Acetal-vinyl sulfide cyclization on sugar substrates: Effect of structure and substituent

Article abstract of DOI:10.1021/jo026163i

A range of 2-deoxyfuranoside and -pyranoside derivatives were fashioned into derivatives that carry a vinyl or propenyl side chain. Extension of the alkene by a Suzuki cross-coupling reaction with 1-bromo-1-(phenylthio)ethene gave thioenol ethers as the cyclization substrates. The treatment of these substrates with BF₃·Et₂O in tert-butylmethyl ether below 0 °C induced cyclization to optically active bicyclic ethers. If the cyclizations are carried out in toluene as the solvent, the isomerization of the terminal thioenol ether to the inner thioenol ether can take place prior to the cyclization. The cyclization reactions can be impeded by steric and electronic factors. The opening of the bicyclic ethers could be illustrated with the base-induced conversion of the ketone 53 to the cyclooctenone 54.

Full text of DOI:10.1021/jo026163i

Aceta l-Vin yl Su lfid e Cycliza tion on Su ga r Su bstr a tes: Effect of
Str u ctu r e a n d Su bstitu en t
Pradip K. Sasmal and Martin E. Maier*
Institut fu¨r Organische Chemie, Universita¨t Tu¨bingen, Auf der Morgenstelle 18,
D-72076 Tu¨bingen, Germany
martin.e.maier@uni-tuebingen.de
Received J uly 9, 2002
A range of 2-deoxyfuranoside and -pyranoside derivatives were fashioned into derivatives that carry
a vinyl or propenyl side chain. Extension of the alkene by a Suzuki cross-coupling reaction with
1-bromo-1-(phenylthio)ethene gave thioenol ethers as the cyclization substrates. The treatment of
these substrates with BF3‚Et2O in tert-butylmethyl ether below 0 °C induced cyclization to optically
active bicyclic ethers. If the cyclizations are carried out in toluene as the solvent, the isomerization
of the terminal thioenol ether to the inner thioenol ether can take place prior to the cyclization.
The cyclization reactions can be impeded by steric and electronic factors. The opening of the bicyclic
ethers could be illustrated with the base-induced conversion of the ketone 53 to the cyclooctenone
54.
In tr od u ction
bicyclic ethers.12,13 We recently proposed an alternative
strategy that utilizes acyclic hydroxyacetals containing
C-nucleophilic groups as the substrates.14 A tandem
cyclization yielding initially a mixed acetal, followed by
the generation of a cyclic oxonium ion and intramolecular
trapping by the nucleophile, provides bicyclic oxacycles
(Figure 1).
We could demonstrate this strategy in a stepwise
fashion. Some isolated examples of this type of cyclization
have been described in the literature.15-19 Prior to our
work, systematic studies have been carried out mainly
by the Overman20-24 and Rychnovsky25 groups on the
cyclization reactions of oxonium ions with nucleophiles
directed at the formation of monocyclic ethers. An il-
lustrative example of Overman’s work is mentioned in
While less common in nature than bicyclic alkaloids,
a range of natural products is known that feature
oxabicyclo substructures. Examples include diterpenes
such as sclerophytin A1,2 and the eleutherobins.3 More-
over, bicyclic ethers are used as synthetic intermediates
for the synthesis of carbocyclic compounds with a distinct
functional-group pattern. Among the bicyclic ethers,
8-oxabicyclo[3.2.1]octane derivatives are very easy to
access by the [4 + 3] cycloaddition reactions of oxyallyl
intermediates with furan.4-6 In the latter case, the second
carbon-carbon-bond formation usually corresponds to an
attack of a nucleophile (enol ether or enolate) at a cyclic
oxonium ion. Furthermore, [5 + 2] pyrone-alkene cyclo-
addition reactions provide access to such systems.7-9
Another route is based on the annulation of bis-nucleo-
philes with suitable 1,4-dicarbonyl compounds.10,11 In
addition, transannular cyclization can provide access to
(12) Alvarez, E.; Zurita, D.; Mart´ın, J . D. Tetrahedron Lett. 1991,
32, 2245-2248.
(13) Person, G.; Keller, M.; Prinzbach, H. Liebigs Ann. Chem. 1996,
507-527.
(14) Sasmal, P. K.; Maier, M. E. Org. Lett. 2002, 4, 1271-1274.
(15) Marson, C. M.; Campbell, J .; Hursthouse, M. B.; Malik, K. M.
A. Angew. Chem. 1998, 110, 1170-1172.
(1) MacMillan, D. W. C.; Overman, L. E.; Pennington, L. D. J . Am.
Chem. Soc. 2001, 123, 9033-9044.
(16) Sonawane, H. R.; Maji, D. K.; J ana, G. H.; Pandey, G. J . Chem.
Soc., Chem. Commun. 1998, 1773-1774.
(2) Bernardelli, P.; Moradei, O. M.; Friedrich, D.; Yang, J .; Gallou,
F.; Dyck, B. P.; Doskotch, R. W.; Lange, T.; Paquette, L. A. J . Am.
Chem. Soc. 2001, 123, 9021-9032.
(17) Ohmura, H.; Smyth, G. D.; Mikami, K. J . Org. Chem. 1999,
64, 6056-6059.
(3) Lindel, T. Angew. Chem. 1998, 110, 806-808; Angew. Chem.,
Int. Ed. 1998, 37, 774-776.
(18) Lo´pez, F.; Castedo, L.; Mascaren˜as, J . L. J . Am. Chem. Soc.
2002, 124, 4218-4219.
(4) Fo¨hlisch, B.; Gehrlach, E.; Henle, G.; Boberlin, U.; Herter, R. J .
Chem. Res., Synop. 1991, 136; J . Chem. Res., Miniprint 1991, 1462-
1492.
(19) Cho, Y. S.; Kim, H. Y.; Cha, J . H.; Pae, A. N.; Koh, H. Y.; Choi,
J . H.; Chang, M. H. Org. Lett. 2002, 4, 2025-2028.
(20) Castan˜eda, A.; Kucery, D. J .; Overman, L. E. J . Org. Chem.
1989, 54, 5695-5707.
(5) Harmata, M.; J ones, D. E. J . Org. Chem. 1997, 62, 1578-1579.
(6) Stark, C. B. W.; Pierau, S.; Wartchow, R.; Hoffmann, H. M. R.
Chem.sEur. J . 2000, 6, 684-691.
(21) Blumenkopf, T. A.; Bratz, M.; Castan˜eda, A.; Look, G. C.;
Overman, L. E.; Rodriguez, D.; Thompson, A. S. J . Am. Chem. Soc.
1990, 112, 4386-4399.
(7) Sammes, P. G. Gazz. Chim. Ital. 1986, 116, 109-114.
