An oxepinone route to carbohydrate based oxepines

Article abstract of DOI:10.1016/j.tet.2009.07.041

Oxepines are ring expanded analogs of glycals that can be used to prepare septanose carbohydrates. A?route to carbohydrate based oxepines that utilizes oxepinones as a key intermediate has been developed. The oxepinone intermediates were prepared via an a

Full text of DOI:10.1016/j.tet.2009.07.041

Tetrahedron 65 (2009) 7921–7926
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An oxepinone route to carbohydrate based oxepines
*
Steve Castro, Courtney S. Johnson, Bikash Surana, Mark W. Peczuh
Department of Chemistry, University of Connecticut, 55 N. Eagleville Road, U-3060, Storrs, CT 06269, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 May 2009
Received in revised form 15 July 2009
Accepted 16 July 2009
Available online 23 July 2009
Oxepines are ring expanded analogs of glycals that can be used to prepare septanose carbohydrates.
A route to carbohydrate based oxepines that utilizes oxepinones as a key intermediate has been de-
veloped. The oxepinone intermediates were prepared via an amine catalyzed cycloisomerization of fu-
ranose hemi-ketals. 1,2-Reduction of the oxepinones followed by acetylation provided the novel ring
expanded enol ether products. Moderate diastereoselectivity was observed for the reduction based on
the starting oxepinone. 1,4-Addition onto the oxepinones was also demonstrated. Overall, the syntheses
reported here will allow for ready access to novel ring expanded carbohydrate analogs.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Carbohydrate based oxepine
Synthesis
Septanose carbohydrate
Cycloisomerization
1. Introduction
For example, McDonald has utilized a photocycloisomerization
reaction to convert diols such as 1 to oxepines 2 (Eq.1).6 We wanted
The development of synthetic routes for the preparation of
septanose carbohydrates continues to be an active area of research.
Interest in this novel class of compounds owes primarily to the
potential biological activities that they possess. A growing body of
results suggest that septanosides and other polyhydroxylated
seven-membered ring structures may be bound by proteins in
a pyranose-mimetic fashion.1,2 As in the synthesis of natural car-
bohydrates, attention has focused on the selective formation of
glycosidic bonds involving the septanose residue. Glycosyl donor
types include anomeric halides,3 thioseptanosides,4 and oxepi-
nesdcyclic enol ethers.5,6
to know whether molecules akin to 4 (Eq. 2) could arise from diol 3
via the same reaction. The acetonide protecting group motif that
was essential for cyclization of 1 was included in 3. Reactant 3
differs, however, from 1 in two significant ways. First, the nucleo-
phile in 1 is a primary alcohol whereas a secondary alcohol operates
in 3. Second, the nature of the propargylic groups of 1 and 3 is
different. The propargylic group in 3 is a free alcohol but in 1 it is
part of an acetonide. Between these two differences, the prop-
argylic alcohol was expected to be especially problematic.
Carbohydrate based oxepines have been key intermediates in
our approach toward the synthesis of septanosides. Epoxidation of
oxepines yields 1,2-anhydroseptanoses that are susceptible to nu-
cleophilic attack.5 Stereoselective epoxidation and inversion of the
1,2-anhydro species resulted in selective glycosidic bond forma-
tion.7 Alternatively, trapping of the 1,2-anhydroseptanose with
thiol/thiolate nucleophiles gave S-septanosides, which are donors
in glycosylation reactions.4 It was the versatility of oxepines that
made them attractive synthetic targets.
W(CO)6, DABCO
O
HO
OH
hv (350 nm)
HO
PhCH3, 70 °C
> 60%
O
ð1Þ
ð2Þ
O
O
O
1
2
Routes to carbohydrate based oxepines have employed ring
closing metathesis (RCM),8 cyclization–elimination,9 and photo-
cycloisomerization strategies.6
O
O
O
W(CO)6, DABCO
hv (350 nm)
O
O
OH
O
O
PhCH3, 70 °C
O
O
OH
OH
* Corresponding author. Tel.: þ1 8604861605; fax: þ1 8604862981.
E-mail address: mark.peczuh@uconn.edu (M.W. Peczuh).
3
4
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.041

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S. Castro et al. / Tetrahedron 65 (2009) 7921–7926
Diol 3, prepared via acetylene addition to mannose di-aceto-
O
O
O
O
O
RO
O
BnO
nide, was subjected to the conditions of the McDonald photo-
isomerization. Repeated attempts resulted in recovery of the
starting material. Other cycloisomerization conditions were also
evaluated. Trost had demonstrated that a combination of Wilkin-
son’s catalyst and phosphine ligands could be used to induce
cycloisomerization of alkynols to generate cyclic enol ethers.10
However, treatment of 3 under the Trost conditions failed to pro-
vide an oxepine product. We speculated that the propargylic al-
cohol present in 3 was interacting with the metal catalyst in such
a manner as to prevent metal vinylidene formation.11
An alternative approach became evident during the in-
vestigation of the photocycloisomerization reaction. After attempts
to selectively protect the propargylic alcohol as its benzyl or silyl
ether failed, we proposed to convert it to the ketone. The ynone
product (masked as the hemi-ketal) would facilitate a cyclization
via conjugate addition to give an oxepinone that could be sub-
sequently reduced to form the desired oxepine. Reported here is the
synthesis of a small family of oxepines based on oxepinones as the
key intermediates.
O
O
O
O
BnO
BnO
OBn
5b
5e
R = Bn
5c
5d R = TBDPS
OH
OH
O
OH
O
O
RO
RO
BnO
BnO
O
O
O
O
OBn
6b
6c R = Bn
6d
6e
R = TBDPS
O
O
O
O
O
BnO
BnO
O
O
O
O
O
7c
7d
R = Bn
R = TBDPS
7b
7e
Figure 1.
2. Results/discussion
As a corollary to the initial photoisomerization attempt, hemi-
ketal 6a was prepared as shown in Scheme 1. Under the conditions
of the photocycloisomerization 6a gave oxepinone 7a in 10% yield.
Despite the low yield, the result was encouraging because it sug-
gested that the reaction could be optimized for the new starting
materials. The reaction also indicated that the propargylic alcohol
indeed affected the reaction as we had suspected.
Triethylamine mediated cyclization of 6a–6e gave 7a–7e in
yields ranging from 8–41%. The highest yields in the group were for
the
In addition to the cyclization of 6a to 7a (10%), formation of the
oxepinone derived from tri-O-benzyl -ribonolactone (7e) was
D-ribonolactone derived hemi-ketals 6c and 6d (38% and 41%).
