CaH2 and stored over 3 Å molecular sieves. Flash
chromatography was performed using silica gel (230−400 mesh)
with indicated solvents. All reactions were monitored by thin-
layer chromatography on 0.25 mm silica plates (F-254)
+
11.1, -5.1, -5.4; HRMS m/z: calcd for C20H32O4Si [M+Na] :
387.1968; found: 387.1975.
1,5-Anhydro-2-deoxy-1,2-C-methylene-4-O-benzyl-6-O-TBS-α-
D-erythro-hex-3-ulose (5a): To a stirred solution of cyclopropane
visualizing
with
UV
light
and
developed
using
alcohol 4a ( 1.82 g, 5 mmol, 1 equiv) in CH2Cl2 (15 mL) at 0 °C
was added Dess–Martin periodinane (DMP) (2.3 g, 5.5 mmol, 1.1
equiv). The progress of the reaction was monitored by TLC.
After complete consumption of the starting material, the reaction
was quenched by adding 10% aqueous solution of Na2S2O3 (20
mL)/ sat. solution of NaHCO3 (aq) (20 mL) with vigorous
stirring. The aqueous layer was extracted with CH2Cl2 (3X50
mL). The combined organic layer was washed with sat. solution
of NaHCO3 (aq) and brine. The organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product provided the corresponding
cyclopropyl ketone 5a in its pure form. Gummy, Rf = 0.51
(hexanes/EtOAc, 8 : 2); Yield: 1.48 g, 82%; [α]25D= +35.5
(CHCl3, c = 1.0); IR (neat): 2954, 2929, 2883, 2857, 1708, 1137,
phosphomolybdate or vanillin solution. 1H, 13C-NMR spectra
were recorded on a 400 MHz NMR spectrometer. Chemical
shifts in ppm, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet), coupling constant in Hertz (Hz), and
number of protons. HRMS were measured with electrospray
ionization (ESI) and quadrupolar mass analyzer. Gaussian 09
program was used for energy minimization.
4.2 Experimental Procedure and Spectral Details
1,5-Anhydro-2-deoxy-4-O-benzyl-6-O-TBS-D-arabino-hex-1-
enitol (3a): To a stirred solution of glycal 2a (11.8 g, 50 mmol, 1
equiv) in DMF (150 mL) at -15 °C was added imidazole (6.8 g,
100 mmol, 2.0 equiv) and TBS-Cl (7.8 g, 52 mmol, 1.05 equiv)
in parts under nitrogen atmosphere. After the addition, the
reaction mixture was allowed to warm to room temperature .The
progress of the reaction was monitored by TLC. After complete
consumption of the starting material, the reaction mixture was
1
1097, 836, 777 cm-1; H-NMR (400 MHz, CDCl3): 7.40-7.26
(5H, m, Ph), 4.96 (1H, d, J = 10.8 Hz, O-CH2Ph), 4.53 (1H, d, J
= 10.8 Hz, O-CH2Ph), 4.14 (1H, dd, J = 4.4 Hz, 8.8 Hz, CH-O),
3.93 (1H, d, J = 10.0 Hz, CH-O), 3.85 (2H, d, J = 10.0 Hz, CH2-

7
OTBS), 3.78 (1 H, dd, J = 3.6 Hz, 1.6 Hz, CH-O), 1.92-1.87 (1H,
m, O=C-CH-CH2), 1.30-1.26 (2H, m, CH-CH2-CH), 0.91 (9H, s,
Si(tBu)), 0.08 (3H, s, Si-Me), 0.08 (3H, s, Si-Me); 13C-NMR (100
MHz, CDCl3): 205.5, 137.7, 128.3, 128.1, 127.8, 82.7, 77.5, 74.3,
62.1, 57.7, 25.9, 25.8, 19.9, 18.3, -5.1, -5.5; HRMS m/z: calcd for
C20H30O4Si [M+Na] +: 385.1811; found: 385.1814.
mmol, 0.1 equiv). The reaction was monitored by TLC. After
ACCEPTED MANUSCRIPT
complete conversion of the starting material and the intermediate
bromide, the reaction mixture was concentrated in vacuo, and
then washed with water (10 mL) extracted with DCM (2 X 10
mL). The organic layer was dried over anhyd. Na2SO4 and
concentrated in vacuo. Flash chromatography of the crude
product afforded the oxepane 12b in its pure form. Rf = 0.56
1,5-Anhydro-2,3-di-deoxy-1,2-C-methylene-4-O-benzyl-6-O-TBS-
α-D-erythro-hexityl-exo-3-methylene (6) To a stirred suspension
1
(hexanes/EtOAc, 7 : 3); Yield: 0.089 g, 74%; H-NMR (400
MHz, CDCl3): 7.69 (1.2H, d, J = 7.2 Hz, Ph), 7.67 (2H, d, J = 7.2
Hz, Ph), 7.35-7.26 (13H, m, Ph), 5.66 (1H, dd, J = 4.0 Hz, 8.8
Hz, C=CH), 5.60 (1H, dd, J = 3.6 Hz, 3.6 Hz, C=CH), 4.94-4.90
(2H, m, -NH), 4.64 (1H, dd, J = 3.6 Hz, 8.8 Hz, O-CH-O), 4.49
(3.6 H, dd, J = 11.2 Hz, 15.2 Hz, O-CH2Ph), 4.07 (1H d, J = 3.2
Hz, CH-O), 3.81-3.73 (4.8H, m, CH2-OTBS, CH2-O), 3.63-3.43
(4H, m, CH2-N), 3.40-3.32 (1.6 H, m, CH-O ), 2.63-2.57 (0.6H,
m, CH-CH2-CH), 2.50-2.45 (1H, m, CH-CH2-CH), 2.41 (4.8H, s,
Me), 2.33-2.25 (1.6H, m, CH-CH2-CH), 1.57-1.50 (3.2H, m,
CH2), 1.39-1.30 (3.2H, m, CH3), 0.93 (5.4H, s, SitBu), 0.89 (9H,
s, SitBu), 0.1 (1.8H, s, SiMe), 0.09 (1.8H, s, SiMe), 0.08 (3H, s,
SiMe), 0.07 (3H, s, SiMe); 13C-NMR (100 MHz, CDCl3): 143.2,
143.1, 138.1, 137.8, 136.9, 136.5, 138.1, 137.8, 136.9, 136.5,
134.2, 129.6, 128.5, 128.4, 127.8, 127.5, 127.1, 127.1, 124.9,
99.4, 98.8, 79.7, 78.8, 72.3, 71.2, 69.8, 68.0, 67.5, 64.4, 63.6,
50.5, 48.4, 36.7, 31.6, 26.0, 25.8, 21.4, 19.3, 19.2, 18.5, 18.3,
13.8, -5.3, -5.5; HRMS m/z: calcd for C32H49NO6SSi [M+Na] +:
626.2948; found: 626.2946.
of phosphonium iodide (0.404 g, 1 mmol, 2 equiv) in THF (6
mL) at -15 °C was added n-BuLi (1.6 M in hexanes, 0.57 mL,
0.90 mmol, 1.8 equiv) under nitrogen atmosphere. After the
addition, the reaction mixture was allowed to stir for 20 min. The
supernatant was cannulated into a solution of 5a (0.18 g, 0.5
mmol, 1 equiv) in THF (3 mL). The progress of the reaction was
monitored by TLC. After complete consumption of the starting
material, the reaction mixture was concentrated in vacuo. The
residue was then washed with water and extracted with CH2Cl2
(2X15 mL). The organic layer was dried over anhydrous Na2SO4
and concentrated in vacuo. Flash chromatography of the crude
product provided the corresponding VCP in its pure form.
Gummy, Rf = 0.50 (hexanes/EtOAc, 8 : 2); Yield: 0.159 mg,
1
87%; [α]25D= +30.6 (CHCl3, c = 0.5); H-NMR (400 MHz,
CDCl3): 7.37-7.28 (5H, m, Ph), 5.24 (1H, s, C=CH2), 5.17 (1H, s,
C=CH2), 4.64 (1H, d, J =11.2 Hz, O-CH2Ph), 4.62 (1H, d, J =
11.2 Hz, O-CH2Ph), 3.85 (1H, d, J = 8.8 Hz, CH-O), 3.76-3.71
(3H, m, CH2-OTBS, CH-O), 3.48-3.44 (1H, m, CH-O), 1.79-1.73
(1H, m, CH-CH-CH2), 0.90 (9H, s, SitBu), 0.88-0.83 (1H, m,
CH-CH2-CH), 0.73-0.69 (1H, m, CH-CH2-CH), 0.08 (3H, s,
SiMe), 0.07 (3H, s, SiMe); 13C-NMR (100 MHz, CDCl3): 144.0,
138.3, 128.3, 127.9, 127.6, 110.2, 80.7, 76.4, 62.8, 53.1, 25.9,
19.0, 18.3, 16.1, -5.0, -5.3; HRMS m/z: calcd for C21H32O3Si
[M+Na] +: 383.2018; found: 383.2003.
(2R,3S)-3-(Benzyloxy)-2-(TBS-oxymethyl)-7-(α/β)-isopropoxy-4-
(N-p-toluenesulfonamidomethyl)-2,3,6,7-tetrahydrooxepine (12c)
To a stirred solution of VCP 6 (0.072 g, 0.2 mmol, 1 equiv) in the
chosen alcohol (1 mL) as nucleophile at rt was added solid
chloramine-T (0.062 g, 0.22 mmol, 1.1 equiv) and
phenyltrimethylammonium tribromide (PTAB, 0.008 g, 0.02
mmol, 0.1 equiv). The reaction was monitored by TLC. After
complete conversion of the starting material and the intermediate
bromide, the reaction mixture was concentrated in vacuo, and
then washed with water (10 mL) extracted with DCM (2 X 10
mL). The organic layer was dried over anhyd. Na2SO4 and
concentrated in vacuo. Flash chromatography of the crude
product afforded the oxepane 12c in its pure form.Rf = 0.52
(2R,3S)-3-(Benzyloxy)-2-(TBS-oxymethyl)-7-(α/β)-methoxy-4-(N-
p-toluenesulfonamido methyl)-2,3,6,7-tetrahydrooxepine (12a)
To a stirred solution of VCP 6 (0.072 g, 0.2 mmol, 1 equiv) in the
chosen alcohol (1 mL) as nucleophile at rt was added solid
chloramine-T (0.062 g, 0.22 mmol, 1.1 equiv) and
phenyltrimethylammonium tribromide (PTAB, 0.008 g, 0.02
mmol, 0.1 equiv). The reaction was monitored by TLC. After
complete conversion of the starting material and the intermediate
bromide, the reaction mixture was concentrated in vacuo, and
then washed with water (10 mL) extracted with DCM (2 X 10
mL). The organic layer was dried over anhyd. Na2SO4 and
concentrated in vacuo. Flash chromatography of the crude
product afforded the oxepane 12a in its pure form. Rf = 0.33
1
(hexanes/EtOAc, 7 : 3); Yield: 0.093 g, 77%; H-NMR (400
MHz, CDCl3): 7.70 (2H, d, J = 8.0 Hz, Ph), 7.35-7.28 (7H, m,
Ph), 5.67 (1H, dd, J = 4.4 Hz, 9.2 Hz, C=CH), 5.07 (1H, dd, J =
5.6 Hz, 6.4 Hz, -NHTs), 4.75 (1H, dd, J = 2.4 Hz, 9.2 Hz, O-CH-
O), 4.50 (2H dd, J = 10.8 Hz, 21.2 Hz,O-CH2Ph), 4.19-4.12 (1H,
m, CH-O), 4.08-4.01 (1H, m, CH-O), 3.87-3.75 (2H, m, CH2-
OTBS), 3.65 (2H, m, CH2-N), 3.45 (1H, dd, J = 4.8 Hz, 13.6 Hz,
Me2CH-O), 2.62-2.56 (1H, m, CH-CH2-CH ), 2.41 (s, 3H, Me),
2.26-2.19 (1H, m, CH-CH2-CH), 1.18 (3H, d, J = 6.4 Hz,
Me2CH), 1.10 (3H, d, J = 6.4 Hz, Me2CH), 0.93 (9H, s, SitBu),
0.10 (3H, s, SiMe), 0.09 (3H, s, SiMe); 13C-NMR (100 MHz,
CDCl3): 143.3, 138.0, 136.9, 136.5, 129.6, 128.4, 128.0, 127.8,
127.1, 125.0, 96.0, 71.3, 69.7, 67.7, 64.4, 48.6, 31.4, 26.0, 23.4,
21.4, 21.0, 18.5, -5.3, -5.4; HRMS m/z: calcd for C31H47NO6SSi
[M+Na]+: 612.2791; found: 612.2799.
1
(hexanes/EtOAc, 7 : 3); Yield: 0.090 g, 80%; H-NMR (400
MHz, CDCl3): 7.68 (2H, d, J = 8.0 Hz, Ph), 7.36-7.26 (7H, m,
Ph), 5.60 (1H, dd, J = 4.8 Hz, 4.8 Hz, C=CH), 4.96 (1H, dd, J =
5.6 Hz, 6.4 Hz, -NHTs), 4.85 (1H, dd, J = 5.Hz, 7.6 Hz, O-CH-
OMe), 4.50 (2H, dd, J = 11.6 Hz, 13.6 Hz, O-CH2Ph), 4.08 (1H,
d, J = 2.8 Hz, CH-O), 3.81-3.75 (2H, m, -CH2OTBS), 3.64-3.56
(3H, m, CH-O, CH2-N), 3.39 (3H, s, -OMe), 2.50 (1H, d, J = 17.2
Hz, CH-CH2-CH), 2.41 (3H, s, Ph-Me), 2.33-2.25 (1H, m, CH-
CH2-CH), 0.90 (9H, s, SitBu), 0.09 (3H, s, SiMe), 0.08 (3H, s, Si-
Me); 13C-NMR (100 MHz, CDCl3): 143.2, 137.7, 137.2, 134.3,
129.6, 128.5, 127.9, 127.1, 127.1, 100.6, 79.7, 78.6, 72.3, 63.6,
55.6, 50.4, 36.4, 29.6, 25.8, 21.4, 18.3, -5.3, -5.5; HRMS m/z:
calcd for C29H43NO6SSi [M+Na] +: 584.2478; found: 584.2479.
1,5-Anhydro-2-deoxy-4-O-benzyl-6-O-TBS-D-lyxo-hex-1-enitol
(3b): To a stirred solution of glycal 2b (11.8 g, 50 mmol, 1
equiv) in DMF (150 mL) at -15 °C was added imidazole (6.8 g,
100 mmol, 2.0 equiv) and TBS-Cl (7.8 g, 52 mmol, 1.05 equiv)
in parts under nitrogen atmosphere. After the addition, the
reaction mixture was allowed to warm to room temperature .The
progress of the reaction was monitored by TLC. After complete
consumption of the starting material, the reaction mixture was
concentrated in vacuo. The residue was then washed with water
and extracted with CH2Cl2 (2X300 mL). The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo. Flash
(2R,3S)-3-(Benzyloxy)-2-(TBS-oxymethyl)-7-(α/β)-butoxy-4-(N-p-
toluenesulfonamidomethyl)-2,3,6,7-tetrahydrooxepine (12b) To a
stirred solution of VCP 6 (0.072 g, 0.2 mmol, 1 equiv) in the
chosen alcohol (1 mL) as nucleophile at rt was added solid
chloramine-T (0.062 g, 0.22 mmol, 1.1 equiv) and
phenyltrimethylammonium tribromide (PTAB, 0.008 g, 0.02