(8) Mascaren˜as, J . L.; Rumbo, A.; Castedo, L. J . Org. Chem. 1997,
62, 8620-8621.
(22) Blumenkopf, T. A.; Look, G. C.; Overman, L. E. J . Am. Chem.
Soc. 1990, 112, 4399-4403.
(9) Rodr´ıguez, J . R.; Rumbo, A.; Castedo, L.; Mascaren˜as, J . L. J .
Org. Chem. 1999, 64, 966-970.
(23) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J . Am.
Chem. Soc. 1995, 117, 5958-5966.
(10) Molander, G. A.; Cameron, K. O. J . Org. Chem. 1991, 56, 2617-
(24) Berger, D.; Overman, L. E.; Renhowe, P. A. J . Am. Chem. Soc.
1997, 119, 2446-2452.
2619.
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4565.
(25) J aber, J . J .; Mitsui, K.; Rychnovsky, S. D. J . Org. Chem. 2001,
66, 4679-4686.
10.1021/jo026163i CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/13/2002
824
J . Org. Chem. 2003, 68, 824-831

Acetal-Vinyl Sulfide Cyclization on Sugar Substrates
SCHEME 1. Syn th esis of th e Th ioen ol Eth er s in
th e F u r a n osid e Ser ies
F IGURE 1. Tandem cyclization of hydroxyacetals containing
a nucleophilic double bond.
F IGURE 2. Representative examples for vinyl sulfide-
oxonium ion cyclizations.
eq 1 (Figure 2). In the preparation of the substrates for
the cyclization, the cyclic acetals served as the starting
material whereby the nucleophilic group, usually a
vinylsilane or thioenol ether, was introduced by a Suzuki
cross-coupling reaction. In our earlier work, we described
the intramolecular acetal-vinyl sulfide cyclization using
five-, six-, and seven-membered oxonium ions (eq 2,
Figure 2).14 It was observed that the ring size of the cyclic
oxonium ions plays an important role in the mechanism
(ene vs Prins) of the cyclization process. The six-
∆
membered oxonium ion gave only the 4,5-bicyclic ether,
whereas the seven-membered oxonium ion led mainly to
the ∆3,4-bicyclic ether. In the case of five-membered
oxonium ions, a mixture of two possible double-bond
isomers was formed.
The advantage in our approach lies in the fact that it
should be easy to prepare optically active substrates
starting from carbohydrate precursors or by asymmetric
synthesis. In this paper, we present studies that employ
carbohydrate precursors with a vinyl sulfide as the
nucleophile. In the course of these studies, some interest-
ing effects of the stereocenters in the cyclic hemiacetals
were observed.
the acetals with the thioenol ether, and the configuration
of the secondary alcohols in the starting sugar. All the
vinyl sulfides described in the study were prepared by
the Suzuki cross-coupling reaction of 1-bromo-1-(phenyl-
thio)ethene26 (2) with sugar-derived alkenes. Thus, the
vinyl sulfide 3 was obtained from the alkene 1, which in
turn can be prepared from D-ribose (Scheme 1).27 The
Suzuki coupling was done under standard conditions.21,28,29
Thus, the hydroboration of the alkene 1 with 9-BBN (1.2
equiv) in THF, followed by the addition of benzene and
aqueous NaOH and the heating of the mixture in the
presence of tetrakis(triphenylphosphine)palladium
[(Ph3P)4Pd], furnished the vinyl sulfide 3 in good yield.
The thioenol ethers can be chromatographed on silica gel,
but they tend to hydrolyze to the corresponding methyl
ketones in acidic solvents.
Resu lts a n d Discu ssion
P r ep a r a tion of th e Cycliza tion Su bstr a tes. For
this study, a range of five- and six-membered sugars were
used as starting materials. Considering the fact that an
alkoxy group next to the acetal makes the formation of
the oxonium ion more difficult, mainly 2-deoxyglycosides
were used as starting materials. Further variations that
were considered were different ring sizes (five- vs six-
membered acetals), the length of the chain connecting
(26) Magriotis, P. A.; Brown, J . T. Org. Synth. 1995, 72, 252-264.
(27) Ugarkar, B. G.; DaRe, J . M.; Kopcho, J . J .; Brown, C. E., III;
Schanzer, J . M.; Wiesner, J . B.; Erion, M. D. J . Med. Chem. 2000, 43,
2883-2893.
(28) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J . Am. Chem. Soc. 1989, 111, 314-321.
(29) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
J . Org. Chem, Vol. 68, No. 3, 2003 825

Sasmal and Maier
SCHEME 2. Syn th esis of th e Th ioen ol Eth er s 15
a n d 18 of th e P yr a n osid e Ser ies
Likewise, the glycoside 4, which is available from
2-deoxyribose,30 was oxidized to the aldehyde using
Swern conditions and subjected to a Wittig olefination,
providing the vinyl derivative 5. Chain extension by
Suzuki coupling gave rise to the vinyl sulfide 6. A
classical one-carbon homologation of the primary alcohol
by the Wittig reaction of the derived aldehyde with
(methoxymethyl)triphenylphosphonium chloride-KO-t-
Bu gave the enol ether 7 (E/Z 3:1).31 The hydrolysis of 7
in the presence of mercuric acetate led to an aldehyde
that was directly subjected to a Wittig olefination,
providing the alkene 8. As before, the Suzuki coupling
of 8 with 2 via the intermediate borane delivered
substrate 9. As a final substrate in the furanoside series,
the alkene 10, which is available from diacetone-D-
glucose,32 was extended by Suzuki coupling to the vinyl
sulfide 11. In this context, it was discovered that catalytic
amounts of pyridinium p-toluenesulfonate in CH2Cl2
induced the quantitative isomerization of the terminal
vinyl sulfide to the internal isomer.
In the pyranoside series, the choice of substrates, on
the one hand, was guided by the ease of availability. On
the other hand, we sought to choose substrates with few
enough stereocenters to allow for a clear-cut interpreta-
tion of the results in the cyclization reaction. Accordingly,
the pyranosylmethyl alcohol 13, available from 3,4,6-tri-
O-acetyl-D-glucal,33 was subjected to Swern oxidation and
the Wittig reaction to afford the vinyl compound 14. The
synthesis continued with a Suzuki extension to deliver
the vinyl sulfide 15. As a related substrate in this series,
the homologated vinyl sulfide 18 could be reached by the
same strategy as that described for compound 9. Thus,
the conversion of the sugar alcohol to the enol ether 16
via the corresponding aldehyde, hydrolysis, and methyl-
enation led to the allyl derivative 17. The Suzuki reaction
of 17 proceeded uneventfully and provided the thioenol
ether 18 (Scheme 2).
