Stereoselective synthetic approaches to highly substituted cyclopentanes via electrophilic additions to mono-, di-, and trisubstituted cyclopentenes

Article abstract of DOI:10.1021/jo000101f

Electrophilic additions to allylically substituted alkenes are of broad synthetic utility. The control of stereoselectivity in such reactions has attracted considerable interest. However, the effect of allylic and homoallylic substituents in cyclopentenyl systems has not been investigated systematically. Studies on a series of mono, di-, and trisubstituted cyclopentenes are reported in which trans-vicinal-additions favor a syn-selective approach of electrophiles to the cyclopentene system. The formal addition of HOBr, HOCl, CH₃SCl, and dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF)/NaN₃ with a variety of cyclopentene substrates has been carried out, and the effects of various allylic substituents on these selectivities have been examined. Additions of HOBr, HOCl, and DMTSF to highly functionalized substrates proceed predictably with syn selectivity, giving predominantly or exclusively one product. Methanesulfenyl chloride additions are less predictable, but can be tuned by suitable alteration of solvent and substrate. Results have proven useful in total syntheses of (+)-trehazolin and (+)-allosamidin.

Full text of DOI:10.1021/jo000101f

4058
J . Org. Chem. 2000, 65, 4058-4069
Ster eoselective Syn th etic Ap p r oa ch es to High ly Su bstitu ted
Cyclop en ta n es via Electr op h ilic Ad d ition s to Mon o-, Di-, a n d
Tr isu bstitu ted Cyclop en ten es
Matthew A. Clark, Bradley K. Goering, J un Li, and Bruce Ganem*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University,
Ithaca, New York 14853-1301
Received J anuary 25, 2000
Electrophilic additions to allylically substituted alkenes are of broad synthetic utility. The control
of stereoselectivity in such reactions has attracted considerable interest. However, the effect of
allylic and homoallylic substituents in cyclopentenyl systems has not been investigated systemati-
cally. Studies on a series of mono, di-, and trisubstituted cyclopentenes are reported in which trans-
vicinal-additions favor a syn-selective approach of electrophiles to the cyclopentene system. The
formal addition of HOBr, HOCl, CH3SCl, and dimethyl(methylthio)sulfonium tetrafluoroborate
(DMTSF)/NaN3 with a variety of cyclopentene substrates has been carried out, and the effects of
various allylic substituents on these selectivities have been examined. Additions of HOBr, HOCl,
and DMTSF to highly functionalized substrates proceed predictably with syn selectivity, giving
predominantly or exclusively one product. Methanesulfenyl chloride additions are less predictable,
but can be tuned by suitable alteration of solvent and substrate. Results have proven useful in
total syntheses of (+)-trehazolin and (+)-allosamidin.
In tr od u ction
The promising biological activity of several new cyclo-
pentane-containing natural products has generated con-
siderable interest in their total synthesis. The polyhy-
droxylated cyclopentane rings in allosamidin 1 (Figure
1), trehazolin 2, the keruffarides and crasserides 3, and
mannostatins A and B (4 and 5, respectively) are thought
to mimic the structure of carbohydrates. As a result,
many of these substances inhibit glycoside-processing
enzymes, and total syntheses of several have been
reported.1-4
In previous synthetic studies reported by our labora-
tory, penta- and hexasubstituted cyclopentane units were
constructed in a two-stage process (Scheme 1). Stage 1
involved the well-precedented heterocycloaddition of a
monosubstituted cyclopentadiene like 6, which, upon
reduction of the intermediate bicyclic adduct 7, afforded
3,4,5-trisubstituted cyclopentenes such as 8. Stage 2 of
the process involved a vicinal functionalization of the bis-
allylically substituted alkene group in 8 to introduce two
(1) Allosamidin: (a) Kassab, D.; Ganem, B. J . Org. Chem. 1999, 64,
1782-1783. (b) Goering, B. K.; Ganem, B. Tetrahedron Lett. 1994, 35,
6997-7000. (c) Trost, B. M.; Van Vranken, D. L. J . Am. Chem. Soc.
1990, 112, 1261-1263. (d) Griffith, D. A.; Danishefsky, S. J . J . Am.
Chem. Soc. 1991, 113, 5863-5864. (e) Takahashi, S.; Terayama, H.;
Kuzuhara, H. Tetrahedron Lett. 1992, 33, 7565-7568.
(2) Trehazolin: (a) Goering, B. K.; Li. J .; Ganem, B. Tetrahedron
Lett. 1995, 36, 8905-8908. (b) Li, J .; Lang, F. R.; Ganem, B. J . Org.
Chem. 1998, 63, 3403-3410. (c) Ogawa, S.; Uchida, C. Chem. Lett.
1993, 173-176. (d) Kobayashi, Y.; Miyazaki, H.; Shiozaki, M. J . Org.
Chem. 1994, 59, 813-822. (e) Ledford, B. E.; Carreira, E. M. J . Am.
Chem. Soc. 1994, 117, 11811-11812.
F igu r e 1. Structures of some naturally occurring cyclopen-
titols.
additional substituents leading to 9. For many stage 2
additions, the factors affecting stereoselectivity are not
well-understood. In the case of vicinal dihydroxylation,
numerous reports of the osmylation of such cyclopentenes
have appeared,5 although no clear stereochemical trend
(3) Mannostatins (a) King, S. B.; Ganem, B. J . Am. Chem. Soc. 1991,
113, 5089-5090. (b) King, S. B.; Ganem, B. J . Am. Chem. Soc. 1994,
116, 562-570. (c) Knapp, S.; Phar, T. G. M. J . Org. Chem. 1991, 56,
4096-4097. (d) Trost, B. M.; Van Vranken, D. L. J . Am. Chem. Soc.
1991, 113, 6317-6318. (e) Ogawa, S.; Kimura, H.; Uchida, C.; Ohashi,
T. J . Chem. Soc., Perkin Trans. 1 1995, 1695-1705. (f) Ling, R.;
Mariano, P. S. J . Org. Chem. 1998, 63, 6072-6076.
(5) See inter alia: (a) Hanselaer, R.; Samson, M.; Vandewalle, M.
Tetrahedron 1978, 34, 2393-2397. (b) Trost, B. M.; Kuo, G.-H.;
Benneche, T. J . Am. Chem. Soc. 1988, 110, 621-622. (c) Poli, G.
Tetrahedron Lett. 1989, 30, 7385-7388. (d) Halterman, R. L.; McEvoy,
M. A. J . Am. Chem. Soc. 1992, 114, 980-985. (e) Donohoe, T. J .; Garg,
R.; Moore, P. R. Tetrahedron Lett. 1996, 37, 3407-3410. (f) Donohoe,
T. J .; Moore, P. R.; Waring, M. J .; Newcombe, N. J . Tetrahedron Lett.
1997, 38, 5027-5030.
(4) For
a recent review, see (g) Berecibar, A.; Grandjean, C.;
Siriwardena, A. Chem. Rev. 1999, 99, 779-844.
10.1021/jo000101f CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/06/2000