8
Tetrahedron
ACCEPTED MANUSCRIPT
chromatography of the crude product provided the title
s, SiMe); 13C-NMR (100 MHz, CDCl3): 202.4, 137.0, 128.3,
compound in its pure form. Rf = 0.57 (hexanes/ EtOAc, 8 : 2);
Yield: 14.5 g, 83%; [α]25D= -10.44 (CHCl3, c = 1.7); IR (neat):
3422, 2955, 2930, 2885, 2858, 1647, 1252, 1233, 1110, 839, 778
127.9, 127.8, 81.8, 79.4, 71.8, 60.5, 58.1, 25.8, 24.2, 19.0, 18.1, -
5.5, -5.6; HRMS m/z: calcd for C20H30O4Si [M+Na] +: 385.1811;
found: 385.1814.
cm-1; H-NMR (400 MHz, CDCl3): 7.36-7.25 (5H, m, Ph), 6.31
1
1,5-Anhydro-2,3-di-deoxy-1,2-C-methylene-4-O-benzyl-6-O-TBS-
β-D-threo-hexityl-3-exo-methylene (7) To a stirred suspension of
(1H, d, J = 6.4 Hz, O-CH=), 4.76 (2H, s, O-CH2Ph), 4.71 (1H,
dd, J = 2.8 Hz, 6.0 Hz, C=CH), 4.33-4.30 (1H, m, CH-O), 4.00-
3.89 (3H, m, CH-O, CH2-OTBS), 3.80 (1H, dd, J = 6.4 Hz, 10.4
Hz, CH-O), 2.68 (1H, d, J = 10.0 Hz, OH), 0.91 (9H, s, SitBu),
0.08 (6H, s, SiMe2); 13C-NMR (100 MHz, CDCl3): 144.2, 137.9,
128.5, 127.9, 102.9, 76.4, 74.1, 72.7, 62.6, 61.0, 25.8, 18.2, -5.4;
phosphonium iodide (0.404 g, 1 mmol, 2 equiv) in THF (6 mL)
at -15 °C was added n-BuLi (1.6 M in hexanes, 0.57 mL, 0.90
mmol, 1.8 equiv) under nitrogen atmosphere. After the addition,
the reaction mixture was allowed to stir for 20 min. The
supernatant was cannulated into a solution of 5b (0.18 g, 0.5
mmol, 1 equiv) in THF (3 mL). The progress of the reaction was
monitored by TLC. After complete consumption of the starting
material, the reaction mixture was concentrated in vacuo. The
residue was then washed with water and extracted with CH2Cl2
(2X15 mL). The organic layer was dried over anhydrous Na2SO4
and concentrated in vacuo. Flash chromatography of the crude
product provided 7 in its pure form. Rf = 0.57 (hexanes/EtOAc, 8
: 2); Yield: 0.152 g, 84%; [α]25D= -71.21 (CHCl3, c = 3.0); IR
(neat): 2955, 2930, 2884, 2858, 1640, 1463, 1093, 1061, 836,
+
HRMS m/z: calcd for C19H30O4Si [M+Na] : 373.1811; found:
373.1812.
1,5-Anhydro-2-deoxy-4-O-benzyl-6-O-TBS-β-1,2-C-methylene-
D-lyxo-hexitol (4b) To a stirred solution of diethyl zinc (1M
solution in toluene, 7.5 mL, 7.5 mmol, 1.5 equiv) in DCM (15
mL) at -15 °C was added a solution of CH2I2 (2.3 g, 8.5 mmol,
1.7 equiv) in DCM (20 mL) drop wise under nitrogen
atmosphere. The solution was stirred for 20 min to form iodozinc
methyl iodide as a yellowish white precipitate. To the reaction
mixture a solution of glycal 2b (1.75 g, 5 mmol, 1 equiv) in
DCM (3X2 mL) was added at -15 °C. After the addition, the
reaction mixture was allowed to warm to room temperature .The
progress of the reaction was monitored by TLC. After complete
consumption of the starting material, the reaction mixture was
poured into ice-cold sat. NH4Cl solution and then washed with
water and extracted with CH2Cl2 (2X100 mL) The organic layer
was dried over anhydrous Na2SO4 and concentrated in vacuo.
Flash chromatography of the crude product provided 4b in its
pure form. Rf = 0.53 (hexanes/EtOAc, 8 : 2); Yield: 1.4 g, 76%;
[α]25D= -39.31 (CHCl3, c = 1.0); IR (neat): 3454, 2954, 2929,
777 cm-1; H-NMR (400 MHz, CDCl3): 7.33-7.23 (5H, m, Ph),
1
5.29 (1H, s, C=CH2), 5.01 (1H, s, C=CH2), 4.63 (1H, d, J = 12.0
Hz,O-CH2Ph), 4.30 (1H, d, J = 12.0 Hz,O-CH2Ph), 3.84-3.81
(2H, m, CH2-OTBS), 3.76-3.66 (2H, m, CH-O), 3.54 (1H, dd, J =
6.0 Hz, 7.2 Hz, CH-O), 1.66-1.60 (1H, m, CH-CH2), 1.21-1.17
(1H, m, CH-CH2-CH), 0.89-0.82 (1H, m, CH-CH2-CH), 0.87
(9H, s, SitBu), 0.04 (6H, s, SiMe) ; 13C-NMR (100 MHz, CDCl3):
139.7, 138.3, 128.2, 127.7, 127.3, 115.1, 79.0, 76.2, 68.9, 61.8,
53.7, 25.9, 18.2, 17.5, 16.2, -5.4, -5.5; HRMS m/z: calcd for
C21H32O3Si [M+Na] +: 383. 1820; found: 383.1835.
(2R,3R)-3-(Benzyloxy)-2-(TBS-oxymethyl)-7-(α/β)-methoxy-4-
(N-p-toluenesulfonamidomethyl)-2,3,6,7-tetrahydrooxepine (13a)
To a stirred solution of VCP 7 (0.072 g, 0.2 mmol, 1 equiv) in the
chosen alcohol (1 mL) as nucleophile at rt was added solid
chloramine-T (0.062 g, 0.22 mmol, 1.1 equiv) and
phenyltrimethylammonium tribromide (PTAB, 0.008 g, 0.02
mmol, 0.1 equiv). The reaction was monitored by TLC. After
complete conversion of the starting material and the intermediate
bromide, the reaction mixture was concentrated in vacuo, and
then washed with water (10 mL) extracted with DCM (2 X 10
mL). The organic layer was dried over anhyd. Na2SO4 and
concentrated in vacuo. Flash chromatography of the crude
product afforded the oxepane 13a in its pure form. Rf = 0.52
(hexanes/EtOAc, 8 : 2); Yield: 0.096 g, 86%;1H-NMR (400
MHz, CDCl3): 7.69 (2H, d, J = 8.0 Hz, Ph), 7.65 (2H, d, J = 8.0
Hz, Ph), 7.34-7.24 (15.4H, m, Ph), 5.73 (1H, dd, J = 3.2 Hz, 9.2
Hz, C=CH), 5.63 (1.1H, dd, J = 6.4 Hz, C=CH), 4.82 (1H, dd, J
= 6.0 Hz, 6.0 Hz, NH), 4.74 (1H, dd, J = 4.0 Hz, 6.4 Hz, O-CH-
O), 4.62-4.57 (4.2H, m, O-CH2Ph), 4.44 (d, J = 12.0 Hz, 1H, CH-
O), 4.13-4.08 (2.1H, m, CH-O), 3.97-3.93 (2.1H, m, CH2-
OTBS), 3.79 (1H, m, CH2-OTBS), 3.69-3.65 (1H, m, CH-O),
3.55-3.34 (5H, m, CH2-N), 3.40 (3H, s, OMe), 3.34 (3H, s,
OMe), 2.73-2.67 (1H, m, CH-CH2-CH), 2.63-2.55 (1H, m, CH-
CH2-CH), 2.41 (3H, s, Me), 2.40 (3H, s, Me), 2.35-2.26 (2.2H,
m, CH-CH2-CH), 0.91 (9H, s, SitBu), 0.90 (10H, s, SitBu), 0.08
(3H, s, SiMe), 0.07 (3H, s, SiMe); 13C-NMR (100 MHz, CDCl3):
143.4, 143.2, 138.5, 138.3, 137.2, 137.0, 136.8, 129.6, 128.5,
128.4, 128.2, 128.0, 127.7, 127.6, 127.4, 127.1, 127.0, 126.0,
104.2, 100.4, 79.4, 76.4, 75.1, 72.3, 71.5, 70.7, 62.9, 62.5, 55.5,
55.1, 50.2, 48.9, 35.4, 32.3, 25.9, 25.8, 21.4, 18.2, 18.2, -5.4,-5.5;
HRMS m/z: calcd for C29H43NO6SSi [M+Na] +: 584.2478; found:
584.2482.
2857, 2884, 1254, 1108, 838, 777 cm-1; H-NMR (400 MHz,
1
CDCl3): 7.35-7.26 (5H, m, Ph), 4.70 (1H, d, J = 11.6 Hz, O-
CH2Ph), 4.64 (1H, d, J = 11.6 Hz, O-CH2Ph), 4.20-4.14 (1H, m,
CH-O), 3.87 (1H, d, J = 5.2 Hz, CH-O), 3.77-3.70 (2H, m, CH2-
OTBS), 3.58 (1H, dd, J = 8.8 Hz, 8.8Hz, CH-O), 3.38 (1H, dd, J
= 5.6 Hz, 8.4 Hz, CH-O), 2.37 (1H, d, J = 10.8 Hz, OH), 1.27-
1.21 (1H, m, CH-CH2), 1.11-1.08 (1H, m, CH-CH2-CH), 0.90
(9H, s, SitBu), 0.62-0.57 (1H, m, CH-CH2-CH ), 0.06 (3H, s,
SiMe), 0.05 (3H, s, SiMe); 13C-NMR (100 MHz, CDCl3): 138.4,
128.4, 127.6, 127.4, 77.3, 76.0, 75.6, 65.4, 61.1, 54.0, 25.8, 18.1,
17.2, 11.2, -5.4, -5.5; HRMS m/z: calcd for C20H32O4Si [M+Na]
+: 387.1968; found: 387.1969.
1,5-Anhydro-2-deoxy-1,2-C-methylene-4-O-benzyl-6-O-TBS-β-
D-threo-hex-3-ulose (5b): To a stirred solution of cyclopropane
alcohol 4b (1.4 g, 3.85 mmol, 1 equiv) in CH2Cl2 (15 mL) at 0 °C
was added Dess–Martin periodinane (DMP) (1.8 g, 4.23 mmol,
1.1 equiv). The progress of the reaction was monitored by TLC.
After complete consumption of the starting material, the reaction
was quenched by adding 10% aqueous solution of Na2S2O3 (20
mL)/ sat. solution of NaHCO3 (aq) (10 mL) with vigorous
stirring. The aqueous layer was extracted with CH2Cl2 (3X50
mL). The combined organic layer was washed with sat. solution
of NaHCO3 (aq) and brine. The organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product provided the corresponding
cyclopropyl ketone in its pure form. Rf = 0.55 (hexanes/EtOAc, 8
: 2); Yield: 1.26 g, 90%; [α]25D= -137.07 (CHCl3, c = 3.0); IR
1
(neat): 2954, 2930, 2858, 2884, 1699, 1252, 1113, 838 cm-1; H-
NMR (400 MHz, CDCl3): 7.34-7.25 (5H, m, Ph), 4.62 (1H, d, J =
11.6 Hz, O-CH2Ph), 4.43 (1H, d, J = 11.6 Hz, O-CH2Ph), 4.14
(1H, dd, J = 5.2 Hz, 8.8 Hz, CH-O), 3.88 (1H, dd, J = 6.8 Hz, 6.8
Hz, CH-O), 3.72 (s, 2H), 3.70 (1H, s, CH-O), 1.89-1.85 (1H, m,
CH-CH2), 1.79-1.74 (1H, m, CH-CH2-CH), 1.26-1.21 (1H, m,
CH-CH2-CH), 0.85 (9H, s, SitBu), 0.03 (3H, s, SiMe), 0.02 (3H,
(2R,3R)-3-(Benzyloxy)-2-(TBS-oxymethyl)-7-(α/β)-butoxy-4-(N-
p-toluenesulfonamidomethyl)-2,3,6,7-tetrahydrooxepine (13b) To