SCHEME 3. Syn th esis of th e Th ioen ol Eth er 21
fr om th e 2,3-Deoxyglu cosid e 13
Certainly, the outcome of the cyclization is dependent
on substituents in the side chain connecting the nucleo-
phile and the cyclic acetal. To gain insight into this issue,
the aldehyde derived from the alcohol 13 was reacted
with isopropenylmagnesium bromide in THF (0-23 °C),
which gave the secondary alcohol 19 as the major product
(dr ) 5:1; Scheme 3). The protection of the alcohol with
benzyl bromide and chromatography gave the diastereo-
merically pure alkene 20. The subsequent hydroboration
and Suzuki coupling delivered the vinyl sulfide 21 (dr )
12:1). The stereochemistry at C-2′ was assigned based
on the Houk model for diastereoselective hydrobora-
tion.34,35 According to this model, an alkyl group occupies
the anti position because it can stabilize the transition
state of the hydroboration. The alkoxy group will be in
the outside position (see structure J , Scheme 3). While
the stereochemistry at C-2′ was difficult to ascertain by
spectroscopic means, the configuration at C-3′ could be
inferred from the NMR data of the cyclic carbonate 24.
This compound was prepared by the hydrogenation of the
benzyl ether 20 using palladium hydroxide on charcoal.
Besides the alcohol 22, some ketone 23 was also formed
in this reaction. The ketone 23 is the major product even
if the hydrogenation is carried out on the alcohol 19.
Treatment of the diol 22 with carbonyldiimidazole pro-
duced the carbonate 24. As an indicator for the config-
uration in the side chain, H-5 of the sugar could be used.
(30) Giuliano, R. M.; Villani, F. J ., J r. J . Org. Chem. 1995, 60, 202-
211.
(31) Crimmins, M. T.; Tabet, E. A. J . Am. Chem. Soc. 2000, 122,
5473-5476.
(32) Liu, Z.; Classon, B.; Samuelsson, B. J . Org. Chem. 1990, 55,
4273-4275.
(33) Stamatatos, L.; Sinay, P.; Pougny, J .-R. Tetrahedron 1984, 40,
1713-1719.
(34) Still, W. C.; Barrish, J . C. J . Am. Chem. Soc. 1983, 105, 2487-
2489.
(35) Houk, K. N.; Rondan, N. G.; Wu, Y.-D.; Metz, J . T.; Paddon-
Row, M. N. Tetrahedron 1984, 40, 2257-2274.
826 J . Org. Chem., Vol. 68, No. 3, 2003

Acetal-Vinyl Sulfide Cyclization on Sugar Substrates
SCHEME 4. Syn th esis of th e Th ioen ol Eth er s 30
a n d 36 fr om 2-Deoxyglycosid es
This proton appears as a doublet of doublets with
coupling constants of 10.5 and 6.5 Hz, respectively, which
is in agreement with a pseudoaxial position for the
isopropyl group. The observed stereoselectivity is in
accordance with the results observed on Grignard reac-
tions on similar 2-deoxyglucopyranoside aldehydes.36
Further substrates were prepared from 2-deoxyglucose
and 2-deoxygalactose. The methyl glucoside 2537,38 was
obtained as mixture of R and â isomers (R/â 7:1) by the
treatment of 2-deoxyglucose with AcCl-MeOH at room
temperature. Selective protection of the primary hydroxyl
group gave the anomeric TIPS ethers 26a and 26b, which
could be separated by flash column chromatography. The
major R anomer was benzylated and converted to the
known primary alcohol 2839 by TBAF treatment. The
oxidation of 28 to the aldehyde and Wittig methylenation
provided the 2-methoxyvinyloxacycle 29. The attachment
of the thioenol ether moiety according to the Suzuki
protocol made compound 30 available. Following the
same sequence of reactions, R-methyl 2-deoxy-D-galacto-
pyranoside40 (31) was converted to the dibenzyl com-
pound 33. The removal of the TIPS protecting group,
Swern oxidation, and Wittig reaction gave rise to the
alkene 35. To complete the synthesis of the cyclization
substrate 36, Suzuki coupling was utilized as before
(Scheme 4).
To complete the range of substrates, the glucoside 3841
was extended to the thioenol ether 39 via the standard
Suzuki protocol. This substrate can be considered an
extreme case because oxonium ion formation as well as
ring flipping are disfavored in comparison to the other
pyranoside substrates (Scheme 5).
Cycliza tion Rea ction s. As became evident in the
course of these investigations, the oxacycles carrying a
thioenol ether side chain can enter into several reaction
channels. Thus, depending on the reaction conditions
(Lewis acid, solvent, temperature) and the substrate,
direct cyclization, isomerization, isomerization followed
by cyclization, and also hydrolysis can take place. The
cyclization reactions were carried out with a substrate
concentration of 0.02 M in the required solvent. Using
SnCl4 in CH2Cl2 between -78 and 0 °C led to the
decomposition of the starting material. Changing the
promoter to TMSOTf resulted in hydrolysis to the cor-
responding ketone. The Lewis acid BF3‚Et2O induced
cyclization in various solvents (toluene, Et2O, THF, CH2-
Cl2), but the reactions were most clean and proceeded
with the highest yields in t-BuOMe. Thus, these acetal-
vinyl sulfide cyclizations were best performed in tert-
butylmethyl ether using borontrifluoride etherate (BF3‚
Et2O, 2 equiv) as the Lewis acid. It is noteworthy that
the isomerization of the terminal vinyl sulfide under
these conditions is very slow below 0 °C. The results of
the cyclization reactions are summarized in Table 1.
SCHEME 5. Syn th esis of th e Th ioen ol Eth er s 39
fr om th e Alk en e 38
(36) van Delft, F. L.; van der Marel, G. A.; van Boom, J . H. Synlett
1995, 1069-1070.
(37) Hughes, I. W.; Overend, W. G.; Stacey, M. J . Chem. Soc. 1949,
2846-2849.
(38) Rauter, A.; Figueiredo, J .; Ismael, M.; Canda, T.; Font, J .;
Figueredo, M. Tetrahedron: Asymmetry 2001, 12, 1131-1146.
(39) Petra´kova´, E.; Kova´cˇ, P.; Glaudemans, C. P. J . Carbohydr. Res.
1992, 233, 101-112.
(40) Overend, W. G.; Shafizadeh, F.; Stacey, M. J . Chem. Soc. 1950,
671-677.
(41) Hung, S.-C.; Wong, C.-H. Angew. Chem. 1996, 108, 2829-2832;
Angew. Chem., Int. Ed. Engl. 1996, 35, 2671-2674.
The treatment of substrate 6 with BF3‚Et2O (2 equiv)
in tert-butylmethyl ether between -30 and 0 °C (standard
conditions) gave a mixture of the ∆3,4- and ∆4,5-bicyclic
ethers 40a and 40b (Figure 3). The homologue of 6, vinyl
sulfide 9, cyclized selectively to the ene-type isomer 41.