D
poor (8%). Notably, the yield for conversion of 6b to 7b was 31% in
our hands. Higher yields correlate primarily with the presence of
the rigidifying acetonide ring on the starting hemi-ketal (e.g., 6b–
6d vss 6e). Hemi-ketal 6a does not follow this trend, but its reduced
cyclization efficiency may be due to multiple factors such as steric
congestion around the nucleophilic oxygen or about the developing
oxepinone itself.
Several parameters were varied in an effort to optimize the re-
action. Variables included the identity of the amine (quinuclidine,
DABCO, DBU, TEA),13 equivalents of amine (cat., 1 equiv, 3 equiv),
temperature (ꢀ78 ꢁC, 0 ꢁC, rt), and solvent (DCM, Et2O, CHCl3).
Results from these experiments suggested that the reaction was
unaffected when base or solvent was varied. The reaction was
significantly slowed at ꢀ78 ꢁC or when less than1 equiv of amine
was used. We found that the initial conditions, adopted from the
reported isomerization of 6b, were the most efficient across all
hemi-ketals investigated. We suggest that the lower yields for cy-
clization reported here better reflect the true efficiency of the
reaction.
O
O
O
O
1)
TMS
OH
O
O
O
O
n-BuLi, THF -78 °C
2) CsF, CH3CN,H2O
78%
O
O
O
5a
6a
W(CO)6, DABCO
hv (350 nm)
PhCH3, 70 °C
O
O
O
10%
O
O
O
7a
Scheme 1.
Consideration of the isomerization mechanism revealed in-
termediates where the reaction course could diverge from the cy-
clization pathway. The mechanism depicted in Scheme 2 shares
features of Baylis–Hillman and oxa-Michael reactions. We propose
that the reaction begins with the acyclic ynone species II, which is
in equilibrium with hemi-ketal I. Triethylamine attack on II pro-
vides enone IV via III. Intramolecular attack by oxygen then gives
A search for related reactions showed that 5b (Fig. 1) had been
converted to its corresponding oxepinone 7b under related reaction
conditions.12 The reported process, however, was not a photo-
cycloisomerization. Instead, simple addition of an amine base
(triethylamine) to hemi-ketal 6b affected cycloisomerization in
high yield (95%). We reasoned that the DABCO used in the photo-
cycloisomerization served the same role that TEA had in the
reported oxepinone synthesis. When those reaction conditions
(3 equiv TEA, DCM, rt) were employed, 6a was again converted to
7a in 10% yield. This confirmed the role of the trialkylamine and
indicated that the reaction was proceeding via a pathway that did
not require metals and/or photo-initiation. Nonetheless, the low
yield in the cyclization reaction was puzzling. In an effort to un-
derstand the factors that contributed to the low yield, hemi-ketals
6b–6e were prepared by TMS/acetylene addition to the corre-
sponding lactones 5b–5e followed by TMS deprotection.
cyclic species V that eliminates the b-triethylammonium group to
form oxepinone VI. Direct intramolecular attack by oxygen onto
ynone II is unlikely based on molecular orbital grounds.14 In addi-
tion to potential side-reactions of the enone functionality in the
product (VI), III may react with electrophiles other than Hþ such as
II, IV, and VI (inset, Scheme 2). Taken together, these alternate
pathways may partly explain the low yield of the desired oxepi-
nones in this series.
Carbohydrate based oxepines are useful intermediates in the
preparation of a number of septanose glycoconjugates; they were
also the primary impetus for this synthetic investigation. In our

S. Castro et al. / Tetrahedron 65 (2009) 7921–7926
7923
NEt3
OH
O H
O
OH
NEt3
H
O
NEt3
R
R
R
R
•
O
O
O
III
IV
I
II
NEt3
O
O
OH
O H
NEt3
E
NEt3
E+
R
R
R
R
•
O
O
O
O
III
VI
VII
V
Scheme 2.
OCH3
O
plan, oxepinones such as 7 were the penultimate intermediate in
the preparation of oxepines. Conversion of the carbonyl group to an
alcohol was necessary to complete the sequence. Reduction of
oxepinones 7a–7d utilized a procedure shown to be selective for
1,2-hydride attack.16 In practice, reduction was followed by acety-
lation of the allylic alcohol to provide oxepines 8a–8d and 9a–9d as
the C3 acetates. Yields (44–64%) and diastereomer ratios (10:1 to
1:3) for the two-step sequence are provided in Scheme 3. The
configuration of diastereomers 8 and 9 was determined by H3,H4 3J
coupling constant analysis. The facial selectivity observed for in-
dividual reductions is governed by the orientation of the dioxolane
in the oxepinone starting material. In 7a, for example, hydride at-
tack opposite to the fused dioxolane should give rise to 8a as the
preferred product. A similar rationale explains 9b–9d as the pre-
O
NaOMe
H
R
O
O
H
HOMe
49%
S
O
O
O
O
10
7b
H
H
R
PhSH, Cs2CO3
THF
SPh
+
O
H
SPh
O
S
O
O
64%
O
O
O
O
11
12
Scheme 4.
ferred products based on the
a
-dioxolane in 7b–7d.
2-deoxy septanoside structures. For example, 1,4-addition of carbo-
hydrate based nucleophiles to 7b would give more elaborate gly-
cosides akin to 10. Similarly, the mixed S,O-acetals 11 and 12 could
be used as glycosyl donors in standard glycosylation reactions.
These possibilities underscore the potential utility of the carbohy-
drate derived oxepinones in the synthesis of septanose
carbohydrates.
1) NaBH4, I2
O
O
O
CH3OH
+
R
R
R
2) Ac2O, Pyr.
O
OAc
OAc
Yield 8:9
7a
7b
7c
64% 10:1
44% 1:2
62% 1:3
56% 1:3
8a
8b
8c
9a
9b
9c
3. Conclusion
*
7d
8d
9d
Key contributions reported in this work range from the details of
the synthesis of oxepinones to the intermediacy of oxepinones in
the synthesis of oxepines and oxepanones. First, furanose hemi-
ketals 6 were converted to oxepinones 7 in an amine base mediated
isomerization. The results for several hemi-ketals collected here
suggest that the efficiency of the reaction is lower than that
reported earlier. We speculate that the lower yields are due to side-
reactions that arise from the inherent reactivity of the product as
well as via intermediates in the isomerization process. The oxepi-
none products were subsequently converted to the corresponding
oxepines via 1,2-reduction. This route to carbohydrate based oxe-
pines is complementary to others in the literature. We have also
demonstrated the conversion of oxepinones to oxepanones via
conjugate addition of methoxide and thiophenylate nucleophiles.
Overall, the syntheses reported here will allow for ready access to
novel ring expanded carbohydrate analogs.