9
a stirred solution of VCP 7 (0.072 g, 0.2 mmol, 1 equiv) in the
chosen alcohol (1 mL) as nucleophile at rt was added solid
chloramine-T (0.062 g, 0.22 mmol, 1.1 equiv) and
phenyltrimethylammonium tribromide (PTAB, 0.008 g, 0.02
mmol, 0.1 equiv). The reaction was monitored by TLC. After
complete conversion of the starting material and the intermediate
bromide, the reaction mixture was concentrated in vacuo, and
then washed with water (10 mL) extracted with DCM (2 X 10
mL). The organic layer was dried over anhyd. Na2SO4 and
concentrated in vacuo. Flash chromatography of the crude
product afforded the oxepane 13b in its pure form. Rf = 0.52
equiv) in DCM (50 mL) drop wise under nitrogen atmosphere.
ACCEPTED MANUSCRIPT
The solution was stirred for 20 min to form iodozinc methyl
iodide as a yellowish white precipitate. To the reaction mixture a
solution of glycal 2c (1.86 g, 10 mmol, 1 equiv) in DCM (3X2
mL) was added at -15 °C. After the addition, the reaction mixture
was allowed to warm to room temperature .The progress of the
reaction was monitored by TLC. After complete consumption of
the starting material, the reaction mixture was poured into ice-
cold sat. NH4Cl solution and then washed with water and
extracted with CH2Cl2 (2X150 mL). The organic layer was dried
over anhydrous Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product provided 3c in its pure
1
(hexanes/EtOAc, 8 : 2); Yield: 0.091 g, 75%; H-NMR (400
1
MHz, CDCl3): 7.68 (1.5H, d, J = 8.0 Hz, 1.5 Hz, Ph), 7.64 (2H,
d, J = 8.0 Hz, Ph), 7.33-7.25 (13.5H, m, Ph), 5.75 (0.7H, dd, J =
2.0 Hz, 8.4 Hz, C=CH), 5.62 (1H, dd, J = 6.0 Hz, 6.0 Hz,
C=CH), 4.84 (1H, dd, J = 4.0 Hz, 6.8 Hz, NH), 4.64-4.57 (3.6H,
m, O-CH-O, O-CH2Ph), 4.45 (0.8H, d, J = 7.6 Hz, CH-O), 4.38
(1H, dd, J = 7.6 Hz, 6.4 Hz, CH-O), 4.33 (1H, d, J = 8.8 Hz, CH-
O), 3.98 (1H, dd, J = 7.6 Hz, 7.6 Hz, CH-O), 3.96 (0.8H, s, CH-
O), 3.87-3.63 (5.7H, m, CH2-OTBS), 3.53 (1H, dd, J = 7.2 Hz,
14.0 Hz, CH-O), 3.44-3.30 (5H, m, CH2-N), 2.73 (0.7H, dd, J =
8.8 Hz, CH-CH2-CH), 2.52 (1H, ddd, J = 4.0 Hz, 6.8 Hz, 16Hz,
CH-CH2-CH), 2.42 (2H, s, Me), 2.41 (3H, s, Me), 2.38-2.27 (2H,
m, CH-CH2-CH), 1.58-1.49 (3.7H, m, CH-CH2-CH2), 1.37-1.32
(3.6H, m, CH2-CH2-CH3), 0.93-0.89 (22H, m, SitBu, CH2-Me),
0.08 (6H, s, SiMe), 0.07 (4H, s, SiMe); 13C-NMR (100 MHz,
CDCl3): 143.4, 143.2, 138.6, 138.3, 137.1, 137.0, 136.5, 129.6,
129.5, 128.4, 128.2, 128.1, 127.8, 127.7, 127.7, 127.4, 127.1,
127.1, 126.0, 103.2, 99.2, 79.5, 76.5, 75.2, 72.6, 71.3, 70.7, 67.9,
67.3, 63.0, 62.3, 50.3, 48.9, 35.7, 32.5, 31.6, 31.5, 25.9, 21.5,
19.4, 19.2, 18.2, 13.9, -5.4, -5.5; HRMS m/z: calcd for
C32H49NO6SSi [M+Na] +: 626.2948; found: 626.2944.
form. Rf = 0.53 (hexanes/EtOAc, 8 : 2); Yield: 1.72 g 86%; H-
NMR (400 MHz, CDCl3): 4.19 (1H, dd, J = 7.6 Hz, CH-O), 3.86
(1H, dd, J = 5.6 Hz, 10.8 Hz, CH-O), 3.80-3.76 (1H, m, CH-O),
3.53 (1H, dd, J = 10.4 Hz, 21.2 Hz, CH-O), 3.35 (1H, dd, J =
11.6 Hz, 18.0 Hz, CH-O), 3.26 (1H, td, J = 5.6 Hz, 10.0 Hz, CH-
O), 2.48 (1H, m, CH-CH2-CH), 1.47 (3H, s, Me), 1.46-1.40 (3H,
s, Me), 0.85-0.76 (2H, m, CH-CH2-CH); 13C-NMR (100 MHz,
CDCl3): 99.3, 74.6, 69.3, 68.6, 61.7, 54.6, 29.0, 19.0, 17.7, 11.7;
+
HRMS m/z: calcd for C10H16O4 [M+Na] : 223.0946; found:
223.0946.
1,5-Anhydro-2-deoxy-4,6-O-isopropylidene-1,2-C-methylene-β-
D-erythro-hex-3-ulose (4c) To a stirred solution of cyclopropane
alcohol 4b (1.72 g, 8.6 mmol, 1 equiv) in CH2Cl2 (45 mL) at 0 °C
was added Dess–Martin periodinane (DMP) (4.0 g, 9.5 mmol, 1.1
equiv). The progress of the reaction was monitored by TLC.
After complete consumption of the starting material, the reaction
was quenched by adding 10% aqueous solution of Na2S2O3 (20
mL)/ sat. solution of NaHCO3 (aq) (20 mL) with vigorous
stirring. The aqueous layer was extracted with CH2Cl2 (3X100
mL). The combined organic layer was washed with sat. solution
of NaHCO3 (aq) and brine. The organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product provided the corresponding
cyclopropyl ketone in its pure form. Rf = 0.56 (hexanes/EtOAc, 8
(2R,3R)-3-(Benzyloxy)-2-(TBS-oxymethyl)-7-(α/β)-isopropoxy-4-
(N-p-toluenesulfonamidomethyl)-2,3,6,7-tetrahydrooxepine (13c)
To a stirred solution of VCP 7 (0.072 g, 0.2 mmol, 1 equiv) in the
chosen alcohol (1 mL) as nucleophile at rt was added solid
chloramine-T (0.062 g, 0.22 mmol, 1.1 equiv) and
phenyltrimethylammonium tribromide (PTAB, 0.008 g, 0.02
mmol, 0.1 equiv). The reaction was monitored by TLC. After
complete conversion of the starting material and the intermediate
bromide, the reaction mixture was concentrated in vacuo, and
then washed with water (10 mL) extracted with DCM (2 X 10
mL). The organic layer was dried over anhyd. Na2SO4 and
concentrated in vacuo. Flash chromatography of the crude
product afforded the oxepane 13c in its pure form. Rf = 0.55
1
: 2); Yield: 1.36 g, 80%; [α]25D= -97.91 (CHCl3, c = 3.0); H-
NMR (400 MHz, CDCl3): 4.21 (1H, dd, J = 5.2 Hz, 9.2 Hz, CH-
O), 4.11 (d, 1H, J = 10.0 Hz, CH-O), 3.95 (1H, dd, J = 5.2 Hz,
10.4 Hz, CH-O), 3.84 (1H, td, J = 5.2 Hz, 10.0 Hz, CH-O), 3.75-
3.70 (1H, m, CH-O), 1.97-1.91 (1H, m, CH-CH2), 1.49 (3H, s,
Me), 1.48 (3H, s, Me), 1.44-1.36 (2H, m, CH-CH2-CH); 13C-
NMR (100 MHz, CDCl3): 200.2, 100.0, 74.3, 73.5, 61.8, 59.0,
28.6, 25.4, 20.5, 18.5; HRMS m/z: calcd for C10H14O4 [M+Na] +:
221.0790; found: 221.0791.
1
(hexanes/EtOAc, 8 : 2); Yield: 0.096 g, 81%; H-NMR (400
1,5-Anhydro-2,3-deoxy-4,6-O-isopropylidene-1,2-C-methylene-β-
MHz, CDCl3): 7.68 (2H,d, J = 8.0 Hz, 1 Hz, Ph), 7.64 (2H d, J =
8.0 Hz, Ph), 7.35-7.25 (12H, m, Ph), 5.75 (0.6H, d, J = 8.0 Hz,
C=CH), 5.63-5.58 (1H, m, C=CH), 4.97-4.94 (1H, m, NH), 4.68-
4.57 (3H, m, NH, O-CH2Ph), 4.47-4.42 (0.7H, m, O-CH2Ph),
4.36-4.31 (1H, m, O-CH2Ph), 4.14-4.10 (1H, m, CH-O), 4.03-
3.91 (3H, m, CH-O, CH2-OTBS), 3.82-3.62 (3H, m, CH2-N),
3.56-3.51 (1H, m, CH2-N), 3.45-3.40 (2H, m, O-CHMe2), 2.49-
2.22 (2H, m, CH-CH2-CH), 2.41 (5H, s, Me), 1.20-1.07 (10H, m,
Me2), 0.93 (9H, s, SitBu), 0.91 (6H, s, SitBu), 0.09 (6H, s, SiMe),
0.07 (3.7H, s, SiMe); 13C-NMR (100 MHz, CDCl3): 143.2, 138.6,
138.3, 137.1, 136.4, 129.6, 129.5, 128.4, 128.2, 128.1, 127.7,
127.4, 127.1, 125.9, 100.7, 96.7, 79.7, 75.3, 72.7, 71.2, 70.7,
68.5, 67.9, 63.2, 62.2, 50.3, 48.9, 36.2, 32.9, 25.9, 23.4, 21.4,
21.1, 18.2, -5.5; HRMS m/z: calcd for C31H47NO6SSi [M+Na]+:
612.2791; found: 612.2790.
D
-erythro-hexityl-exo-3-methylene (8) To a stirred suspension of
phosphonium iodide (0.404 g, 1 mmol, 2 equiv) in THF (6 mL)
at -15 °C was added n-BuLi (1.6 M in hexanes, 0.57 mL, 0.90
mmol, 1.8 equiv) under nitrogen atmosphere. After the addition,
the reaction mixture was allowed to stir for 20 min. The
supernatant was cannulated into a solution of 4c (0.1 g, 0.5
mmol, 1 equiv) in THF (3 mL). The progress of the reaction was
monitored by TLC. After complete consumption of the starting
material, the reaction mixture was concentrated in vacuo. The
residue was then washed with water and extracted with CH2Cl2
(2X15 mL). The organic layer was dried over anhydrous Na2SO4
and concentrated in vacuo. Flash chromatography of the crude
product provided the corresponding VCP 8 in its pure form. Rf =
0.59 (hexanes/EtOAc, 8 : 2); Yield: 0.082 g, 84%; [α]25D= -97.91
1
(CHCl3, c = 3.0); H-NMR (400 MHz, CDCl3): 5.11 (2H, d, J =
1,5-Anhydro-2-deoxy-4,6-O-isopropylidene-β-1,2-C-methylene-
8.4 Hz, C=CH2), 3.93 (1H, d, J = 10.0 Hz, CH-O), 3.87 (1H, dd,
J = 9.2 Hz, 10.8 Hz, CH-O), 3.81 (1H, td, J = 2.8 Hz, 6.4 Hz,
CH-O), 3.59 (1H, dd, J = 10.4 Hz, CH-O), 3.34 (1H, td, J = 5.6
Hz, 10.0 Hz, CH-O), 1.84-1.78 (1H, m, CH-CH2), 1.49 (s, 3H),
D-arabino-hexitol (3c) To a stirred solution of diethyl zinc (1M
solution in toluene, 15 mL, 15.0 mmol, 1.5 equiv) in DCM (30
mL) at -15 °C was added a solution of CH2I2 (4.6 g, 17 mmol, 1.7