The part containing the ether oxygen is an oxocene ring.
Under the same conditions (-30 to 0 °C), the vinyl sulfide
J . Org. Chem, Vol. 68, No. 3, 2003 827

Sasmal and Maier
TABLE 1. Resu lts of th e Tr ea tm en t of Va r iou s Th ioen ol
Eth er s w ith Lew is Acid
entry
substrate
conditionsa
products/results
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
6
9
3
3
3
A
A
A
Ab
B
A
C
C
A
A
A
B
A
A
C
A
C
C
40a , 40b (3.5:1, 71%)
41 (51%)
no reaction
43 (100%)c
42 (63%)
no reaction
44 (38%)
44 (42%)
45 (70%)
46 (48%)
no reaction
47 (71%)
48 (41%)
11
11
12
15
18
39
39
21
30
30
36
36
37
no reaction
49 (2 isomers, 25%, 16%)
50 (60%)d
52a (69%), 52b (4%)
52a (70%)
a
Conditions A: BF3‚Et2O (2 equiv), t-BuOMe, -30 to 0 °C.
Conditions B: TMSOTf (1.5 equiv), CH2Cl2, -78 to 0 °C. Condi-
b
tions C: BF3‚Et2O (2 equiv), toluene, -30 to 10 °C. Conditions
A with BF3‚Et2O (6 equiv), t-BuOMe, 23 °C, 2 d. c Quantitative
d
conversion by analyzing the crude reaction mixture. A pure
compound was not obtained, and the structure and yield (∼60%)
were confirmed by converting 50 to the ketone 51 (Figure 3).
3 was recovered unchanged. Stirring the mixture for 2 d
at room temperature with additional BF3‚Et2O (6 equiv)
induced complete isomerization to the internal vinyl
sulfide 43. Changing the promoter and the solvent
[TMSOTf, 1.5 equiv; CH2Cl2, -78 to 0 °C] produced the
known ketone 42.42 Thus, it can be concluded that
compounds 3 and 43 are difficult to convert to the
corresponding oxonium ions. The 1,2-di-O-isopropylidene
substrate 11 also remained unchanged under the stan-
dard conditions. Changing the solvent to toluene resulted
in the formation of the bicyclic ether 44. The formation
of this compound can be explained by invoking the
cyclization of the internal vinyl sulfide 12 followed by a
1,2 shift of the thiophenyl group and the trapping of the
more stable carbocation with water. The same product
was obtained by subjecting the internal vinyl sulfide 12
to the same reaction conditions.
In line with the expectations, the 2,3-deoxypyranoside
derivatives 15 and 18 could be induced to cyclize under
standard conditions. While the yield for the formation of
the seven-membered unsaturated ether 45 was reason-
able (70%), the corresponding eight-membered ether 46
formed with less efficiency (48%). Both compounds cor-
respond to the ene-type cyclization product. The substrate
39, with three benzyloxy substituents in equatorial
positions, could not be forced to cyclize. While the
standard conditions left 39 unchanged, TMSOTf in CH2-
Cl2 (-78 to 0 °C) produced the methyl ketone 47. With
four equatorial substituents, the ring flipping that is
required for cyclization is clearly strongly disfavored.
Substrate 21, which features two stereocenters in the
nucleophilic side chain, also did not cyclize. Instead, the
enol ether (glycal) 48 was isolated in 41% yield. This can
be rationalized by looking at the prospective product. It
features a gauche-type arrangement of the methyl and
benzyloxy groups. Plus, there is an unfavorable syn-
F IGURE 3. Structures of the compounds obtained in the
cyclization reactions (for conditions, see Table 1).
pentane-type interaction between the two alkoxy groups.
Thus, while the oxonium ion is formed, the geometry that
enables the cyclization cannot be reached.
In a substrate with benzyloxy groups at positions 3 and
4, cis- and trans-relative configurations are, in principle,
possible. The 2-deoxyglucose-derived vinyl sulfide 30
should flip more easily than compound 39. Furthermore,
the oxonium ion should form faster. Nevertheless, the
reaction of 30 under standard conditions left the starting
material unchanged. However, when the solvent tert-
butylmethyl ether was replaced by toluene, a solvent that
favors isomerization of the thioenol ether, the oxabicyclo-
[3.2.1]octane 49 was isolated as a mixture of double-bond
isomers. As compared to 30, the galactose-derived sub-
strate 36 should be able to occupy the other chair
conformation more easily because of the axial substituent
at C-4. This is indeed reflected in the outcome of the
cyclization experiments. Thus, 36 cyclized under the
standard conditions to the bicyclic compound 50. Because
the Prins- and ene-type isomers could not be separated,
the mixture was hydrolyzed to the ketone 51 with HCl
in THF. The yield for the two steps amounted to 50%.
Most likely, after the cyclization, the axial-positioned C-3
benzyloxy group is expelled by elimination. If the cycliza-
tion is run in toluene as the solvent, the cyclization is
preceded by the isomerization of the thioenol ether. This
(42) Kim, K. S.; Szarek, W. A. Carbohydr. Res. 1982, 100, 169-176.
828 J . Org. Chem., Vol. 68, No. 3, 2003

Acetal-Vinyl Sulfide Cyclization on Sugar Substrates
Con clu sion
Particularly, 2-deoxypyranoside derivatives are suit-
able substrates for vinyl sulfide-oxonium ion cycliza-
tions. These kinds of cyclizations are best performed in
tert-butylmethyl ether with BF3‚Et2O as the promoter at
temperatures below 0 °C. Under these conditions, the
isomerization of the thioenol ether is repressed. The
combination of BF3‚Et2O in toluene promotes a relatively
fast isomerization of the thioenol ether to the thermo-
dynamically more stable isomer. These conditions are
then recommended for the synthesis of the smaller
bicyclic ether. In one instance, the chiral bicyclic ether
(ketone 53) was opened by base treatment to the cyclo-
octenone 54. In general, the overall strategy is very
concise and delivers the bicyclic compounds in good
yields, provided that the steric and electronic situation
in the substrate is suitable. On the basis of our study,
appropriate substrates can now be easily identified.
F IGURE 4. Mechanistic pathways (ene vs Prins) for the
reaction of cyclic oxonium ions with vinyl sulfides.
SCHEME 6. Rin g Op en in g of th e Bicyclic Keton e
u n d er th e In flu en ce of LDA To Yield th e
Cycloocten on e 54
Exp er im en ta l Section
Gen er a l P r oced u r e for Su zu k i Rea ction . A stirred
solution of the olefin (1 equiv) in THF (2 mL per 1 mmol) was
treated with 9-BBN (0.5 M in THF, 1.2 equiv) at 0 °C under
nitrogen. Stirring was continued at the same temperature for
1 h and then at room temperature for 3 h. The excess borane
reagent was quenched with degassed water (1 equiv) and the
mixture diluted with benzene (twice the total volume of THF).