Scheme 3. *Compound 8c was isolated as the allylic alcohol. See note 15.
Yields of up to 18% for the five-step sequence (71% average yield
per transformation) were obtained. While this synthesis of oxe-
pines is less efficient than our RCM based approach, it is similar in
efficiency to the cyclization–elimination approach we have de-
scribed. It has the added advantages, however, of accommodating
acid sensitive functionalities, which was not possible with the cy-
clization-elimination protocol, and scaleability, which is trouble-
some in the RCM approach.
The enone functionality in the oxepinones 7 provided an op-
portunity to access novel oxepanone structures. This reactivity was
demonstrated using 7b as a model (Scheme 4). Methoxide addition
to 7b gave 10 in 49% yield as a single diastereomer. Addition of
thiophenol to 7b provided a 1:1 mixture of the diastereomeric S,O-
acetals 11 and 12 (64% combined yield). Stereochemistry at C1 in
10–12 was assigned based on NOESY spectra taken on 10 and 12.
Compound 10 was assigned based on an NOE between the methyl
group of the methyl acetal and the pro-R H2. Oxepanone 12, on the
other hand, showed NOEs between H1 and the pro-R H6.17 The
highly substituted oxepanones 10–12 suggest potential routes to
4. Experimental
4.1. General
Unless stated otherwise, all reactions were conducted at room
temperature (rt) under nitrogen atmosphere. Reactions were

7924
S. Castro et al. / Tetrahedron 65 (2009) 7921–7926
monitored by TLC (silica gel, 60 Å, F254, 250
mm). Visualization was
quenched with satd NH4Cl (aq) (25 mL). The aqueous phase was
conducted either under UV light or by charring with 2.5% p-ani-
saldehyde in H2SO4, acetic acid, and ethanol solution or aqueous
KMnO4, K2CO3, and KOH. Preparative chromatography was con-
extracted with EtOAc (3ꢃ50 mL). The combined organic phases
were dried over Na2SO4 and concentrated in vacuo. The crude
product was purified by column chromatography (3:1 Hex/EtOAc)
to yield a mixture of the TMS-protected material and the depro-
tected product 6. The TMS group of the protected material was then
removed under conditions noted below to give 6a–6e.
ducted on silica gel (60 Å, F254, 250 mm). Melting points are un-
corrected. Optical rotations were measured at 22ꢂ2 ꢁC. 1H NMR
spectra were collected at either 400 MHz or 300 MHz with chem-
ical shifts referenced to CHCl3 (
dH 7.27 ppm). 13C NMR were col-
lected at 100 MHz or 75 MHz and referenced to CDCl3
(
dC
4.4.1. 1-Ethynyl-[2,3:5,6]-di-O-isopropylidene-D-manno-furanose
77.2 ppm). Known compounds 5b,12 5c,18 5d,19 6b,12 and 7b12 that
were prepared by us gave physical data that were in accordance
with the literature.
(6a). To a solution of the TMS-protected analog of alkyne 6a (1.26 g,
3.53 mmol) in MeCN/H2O (45 mL:1.5 mL) at 0 ꢁC was added CsF
(0.644 g, 4.24 mmol) in two portions at an interval of 10 min. The
reaction mixture was allowed to warm to rt and stirred for 4 h. The
reaction was then quenched with H2O (30 mL) and extracted with
Et2O (3ꢃ30 mL). The organic layer was washed with H2O
(3ꢃ20 mL) and brine (20 mL), then dried with Na2SO4 and con-
centrated in vacuo. The crude material was purified by column
chromatography (3:1 Hex/EtOAc) to yield 6a as a white solid
(0.86 g, 86%). The combined yield of the two-step sequence was
4.2. [4,5:7,8]-Di-O-isopropylidene-1,2-dideoxy-D-manno-
hept-1-ynitol (3)
Ethylene diamine/lithium acetylide (2.12 g, 23.1 mmol) was
dissolved in THF (50 mL). This solution was cooled to 0 ꢁC, and
HMPA (1.34 mL, 7.68 mmol) was added. In a separate flask,
[2,3:5,6]-di-O-isopropylidene-
D-mannose (2.00 g, 7.68 mmol) was
78%. Mp 128–130 ꢁC; [
(CDCl3)
a
]
D þ47.8 (c 0.56, CHCl3); 1H NMR 400 MHz
dissolved in THF (20 mL). This solution was cooled to 0 ꢁC and
n-BuLi was added dropwise. After 0.5 h, the furanose solution was
added dropwise to the lithium acetylide solution at 0 ꢁC. The re-
action mixture was allowed to warm to rt and was stirred over-
night. After, excess base was quenched with the addition of
a saturated solution of NH4Cl (20 mL). The reaction mixture was
concentrated in vacuo and the remaining aqueous layer was
extracted with DCM (3ꢃ100 mL) and purified by column chroma-
tography (7:3 Hex/EtOAc) to give 3 (1.34 g, 79%) as a white solid. 1H
d
4.86 (dd, J¼5.6, 3.6 Hz, 1H), 4.61 (d, J¼5.7 Hz, 1H), 4.44 (m,
1H), 4.14–4.02 (m, 3H), 3.60 (s, 1H), 2.73 (s, 1H), 1.53 (s, 3H), 1.46 (s,
3H), 1.38 (s, 3H), 1.37 (s, 3H); 13C NMR 100 MHz (CDCl3)
d
113.5,
109.4, 99.1, 86.6, 79.9, 79.4, 79.3, 74.7, 73.0, 72.6, 66.6, 26.9, 26.0,
25.2, 24.9; HRMS m/z for C14H20O6Na calcd 307.1158, found
307.1183.
4.4.2. 1-Ethynyl-[2,3]-O-isopropylidene-5-O-benzyl-D-ribofuranose
(6c). CsF (0.24 g, 1.55 mmol) was added to a solution of TMS-pro-
tected analog of alkyne 6c (0.54 g, 1.29 mmol) in MeCN/H2O
(30 mL:1 mL). The reaction mixture was stirred for 4 h at rt. After,
H2O and (50 mL) and EtOAc (200 mL) were added. The organic
phase was separated, dried over Na2SO4, and concentrated in vacuo
yielding 6c (0.37 g, 95%) as an oil in a 3:1 mixture of diastereomers.
The combined yield of the addition–deprotection sequence was
NMR 300 MHz (CDCl3)
d
4.78 (dd, J¼2.1, 6.3 Hz, 1H), 4.48 (dd, J¼7.3,
0.8 Hz, 1H), 4.35 (dd, J¼6.8, 6.9 Hz, 1H), 4.08 (m, 3H), 3.86 (d,
J¼6.8 Hz, 1H), 2.55 (s, 1H), 1.55 (s, 3H), 1.42 (d, J¼5.0 Hz, 6H), 1.36 (s,
3H); 13C NMR 75 MHz (CDCl3)
d 109.4, 109.1, 81.5, 79.7, 76.2, 75.3,
74.7, 69.6, 67.0, 61.3, 26.8, 26.5, 25.3, 24.6.