10
Tetrahedron
ACCEPTED MANUSCRIPT
1.43 (s, 3H), 0.96-0.91 (m, 1H), 0.84-0.80 (m, 1H); 13C-NMR
monitored by TLC. After complete conversion of the starting
(100 MHz, CDCl3): 141.6, 106.8, 99.2, 71.8, 70.2, 62.4, 54.2,
29.0, 19.7, 18.9, 16.3; HRMS m/z: calcd for C11H16O3 [M+Na] +:
219.0997; found: 219.1001.
material and the intermediate bromide, the reaction mixture was
concentrated in vacuo, and then washed with water (10 mL)
extracted with DCM (2 X 10 mL). The organic layer was dried
over anhyd. Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product afforded 14c in its pure
(4aR,9aS)-6-(α/β)-Methoxy-2,2-dimethyl-9-(N-p-toluenesulf
amidomethyl)-4a,6,7,9a-tetrahydro-4H-[1,3]dioxino[5,4-
1
form.Rf = 0.51 (hexanes/EtOAc, 8 : 2); Yield: 0.070 g 82%; H-
b]oxepine (14a) To a stirred solution of VCP 8 (0.039 g, 0.2
mmol, 1 equiv) in the chosen alcohol (1 mL) as nucleophile at rt
was added solid chloramine-T (0.062 g, 0.22 mmol, 1.1 equiv)
and phenyltrimethylammonium tribromide (PTAB, 0.008 g, 0.02
mmol, 0.1 equiv). The reaction was monitored by TLC. After
complete conversion of the starting material and the intermediate
bromide, the reaction mixture was concentrated in vacuo, and
then washed with water (10 mL) extracted with DCM (2 X 10
mL). The organic layer was dried over anhyd. Na2SO4 and
concentrated in vacuo. Flash chromatography of the crude
product afforded the oxepane 14a in its pure form. Rf = 0.54
NMR (400 MHz, CDCl3): 7.71 (2H, d, J = 8.0 Hz, Ph), 7.30 (2H,
d, J = 8.0 Hz, Ph), 5.55-5.53 (1H, m, C=CH), 4.97 (1H, dd, J =
6.8 Hz, 6.8 Hz, NH), 4.28-4.23 (2H, m, CH2-OTBS), 3.87-3.58
(4H, m, CH2-N, CH-O), 3.14 (1H, td, J = 6.0 Hz, 9.2 Hz, CH-O),
2.42 (3H, s, Me), 2.26-2.21 (2H, m, CH-CH2-CH), 1.40 (3H, s,
Me), 1.38 (3H, s, Me), 1.17 (3H, d, J = 6.4 Hz, MeCH), 1.10
(3H, d, J = 6.4 Hz, MeCH); 13C-NMR (100 MHz, CDCl3): 143.0,
138.5, 138.0, 129.4, 127.2, 124.3, 99.8, 98.4, 73.7, 70.8, 69.6,
62.4, 48.0, 36.0, 28.5, 23.4, 21.4, 18.7; HRMS m/z: calcd for
C21H31NO6S [M+Na] +: 448.1770; found: 448.1770.
1
(hexanes/EtOAc, 8 : 2); Yield: 0.066 g, 85%; H-NMR (400
1,5-Anhydro-2,3-deoxy-4,6-O-di-tert-butylsilyl-1,2-C-methylene-
MHz, CDCl3): 7.21 (2H, d, J = 8.0 Hz, Ph), 7.30 (2H, d, J = 8.0
Hz, Ph), 5.55-5.54 (1H, m, C=CH), 4.97 (1H, dd, J = 6.0 Hz, 6.0
Hz, NH), 4.25 (1H, d, J = 8.8 Hz, O-CH-O), 4.10 (1H, d, J = 7.2
Hz, CH2-O), 3.82 (1H, dd, J = 5.6 Hz, 11.6 Hz, CH-O), 3.73 (1H,
dd, J = 8.0 Hz, 14.0 Hz, CH-O), 3.67-3.58 (2H, m, CH2-N), 3.35
(3H, s, OMe), 3.20 (1H, td, J 6.4 Hz, 9.2 Hz, CH-O), 2.43 (3H, s,
Me), 2.32-2.20 (2H, m, CH2), 1.41 (3H, s, Me), 1.38 (3H, s, Me);
13C-NMR (100 MHz, CDCl3): 143.1, 138.5, 138.0, 129.4, 127.2,
123.9, 102.8, 98.5, 73.6, 70.8, 62.3, 55.6, 47.9, 35.1, 28.4, 21.4,
β- D-threo-hexityl-exo-3-methylene (9) To a stirred suspension of
phosphonium iodide (0.404 g, 1 mmol, 2 equiv) in THF (6 mL)
at -15 °C was added n-BuLi (1.6 M in hexanes, 0.57 mL, 0.90
mmol, 1.8 equiv) under nitrogen atmosphere. After the addition,
the reaction mixture was allowed to stir for 20 min. The
supernatant was cannulated into a solution of 4d (0.15 g, 0.5
mmol, 1 equiv) in THF (3 mL). The progress of the reaction was
monitored by TLC. After complete consumption of the starting
material, the reaction mixture was concentrated in vacuo. The
residue was then washed with water and extracted with CH2Cl2
(2X15 mL). The organic layer was dried over anhydrous Na2SO4
and concentrated in vacuo. Flash chromatography of the crude
product provided 9 in its pure form. Rf = 0.52 (hexanes/EtOAc, 8
+
18.7; HRMS m/z: calcd for C19H27NO6S [M+Na] : 420.1457;
found: 420.1457.
(4aR,9aS)-6-(α/β)-Butoxy-2,2-dimethyl-9-(N-p-
toluenesulfamidomethyl)-4a,6,7,9a-tetrahydro-4H-
1
: 2); Yield: 0.122 g, 83%; [α]25D= -29.11° (CHCl3, c = 1.8); H-
[1,3]dioxino[5,4-b]oxepine (14b) To a stirred solution of VCP 8
(0.039 g, 0.2 mmol, 1 equiv) in the chosen alcohol (1 mL) as
nucleophile at rt was added solid chloramine-T (0.062 g, 0.22
mmol, 1.1 equiv) and phenyltrimethylammonium tribromide
(PTAB, 0.008 g, 0.02 mmol, 0.1 equiv). The reaction was
monitored by TLC. After complete conversion of the starting
material and the intermediate bromide, the reaction mixture was
concentrated in vacuo, and then washed with water (10 mL)
extracted with DCM (2 X 10 mL). The organic layer was dried
over anhyd. Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product afforded 14b in its pure
NMR (400 MHz, CDCl3): 5.22 (1H, s, C=CH2), 5.15 (1H, s,
C=CH2), 4.56 (1H, s, CH-O), 4.23-4.15 (2H, m, CH2OSi), 3.85
(1H, td, J = 2.8 Hz, 6.0 Hz, CH-O), 3.42 (1H, s, CH-O), 1.57
(1H, dt, J = 6.4 Hz, 10.4 Hz, CH-CH2), 1.32 (1H, td, J = 3.2 Hz,
6.4 Hz, CH-CH2-CH), 1.06 (9H, s, SitBu), 1.04 (9H, s, SitBu),
0.95-0.88 (1H, m, CH-CH2-CH); 13C-NMR (100 MHz, CDCl3):
142.7, 114.8, 75.1, 74.4, 67.6, 53.9, 27.7, 27.5, 23.3, 20.5, 16.1,
+
15.6; HRMS m/z: calcd for C16H28O3Si [M+Na] : 319.1705;
found: 319.1705.
(4aR,9aR)-2,2-Di-tert-butyl-6-methoxy-9-(N-p-
toluenesulfonamidomethyl)-4a,6,7,9a-tetrahydro-4H-
1
form. Rf = 0.50 (hexanes/EtOAc, 8 : 2); Yield: 0.068 g, 78%; H-
NMR (400 MHz, CDCl3): 7.71 (2.6H, d, J = 8.0 Hz, Ph), 7.30
(2.6H, d, J = 8.0 Hz, Ph), 5.56-5.53 (1.3H, m, C=CH), 4.94 (1H,
dd, J = 6.0 Hz, 6.0 Hz, NH), 4.25 (1H, d, J = 8.8 Hz, O-CH-O),
4.21 (1H, d, J = 8.8 Hz, CH-O), 4.16 (1H, dd, J = 4.8 Hz, 4.8 Hz,
CH-O), 3.82-3.77 (1.3H, m, CH-O), 3.75-3.68 (2.6H, m, CH2-
OTBS), 3.67-3.58 (2.6H, m, CH2-N), 3.33-3.27 (1.3H, m, CH-O),
3.15 (1H, td, J = 6.0 Hz, 9.2 Hz, CH-O), 2.43 (4H, s, Me), 2.26
(2.2H, dd, J = 6.0 Hz, 6.0 Hz, CH-CH2-CH2), 1.55 (2H, m, CH2-
CH2), 1.42-1.32 (11H, m, Me2), 0.91 (4H, t, J = 7.2 Hz, CH2-
CH3); 13C-NMR (100 MHz, CDCl3): 143.1, 138.5, 138.0, 129.4,
127.2, 124.2, 123.9, 101.9, 98.7, 98.4, 74.0, 73.7, 70.7, 68.3,
67.6, 63.1, 62.4, 48.0, 47.5, 35.5, 33.0, 31.5, 28.5, 21.4, 19.2,
[1,3,2]dioxasilino[5,4-b]oxepine (15a) To a stirred solution of
VCP 9 (0.072 g, 0.2 mmol, 1 equiv) in the chosen alcohol (1 mL)
as nucleophile at rt was added solid chloramine-T (0.060 g, 0.22
mmol, 1.1 equiv) and phenyltrimethylammonium tribromide
(PTAB, 0.008 g, 0.02 mmol, 0.1 equiv). The reaction was
monitored by TLC. After complete conversion of the starting
material and the intermediate bromide, the reaction mixture was
concentrated in vacuo, and then washed with water (10 mL)
extracted with DCM (2 X 10 mL). The organic layer was dried
over anhyd. Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product afforded the oxepane 15a in
its pure form. Rf = 0.54 (hexanes/EtOAc, 8 : 2); Yield: 0.089g
92%; IR (neat): 3278, 2934, 2860, 1462, 1329, 1161, 1064, 898,
+
18.9, 18.7, 13.7; HRMS m/z: calcd for C22H33NO6S [M+Na] :
462.1926; found: 462.1926.
1
781 cm-1; H-NMR (400 MHz, CDCl3): 7.75-7.72 (2.5H, m, Ph),
7.32-7.30 (2.5H, m, Ph), 5.53 (1H, dd, J = 2.8 Hz, 8.4 Hz,
C=CH), 5.52-5.48 (0.3H, m, NH), 5.03 (0.3H, dd, J = 4.0 Hz, 6.8
Hz, O-CH-O), 4.96-4.93 (1H, m, O-CH-O), 4.68 (0.3H, dd, J =
4.8 Hz, .4 Hz, CH-O), 4.64 (0.3H, s, CH-O), 4.56 (1H, s, CH-O),
4.30 (1H, d, J = 8.4 Hz, CH2-OTBS), 4.28 (0.3H d, J = 8.4 Hz,
CH-O), 4.24-4.10 (3H, m, OCH2), 3.75 (0.3H, dd, J = 8.0 Hz, 9.2
Hz, CH-O), 3.66 (1H, dd, J = 7.2 Hz, 13.2 Hz, CH-O), 3.50 (1H,
dd, J = 4.0 Hz, 13.6 Hz,CH2-N), 3.39 (3H, s, OMe), 3.35 (0.9H,
(4aR,9aS)-6-(α/β)-Isopropoxy-2,2-dimethyl-9-(N-p-
toluenesulfamidomethyl)-4a,6,7,9a-tetrahydro-4H-
[1,3]dioxino[5,4-b]oxepine (14c) To a stirred solution of VCP 8
(0.039 g, 0.2 mmol, 1 equiv) in the chosen alcohol (1 mL) as
nucleophile at rt was added solid chloramine-T (0.062 g, 0.22
mmol, 1.1 equiv) and phenyltrimethylammonium tribromide
(PTAB, 0.008 g, 0.02 mmol, 0.1 equiv). The reaction was