To the mixture were added an aqueous 3 N NaOH solution (4
equiv), Pd(PPh3)3 (3 mol %), and 226 (1 equiv), and the reaction
mixture was refluxed for 4 h. After cooling to room tempera-
ture, the organic layer was separated and the aqueous layer
extracted with ether twice. The combined organic layers were
washed with water and brine, dried (Na2SO4), filtered, and
concentrated in vacuo. Purification by flash chromatography
(ethyl acetate-petroleum ether) afforded the desired vinyl
sulfide.
Gen er a l P r oced u r e for Bicyclic Eth er F or m a tion . To
a stirred solution of the acetal-vinyl sulfide derivative (0.02
M in t-BuOMe or toluene) was added BF3‚Et2O (2.0 equiv) at
-30 °C. After stirring for 1 h at the same temperature, the
reaction mixture was slowly warmed to 0 °C (reaction in
t-BuOMe) or 10 °C (reaction in toluene) over a period of 4 h
and then quenched with an aqueous 2 N NaOH solution. The
organic layer was separated and the aqueous layer extracted
with dichloromethane twice. The combined organic layers were
washed with water and brine, dried (Na2SO4), filtered, and
concentrated in vacuo using a rotavapor. The crude products
were subjected to flash chromatography (ethyl acetate-
petroleum ether), yielding the bicyclic ethers.
(2R,3S,5S)-3-(Ben zyloxy)-5-m et h oxy-2-vin ylt et r a h y-
d r ofu r a n (5). A solution of DMSO (0.9 mL, 12.9 mmol) in CH2-
Cl2 (5 mL) was added dropwise at -78 °C to a solution of oxalyl
chloride (0.6 mL, 6.878 mmol) in CH2Cl2 (40 mL). After 5 min,
a solution of 4 (1.36 g, 5.71 mmol) in CH2Cl2 (5 mL) was added
dropwise to the reaction mixture. Stirring was continued for
20 min at -78 °C, before Et3N (4.0 mL, 28.7 mmol) was added
in a dropwise fashion. Thereafter, the reaction mixture was
allowed to warm to 0 °C over a period of 3 h. The reaction
mixture was quenched by the addition of water and diluted
with ether (150 mL). The organic layer was separated and the
aqueous layer extracted with additional ether (2 × 50 mL).
The combined organic layers were washed with water and
brine, dried (Na2SO4), filtered, and concentrated to give the
crude aldehyde (1.27 g), which was immediately used in the
next step without further purification. A solution of this
led mainly to the bicyclic ether 52a together with a small
amount of the isomer 52b. Support for this came from
the cyclization of the inner thioenol ether 37 to afford
52a in 70% yield. The position of the Me group was
confirmed by a NOESY spectrum of 52a , which is
characterized by the appearance of a strong cross-peak
between H-5 and the methyl group.
On the basis of our previous and current experimental
observations, it can be ascribed that both the existing
and newly formed rings influence the cyclization path-
way. If the steric and stereoelectronic factors fit the
formation of a six-membered, cyclic, boatlike transition
state L, the cyclization will proceed through the ene
pathway; otherwise, the Prins pathway will prevail
(Figure 4).
The utility of the bicyclic ethers was demonstrated by
the base-induced ring opening of the ketone 53, which is
available in 71% yield from the alkenyl sulfides 40a and
40b. The treatment of 53 with LDA (3 equiv) in THF
followed by the acetylation of the hydroxyl group with
acetic anhydride gave rise to the optically active cyclo-
octenone 54 (Scheme 6). One of many applications for
such compounds could be to utilize them as higher
homologues of inositols and precursors to protein â-turn
mimetics.43 This method complements other methods for
the synthesis of polyhydroxylated carbocycles such as the
ring-closing metathesis strategy.44,45
(43) Olson, G.; Voss, M. E.; Hill, D. E.; Kahn, M.; Madison, V. S.;
Cook, C. M. J . Am. Chem. Soc. 1990, 112, 323-333.
(44) Hanna, I.; Ricard, L. Org. Lett. 2000, 2, 2651-2654.
(45) Boyer, F.-D.; Hanna, I.; Nolan, S. P. J . Org. Chem. 2001, 66,
4094-4096.
J . Org. Chem, Vol. 68, No. 3, 2003 829

Sasmal and Maier
aldehyde in THF (5 mL) was added dropwise to a cold solution
(-78 °C) of methylene(triphenyl)phosphorane (3 equiv) in THF
[generated by the addition of n-BuLi (6.8 mL, 2.5 M solution
in hexane, 17.0 mmol) to methyltriphenylphosphonium bro-
mide (6.1 g, 17.1 mmol) and dissolution in THF (40 mL) at 0
°C, followed by stirring at 0 °C for 30 min and then at room
temperature for 30 min]. The reaction mixture was stirred at
-78 °C for 30 min and then allowed to warm to room
temperature over a period of 4 h. Subsequently, the mixture
was treated with acetone (10 mL) and stirred for 30 min.
Sufficient ether (∼200 mL) was added and the mixture stirred
for 1 h. The solid was filtered through a pad of Celite and
washed with ether twice. The combined filtrate and washings
were concentrated under vacuum, and the crude product was
flash chromatographed using 10% ethyl acetate in petroleum
ether to afford 5 (869 mg, 65% yield in two steps) as a colorless,
thin liquid. [R]25D: +103.6° (c 0.84, CH2Cl2). 1H NMR (400
MHz, CDCl3): δ 7.26-7.16 (m, 10H), 5.74 (ddd, J ) 6.5, 10.0,
17.0 Hz, 1H), 5.28 (ddd, J ) 1.3, 1.3, 17.0 Hz, 1H), 5.10 (ddd,
J ) 1.3, 1.3, 10.0 Hz, 1H), 4.96 (dd, J ) 1.7, 5.5 Hz, 1H), 4.47
(AB q, J ) 12.4 Hz, ∆ν ) 8.3 Hz, 2H), 4.41 (br dd, J ) 5.3, 6.6
Hz, 1H), 3.72 (ddd, J ) 3.5, 5.0, 8.0 Hz, 1H), 3.16 (s, 3H), 2.20
(ddd, J ) 5.5, 8.0, 14.0 Hz, 1H), 1.92 (ddd, J ) 1.7, 3.8, 14.0
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 137.9, 136.3, 128.3,
127.63, 127.57, 116.8, 104.6, 83.1, 81.7, 71.6, 55.1, 38.6. IR
(neat): 2905, 1496, 1454, 1360, 1210, 1094, 1040 cm-1. API-
ES MS (90 V) m/z (%): 257 (27) [M + Na]+, 203 (12) [M -
OMe]+, 185 (12), 167 (13), 159 (36), 131 (100), 91 (53). HRMS
(FT-ICR): calcd for C14H18O3Na, 257.1148; found, 257.1149.