4.3. [2,3:5,6]-Di-O-isopropylidene- -manno-lactone (5a)
D
76%. Rf 0.5 (7:3 Hex/EtOAc); [
a
]
ꢀ38.7 (c 0.47, CHCl3); 1H NMR
D
400 MHz (CDCl3)
d
7.41–7.26 (m, 20H), 5.21 (s, 3H), 4.83 (dd, J¼5.8,
To a solution of oxalyl chloride (2.33 mL, 27.05 mmol) in DCM
(6 mL) cooled to ꢀ60 ꢁC, a solution of DMSO (5.83 mL, 54.1 mmol)
in DCM (6 ml) was slowly added and stirred for 5 min. A solution of
1.2 Hz, 3H), 4.80 (m, 1H), 4.65, (s, 1H), 4.62 (s, 3H), 4.61–4.52 (m,
10H), 4.43 (m, 3H), 4.34 (m, 1H), 3.64 (dd, J¼3.6, 3.6 Hz, 8H), 2.71 (s,
3H), 2.59 (s, 1H), 1.60 (s, 3H), 1.56 (s, 9H), 1.40 (s, 3H), 1.36 (s, 9H);
[2,3:5,6]-di-O-isopropylidene-
D-mannose (6.4 g, 24.6 mmol) in
13C NMR 100 MHz (CDCl3)
d 136.1, 129.8, 128.8, 128.5, 128.4, 128.1,
DCM (96 mL) was then added dropwise to the reaction mixture and
stirred for 15 min. Triethyl amine (34.3 mL, 249.5 mmol) was then
added dropwise to the reaction mixture and stirred for 10 min. The
mixture was warmed to rt and stirred for an additional 1 h. The
reaction was quenched with H2O (30 mL) and extracted with DCM
(3ꢃ30 mL). The combined organic layers were then washed with
H2O (3ꢃ30 mL), brine (30 mL), dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy using (4:1 Hex/EtOAc) as eluent to give the lactone as a white
127.8, 113.4, 101.5, 88.4, 85.2, 85.1, 82.1, 81.7, 81.4, 79.3, 74.1, 74.0,
73.5, 72.5, 70.8, 69.5, 26.6, 26.2, 25.4, 25.0; HRMS m/z for
C17H20O5Na calcd 327.1208, found 327.1179.
4.4.3. 1-Ethynyl-[2,3]-O-isopropylidene-5-O-t-butyldiphenylsilyl-D-
ribofuranose (6d). To a solution of the TMS-protected analog of
alkyne 6d (1.02 g, 1.94 mmol) in MeCN (20 mL) cooled to ꢀ20 ꢁC
was added K2CO3 (0.081 g, 0.58 mmol) in two portions at an in-
terval of 10 min. The mixture was allowed to warm to 0 ꢁC and then
stirred for 2 h. The reaction was quenched with H2O (30 mL) and
extracted with Et2O (3ꢃ30 mL). The organic layer was washed with
H2O (3ꢃ20 mL) and brine (20 mL), then dried over Na2SO4 and
concentrated in vacuo. The crude material was purified by column
chromatography (3:1 Hex/EtOAc) to yield a 3:1 diastereomeric
mixture of 6d as a yellow oil (0.249 g, 28%). The combined yield for
the addition–deprotection sequence was 25%. 1H NMR 300 MHz
solid (4.5 g, 71%). Mp 121–124 ꢁC; Rf 0.5 (7:3 Hex/EtOAc); [
a
]
D þ55.6
(c 0.66, CHCl3); 1H NMR 300 MHz (CDCl3)
d
4.86 (dd, J¼5.2, 3.1 Hz,
1H), 4.83 (d, J¼5.3 Hz, 1H), 4.4 (m, 2H), 4.13 (dd, J¼9.2, 5.7 Hz, 1H),
4.05 (dd, J¼9.2, 3.7 Hz, 1H), 1.46 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H), 1.37
(s, 3H); 13C NMR 75 MHz (CDCl3)
d 173.4, 114.5, 109.9, 78.2, 76.1,
75.9, 72.6, 66.5, 27.0, 26.8, 25.9, 25.1; HRMS m/z for C12H18O6Na
calcd 281.1001, found 281.1017.
(CDCl3)
d
7.77–7.67 (m, 16H), 7.48–7.39 (m, 24H), 4.90 (dd, J¼6.8,
4.4. General procedure for formation of hemi-ketals
from furanolactones
2.5 Hz, 1H), 4.85 (dd, J¼5.8, 1.2 Hz, 3H), 4.79 (s, 3H), 4.76 (d,
J¼6.6 Hz, 1H), 4.63 (d, J¼5.8 Hz, 3H), 4.38 (s, 1H), 4.36 (m, 3H), 4.30
(m, 1H), 3.86 (dd, J¼4.9, 4.9 Hz, 3H), 3.83 (d, J¼5.1 Hz, 2H), 3.71 (dd,
J¼11.2, 4.0 Hz, 1H), 2.67 (s, 3H), 2.49 (s, 1H), 1.60 (s, 3H), 1.56 (s, 9H),
1.40 (s, 3H), 1.38 (s, 9H), 1.13 (s, 27H); 13C NMR 75 MHz (CDCl3)
TMS/acetylene (1.8 mL, 12.65 mmol) in THF (15 mL) was cooled
to ꢀ78 ꢁC under N2. To this was added a hexanes solution of n-BuLi
(8.3 mL, 1.6 M) dropwise. The reaction mixture was stirred for
30 min at ꢀ78 ꢁC and then a solution of 5 (6.32 mmol) in 10 mL THF
was added. The reaction was maintained at ꢀ78 ꢁC for 2 h and then
d
135.7, 135.6, 133.2, 133.0, 132.1, 132.0, 130.3, 130.1, 129.9, 129.8,
128.0 (2), 127.8 (2), 115.2, 113.3, 101.0, 96.1, 87.9, 86.8, 85.3, 82.7,
82.5, 82.0, 81.4, 79.5, 74.2, 72.5, 65.1, 63.3, 60.4, 31.6, 26.9, 26.7, 26.2,

S. Castro et al. / Tetrahedron 65 (2009) 7921–7926
7925
25.6, 25.0, 22.6, 21.0, 19.2, 19.1, 14.2, 14.1; HRMS m/z for
C26H32O5SiNa calcd 475.1917, found 475.1874.