11
s, OMe), 2.55 (1H, dd, J = 8.8 Hz, 16.4 Hz, CH-CH2-CH), 2.43
(3.9H, s, Me), 2.30 (1.3H, dd, J= 8.0 Hz, 16.0 Hz, CH-CH2-CH),
1.04-1.01 (23H, m, SitBu2); 13C-NMR (100 MHz, CDCl3): 143.4,
136.8, 136.7, 129.6, 129.5, 127.2, 126.5, 104.7, 101.3, 75.0, 74.7,
68.9, 69.5, 67.4, 60.3, 55.3, 55.0, 50.9, 35.5, 30.9, 27.4, 27.1,
23.3, 21.4, 20.9, 14.1; HRMS m/z: calcd for C24H39NO6SSi
[M+Na] +: 520.2165; found: 520.2164.
CH), 1.20 (3H, d, J = 6.0 Hz, MeCH), 1.16 (1.5H, d, J = 6.0
ACCEPTED MANUSCRIPT
Hz, MeCH), 1.10 (4.5H, d, J = 6.0 Hz, MeCH), 1.05 (9H, s,
SitBu2), 1.04 (9H, s, SitBu2), 1.02 (4.5H, s, SitBu2), 1.00 (4.5H, s,
SitBu2); 13C-NMR (100 MHz, CDCl3): 143.4, 137.2, 136.9,
136.8, 136.5, 129.6, 129.5, 127.2, 127.2, 127.1, 123.5, 101.6,
97.9, 75.0, 74.7, 69.2, 69.1, 68.5, 68.5, 67.2, 51.1, 48.7, 36.2,
31.4, 29.6, 27.5, 27.4, 27.2, 23.6, 23.4, 23.3, 23.2, 21.6, 21.5,
+
21.0, 20.6; HRMS m/z: calcd for C26H43NO6SSi [M+Na] :
(4aR,9aR)-2,2-Di-tert-butyl-6-butoxy-9-(N-p-
toluenesulfonamidomethyl)-4a,6,7,9a-tetrahydro-4H-
548.2478; found: 548.2480.
[1,3,2]dioxasilino[5,4-b]oxepine (15b) To a stirred solution of
VCP 9 (0.072 g, 0.2 mmol, 1 equiv) in the chosen alcohol (1 mL)
as nucleophile at rt was added solid chloramine-T (0.060 g, 0.22
mmol, 1.1 equiv) and phenyltrimethylammonium tribromide
(PTAB, 0.008 g, 0.02 mmol, 0.1 equiv). The reaction was
monitored by TLC. After complete conversion of the starting
material and the intermediate bromide, the reaction mixture was
concentrated in vacuo, and then washed with water (10 mL)
extracted with DCM (2 X 10 mL). The organic layer was dried
over anhyd. Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product afforded the oxepane 15b
in its pure form. Rf = 0.52 (hexanes/EtOAc, 8 : 2); Yield: 0.088 g,
84%; IR (neat): 3289, 2934, 2860, 1473, 1337, 1161, 1038, 904
1,5-Anhydro-2-deoxy-1,2-C-(exo-carbmethoxymethylene)-3,6-O-
di-TBS-4-O-benzyl-α-
D-arabino-hexitol (16a): To a stirred
solution of glucal (3.0 g, 6.4 mmol, 1 equiv) in DCM (100 mL)
at room temperature was added Rh2(OAc)4 (0.141 g, 0.32 mmol,
0.05 equiv) and allowed to stir under nitrogen atmosphere. A
solution of methyldiazoacetate (0.96 g, 9.6 mmol, 1.5 equiv) in
DCM (70 mL) was added drop wise using a dropping funnel
under nitrogen atmosphere. After the addition, the reaction
mixture was allowed to stir for 6 h. The progress of the reaction
was monitored by TLC. After complete consumption of the
starting material, the reaction mixture was concentrated in vacuo.
Flash chromatography of the crude product provided the
cyclopropyl ester 16a in its pure form. Rf = 0.53 (hexanes/EtOAc,
8 : 2); Yield: 1.98 g, 73%; [α]25D= +31.95 (CHCl3, c = 1.7) IR
(neat): 2954, 2930, 2858, 1729, 1257, 1122, 1096, 837, 777 cm-1;
1H-NMR (400 MHz, CDCl3): 7.35-7.28 (5H, m, Ph), 4.64 (2H,
dd, J = 11.6 Hz, 23.2 Hz, PhCH2O), 3.95 (1H, dd, J = 2.0 Hz, 5.6
Hz, CH-O), 3.90-3.85 (2H, m, CH-O), 3.68-3.60 (2H, m, CH2O),
3.66 (3H, s, OMe), 3.40 (1H, dd, J = 5.6 Hz, 5.6 Hz, CH-O), 2.03
(1H, dd, J = 1.6 Hz, 6.0 Hz, CH), 1.68-1.65 (1H, m, CH), 0.90
(18H, s, SitBu), 0.06 (12H, s, SiMe); 13C-NMR (100 MHz,
CDCl3): 172.2, 138.1, 128.3, 127.7, 127.6, 73.0, 69.3, 62.8, 57.1,
51.7, 28.1, 25.9, 25.3, 18.3, 17.8, -5.3, -5.4; HRMS m/z: calcd for
C28H48O6Si2 [M+Na] +: 559.2887; found: 559.2889.
1
cm-1; H-NMR (400 MHz, CDCl3): 7.75-7.72 (3.3H, m, Ph),
7.14-7.28 (3.3H, m, Ph), 5.53 (1H, dd, J = 2.4 Hz, 8.0 Hz,
C=CH), 5.49 (0.7H, dd, J = 4.0 Hz, 8.8 Hz, C=CH), 5.04 (0.7H,
dd, J = 4.0 Hz, 6.4 Hz, NH), 4.98-4.90 (1H, m, NH), 4.77 (0.7H,
dd, J = 4.4 Hz, 8.4 Hz, O-CH-O), 4.64 (0.7H, s, CH-O), 4.55
(1H, s, CH-O), 4.37 (1H, d, J = 8.4 Hz, CH-O), 4.26-4.15 (2.8H,
m, CH2-OTBS), 4.07-4.04 (0.7H, m, CH-O), 3.93 (0.7H, s, CH-
O), 3.81-3.62 (3.5H, m, CH2-N), 3.53-3.49 (1.6H, m, CH-O),
3.40-3.33 (2.6H, m, CH2), 2.60-2.55 (1.6H, m, CH-CH2-CH),
2.43 (3H, s, Me), 2.42 (2.5H, s, Me), 2.31-2.22 (1.7H, m, CH-
CH2-CH), 1.57-1.48 (3.5H, m, CH2-CH2), 1.41-1.29 (4.3H, m,
CH2-CH2), 1.04-1.01 (30H, s, SitBu2), 0.91 (5H, t, J = 7.2 Hz,
CH2-CH3); 13C-NMR (100 MHz, CDCl3): 143.4, 143.2, 137.2,
136.9, 136.8, 129.6, 129.5, 127.2, 126.8, 123.5, 103.4, 99.9, 76.8,
75.0, 74.7, 69.0, 68.5, 67.5, 60.3, 51.0, 48.7, 35.7, 31.6, 31.6,
31.1, 27.5, 27.4, 27.2, 23.3, 23.2, 21.5, 21.0, 20.6, 19.3, 14.1,
1,5-Anhydro-2-deoxy-1,2-C-(exo-carbmethoxymethylene)-4-O-
benzyl-α-
D-arabino-hexitol (16b): To a stirred solution of
protected sugar 16a (1.98 g, 3.5 mmol, 1 equiv) in THF (25 mL)
was added a 1 M solution of TBAF (5.2 mL, 5.2 mmol, 1.5
equiv) in THF at 0 °C. The reaction was monitored by TLC.
After complete conversion of the starting material, the reaction
mixture was washed with water (50 mL) and extracted with
DCM (2 X 80 mL). The organic layer was dried over anhyd.
Na2SO4 and concentrated in vacuo. Flash chromatography of the
crude product afforded the desired deprotected product in its pure
form. Rf = 0.54 (hexanes/EtOAc, 8 : 2); Yield: 1.37 g, 93%;
[α]25D= +28.15 (CHCl3, c = 3.2) IR (neat): 3247, 3029, 2953,
+
13.8, 13.7; HRMS m/z: calcd for C27H45NO6SSi [M+Na] :
562.2634; found: 562.2678.
(4aR,9aR)-2,2-Di-tert-butyl-6-isopropoxy-9-(N-p-toluenesulfon
amidomethyl)-4a,6,7,9a-tetrahydro-4H-[1,3,2]dioxasilino[5,4-
b]oxepine (15c) To a stirred solution of VCP 9 (0.072 g, 0.2
mmol, 1 equiv) in the chosen alcohol (1 mL) as nucleophile at rt
was added solid chloramine-T (0.060 g, 0.22 mmol, 1.1 equiv)
and phenyltrimethylammonium tribromide (PTAB, 0.008 g, 0.02
mmol, 0.1 equiv). The reaction was monitored by TLC. After
complete conversion of the starting material and the intermediate
bromide, the reaction mixture was concentrated in vacuo, and
then washed with water (10 mL) extracted with DCM (2 X 10
mL). The organic layer was dried over anhyd. Na2SO4 and
concentrated in vacuo. Flash chromatography of the crude
product afforded the oxepane 15c in its pure form. Rf = 0.56
(hexanes/EtOAc, 8 : 2); Yield: 0.091 g, 87%; IR (neat): 3283,
2969, 2860, 1474, 1332, 1161, 1035, 902, 825, 780, 651 cm-1;
1H-NMR (400 MHz, CDCl3): 7.75-7.72 (3H, m, Ph), 7.32-7.28
(3H, m, Ph), 5.53 (1H, dd, J = 4.4 Hz, 9.2 Hz, C=CH), 5.49
(0.5H, dd, J = 4.4 Hz, 9.2 Hz, C=CH), 5.05-4.82(2H, m, NH),
4.64 (0.5H, s, O-CH-O), 4.53 (1H, s, O-CH-O), 4.47 (1H, d, J =
8.4 Hz, CH-O), 4.25-4.04 (3H, m, CH2O), 3.97-3.87 (2H, m, CH-
O), 3.73 (0.5H, dd, J = 8.0Hz, 13.2 Hz, CH-O), 3.64 (1H, dd, J =
6.8 Hz, 13.2 Hz, CH2-N), 3.55-3.51 (1H, m, CH2-N), 3.51-3.44
(0.5H, s, CH-O), 3.36 (1H, s, CH-O), 2.58 (1H, dd, J = 9.6 Hz,
20 Hz, CH-CH2-CH), 2.43 (3H, s, Me), 2.42 (2H, s, Me), 2.24
(1H, dd, J = 8.4 Hz, 16.8 Hz, CH-CH2-CH), 2.20-2.16 (0.5H, m,
1
1725, 1599, 1443, 1297, 1089, 748 cm-1; H-NMR (400 MHz,
CDCl3): 7.34-7.21 (5H, m, Ph), 4.65 (2H, dd, J = 11.6 Hz, 16.0
Hz, PhCH2O), 4.03 (1H, d, J = 5.2 Hz, CH-O), 3.97 (1H, dd, J =
1.6 Hz, 7.2 Hz, CH-O), 3.80-3.72 (2H, m, CH2OH), 3.64 (3H, s,
OMe), 3.54 (1H, dd, J = 5.2 Hz, 9.6 Hz, CH-O), 3.39 (1H, dd, J
= 5.6 Hz, CH-O), 2.12 (1H, dd, J = 1.6 Hz, 6.4 Hz, CH), 1.75
(1H, dd, J = 6.4 Hz, 6.4 Hz, OH); 13C-NMR (100 MHz, CDCl3):
172.5, 137.8, 128.5, 127.9, 127.8, 77.4, 73.9, 73.0, 67.4, 62.2,
57.9, 51.9, 26.5, 23.7; HR-MS m/z: calcd for C16H20O6 [M+Na] +:
331.1158; found: 331.1155.
1,5-Anhydro-2-deoxy-1,2-C-(exo-carbmethoxymethylene)-4-O-
benzyl-6-O-TBS-α- D-arabino-hexitol (16c): To a stirred solution
of 16b (0.9 g, 2.9 mmol, 1 equiv) in DMF (10 mL) at -15 °C was
added imidazole (1 mmol, 5.8 equiv) and TBS-Cl (3.0 mmol,
1.05 equiv) in parts under nitrogen atmosphere. After the
addition, the reaction mixture was allowed to warm to room
temperature .The progress of the reaction was monitored by TLC.
After complete consumption of the starting material, the reaction
mixture was concentrated in vacuo. The residue was then washed