chromatography (using 20% ethyl acetate in petroleum ether)
afforded the enol ether 7 (1.86 g, E/Z 3.5:1, 70% yield in two
steps) as a colorless oil. 1H NMR (400 MHz, CDCl3): (E isomer)
δ 7.30-7.18 (m, 5H), 6.57 (d, J ) 12.6 Hz, 1H), 4.91 (dd, J )
2.0, 5.8 Hz, 1H), 4.63 (dd, J ) 9.0, 12.6 Hz, 1H, olefin), 4.48
(AB q, J ) 12.4 Hz, ∆ν ) 10.7 Hz, 2H), 4.31 (dd, J ) 5.8, 9.0
Hz, 1H), 3.75-3.68 (m, 1H), 3.48 (s, 3H), 3.32 (s, 3H), 2.31
(ddd, J ) 5.8, 8.3, 14.0 Hz, 1H), 1.95-1.88 (ddd, J ) 2.0, 4.5,
14.0 Hz, 1H); (Z isomer) δ 7.30-7.18 (m, 5H), 5.99 (br d, J )
6.3 Hz, 1H), 4.96-4.93 (m, 2H), 4.51 (AB q, J ) 12.4 Hz, ∆ν )
41.2 Hz, 2H), 4.34 (dd, J ) 6.3, 9.0 Hz, 1H), 3.75-3.68 (m,
1H), 3.48 (s, 3H), 3.33 (s, 3H), 2.24 (ddd, J ) 5.5, 8.0, 14.0 Hz,
1H), 1.95-1.88 (m, 1H). 13C NMR (100 MHz, CDCl3): (E
isomer) δ 151.4, 138.0, 128.2, 127.6, 127.5, 103.8, 100.9, 82.4,
80.4, 71.7, 55.9, 55.0, 39.0; (Z isomer) δ 149.2, 138.3, 128.1,
127.6, 127.3, 104.9, 104.2, 82.4, 76.1, 71.2, 60.0, 54.9, 39.3. IR
(neat): 2933, 1692, 1454, 1363, 1211 cm-1. EIMS m/z (%): 264
(5) [M]+, 232 (7) [M - MeOH]+, 200 (17), 178 (67), 146 (28),
91 (100). HRMS (EI): calcd for C15H20O4, 264.1361; found,
264.1352.
(2R,3S,5S)-2-Allyl-3-(ben zyloxy)-5-m eth oxytetr a h yd r o-
fu r a n (8). To a solution of 7 (1.31 g, 4.96 mmol) in a mixture
of THF-H2O (10:1, 60 mL) was added mercuric acetate (4.74
g, 14.87 mmol) at room temperature. After vigorous stirring
for 1 h at the same temperature, a freshly prepared saturated
aqueous KI solution (100 mL) was added to the mixture. After
stirring for 20 min, the reaction mixture was extracted with
ether three times. The combined extracts were washed with
saturated KI solution, dried (Na2SO4), filtered, and concen-
trated with a rotavapor to give the crude aldehyde (870 mg)
as a pale yellow viscous oil, which was used in the next step
without further purification. A solution of this aldehyde in
THF (5 mL) was added dropwise to a cold solution (-78 °C) of
methylene(triphenyl)phosphorane in THF [generated by the
treatment of n-BuLi (5.9 mL, 2.5 M solution in hexane, 14.75
mmol) to a solution of methyltriphenylphosphonium bromide
(5.32 g, 14.89 mmol) in THF (40 mL) at 0 °C for 30 min and
then at room temperature for 30 min]. The reaction mixture
was stirred at -78 °C for 30 min and then warmed to room
temperature over a period of 4 h. Then it was treated with
acetone (10 mL) and stirred for 30 min. Sufficient ether (∼200
mL) was added, and it was stirred for 1 h. The solid was
filtered through a pad of Celite and washed with ether twice.
The combined filtrate and washings were concentrated under
vacuum, and the crude product was flash chromatographed
using 10% ethyl acetate in petroleum ether to afford 8 (529
mg, 43% yield in two steps) as a colorless, thin liquid. 1H NMR
(400 MHz, CDCl3): δ 7.28-7.18 (m, 5H), 5.72 (dddd, J ) 6.8,
6.8, 10.4, 17.2 Hz, 1H), 5.03-4.91 (m, 3H), 4.44 (AB q, J )
12.0 Hz, ∆ν ) 38.5 Hz, 2H), 4.05 (ddd, J ) 5.8, 5.8, 5.8 Hz,
1H), 3.66 (ddd, J ) 3.0, 4.8, 8.0 Hz, 1H), 3.30 (s, 3H), 2.80-
2.17 (m, 2H), 2.12 (ddd, J ) 5.6, 8.0, 14.0 Hz, 1H), 1.92 (ddd,
J ) 1.3, 3.0, 14.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
138.0, 134.0, 128.3, 127.8, 127.6, 117.3, 104.5, 81.5, 80.6, 71.6,
(2R,3S,5S)-3-(Ben zyloxy)-5-m eth oxy-2-[3-(p h en ylth io)-
bu t-3-en yl]tetr a h yd r ofu r a n (6). Following the general pro-
cedure for the Suzuki coupling, alkene 5 (525 mg, 2.24 mmol)
was converted to compound 6 (556 mg, 67% yield), a pale
yellow, viscous oil. [R]25D: +92.5° (c 1.0, CH2Cl2). 1H NMR (400
MHz, CDCl3): δ 7.50-7.28 (m, 10H), 5.23 (s, 1H), 5.01 (dd, J
) 1.5, 5.5 Hz, 1H), 4.97 (s, 1H), 4.54 (AB q, J ) 12.0 Hz, ∆ν )
36.6 Hz, 2H), 4.07 (ddd, J ) 5.0, 5.0, 8.0 Hz, 1H), 3.71 (ddd, J
) 3.5, 5.0, 8.0 Hz, 1H), 3.40 (s, 3H), 2.48-2.32 (m, 2H), 2.26
(ddd, J ) 5.5, 8.0, 14.0 Hz, 1H), 2.01 (ddd, J ) 1.5, 3.5, 14.0
Hz, 1H), 1.97-1.89 (m, 1H), 1.83-1.74 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 145.1, 137.9, 133.0, 132.9, 129.0, 128.3, 127.7,
127.5, 113.2, 104.1, 81.5, 80.9, 71.5, 54.7, 38.7, 32.7, 32.5. IR
(neat): 2912, 1583, 1476, 1454, 1439 cm-1. EIMS m/z (%): 370
(3) [M]+, 339 (5) [M - OMe]+, 312 (11), 279 (14), 203 (17), 150
(100), 135 (23), 91 (76). HRMS (EI): calcd for C22H26O3S,
370.1603; found, 370.1610.