75 MHz (CDCl3)
d
195.1, 161.5, 137.9, 137.5, 128.5, 128.4, 128.3 (2),
127.9,127.7,127.6,112.3, 85.7, 85.6, 80.3, 74.0, 73.4, 72.6, 69.5; HRMS
m/z for C28H28O5Na calcd 467.1834, found 467.1835.
4.4.4. 1-Ethynyl-2,3,5-tri-O-benzyl-D-ribofuranose (6e). To a solu-
tion of 3e (0.76 g, 1.47 mmol) in MeCN/H2O (45 mL:1.5 mL) cooled
to 0 ꢁC, CsF (0.268 g, 1.77 mmol) was added in two portions at an
interval of 10 min. The reaction mixture was allowed to warm to rt
and stirred for 4 h and then quenched with H2O (30 mL). The
product was extracted from the mixture with Et2O (3ꢃ30 mL). The
combined organic layers were washed with H2O (3ꢃ20 mL) and
brine (20 mL) then dried over Na2SO4 and concentrated in vacuo.
The crude material was purified by column chromatography (3:1
Hex/EtOAc) to yield 4e as a pale yellow oil (0.388 g, 60%). The
combined yield for the addition–deprotection sequence was 37%. Rf
4.6. General procedure for 1,2-reduction and acetylation
of oxepinones
To a solution of 7 (0.500 mmol) in THF (10 mL) cooled to 0 ꢁC
under N2 was added NaBH4 (0.022 g, 0.600 mmol). Next iodine
(0.035 g, 0.136 mmol) in a solution of THF (10 mL) was added
dropwise over 30 min. The reaction mixture was stirred at 0 ꢁC for
an additional 10 min and then quenched with 5 mL of a 1:1 H2O/
DCM mixture. Product material was then extracted with DCM
(3ꢃ5 mL). The combined organic layers were washed with H2O
(3ꢃ5 mL) and brine (2ꢃ5 mL), then dried over Na2SO4 and con-
centrated in vacuo. The residue was then dissolved in DCM (20 mL)
and cooled to 0 ꢁC under N2. DMAP (0.005 g, 0.04 mmol), Et3N
(0.064 mL, 0.461 mmol), and Ac2O (0.064 mL, 0.678 mmol) were
added sequentially and the reaction mixture was allowed to warm
to rt overnight. The reaction was quenched by the addition 20 mL of
NH4Cl (aq) solution. Products were then extracted from the re-
action mixture using DCM (3ꢃ5 mL). The organic layers were
washed with H2O (3ꢃ5 mL) and brine (2ꢃ5 mL), then dried over
Na2SO4 and concentrated in vacuo. The crude material was purified
by column chromatography (4:1 Hex/EtOAc) to yield product
oxepines.
0.4 (7:3 Hex/EtOAc); 13C NMR 75 MHz (CDCl3)
d 186.5, 137.8, 137.7,
137.5, 137.3, 137.2, 137.1, 137.0, 128.2, 128.2, 128.2, 128.1, 128.0, 127.9,
127.8, 127.8, 127.8, 127.7, 127.6, 127.5, 127.4, 98.9, 95.7, 83.5, 82.1,
81.8, 81.5, 81.3, 80.6, 80.5, 80.4, 77.7, 77.4, 77.2, 73.6, 73.3, 73.1 (3),
72.7, 72.6, 72.3, 71.9, 70.3, 69.5, 69.3, 68.9; HRMS m/z for
C28H28O5Na calcd 467.1834, found 467.1811.
4.5. General cycloisomerization procedure
To a rt solution of hemi-ketal 6 (3.00 mmol) in 150 mL CHCl3
was added TEA (0.89 mL, 6.35 mmol). The mixture was stirred for
30 min and then concentrated in vacuo. The crude material was
purified by column chromatography (3:1 Hex/EtOAc) to give the
oxepinone product 7.
4.6.1. 1,6-Anhydro-[4,5;7,8]-di-O-isopropylidene-3-O-acetyl-2-de-
oxy-
solid in 59% yield. Rf 0.4 (8:2 Hex/EtOAc); [
1H NMR 300 MHz (CDCl3)
D
-glycero-
D
-talosept-1-enitol (8a). Obtained as an off-white
4.5.1. Z-(5R,6R-[2,2]-Dimethyl-1,3-dioxolo)-7R-(3S-[2,2]-dimethyl-
1,3-dioxolanyl)-oxepin-4-one (7a). Obtained as a pale yellow oil
a]
D þ8.0 (c 1.26, CHCl3);
d
6.21 (dd, J¼7.5, 2.3 Hz, 1H), 6.04 (m,1H),
(10%). [
a
]
D þ62.8 (c 1.14, CHCl3); 1H NMR 300 MHz (CDCl3)
d
7.03 (d,
4.55 (m,2H), 4.33 (ddd, J¼7.3, 1.7, 1.7 Hz, 1H), 4.21 (ddd, J¼8.2, 6.3,
4.7 Hz, 1H), 4.08 (dd, J¼8.7, 6.3, Hz, 1H), 3.9 (dd, J¼8.9, 4.6 Hz, 1H),
3.84 (d, J¼8.2 Hz, 1H), 1.53 (s,3H), 1.41 (s, 3H), 1.40 (s, 3H), 1.34 (s,
J¼6.6 Hz,1H), 5.23 (dd, J¼6.6,1.7 Hz,1H), 4.72 (d, J¼7.4 Hz,1H), 4.58
(dd, J¼7.4, 1.7 Hz, 1H), 4.34 (ddd, J¼6.2, 8.0, 4.5 Hz, 1H), 4.10 (dd,
J¼9.0, 6.2 Hz, 1H), 3.91 (dd, J¼9.0, 4.5 Hz, 1H), 3.79 (d, J¼8.0 Hz, 1H),
3H); 13C NMR 75 MHz (CDCl3)
d 170.3, 145.3, 110.4, 109.7, 101.7, 82.2,
1.51 (s, 3H), 1.33 (m, 9H); 13C NMR 75 MHz (CDCl3)
d
197.3, 159.5,
78.6, 75.4, 73.6, 69.9, 67.1, 26.9, 26.3, 25.5, 25.1, 21.1; HRMS m/z for
111.9, 110.2, 106.9, 86.4, 84.0, 78.6, 73.7, 67.0, 27.0, 26.0, 25.5, 25.3;
C16H24O7Na calcd 351.1420, found 351.1415.
HRMS m/z for C14H21O6 calcd 285.1338, found 285.1337.