12
Tetrahedron
with water and extracted with CH2Cl2 (3X20 mL). The
2.37 (1H, dd, J = 6.4 Hz, 6.4 Hz, CH-CO), 0.82 (9H, s, SitBu),
ACCEPTED MANUSCRIPT
organic layer was dried over anhydrous Na2SO4 and concentrated
in vacuo. Flash chromatography of the crude product provided
the corresponding mono-O-TBS protected compound in its pure
form. Rf = 0.51 (hexanes/EtOAc, 8 : 2); Yield: 1.1 g, 91%;
[α]25D= -32.08 (CHCl3, c = 0.6) IR (neat): 3451, 2954, 2930,
0.01 (3H, s, SiMe), 0.00 (3H, s, SiMe) ; 13C-NMR (100 MHz,
CDCl3): 172.0, 137.7, 133.4, 128.4, 127.8, 127.5, 119.4, 75.9,
69.3, 61.5, 57.7, 51.8, 29.4, 27.9, 25.7, 18.0, -5.5, -5.6; HRMS
m/z: calcd for C23H34O5Si [M+Na] +: 441.2073; found: 441.2073.
1,5-Anhydro-2-deoxy-1,2-C-(exo-carbmethoxymethylene)-3-O-
TBS-4,6-O-isopropylidene-α-D-arabino-hexitol (17a) To a stirred
2858, 1726, 1120, 1095, 837 cm-1; H-NMR (400 MHz, CDCl3):
1
7.37-7.27 (5H, m, Ph), 4.65 (2H, d, J = 12.4 Hz, 12.4 Hz,
PhCH2O), 3.98 (1H, d, J = 4.8 Hz, CH-O), 3.94 (1H, d, J = 7.2
Hz, CH-O), 3.87-3.78 (3H, m, CH2O), 3.64 (3H, s, OMe), 3.59
(1H, d, J = 3.6 Hz, 7.6 Hz, CH-O), 3.50 (1H, dd, J = 5.2 Hz, 5.2
Hz, CH-O), 2.09 (1H, dd, J = 1.2 Hz, 5.6 Hz, CH), 1.78 (1H, dd,
J = 6.8 Hz, 6.8 Hz, OH), 0.92 (9H, s, SitBu), 0.12 (3H, s, SiMe),
0.10 (3H, s, SiMe); 13C-NMR (100 MHz, CDCl3): 172.2, 137.9,
128.5, 127.8, 127.7, 78.1, 74.9, 72.7, 66.6, 63.9, 57.9, 51.7, 26.9,
25.7, 24.9, 18.2, -5.3, -5.6; HRMS m/z: calcd for C22H34O6Si
[M+Na] +: 445.2022; found: 445.2021.
solution of glucal (1.50 g, 5 mmol, 1 equiv) in DCM (10 mL) at
room temperature was added Rh2(OAc)4 (0.11 g, 0.25 mmol, 0.05
equiv) and allowed to stir under nitrogen atmosphere. A solution
of methyldiazoacetate (0.75 g, 7.5 mmol, 1.5 equiv) in DCM (10
mL) was added drop wise using a dropping funnel under nitrogen
atmosphere. After the addition, the reaction mixture was allowed
to stir for 6 h. The progress of the reaction was monitored by
TLC. After complete consumption of the starting material, the
reaction mixture was concentrated in vacuo. Flash
chromatography of the crude product provided the cyclopropyl
ester 17a in its pure form. Rf = 0.57 (hexanes/EtOAc, 8 : 2);
Yield: 1.19 g, 65%; [α]25D= +43.1 (CHCl3, c = 0.8) IR (neat):
2994, 2954, 2932, 2892, 2858, 1731, 1294, 1265, 1117, 1102,
1,5-Anhydro-2-deoxy-1,2-C-(exo-carbmethoxymethylene)-4-O-
benzyl-6-O-TBS-α- D-erythro-hex-1-en-3-ulose (16d) To a stirred
solution of cyclopropane alcohol 16c (1.1 g, 2.6 mmol, 1 equiv)
in CH2Cl2 (15 mL) at 0 °C was added Dess–Martin periodinane
(DMP) (1.2 g, 2.86 mmol, 1.1 equiv). The progress of the
reaction was monitored by TLC. After complete consumption of
the starting material, the reaction was quenched by adding 10%
aqueous solution of Na2S2O3 (8 mL)/ sat. solution of NaHCO3
(aq) (8 mL) with vigorous stirring. The aqueous layer was
extracted with CH2Cl2 (3X50 mL). The combined organic layer
was washed with sat. solution of NaHCO3 (aq) and brine. The
organic layer was dried over anhydrous Na2SO4 and concentrated
in vacuo. Flash chromatography of the crude product provided
the corresponding cyclopropyl ketone 16d in its pure form. Rf =
0.50 (hexanes/EtOAc, 8 : 2); Yield: 1.02 g, 93%; [α]25D= +56.11
(CHCl3, c = 1.4) IR (neat): 2955, 2931, 2860, 1725, 1120, 837
1
838, 779 cm-1; H-NMR (400 MHz, CDCl3): 3.95 (1H, dd, J =
2.8 Hz, 7.6 Hz, CH-O), 3.83-3.78 (2H, m, CH2O), 3.69 (3H, s,
OMe), 3.63 (1H, dd, J = 10.4 Hz, 10.4 Hz, CH-O), 3.53 (1H, dd,
J = 8.4Hz, 10.0 Hz, CH-O), 3.09 (1H, td, J = 5.6 Hz, 10.0 Hz,
CH-O), 2.03 (1H, dd, J = 2.4 Hz, 6.0 Hz, CHCO2Me), 1.64 (1H,
dd, J = 6.0 Hz, 6.0 Hz, CH), 1.46 (3H, s, Me), 1.36 (3H, s, Me),
0.90 (9H, s, SitBu), 0.1 (3H, s, SiMe), 0.08 (3H, s, SiMe); 13C-
NMR (100 MHz, CDCl3): 172.2, 99.4, 73.4, 69.7, 64.0, 62.2,
59.9, 51.9, 28.9, 26.8, 25.8, 20.6, 18.8, 18.2, -4.6, -5.0; HRMS
m/z: calcd for C18H32O6Si [M+Na] +: 395.1866; found: 395.1865.
1,5-Anhydro-2-deoxy-1,2-C-(exo-carbmethoxymethylene)-4,6-O-
isopropylidene-α-D-arabino-hexitol (17b): To a stirred solution
of protected sugar (1.19 g, 3.1 mmol, 1 equiv) in THF (15 mL)
was added a 1 M solution of TBAF (4.6 mL, 4.6 mmol, 1.5
equiv) in THF at 0 °C. The reaction was monitored by TLC.
After complete conversion of the starting material, the reaction
mixture was washed with water (20 mL) and extracted with
DCM (2 X 50 mL). The organic layer was dried over anhyd.
Na2SO4 and concentrated in vacuo. Flash chromatography of the
crude product afforded the desired deprotected product in its pure
form. Rf = 0.53 (hexanes/EtOAc, 8 : 2); Yield: 0.761 g, 95%;
[α]25D= +66.5 (CHCl3, c = 0.8) IR (neat): 3468, 2998, 2895, 1716,
1
cm-1; H-NMR (400 MHz, CDCl3): 7.35-7.29 (5H, m, Ph), 4.78
(1H, d, J = 13.2 Hz, PhCH2O), 4.51 (1H, d, J = 13.2 Hz,
PhCH2O), 4.29 (1H, dd, J = 2.4 Hz, 6.4 Hz, CH-O), 3.96 (1H, dd,
J = 4.0 Hz, 8.0 Hz, CH-O), 3.78-3.75 (3H, m, CH2O), 3.69 (3H,
s, OMe), 2.99 (1H, dd, J = 2.4 Hz, 5.2 Hz, CH-CO), 2.38 (1H,
dd, J = 6.0 Hz, 6.0 Hz, CH), 0.87 (9H, s, SitBu), 0.05 (3H, s,
SiMe), 0.04 (3H, s, SiMe); 13C-NMR (100 MHz, CDCl3): 198.0,
169.9, 136.8, 128.4, 128.2, 128.0, 78.6, 78.0, 72.7, 63.2, 61.2,
52.3, 31.8, 28.4, 25.7, 18.2, -5.6, -5.7; HRMS m/z: calcd for
C22H32O6Si [M+Na] +: 443.1866; found: 443.1861.
1
1446, 1199, 1088, 1048, 868, 828 cm-1; H-NMR (400 MHz,
1,5-Anhydro-2-deoxy-1,2-C-(exo-carbmethoxymethylene)-4-O-
benzyl-6-O-TBS-α-D-erythro-hexityl-exo-3-methylene (16) To a
CDCl3): 3.98 (1H, dd, J = 2.4 Hz, 7.6 Hz, CH-O), 3.89-3.87 (1H,
m, CH2O), 3.83 (1H, dd, J = 5.6 Hz, 10.8 Hz, CH2O), 3.68 (3H,
s, OMe), 3.66 (1H, dd, J = 10.8 Hz, 10.8 Hz, CH-O), 3.57 (1H,
dd, J = 8.4 Hz, 10.0 Hz, CH-O), 3.12 (1H, td, J = 5.6 Hz, 10.0
Hz, CH), 2.94-2.92 (1H, m, OH), 2.04 (1H, dd, J = 2.8 Hz, 5.6
Hz, CH-CO2Me), 1.71 (1H, dd, J = 6.8 Hz, 6.8 Hz, CH), 1.50
(3H, s, Me), 1.39 (3H, s, Me); 13C-NMR (100 MHz, CDCl3):
172.1, 99.8, 73.6, 68.9, 63.7, 62.0, 59.3, 51.9, 28.8, 25.1, 21.2,
18.9; HRMS m/z: calcd for C12H18O6 [M+Na] +: 281.1001; found:
281.1000.
stirred suspension of phosphonium iodide (0.404 g, 1 mmol, 2
equiv) in THF (6 mL) at -15 °C was added n-BuLi (1.6 M in
hexanes, 0.57 mL, 0.90 mmol, 1.8 equiv) under nitrogen
atmosphere. After the addition, the reaction mixture was allowed
to stir for 20 min. The supernatant was cannulated into a solution
of 16c (0.21 g, 0.5 mmol, 1 equiv) in THF (3 mL). The progress
of the reaction was monitored by TLC. After complete
consumption of the starting material, the reaction mixture was
concentrated in vacuo. The residue was then washed with water
and extracted with CH2Cl2 (2X15 mL). The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product provided the corresponding
VCP in its pure form. Rf = 0.55 (hexanes/EtOAc, 8 : 2); Yield:
0.17 g, 82%; [α]25D= +32.71 (CHCl3, c = 1.2) IR (neat): 2953,
1,5-Anhydro-2-deoxy-1,2-C-(exo-carbmethoxymethylene)-4,6-O-
isopropylidene-α-
D-erythro-hex-3-ulose (17c) To a stirred
solution of cyclopropane alcohol 17b (0.516 g, 2.0 mmol, 1
equiv) in CH2Cl2 (5 mL) at 0 °C was added Dess–Martin
periodinane (DMP) (0.932 g, 2.2 mmol, 1.1 equiv). The progress
of the reaction was monitored by TLC. After complete
consumption of the starting material, the reaction was quenched
by adding 10% aqueous solution of Na2S2O3 (8 mL)/ sat. solution
of NaHCO3 (aq) (8 mL) with vigorous stirring. The aqueous
layer was extracted with CH2Cl2 (3X10 mL). The combined
organic layer was washed with sat. solution of NaHCO3 (aq) and
1
2928, 2857, 1725, 1444, 1117, 837, 777 cm-1; H-NMR (400
MHz, CDCl3): 7.36-7.26 (5H, m, Ph), 5.47 (1H, s, CH2), 5.13
(1H, s, CH2), 4.65 (1H, d, J = 12.0 Hz, PhCH2-O), 4.38 (1H, d, J
= 12.0 Hz, PhCH2-O), 3.95-3.92 (2H, m, CH2OTBS), 3.85 (1H, s,
CH), 3.70-3.66 (1H, m, CH-O), 3.67 (3H, s, OMe), 3.48 (1H dd,
J = 10.0 Hz, 10.0 Hz, CH-O), 2.55-2.53 (1H, m, CH-CO2Me),

13
brine. The organic layer was dried over anhydrous Na2SO4 and
1,5-Anhydro-2-deoxy-1,2-C-(exo-
ACCEPTED MANUSCRIPT
concentrated in vacuo. Flash chromatography of the crude
product provided the corresponding cyclopropyl ketone 17c in its
pure form. Rf = 0.59 (hexanes/EtOAc, 8 : 2); Yield: 0.456 g, 89%;
[α]25D= +74.94 (CHCl3, c = 0.8) IR (neat): 3012, 2930, 1733,
benzoxymethyloxymethylene)-3-O-TBS-4,6-O-isopropylidene-α-
-arabino-hexitol (18b): To a stirred suspension of NaH (60%)
D
(0.32 g, 8 mmol, 2 equiv) in DMF (30 mL) at 0 °C was added
dropwise a solution of the cyclopropane methanol 18a (1.4 g, 4
mmol, 1 equiv) in DMF (10 mL). After the reaction mixture was
warmed to room temperature while stirring for 3 h, it was
quenched by the addition of EtOAc at 0 °C, followed by the
treatment of sat. citric acid solution. The mixture was extracted
with EtOAc (2 X 50 mL) and the organic layer was dried over
anhyd. Na2SO4 and concentrated in vacuo. Flash chromatography
provided the benzyl ether 18b in its pure form. Rf = 0.57
(hexanes/EtOAc, 8 : 2); Yield: 1.67 g, 96%; [α]25D= +23.46
(CHCl3, c = 1.0) IR (neat): 2930, 2888, 2857, 1265, 1101, 859,
1
1719, 1523, 1181, 868, 820 cm-1; H-NMR (400 MHz, CDCl3):
4.27 (1H, dd, J = 2.8 Hz, 6.4 Hz, CH2-O), 4.23 (1H, d, J = 14.8
Hz, CH-O), 3.91 (dd, J = 5.2 Hz, 10.8 Hz, 1H), 3.79 (dd, J = 11.6
Hz, 1H), 3.71 (s, 3H), 3.63 (1H, td, J = 5.6 Hz, 10.4 Hz, CH-O),
2.80 (1H, dd, J = 2.8 Hz, 5.2 Hz, CH-CO2Me), 2.35 (1H, dd, J =
5.6 Hz, 5.6 Hz, CH), 1.50 (3H, s, Me), 1.47 (3H, s, Me); 13C-
NMR (100 MHz, CDCl3): 169.9, 100.8, 74.5, 63.5, 62.2, 58.9,
52.5, 28.6, 28.5, 20.2, 18.4; HRMS m/z: calcd for C12H16O6
[M+Na] +: 279.0845; found: 279.0846.
838 cm-1; H-NMR (400 MHz, CDCl3): 7.36-7.25 (5H, m, Ph),
1
1,5-Anhydro-2,3-deoxy-1,2-C-(exo-carbmethoxymethylene)-4,6-
4.49 (2H, dd, J = 18.0 Hz, 18.4 Hz, OCH2Ph), 3.82-3.77 (2H, m,
CH2-OTBS), 3.61 (1H, dd, J = 9.8 Hz, 9.8 Hz, CH-O), 3.48-3.46
(2H, m, CH2-O), 3.34 (1H, dd, J = 6.8 Hz, 10.4 Hz, CH-O), 3.26
(1H, dd, J = 6.8 Hz, 10.4 Hz, CH-O), 3.10 (1H, td, J = 5.6 Hz,
10.0 Hz, CH-O), 1.44 (3H, s, Me), 1.35 (3H, s, Me), 0.91 (9H, s,
SitBu), 0.91-0.89 (1H, m, CH-CH-CH), 0.11 (3H, s, CH-CH-
CH), 0.09 (6H, s, SiMe); 13C-NMR (100 MHz, CDCl3): 138.2,
128.3, 127.5, 127.5, 99.2, 73.9, 72.3, 70.7, 70.6, 63.6, 62.5, 57.0,
28.9, 21.8, 18.9, 18.3, 18.2, -4.6, -4.9; HRMS m/z: calcd for
C24H38O5Si [M+Na] +: 457.2386; found: 457.2387.
O-isopropylidene-α-D-erythro-hexityl-exo-3-methylene (17) To a
stirred suspension of phosphonium iodide (0.404 g, 1 mmol, 2
equiv) in THF (6 mL) at -15 °C was added n-BuLi (1.6 M in
hexanes, 0.57 mL, 0.90 mmol, 1.8 equiv) under nitrogen
atmosphere. After the addition, the reaction mixture was allowed
to stir for 20 min. The supernatant was cannulated into a solution
of 17c (0.128 g, 0.5 mmol, 1 equiv) in THF (3 mL). The progress
of the reaction was monitored by TLC. After complete
consumption of the starting material, the reaction mixture was
concentrated in vacuo. The residue was then washed with water
and extracted with CH2Cl2 (2X15 mL). The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product provided the corresponding
VCP 17 in its pure form. Rf = 0.56 (hexanes/EtOAc, 8 : 2); Yield:
0.108 g, 85%; [α]25D= +13.95 (CHCl3, c = 0.8) IR (neat): 2993,
1,5-Anhydro-2-deoxy-1,2-C-(exo-benzoxymethyloxymethylene)-
4,6-O-isopropylidene-α-D-arabino-hexitol (18c): To a stirred
solution of protected sugar 18b (1.67g, 3.84 mmol, 1 equiv) in
THF (25 mL) was added a 1 M solution of TBAF (5.8 mL, 5.8
mmol, 1.5 equiv) in THF at 0 °C. The reaction was monitored by
TLC. After complete conversion of the starting material, the
reaction mixture was washed with water (20 mL) and extracted
with DCM (2 X 70 mL). The organic layer was dried over anhyd.
Na2SO4 and concentrated in vacuo. Flash chromatography of the
crude product afforded the desired deprotected product 18c in its
pure form. Rf = 0.53 (hexanes/EtOAc, 8 : 2); Yield: 1.13 g, 92%;
[α]25D= +34.39 (CHCl3, c = 2.0) IR (neat): 3430, 2993, 2942,
2885, 1374, 1269, 1093, 1079, 870, 742, 521 cm-1; 1H-NMR (400
MHz, CDCl3): 7.35-7.26 (5H, m, Ph), 4.49 (2H, dd, J = 13.2 Hz,
13.2 Hz, OCH2Ph), 3.80 (2H dd, J = 7.2 Hz, 12. 4 Hz, CH2O),
3.65-3.59 (1H, m, CH-O), 3.52-3.46 (2H, m, CH2-OBn), 3.30
(2H, d, J = 6.8 Hz, CH-O), 3.11 (1H, td, J = 5.6 Hz, 10.0 Hz,
CH-O), 1.48 (3H, s, Me), 1.38 (3H, s, Me), 1.20-1.15 (1H, m,
CH-CH-CH), 0.91 (1H, dd, J = 6.8 Hz, 6.8 Hz, CH-CH-CH);
13C-NMR (100 MHz, CDCl3): 138.0, 128.4, 127.6, 99.6, 74.1,
72.5, 70.4, 69.9, 63.3, 62.3, 56.6, 29.0, 20.2, 19.0, 18.7; HRMS
m/z: calcd for C18H24O5 [M+Na] +: 343.1521; found: 343.1522.
1
2936, 2832, 1729, 1290, 1265, 1116, 1102, 866, 776 cm-1; H-
NMR (400 MHz, CDCl3): 5.41 (1H, s, CH2), 5.27 (1H, s, CH2),
4.11 (1H, d, J = 10.4 Hz, CH2O), 4.02 (1H, dd, J = 2.4 Hz, 7.2
Hz, CH2O), 3.83 (1H, dd, J = 5.6 Hz, 11.2 Hz, CH-O), 3.73-3.66
(1H, m, CH-O), 3.69 (3H, s, OMe), 3.22 (1H, td, J = 5.2 Hz, 10.0
Hz, CH-O), 2.35 (1H, dd, J = 6.0 Hz, 6.4 Hz, CH-CO2Me), 2.26-
2.24 (1H, m, CH), 1.50 (3H, s, Me), 1.43 (3H, s, Me); 13C-NMR
(100 MHz, CDCl3): 172.1, 137.5, 112.9, 99.8, 68.9, 65.6, 62.6,
59.3, 51.9, 29.6, 29.0, 23.5, 18.9; HRMS m/z: calcd for C13H18O5
[M+Na] +: 277.1052; found: 277.1065.
1,5-Anhydro-2-deoxy-1,2-C-(exo-hydroxymethylmethylene)-3-O-
TBS-4,6-O-isopropylidene-α-D-arabino-hexitol (18a): To
a
stirred suspension of LiAlH4 (0.2 g, 5 mmol, 1 equiv) in THF (30
mL) at 0 °C was added dropwise a solution of the cyclopropane
ester 17a (1.86 g, 5 mmol, 1 equiv) in THF (10 mL). After the
reaction mixture was warmed to room temperature while stirring
for 3 h, it was quenched by the addition of EtOAc at 0 °C,
followed by the treatment of sat. citric acid solution. The mixture
was extracted with EtOAc (2 X 50 mL) and the organic layer was
dried over anhyd. Na2SO4 and concentrated in vacuo. Flash
chromatography provided the alcohol 18a in its pure form. Rf =
1,5-Anhydro-2-deoxy-1,2-C-(exo-benzoxymethyloxymethylene)-
4,6-O-isopropylidene-α- D-erythro-hex-3-ulose (18d) To a stirred
solution of cyclopropane alcohol 18c (0.8 g, 2.5 mmol, 1 equiv)
in CH2Cl2 (15 mL) at 0 °C was added Dess–Martin periodinane
(DMP) (1.17 g, 2.75 mmol, 1.1 equiv). The progress of the
reaction was monitored by TLC. After complete consumption of
the starting material, the reaction was quenched by adding 10%
aqueous solution of Na2S2O3 (15 mL)/ sat. solution of NaHCO3
(aq) (15 mL) with vigorous stirring. The aqueous layer was
extracted with CH2Cl2 (3X20 mL). The combined organic layer
was washed with sat. solution of NaHCO3 (aq) and brine. The
organic layer was dried over anhydrous Na2SO4 and concentrated
in vacuo. Flash chromatography of the crude product provided
the corresponding cyclopropyl ketone 18d in its pure form. Rf =
0.56 (hexanes/EtOAc, 8 : 2); Yield: 92%; [α]25D= -1.76 (CHCl3,
c = 2.0) IR (neat): 2994, 2924, 2868, 1725, 1258, 1199, 1128,
0.52 (hexanes/EtOAc, 8 : 2); Yield: 1.445 g, 84%; [α]25
=
D
+25.23 (CHCl3, c = 1.8) IR (neat): 3420, 2953, 2930, 2890, 2859,
1
1265, 1105, 1036, 838, 779 cm-1; H-NMR (400 MHz, CDCl3):
3.71 (2H, dd, J = 5.2 Hz, 5.2 Hz, CH2-O), 3.54 (1H, dd, J = 10.4
Hz, 10.4 Hz, CH-O), 3.43-3.39 (2H, m, CH2O), 3.29 (1H, dd, J =
7.2 Hz, 11.2 Hz, CH-O), 3.03 (1H, td, J = 5.6 Hz, 10.0 Hz, CH-
O), 2.08 (1H, s, OH), 1.37 (3H, s, Me), 1.28 (3H, s, Me), 1.20-
1.10 (1H, m, CH-CH-CH), 0.84 (9H, s, SitBu), 0.77 (1H, dd, J =
6.4 Hz, 6.4 Hz, CH-CH-CH), 0.03 (3H, s, SiMe), 0.02 (3H, s,
SiMe); 13C-NMR (100 MHz, CDCl3): 99.3, 73.8, 63.9, 63.4, 62.4,
56.8, 28.9, 25.7, 21.4, 20.9, 18.8, 18.2, -4.6, -4.9; HRMS m/z:
calcd for C17H32O5Si [M+Na] +: 367.1917; found: 367.1915.
1
1089, 869, 743, 699 cm-1; H-NMR (400 MHz, CDCl3): 7.36-
7.27 (5H, m, Ph), 4.49 (2H, s, PhCH2O), 4.10 (1H, d, J = 10.4