Meth yl (5E,Z)-3-O-Ben zyl-2,5-d id eoxy-6-O-m eth yl-r-D-
er yth r o-h ex-5-en ofu r a n osid e (7). A solution of DMSO (1.6
mL, 22.6 mmol) in CH2Cl2 (5 mL) was added dropwise at -78
°C to a solution of oxalyl chloride (1.0 mL, 11.5 mmol) in CH2-
Cl2 (50 mL). After 5 min, a solution of the alcohol 4 (2.40 g,
5.71 mmol) in CH2Cl2 (5 mL) was added dropwise to the
reaction mixture. Stirring was continued for 20 min at -78
°C, before Et3N (7.0 mL, 50.2 mmol) was added dropwise.
Thereafter, the reaction mixture was allowed to warm to 0 °C
over a period of 3 h. Workup was initiated by the addition of
water and ether (200 mL). The organic layer was separated
and the aqueous layer extracted with additional ether (2 ×
75 mL). The combined organic layers were washed with water
and brine, dried (Na2SO4), filtered, and concentrated to give
the crude aldehyde (1.86 g), which was immediately used in
the next step without further purification. In a different flask,
(methoxymethyl)triphenylphosphonium chloride (10.36 g, 30.22
mmol) was suspended in THF (60 mL). The slurry was treated
at 0 °C, in portions, with potassium tert-butoxide (2.26 g, 20.14
mmol) over a period of 15 min. After 1 h at 0 °C, a solution of
the above crude aldehyde in THF (10 mL) was added dropwise
to the ylide solution. After being stirred for 30 min at the same
temperature, the mixture was treated with water and ex-
tracted with ether three times. The combined organic extracts
were washed with water and brine, dried (Na2SO4), filtered,
and concentrated. Purification of the crude product by flash
54.9, 38.6, 37.6. IR (neat): 2919, 1497, 1454, 1205, 1058 cm-1
.
(2R,3S,5S)-3-(Ben zyloxy)-5-m eth oxy-2-[4-(p h en ylth io)-
p en t-4-en yl]tetr a h yd r ofu r a n (9). Following the general
procedure, alkene 8 (170 mg, 0.68 mmol) was extended to the
vinyl sulfide 9 (192 mg, 73% yield), a pale yellow, viscous oil.
[R]23D: +89.2° (c 0.75, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ
7.32-7.27 (m, 2H), 7.22-7.13 (m, 8H), 5.02 (s, 1H), 4.86 (dd,
J ) 1.5, 5.5 Hz, 1H), 4.77 (s, 1H), 4.45 (A of AB q, J ) 12.0
Hz, 1H), 4.35 (B of AB q, J ) 12.0 Hz, 1H), 3.88 (ddd, J ) 5.3,
5.3, 7.0 Hz, 1H), 3.56 (ddd, J ) 3.5, 5.0, 8.0 Hz, 1H), 3.24 (s,
3H), 2.16-2.06 (m, 3H), 1.85 (ddd, J ) 1.5, 3.0, 14.0 Hz, 1H),
1.58-1.33 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 145.5, 138.1,
133.1, 129.1, 128.4, 127.8, 127.7, 113.1, 104.3, 81.7, 81.6, 71.7,
54.9, 38.8, 36.3, 32.8, 24.6. IR (neat): 2926, 1607, 1439, 1364,
1208, 1091, 1043 cm-1. EIMS m/z (%): 384 (3) [M]+, 353 (6)
[M - OMe]+, 293 (3) [M - 91]+, 277 (7), 235 (12), 217 (20),
167 (69), 91 (100). HRMS (EI): calcd for C23H28O3S, 384.1759;
found, 384.1752.
830 J . Org. Chem., Vol. 68, No. 3, 2003

Acetal-Vinyl Sulfide Cyclization on Sugar Substrates
(1R,6R,7S)-7-(Ben zyloxy)-3-(p h en ylth io)-9-oxa bicyclo-
[4.2.1]n on -2-en e (40a ) a n d (1R,6R,7S)-7-(Ben zyloxy)-3-
(p h en ylth io)-9-oxa bicyclo[4.2.1]n on -3-en e (40b). Follow-
ing the general procedure, compound 6 (200 mg, 0.54 mmol)
was cyclized to an inseparable mixture of compounds 40a and
40b (3.5:1, 129 mg, 71% yield), a pale yellow, viscous oil. All
data reported are for 40a . 1H NMR (400 MHz, C6D6): δ 7.40-
6.93 (m, 10H), 5.91 (d, J ) 5.5 Hz, 1H), 4.56 (ddd, J ) 2.5,
5.5, 8.0 Hz, 1H), 4.42 (dd, J ) 5.0, 5.0 Hz, 1H), 4.17 (AB q, J
) 12.0 Hz, ∆ν ) 6.8 Hz, 2H), 3.71 (dd, J ) 2.5, 7.0 Hz, 1H),
2.57 (ddd, J ) 3.5, 8.0, 16.4 Hz, 1H), 2.09-1.98 (m, 2H), 1.80-
1.70 (m, 2H), 1.25 (dddd, J ) 3.5, 4.5, 8.0, 14.0 Hz, 1H). 13C
NMR (100 MHz, C6D6): δ 138.9, 136.8, 136.7, 131.6, 129.4,
129.5-127.2 (several lines), 84.9, 81.8, 76.6, 71.0, 39.9, 33.3,
Hz, 1H, H-5), 1.51 (dddd, J ) 3.0, 4.3, 7.0, 14.5 Hz, 1H, H-5).
13C NMR (100 MHz, CDCl3): δ 210.5 (C-3), 137.7, 128.5, 127.8,
127.7, 84.1 (C-7), 82.2 (C-6), 72.9 (C-1), 71.0 (benzylic), 51.6
(C-2), 40.2 (C-4), 38.5 (C-8), 28.1 (C-5). IR (neat): 2941, 1699,
1496, 1455, 1365, 1248, 1196, 1091 cm-1. API-ES MS (70 V)
m/z (%): 269 (28) [M + Na]+, 247 (26) [M + H]+, 155 (8) [M -
91]+, 139 (17), 91 (100). HRMS (FT-ICR): calcd for C15H18O3-
Na, 269.1148; found, 269.1147.