4.6.2. 1,6-Anhydro-[4,5;7,8]-di-O-isopropylidene-3-O-acetyl-2-de-
4.5.2. Z-(5S,6S-[2,2]-Dimethyl-1,3-dioxolo)-7R-benzyloxymethyl-ox-
epin-4-one (7c). Obtained as a pale yellow oil in 38% yield. Rf 0.36
oxy-
orless oil in 6% yield. Rf 0.45 (8:2 Hex/EtOAc); [
CHCl3); 1H NMR 300 MHz (CDCl3)
D
-glycero-
D
-galactosept-1-enitol (9a). Obtained as a clear col-
a]
D
þ107.8 (c 0.16,
(7:3 Hex/EtOAc); [
(CDCl3)
a
]
þ47.9 (c 0.86, CHCl3); 1H NMR 400 MHz
d
6.37 (d, J¼7.1 Hz, 1H), 5.45 (dd,
D
d
7.40–7.30 (m, 5H), 7.15 (d, J¼7.2 Hz, 1H), 5.29 (d, J¼7.1 Hz,
J¼4.8 Hz, 1H), 4.7 (dd, J¼7.4, 7.4 Hz, 1H), 4.55 (d, J¼7.3 Hz, 1H), 4.48
1H), 4.81 (d, J¼7.8 Hz, 1H), 4.72 (dd, J¼10.2, 1.2 Hz, 1H), 4.65 (d,
J¼6.24 Hz, 2H), 4.10 (ddd, J¼10.2, 5.1, 2.0 Hz, 1H), 3.86 (m, 2H), 1.57
(m, 1H), 4.28 (s,2H), 4.08 (m, 1H), 4.01 (m, 1H), 2.07 (s, 3H), 1.49 (s,
3H), 1.44 (s, 3H), 1.38 (s, 6H); 13C NMR 75 MHz (CDCl3)
d 169.5,
(s, 2H), 1.52 (s, 3H), 1.43 (s, 3H); 13C NMR 100 MHz (CDCl3)
d
195.1,
150.5, 110.1, 109.5, 98.9, 81.3, 76.3, 76.1, 74.2, 68.5, 66.8, 27.0, 26.2,
25.4, 25.2, 21.1; HRMS m/z for C16H24O7Na calcd 351.1420, found
351.1432.
159.2, 128.5, 127.8, 127.7, 110.5, 106.0, 83.8, 83.6, 76.2, 73.7, 69.5,
27.0, 25.2; HRMS m/z for C17H20O5Na calcd 327.1208, found
327.1185.
4.6.3. 1,6-Anhydro-[4,5]-O-isopropylidene-3-O-acetyl-2-deoxy-
arabinosept-1-enitol (8b) and 1,6-anhydro-[4,5]-O-isopropylidene-
3-O-acetyl-2-deoxy- -ribosept-1-enitol (9b). Isolated as an
D-
4.5.3. Z-(5S,6S-[2,2]-Dimethyl-1,3-dioxolo)-7R-tert-butyldiphenylsil-
oxymethyl-oxepin-4-one (7d). Obtained as a clear colorless oil
D
(41%). Rf 0.4 (7:3 Hex/EtOAc); [
300 MHz (CDCl3)
a
]
þ70.5 (c 0.24, CHCl3); 1H NMR
inseparable mixture of diastereomers in 44% yield as a clear col-
D
d
7.67–7.80 (m, 4H), 7.52–7.32 (m, 6H), 7.12 (d,
orless oil. Rf 0.6 (7:3 Hex/EtOAc); [
a
]
D ꢀ4.9 (c 0.14, CHCl3); 1H NMR
J¼7.1 Hz, 1H), 5.28 (d, J¼7.1 Hz, 1H), 4.79 (m, 2H), 4.05 (m, 3H), 1.49
300 MHz (CDCl3)
d
6.34 (d, J¼7.4 Hz, 2H), 6.21 (dd, J¼7.6,1.5 Hz,1H),
(s, 3H), 1.40 (s, 3H), 1.11 (s, 9H); 13C NMR 75 MHz (CDCl3)
d
195.5,
5.78 (ddd, J¼7.9, 3.8, 1.5 Hz, 1H), 5.56 (dd, J¼6.6, 2.6 Hz, 2H), 4.61
(dd, J¼7.2, 6.8 Hz, 2H), 4.54–4.41 (m, 6H), 4.40–4.31 (m, 4H), 4.24
(m, 2H), 4.20 (m, 2H), 2.12 (s, 6H), 2.11 (s, 3H), 1.51 (s, 6H), 1.49 (s,
159.6, 135.8(2), 133.4, 133.3, 130.0, 129.9, 127.9, 127.8, 110.6, 106.0,
85.4, 83.7, 76.2, 64.0, 27.0, 26.9, 25.3, 19.5; HRMS m/z for
C26H32O5SiNa calcd 475.1917, found 475.1909.
3H), 1.38 (s, 9H); 13C NMR 100 MHz (CDCl3)
d 170.1, 150.2, 147.5,
109.7, 109.5, 100.7, 98.4, 78.8, 78.1, 75.2, 75.1, 69.9, 69.4, 68.5, 67.6,
26.9, 26.3, 24.9, 24.8, 21.4, 21.2.