14
Tetrahedron
Hz, CH-O), 3.97 (1H, dd, J = 3.6 Hz, 5.6 Hz, CH-O), 3.88
62.7, 55.6, 55.3, 48.1, 43.4, 42.4, 29.6, 28.9, 28.1, 21.4, 19.0,
ACCEPTED MANUSCRIPT
+
(1H, dd, J = 5.2 Hz, 10.8 Hz, CH-O), 3.75 (1H, dd, J = 9.6 Hz,
9.6 Hz, CH-O), 3.68-3.57 (2H, m, CH2-O), 3.35 (1H, dd, J = 5.6
Hz, 10.4 Hz, CH-O), 2.37-2.32 (1H, m, CH-CO), 1.76 (1H, dd, J
= 5.6 Hz, 5.6 Hz, CH-CH-CH), 1.48 (3H, s, Me), 1.47 (3H, s,
Me); 13C-NMR (100 MHz, CDCl3): 197.8, 137.6, 128.4, 127.8,
127.6, 100.7, 74.7, 72.7, 68.0, 62.7, 62.5, 57.3, 28.7, 25.4, 19.3,
18.4; HRMS m/z: calcd for C18H22O5 [M+Na] +: 341.1365; found:
341.1363.
18.7; HRMS m/z: calcd for C27H35NO7S [M+Na] : 540.2032;
found: 540.2034.
(5S,6R)-5-(benzyloxy)-7-(TBS-oxy)-6-hydroxy-4-methylene hept-
2-E-enal (20a) To a stirred solution of VCP 6 (0.5 mmol, 1
equiv) in moist MeCN (0.5 mL H2O/ 5mL MeCN) (3 mL) as
nucleophile at rt was added solid chloramine-T (0.155 g, 0.55
mmol, 1.1 equiv) and phenyltrimethylammonium tribromide
(PTAB, 0.019 g, 0.05 mmol, 0.1 equiv). The reaction was
monitored by TLC. After complete consumption of the starting
material and the intermediate bromide, the reaction mixture was
concentrated in vacuo, and then washed with water (10 mL)
extracted with DCM (2 X 20 mL). The organic layer was dried
over anhyd. Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product afforded the oxepane in its
pure form. Rf = 0.56 (hexanes/EtOAc, 8 : 2); Yield: 0.154 g, 82%;
1H-NMR (400 MHz, CDCl3): 9.57 (1H, d, J = 7.6 Hz, CHO),
7.29-7.26 (5H, m, Ph), 7.22 (1H, d, J = 16.0 Hz, CH-CHO), 6.53
(1H, dd, J = 8.0 Hz, 16.0 Hz, CH=CHCHO), 5.84 (1H, s,
C=CH2), 5.70 (1H, s, C=CH2), 4.53 (1H d, J = 11.6 Hz,
PhCH2O), 4.29 (1H, d, J = 11.6 Hz, PhCH2O), 4.09 (1H, d, J =
7.6 Hz, CH-O), 3.80-3.71 (2H, m, CH2-O), 3.36-3.33 (1H, m,
CH-O), 2.47 (1H, d, J = 4.4 Hz, OH), 0.89 (9H, s, SitBu), 0.07
(3H, s, SiMe), 0.06 (3H, s, SiMe); 13C-NMR (100 MHz, CDCl3):
194.2, 151.5, 142.3, 137.4, 130.0, 128.4, 127.8, 126.5, 79.8, 72.3,
70.7, 63.5, 25.8, 18.2, -5.5; HRMS m/z: calcd for C21H32O4Si
[M+Na] +: 399.1968; found: 399.1965.
1,5-Anhydro-2-deoxy-1,2-C-(exo-benzoxymethyloxymethylene)-
4,6-O-isopropylidene-α-
D-erythro-hexityl-exo-3-methylene (18)
To a stirred suspension of phosphonium iodide (0.404 g, 1 mmol,
2 equiv) in THF (6 mL) at -15 °C was added n-BuLi (1.6 M in
hexanes, 0.57 mL, 0.90 mmol, 1.8 equiv) under nitrogen
atmosphere. After the addition, the reaction mixture was allowed
to stir for 20 min. The supernatant was cannulated into a solution
of 18d (0.159 g, 0.5 mmol, 1 equiv) in THF (3 mL). The progress
of the reaction was monitored by TLC. After complete
consumption of the starting material, the reaction mixture was
concentrated in vacuo. The residue was then washed with water
and extracted with CH2Cl2 (2X15 mL). The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product provided the corresponding
VCP 18 in its pure form. Rf = 0.52 (hexanes/EtOAc, 8 : 2); Yield:
0.128 g, 81%; [α]25D= +39.74 (CHCl3, c = 1.0) IR (neat): 2994,
2927, 2856, 1375, 1198, 1126, 1086, 866, 736, 698 cm-1; H-
1
NMR (400 MHz, CDCl3): 7.34-7.25 (5H, m, Ph), 5.31 (1H, s,
C=CH2), 5.16 (1H, s, C=CH2), 4.52 (2H, dd, J = 12.4 Hz, 16.8
Hz, CH2O), 4.08 (1H, d, J = 9.6 Hz, CH-O), 3.82 (1H, dd, J = 5.6
Hz, 11.2 Hz, CH-O), 3.67 (1H dd, J = 10.8 Hz, 10.8 Hz, CH-O),
3.57 (1H, dd, J = 3.2 Hz, 7.2 Hz, CH-O), 3.39 (2H, d, J = 6.8 Hz,
CH-O), 3.26 (1H, dt, J = 5.6 Hz, 10.0 Hz, CH-O), 2.32-2.36 (1H,
m, CH-C=), 1.74-1.72 (1H, m, CH-CH-CH), 1.50 (3H, s, Me),
1.43 (3H, s, Me); 13C-NMR (100 MHz, CDCl3): 140.0, 138.5,
128.5, 127.5, 110.7, 99.8, 72.5, 70.4, 69.8, 65.1, 32.9, 56.8, 29.9,
28.2, 21.0, 19.1, 18.8; HRMS m/z: calcd for C19H24O4 [M+Na] +:
339.1572; found: 339.1574.
(5R,6R)-5-(benzyloxy)-7-(TBS-oxy)-6-hydroxy-4-methylene hept-
2-E-enal (20b) To a stirred solution of VCP 7 (0.5 mmol, 1
equiv) in moist MeCN (0.5 mL H2O/ 5mL MeCN) (3 mL) as
nucleophile at rt was added solid chloramine-T (0.155 g, 0.55
mmol, 1.1 equiv) and phenyltrimethylammonium tribromide
(PTAB, 0.019 g, 0.05 mmol, 0.1 equiv). The reaction was
monitored by TLC. After complete consumption of the starting
material and the intermediate bromide, the reaction mixture was
concentrated in vacuo, and then washed with water (10 mL)
extracted with DCM (2 X 20 mL). The organic layer was dried
over anhyd. Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product afforded the oxepane in its
pure form. Rf = 0.53 (hexanes/EtOAc, 8 : 2); Yield: 0.162 g,
(4aR,7R,9aS)-7-(Benzyloxymethyl)-6-methoxy-2,2-dimethyl-9-(N-
p-toluenesulfonamidomethyl)-4a,6,7,9a-tetrahydro-4H-
[1,3]dioxino [5,4-b]oxepine (19) To a stirred solution of VCP 18
(0.063 g, 0.2 mmol, 1 equiv) in the chosen alcohol (1 mL) as
nucleophile at rt was added solid chloramine-T (0.060 g, 0.22
mmol, 1.1 equiv) and phenyltrimethylammonium tribromide
(PTAB, 0.008 g, 0.02 mmol, 0.1 equiv). The reaction was
monitored by TLC. After complete conversion of the starting
material and the intermediate bromide, the reaction mixture was
concentrated in vacuo, and then washed with water (10 mL)
extracted with DCM (2 X 10 mL). The organic layer was dried
over anhyd. Na2SO4 and concentrated in vacuo. Flash
chromatography of the crude product afforded the oxepane 19 in
its pure form. Rf = 0.51 (hexanes/EtOAc, 8 : 2); Yield: 0.077 g,
74%; IR (neat): 3293, 2922, 2855, 1329, 1161, 1113, 1093, 1075,
1
87%; H-NMR (400 MHz, CDCl3): 9.57 (1H, d, J = 7.6 Hz, ,
CHO), 7.37-7.29 (5H, m, Ph), 7.18 (1H, d, J = 16.0 Hz, CH-
CHO), 6.42 (1H, dd, J = 7.6 Hz, 16.0 Hz, CH=CHCHO), 5.81
(1H, s, C=CH2), 5.76 (1H, s, C=CH2), 4.60 (1H, d, J = 11.6 Hz,
CH-O), 4.37-4.33 (2H, m, PhCH2-O), 3.71-3.56 (3H, m, CH2-O,
CH-O), 2.52 (1H, d, J = 5.6 Hz, OH), 0.88 (9H, s, SitBu), 0.04
(6H, s, SiMe); 13C-NMR (100 MHz, CDCl3): 193.8, 151.3, 141.7,
137.3, 129.6, 128.5, 128.0, 126.0, 77.9, 73.2, 71.3, 63.2, 25.8,
18.2, -5.5; HRMS m/z: calcd for C21H32O4Si [M+Na]
399.1968; found: 399.1967.
+
:
Methyl-1,6-anhydro-2-deoxy-5-O-benzyl-6-O-TBS-4-(N-p-
toluene sulfonamidomethyl)-(β)-
D-talo-septanoside (21): To a
814, 664 cm-1; H-NMR (400 MHz, CDCl3): 7.71-7.68 (4H, m,
1
stirred solution of unsaturated oxepane derivative β -12a (0.056
g, 0.1 mmol, 1 equiv) in t-butyl alcohol (1.5 mL) was added solid
NMMO (0.018 g, 0.15 mmol, 1.5 equiv) and a crystal OsO4
weighing 0.3 mg was added at rt. The reaction was refluxed at
the boiling point of t-butyl alcohol and monitored by TLC. After
complete conversion of the starting material, the reaction mixture
was washed with water (20 mL) and extracted with EtOAc (2 X
20 mL). The organic layer was dried over anhyd. Na2SO4 and
concentrated in vacuo. Flash chromatography of the crude
product afforded the desired deprotected product 21 in its pure
form. Rf = 0.57 (hexanes/ EtOAc, 8 : 2); Yield: 0.053 g, 89%; 1H-
NMR (400 MHz, CDCl3): 7.71 (2H, d, J = 8.0 Hz, Ph), 7.34-7.26
Ph), 7.36-7.23 (14H, m, Ph), 5.44 (1H, d, J = 3.6 Hz, C=CH),
5.29 (1H, s, C=CH), 4.91 (1H dd, J = 3.6 Hz, 7.6 Hz, O-CH-O),
4.84 (1H, dd, J = 3.6 Hz, 7.6 Hz, O-CH-O), 4.59 (1H, d, J = 6.0
Hz, CH-O), 4.53-4.46 (5H, m, PhCH2O), 4.33 (1H, dd, J = 8.8
Hz, CH-O), 4.19 (1H d, J= 9.6 Hz, CH-O), 3.96-3.87 (1H, m,
CH-O), 3.84-3.52 (7H, m, CH2O, CH2-O), 3.51-3.37 (6H, m,
CH2-N), 3.31 (3H, s, OMe), 3.28 (3H, s, OMe), 2.74-2.72 (1H,
m, CH-CH2OBn), 2.67-2.65 (m, CH-CH2OBn), 2.41 (3H, s, Me),
2.39 (3H, s, Me), 1.42 (3H, s, MeC), 1.37 (6H, s, MeC); 13C-
NMR (100 MHz, CDCl3): 143.1, 143.0, 137.9, 137.7, 137.3,
135.9, 134.9, 129.5, 128.4, 127.7, 127.2, 127.1, 127.0, 103.0,
102.0, 99.0, 98.7, 73.7, 73.1, 72.7, 71.3, 69.7, 69.6, 63.4, 63.3,