(1R,2S)-2-(Ben zyloxy)-6-oxocyclooct-4-en -1-yl Aceta te
(54). To a solution of LDA (0.366 mmol) in THF (3 mL)
[generated from n-BuLi (122 µL, 2.5 M solution, 0.305 mmol)
and i-Pr2NH (50 µL, 0.357 mmol) at -10 °C] was added a
solution of the ketone 53 (30 mg, 0.122 mmol) in THF (1 mL)
dropwise at 0 °C. The reaction mixture was allowed to reach
room temperature and was stirred for 16 h before it was
quenched with an aqueous NH4Cl solution and extracted with
ether three times. The combined organic layers were washed
with water and brine, dried (Na2SO4), filtered, and concen-
trated in vacuo. The residue was dissolved in dichloromethane
(4 mL) and treated with DMAP (15 mg, 0.123 mmol), triethyl-
amine (102 µL, 0.732 mmol), and acetic anhydride (46 µL,
0.487 mmol) at 0 °C. The reaction mixture was warmed to
room temperature and stirred for 2 h. Then it was quenched
with an aqueous NaHCO3 solution and extracted with dichloro-
methane. The dichloromethane layer was washed with water
and brine, dried (Na2SO4), and filtered. Concentration and
chromatographic purification (25% ethyl acetate in petroleum
ether) afforded the cyclooctenone 54 as a colorless, viscous oil
30.8. IR (neat): 3030, 2935, 1582, 1475, 1439, 1360, 1208 cm-1
.
HRMS (FT-ICR): calcd for C21H22O2SNa, 361.1233; found,
361.1231.
(1R,7R,8S)-8-(Ben zyloxy)-3-(ph en ylth io)-10-oxabicyclo-
[5.2.1]d ec-3-en e (41). Following the general procedure, com-
pound 9 (525 mg, 2.24 mmol) was cyclized to compound 41
(556 mg, 67% yield), a pale yellow, viscous oil. [R]25D: -114.0°
(c 0.15, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.38-7.26 (m,
10H, aromatic), 5.71 (t, J ) 8.6 Hz, 1H, H-4), 4.61 (ddd, J )
2.0, 4.0, 7.0 Hz, 1H, H-1), 4.45 (AB q, J ) 11.6 Hz, ∆ν ) 29.8
Hz, 2H, benzylic), 4.25 (dd, J ) 4.8, 7.0 Hz, 1H, H-7), 4.14
(ddd, J ) 4.8, 7.6, 7.6 Hz, 1H, H-8), 2.70 (d, J ) 15.0 Hz, 1H,
H-2), 2.55 (dd, J ) 7.6, 12.5 Hz, 1H, H-9), 2.48 (ddd, J ) 3.5,
3.5, 12.5 Hz, 1H, H-5), 2.22-2.14 (m, 1H, H-6), 2.11-1.93 (m,
3H, H-2, H-5, and H-9), 1.68 (ddd, J ) 3.5, 13.5, 13.5 Hz, 1H,
H-6). 13C NMR (100 MHz, CDCl3): δ 138.2, 134.5, 133.7, 132.4
(C-4), 132.1, 129.2, 128.4, 127.7, 127.4, 85.6 (C-8), 83.0 (C-7),
81.6 (C-1), 71.6 (benzylic), 39.4 (C-2), 36.9 (C-9), 35.2 (C-6),
23.8 (C-5). IR (neat): 2922, 1583, 1496, 1439, 1363 cm-1. EIMS
m/z (%): 352 (6) [M]+, 261 (4) [M - 91]+, 243 (32), 165 (44),
151 (69), 91 (100). HRMS (EI): calcd for C22H24O2S, 352.1497;
found, 352.1517.
1
(18 mg, 51% yield). [R]24D: -14.7° (c 0.28, CH2Cl2). H NMR
(400 MHz, CDCl3): δ 7.35-7.27 (m, 5H, aromatic), 6.32 (ddd,
J ) 6.8, 7.6, 12.6 Hz, 1H, H-4), 5.98 (d, J ) 12.6 Hz, 1H, H-5),
5.20 (ddd, J ) 3.0, 3.0, 9.8 Hz, 1H, H-1), 4.55 (AB q, J ) 12.0
Hz, ∆ν ) 16.0 Hz, 2H, benzylic), 3.76 (ddd, J ) 3.0, 3.0, 9.0
Hz, 1H, H-2), 3.03-2.86 (m, 2H), 2.69-2.50 (m, 2H), 2.30-
2.21 (m, 1H), 2.06 (s, 3H, OCOMe), 1.97-1.90 (m, 1H). 13C
NMR (100 MHz, CDCl3): δ 203.1, 170.2, 137.8, 128.5, 127.9,
127.7, 74.6, 72.5, 71.8, 39.1, 31.7, 24.2, 21.2. IR (neat): 2925,
1735, 1684, 1668, 1369, 1242 cm-1. EIMS m/z (%): 288 (0.3)
[M]+, 228 (7), 181 (10), 137 (42), 122 (67), 91 (100). HRMS (FT-
ICR): calcd for C17H20O4Na, 311.1254; found, 311.1256.
(1R,6R,7S)-7-(Ben zyloxy)-9-oxa bicyclo[4.2.1]n on a n -3-
on e (53). To a stirred solution of the bicyclic vinyl sulfide 40
(100 mg, 0.30 mmol) in THF (10 mL) was added an aqueous 3
N HCl solution (3 mL) at 0 °C, and the reaction mixture was
stirred overnight at room temperature. Solid NaHCO3 was
added to neutralize the acid. The mixture was treated with
water and extracted with ether three times. The combined
organic layers were washed with water and brine, dried (Na2-
SO4), filtered, and concentrated in vacuo. Chromatographic
purification (30% ethyl acetate in petroleum ether) furnished
Ack n ow led gm en t. Financal support by the Deut-
sche Forschungsgemeinschaft and the Fonds der Che-
mischen Industrie is gratefully acknowledged. P.K.S.
thanks the Alexander von Humboldt Foundation for a
fellowship.
the ketone 53 as a colorless oil (63 mg, 87% yield). [R]28
:
D
1
+35.9° (c 0.90, CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.34-
7.22 (m, 5H, aromatic), 4.64 (dddd, J ) 1.3, 4.0, 5.3, 9.4 Hz,
1H, H-1), 4.48 (dd, J ) 2.3, 5.0 Hz, 1H, H-6), 4.44 (s, 2H,
benzylic), 3.99 (dd, J ) 1.5, 6.8 Hz, 1H, H-7), 2.87 (dd, J )
6.0, 16.0 Hz, 1H, H-2), 2.55 (ddd, J ) 4.8, 7.0, 12.6 Hz, 1H,
H-4), 2.40-2.28 (m, 3H, H-2, H-4, and H-8), 2.07 (ddd, J )
3.8, 6.8, 14.5 Hz, 1H, H-8), 1.93 (dddd, J ) 5.0, 5.0, 10.6, 14.5
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of all new compounds and the NMR
spectra for these compounds (1H, 13C). This material is
available free of charge via the Internet at http://pubs.acs.org.
J O026163I
J . Org. Chem, Vol. 68, No. 3, 2003 831