4.5.4. Z-(5S,6S-Di-O-benzyl)-7R-benzyloxymethyl-oxepin-4-one
(7e). Obtained as a clear colorless oil (8%). Rf 0.4 (8:2 Hex/EtOAc);
[
a
]
D þ77.2 (c 0.55, CHCl3); 1H NMR 300 MHz (CDCl3)
d
7.45-7.24 (m,
4.6.4. 1,6-Anhydro-7-O-benzyl-[4,5]-O-isopropylidene-2-deoxy-D-al-
15H), 7.22 (d, J¼6.7 Hz, 1H), 5.54 (d, J¼6.6 Hz, 1H), 4.96 (d, J¼5.7 Hz,
1H), 4.93 (d, J¼6.0 Hz, 1H), 4.60-4.42 (m,6H), 4.38 (dd, J¼7.5, 3.4 Hz,
1H), 4.08 (ddd, J¼11.5, 7.9, 4.0 Hz, 1H), 3.58 (m, 2H); 13C NMR
trosept-1-enitol (8c). Obtained as a pale yellow oil in 19% yield. Rf
0.43 (7:3 Hex/EtOAc) [
a
]
D þ68.1 (c 2.80, CHCl3); 1H NMR 400 MHz
(CDCl3)
d
7.40–7.27 (m, 5H), 6.50 (d, J¼7.4 Hz, 1H), 4.90 (ddd, J¼9.8,

7926
S. Castro et al. / Tetrahedron 65 (2009) 7921–7926
4.8, 2.1 Hz, 1H), 4.75 (dd, J¼8.6, 7.4 Hz, 1H), 4.67 (d, J¼12.3 Hz, 1H),
4.60 (d, J¼12.3 Hz, 1H), 4.45 (dd, J¼9.9, 7.6 Hz, 1H), 4.27 (dd, J¼7.5,
3.1 Hz,1H), 4.22 (ddd, J¼8.5, 2.7, 1.6 Hz,1H), 3.83 (dd, J¼10.9, 2.1 Hz,
1H), 3.73 (dd, J¼11.0, 5.0 Hz, 1H), 1.53 (s, 3H), 1.40 (s, 3H); 13C NMR
4.8.1. (1S)-S-Phenyl-(5R,6R-[2,2]-dimethyl-1,3-dioxolo)-oxepan-4-
one (11). Obtained as a clear colorless oil. Rf 0.52 (7:3 Hex/EtOAc);
[
a
]
ꢀ406.9 (c 0.24, CHCl3); 1H NMR 400 MHz (CDCl3)
d 7.52–7.47
D
(m, 2H), 7.36–7.26 (m, 3H), 5.46 (dd, J¼10.1, 5.4 Hz, 1H), 4.65 (d,
J¼7.5 Hz, 1H), 4.47 (m, 2H), 4.01 (dd, J¼15.1, 3.5 Hz, 1H), 3.03 (dd,
J¼12.2, 5.3 Hz,1H), 2.93 (dd, J¼12.0,10.1 Hz,1H),1.57 (s, 3H), 1.42 (s,
100 MHz (CDCl3)
d 151.0, 138.3, 128.3, 127.6, 127.5, 108.1, 99.0, 77.9,
77.8, 74.8, 73.5, 70.2, 64.9, 26.3, 24.0; HRMS m/z for C17H22NaO5
calcd 329.1359, found 329.1351.
3H); 13C NMR 100 MHz (CDCl3)
d 201.6, 133.5, 131.9, 129.2, 128.0,
110.9, 83.0, 82.9, 74.2, 60.7, 43.4, 27.1, 25.6. HRMS m/z for
4.6.5. 1,6-Anhydro-7-O-benzyl-[4,5]-O-isopropylidene-3-O-acetyl-2-
C15H18O4SNa calcd 317.0824, found 317.0839.
deoxy-
yield. Rf 0.68 (7:3 Hex/EtOAc); [
400 MHz (CDCl3)
D-allosept-1-enitol (9c). Obtained as a pale yellow oil in 43%
a
]
D
þ35.2 (c 0.86, CHCl3); 1H NMR
4.8.2. (1R)-S-phenyl-(5R,6R-[2,2]-dimethyl-1,3-dioxolo)-oxepan-4-
d
7.41–7.28 (m, 5H), 6.30 (dd, J¼7.8, 2.3 Hz, 1H),
one (12). Obtained as a white solid. Mp 98.5–101.0 ꢁC; Rf 0.69 (7:3
5.89 (ddd, J¼10.2, 10.2 1.9 Hz, 1H), 4.67 (d, J¼12.3 Hz, 1H), 4.60 (d,
J¼12.3 Hz, 1H), 4.52 (dd, J¼10.5, 6.8 Hz, 2H), 4.38 (dd, J¼10.1, 6.8 Hz,
1H), 4.25–4.35 (m, 2H), 3.83 (dd, J¼10.9, 1.9 Hz, 1H), 3.72 (dd,
J¼10.9, 5.4 Hz, 1H), 2.14 (s, 3H), 1.45 (s, 3H), 1.37 (s, 3H); 13C NMR
Hex/EtOAc); [
a
]
D þ234.2 (c 0.49, CHCl3); 1H NMR 400 MHz (CDCl3)
d
7.58–7.42 (m, 2H), 7.38–7.26 (m, 3H), 5.17 (dd, J¼8.9, 4.2 Hz, 1H),
4.65 (d, J¼10.2, 6.9 Hz, 3H), 4.40 (ddd, J¼7.3, 7.3, 3.1 Hz, 1H), 4.20
(dd, J¼13.5, 7.2 Hz, 1H), 3.54 (dd, J¼13.5, 3.0 Hz, 1H), 3.43 (dd,
J¼11.6, 8.9 Hz, 1H), 2.87 (ddd, J¼11.7, 4.1, 1.0 Hz, 1H), 1.61 (s, 3H),
100 MHz (CDCl3)
d 170.3, 146.1, 128.4, 127.6, 109.7, 102.9, 78.9, 78.0,
74.5, 73.5, 70.4, 70.1, 27.6, 25.4, 21.2; HRMS m/z for C19H24O6Na
1.40 (s, 3H); 13C NMR 100 MHz (CDCl3)
d 203.1, 133.3, 132.6, 130.7,
calcd 371.1471, found 371.1441.
129.3, 129.2, 128.2, 112.0, 85.0, 82.9, 73.8, 66.3, 45.8, 27.2, 25.4;
HRMS m/z for C15H18O4SNa calcd 317.0824, found 317.0820.
4.6.6. 1,6-Anhydro-7-O-tert-butyldiphenylsilyl-[4,5]-O-isopro-
pylidene-3-O-acetyl-2-deox.y-
hydro-7-O-tert-butyldiphenylsilyl-[4,5]-O-isopropylidene-3-O-ace-
tyl-2-deoxy- -allosept-1-enitol (9d). This material was obtained as
clear colorless oil in 56% yield as a 3:1 mixture of diastereomers. Rf
0.5 (8:2 Hex/EtOAc); 1H NMR 300 MHz (CDCl3)
7.77–7.69 (m,16H),
D-altrosept-1-enitol (8d) and 1,6-an-
Acknowledgements
D
This research was supported by an NSF CAREER award to MWP
(CHE-0546311). The authors thank Martha D. Morton and Srikanth
Rapole for help collecting NMR and HRMS data, respectively. Nick E.
Leadbeater and C. Vijaya Kumar are thanked for loaned equipment
necessary for the photoisomerization reaction.
d
7.47–7.35 (m, 24H), 6.47 (d, J¼7.3 Hz, 1H), 6.28 (dd, J¼7.4, 2.2, Hz,
3H), 5.85 (ddd, J¼10.2, 1.8, 1.8 Hz, 3H), 5.29 (dd, J¼9.5, 3.1 Hz, 1H),
4.78 (dd, J¼8.6, 7.3 Hz, 1H), 4.54 (m, 4H), 4.37 (dd, J¼10.2, 6.9 Hz,
3H), 4.30 (dd, J¼7.6, 1.6 Hz, 3H), 4.16 (ddd, J¼7.2, 5.3, 2.1 Hz 1H),
4.05 (dd, J¼11.5, 1.6 Hz, 1H), 4.00–3.95 (m, 3H), 3.87 (dd, J¼11.3,
5.2 Hz, 1H), 2.13 (s, 9H), 2.06 (s,3H), 1.45 (s, 3H), 1.43 (s, 9H), 1.35 (s,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.07.041.