15
13. Rychnovsky, S. D.; Dahanukar, V. H., Tetrahedron Lett. 1996, 37,
(7H, m, Ph), 4.86 (1H, dd, J = 4.0 Hz, 10.4 Hz, NH), 4.75 (dd, J
= 2.4 Hz, 9.6 Hz, 1H, O-CH-OMe), 4.60 (2H, s, PhCH2O), 4.31
(1H, s, CH-O), 4.08-4.05 (2H, m, CH2OTBS), 3.59-3.56 (2H, m,
CH-O), 3.49 (1H, dd, J = 4.8 Hz, 10.4 Hz, CH-O), 3.36 (3H, s,
OMe), 3.35 (1H, dd, J = 10.4 Hz, 18.8 Hz, CH-O), 2.89-2.85
(2H, m, CH2N), 2.41 (3H, s, Me), 2.31-2.24 (1H, m, CH-CH2-
CH), 2.08-2.02 (1H, m, CH-CH2-CH), 0.92 (9H, s, SitBu), 0.09
(6H, s, SiMe); 13C-NMR (100 MHz, CDCl3): 143.5, 137.8, 136.4,
129.7, 128.4, 128.2, 127.9, 127.0, 99.1, 77.5, 75.9, 74.5, 73.6,
68.8, 65.8, 55.4, 47.1, 36.6, 25.9, 21.4, 18.3, -5.4, -5.5; HRMS
m/z: calcd for C29H45NO8SSi[M+Na] +: 618.2533; found:
618.2535.
ACCEPTED MANUSCRIPT
339-342.
14. Sugita, Y.; Kawai, K.; Hosoya, H.; Yokoe, I., Heterocycles 1999, 51,
2029-2029.
15. Davies, M. J.; Moody, C. J., J. Chem. Soc., Perkin Trans. 1 1991, 9-9.
16. Gurjar, M. K.; Rao, B. V.; Krishna, L. M.; Chorghade, M. S.; Ley, S. V.,
Tetrahedron: Asymmetry 2005, 16, 935-939.
17. Piccialli, V.; Borbone, N.; Oliviero, G., Tetrahedron Lett. 2007, 48,
5131-5135.
18. Cox, J. M.; Owen, L. N., J. Chem. Soc. C: 1967, 1121-1130.
19. Anet, E. F. L. J., Carbohydr. Res. 1968, 8, 164-174.
20. Stevens, J. D., Carbohydr. Res. 1972, 21, 490-492.
21. Contour, M. O.; Fayet, C.; Gelas, J., Carbohydr. Res. 1990, 201, 150-
152.
22. Markad, S. D.; Miller, S. M.; Morton, M.; Peczuh, M. W., Tetrahedron
Lett. 2010, 51, 1209-1212.
23. Beck, J. M.; Miller, S. M.; Peczuh, M. W.; Hadad, C. M., J. Org. Chem.
2012, 77, 4242-4251.
24. Duff Jr, M. R.; Fyvie, W. S.; Markad, S. D.; Frankel, A. E.; Kumar, C.
V.; Gascón, J. A.; Peczuh, M. W., Org. Biomol. Chem. 2011, 9, 154-164.
25. Matsukura, H.; Morimoto, M.; Koshino, H.; Nakata, T.-i., Tetrahedron
Lett. 1997, 38, 5545-5548.
26. Nicolaou, K. C.; Hwang, C. K.; Duggan, M. E.; Nugiel, D. A.; Abe, Y.;
Reddy, K. B.; DeFrees, S. A.; Reddy, D. R.; Awartani, R. A., J. Am.
Chem. Soc. 1995, 117, 10227-10238.
27. Tripathi, S.; Roy, B. G.; Drew, M. G. B.; Achari, B.; Mandal, S. B., J.
Org. Chem. 2007, 72, 7427-7430.
28. Bhattacharjya, A.; Chattopadhyay, P.; McPhail, A. T.; McPhail, D. R., J.
Chem. Soc., Chem. Commun. 1990, 1508-1508.
29. Boeckman, R. K.; Shair, M. D.; Vargas, J. R.; Stolz, L. A., J. Org.
Chem., 1993, 58, 1295-1297.
30. Chou, W. N.; White, J. B.; Smith, W. B., J. Am. Chem. Soc. 1992, 114,
4658-4667.
Methyl-1,6-anhydro-2-deoxy-5,6-O-(di-tert-butylsilyl)-4-(N-p-
toluenesulfonamidomethyl)-(α/β)- D-manno-septanoside (22): To
a stirred solution of unsaturated oxepane derivative 15a (0.050
g, 0.1 mmol, 1 equiv) in t-butyl alcohol (1.5 mL) was added solid
NMMO (0.018 g, 0.15 mmol, 1.5 equiv) and a crystal OsO4
weighing 0.3 mg was added at rt. The reaction was refluxed at
the boiling point of t-butyl alcohol and monitored by TLC. After
complete conversion of the starting material, the reaction mixture
was washed with water (20 mL) and extracted with EtOAc (2 X
20 mL). The organic layer was dried over anhyd. Na2SO4 and
concentrated in vacuo. Flash chromatography of the crude
product afforded the desired deprotected product in its pure form.
1
Rf = 0.55 (hexanes/EtOAc, 8 : 2); Yield: 0.046 g, 86%; H-NMR
(400 MHz, CDCl3): 7.73 (2H, d, J = 8.0 Hz, Ph), 7.31 (2H, d, J =
8.0 Hz, Ph), 5.40 (1H, dd, J = 6.0 Hz, 6.0 Hz, NH), 4.64 (1H, dd,
J = 4.4 Hz, 4.4 Hz, O-CH-O), 4.45-4.42 (1H, m, CH-O), 4.19-
4.10 (3H, m, CH2-OSi), 3.70 (1H, s, CH-O), 3.40 (3H, s, OMe),
3.37-3.18 (2H, m, CH-O), 2.64 (1H, s, OH), 2.43 (3H, s, Me),
2.38-2.33 (1H, m, CH-CH2-CH), 2.04-1.98 (1H, m, CH-CH2-
CH), 1.02 (9H, s, SitBu), 1.00 (9H, s, SitBu); 13C-NMR (100
MHz, CDCl3): 143.7, 136.1, 129.8, 127.00, 101.9, 79.5, 76.4,
70.8, 68.6, 67.5, 55.8, 49.5, 38.3, 27.5, 27.3, 23.1, 21.5, 20.7;
HRMS m/z: calcd for C24H41NO8SSi [M+Na] +: 554.2220; found:
554.2221.
31. Robinson, R. A.; Clark, J. S.; Holmes, A. B., J. Am. Chem. Soc. 1993,
115, 10400-10401.
32. Ovaa, H.; Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.;
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33. Peczuh, M. W.; Snyder, N. L., Tetrahedron Lett. 2003, 44, 4057-4061.
34. Köver, A.; Matheu, M. I.; Díaz, Y.; Castillón, S., Arkivoc 2007, 364-379.
35. Sugita, Y.; Kimura, C.; Hosoya, H.; Yamadoi, S.; Yokoe, I., Tetrahedron
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36. Sridhar, P. R.; Venukumar, P., Org. Lett. 2012, 14, 5558-5561.
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38. Dey, S.; Jayaraman, N., Beilstein J. Org. Chem. 2012, 8, 522-527.
39. Ganesh, N. V.; Jayaraman, N., J. Org. Chem. 2007, 72, 5500-5504.
40. Ganesh, N. V.; Jayaraman, N., J. Org. Chem. 2008, 74, 739-746.
41. Ganesh, N. V.; Raghothama, S.; Sonti, R.; Jayaraman, N., J. Org. Chem.
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42. Batchelor, R.; Harvey, J. E.; Northcote, P. T.; Teesdale-Spittle, P.;
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5. Acknowledgments
We thank CSIR, New Delhi for Shyama Prasad Mukherjee
Fellowship to V.G., postdoctoral Fellowship to T.K. and DST for
the SERB Distinguished Fellowship to S.C.N. We also thank
the Supercomputer Education and Research Center (SERC), IISc,
for the computational facility.
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ACCEPTED MANUSCRIPT
σ–Ferrier Rearrangement of Carbohydrate Derived
Vinylcyclopropanes: A Facile Approach to Oxepane
Analogs.
Venkataraman Ganesh,† Taraknath Kundu† and Srinivasan
Chandrasekaran#*
Department of Organic Chemistry, Indian Institute of Science,
Bangalore – 560 012, India.
-
PhMe3N+ Br3
(10 mol%)
OR'
O
TBSO
BnO
O
Na
N
TBSO
BnO
R
R
Ts
Cl
R'OH, rt
TsHN
O
TBSO
BnO
R
Br
Intermediate - DFT calculations
Supporting Information
1. General Information
2. Spectral Details
2
3
1

ACCEPTED MANUSCRIPT
Experimental section
General Information: All solvents for routine isolation of products and chromatography were
reagent grade and redistilled. Acetonitrile and DCM used for the reaction were dried under reflux
over CaH2 and stored over 3 Å molecular sieves. Flash chromatography was performed using
silica gel (230−400 mesh) with indicated solvents. All reactions were monitored by thin-layer
chromatography on 0.25 mm silica plates (F-254) visualizing with UV light and developed using
phosphomolybdate or vanillin solution. 1H, 13C NMR spectra were recorded on a 400 MHz NMR
spectrometer. Chemical shifts, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet), coupling constant in hertz (Hz), and number of protons. HRMS were measured with
electrospray ionization (ESI) and quadrupolar mass analyzer. Gaussian 09 program was used for
energy minimization.
2

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Spectral Details
O
TBSO
BnO
OH
3

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4

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O
TBSO
BnO
OH
5

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6

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O
TBSO
BnO
O
7

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8

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O
TBSO
BnO
CH2
9

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10

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OMe
O
TBSO
BnO
TsHN
11

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12

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13