12H), 1.09 (s, 9H), 1.08 (s, 27H); 13C NMR 75 MHz (CDCl3)
d 170.3,
170.1, 152.0, 146.3, 135.7, 135.7, 133.5, 133.4, 129.7, 129.6, 127.7, 127.6,
109.6, 108.9, 102.7, 100.0, 97.9, 79.9, 79.4, 78.9, 74.5, 74.3, 70.4, 67.6,
64.6, 64.5, 27.6, 26.8, 26.4, 25.4, 24.8, 21.5, 21.2, 19.4 (2); HRMS m/z
for C28H36O6SiNa calcd 519.2179, found 519.2159.
References and notes
1. Castro, S.; Duff, M.; Snyder, N. L.; Morton, M.; Kumar, C. V.; Peczuh, M. W. Org.
Biomol. Chem. 2005, 3, 3869–3872.
2. Tauss, A.; Steiner, A. J.; Stu¨tz, A. E.; Tarling, C. A.; Withers, S. G.; Wrodnig, T. M.
Tetrahedron: Asymmetry 2006, 17, 234–239.
3. Micheel, F.; Suckfu¨ll, F. Liebigs Ann. Chem. 1933, 502, 85–98.
4. Castro, S.; Fyvie, W. S.; Hatcher, S. A.; Peczuh, M. W. Org. Lett. 2005, 7,
4709–4712.
5. Peczuh, M. W.; Snyder, N. L.; Fyvie, W. S. Carbohydr. Res. 2004, 339, 1163–1171.
6. (a) Alcazar, E.; Pletcher, J. M.; McDonald, F. E. Org. Lett. 2004, 6, 3877–3880; (b)
Boone, M. A.; McDonald, F. E.; Lichter, J.; Lutz, S.; Caao, R.; Hardcastle, K. I. Org.
Lett. 2009, 11, 851–854.
4.7. (1R)-O-Methyl-(5R,6R-[2,2]-dimethyl-1,3-dioxolo)-
oxepan-4-one (10)
Compound 7b (0.18 g, 0.998 mmol) was dissolved in MeOH
(15 mL) and solid NaOMe (1.5 mg, 0.0278 mmol) was added to the
reaction. The mixture was stirred at rt for 30 h then concentrated in
vacuo. The residue was purified by column chromatography (3:1
Hex/EtOAc) to yield 105 mg (49%) of 10. Rf 0.37 (7:3 Hex/EtOAc);
7. Markad, S.; Xia, S.; Surana, B.; Morton, M. D.; Hadad, C. M.; Peczuh, M. W. J. Org.
Chem. 2008, 73, 6341–6354.
[
a
]
ꢀ117.7 (c 4.29, CHCl3); 1H NMR 300 MHz (CDCl3)
d 4.76 (dd,
D
8. Peczuh, M. W.; Snyder, N. L. Tetrahedron Lett. 2003, 44, 4057–4061.
9. Castro, S.; Peczuh, M. W. J. Org. Chem. 2005, 70, 3312–3315.
10. Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125, 7482–7483.
11. Wipf, P.; Graham, T. H. J. Org. Chem. 2003, 68, 8798–8807.
12. (a) Pitsch, W.; Russel, A.; Zabel, M.; Konig, B. Tetrahedron 2001, 57, 2345–2347;
(b) Pitsch, W. Synthese, Struktur und Eigenschaften funktionalisierter, cy-
clischer Endiine. Ph.D. Thesis, University of Regensburg, Regensburg, de, 2001.
13. Attempted cyclization in CHCl3 using PBu3 as promoter resulted in complex
product mixtures with low (<5%) product yield.
J¼7.1, 5.0 Hz,1H), 4.59 (d, J¼7.6 Hz,1H,), 4.38 (ddd, J¼7.5, 2.5, 1.5 Hz,
1H), 4.15 (dd,, J¼14.6, 1.1 Hz, 1H), 3.91 (dd, J¼14.6, 2.9 Hz, 1H), 3.38
(s, 3H), 2.90 (dd, J¼12.3, 5.0 Hz, 2H), 2.80 (dd, J¼12.2, 7.1 Hz, 1H),
1.57 (s, 3H), 1.40 (s, 3H); 13C NMR 75 MHz (CDCl3)
d 201.2, 110.8,
97.2, 83.1, 74.6, 58.5, 55.6, 43.5, 27.0, 25.6; HRMS m/z for
C10H16O5Na calcd 239.0895, found 239.0902.
14. Levallee, J.-F.; Berthiaume, G.; Deslongchamps, P.; Grein, F. Tetrahedron Lett.
1986, 27, 5455–5458.
4.8. Thiophenyl oxepanones 11 and 12
15. Compound 8c was consistently obtained without acetyl protection at C3 under
our standard acetylation conditions. Compound data reported are for the al-
cohol corresponding to 8c.
16. Singh, J.; Kaur, I.; Kaur, J.; Bhalla, A.; Kad, G. L. Synth. Commun. 2003, 33,
191–197.
17. Diagnostic NOEs are for protons that are suprafacial based on the assigned
stereochemistry. The NOESY spectrum and a graphical representation of the
noted cross peaks are in Supplementary data.
18. (a) Csuk, R.; Doerr, P. J. Carbohydr. Chem. 1995, 14, 35–44; (b) Mocerino, M.;
Stick, R. V. Tetrahedron Lett. 1990, 31, 3051–3054.
Compound 7b (0.18 g, 0.998 mmol) was dissolved in dry THF
(25 mL) and cooled to 0 ꢁC and Cs2CO3 (0.33 g, 0.998 mmol) was
added. To this mixture was added thiophenol (0.409 mL,
3.99 mmol) under N2. The solution was stirred at 0 ꢁC for 30 min
and the reaction was then quenched with H2O (20 mL) and
extracted with DCM (3ꢃ15 mL). The organic layers were combined,
dried over Na2SO4, and concentrated in vacuo. The crude material
was purified by column chromatography (3:1 Hex/EtOAc) yielding
8 and 9 in a combined yield of 0.189 g (64%, 1:1 dr).
19. (a) Sasaki, S.; Taniguchi, Y.; Takahashi, R.; Senko, Y.; Kodama, K.; Nagatsugi, F.;
Maeda, M. J. Am. Chem. Soc. 2004, 126, 516–528; (b) Ogura, H.; Takahashi, H.;
Itoh, T. J. Org. Chem. 1972, 37, 72–75.