Electrophilic Additions to Substituted Cyclopentenes
J . Org. Chem., Vol. 65, No. 13, 2000 4059
Sch em e 1
Sch em e 3
Sch em e 2
has emerged.6 Electrophilic addition reactions to allyl-
ically substituted alkenes are of broad synthetic utility,
and the control of stereoselectivity in such reactions has
attracted considerable interest7,8 However, the effect of
allylic and homoallylic substituents in cyclopentenyl
systems has not been investigated systematically.9
Here we report studies on a series of mono, di-, and
trisubstituted cyclopentenes in which we have observed
a pattern of trans-vicinal-additions derived from the
approach of electrophiles syn to allylic substituents on
the cyclopentene system. The stereochemical outcome
with a variety of substrates and the effect of various
allylic substituents on these selectivities have been
examined. Our results have proven useful in total
syntheses of (+)-trehazolin2a,b and (+)-allosamidin1a
Sch em e 4
Resu lts
HOX Ad d ition s. Prior to the present study, the
stereoselectivity of HOBr addition to a substituted cy-
clopentene, formally achieved using NBS-H2O, has been
examined in the case of 3-methylcyclopentene 10 (Scheme
2).10 Reaction of 10 with NBS in water was reported to
give a mixture of bromohydrins 11 and 12, in ratios of
3:1 to 7:1. Encouraged by that finding, our laboratory
subsequently examined the reaction of 2-cyclopentenol
13 (Scheme 3) with NBS in H2O which afforded bromo-
diols 16 and 17 (4:1 ratio) in 78% overall yield.11 Direct
NMR monitoring of the addition in D2O confirmed that
13 was completely consumed, that no other products were
formed, and that the 4:1 product ratio was unaffected
by the workup and isolation. The minor product 17 arises
by the expected trans-opening of anti-bromonium ion 15,
and its meso-structure was readily established by NMR.
The major product 16 can be seen to arise from the syn-
bromonium ion 14 by a similar mechanism.1b
As an additional test of the method, 3-azidocyclopen-
tene12 18 (Scheme 4) was exposed to NBS in H2O (with
DMSO as a cosolvent to improve solubility), affording a
mixture of two products (3:1 ratio) in 91% yield. The
(6) Goering, B. K.; Ph.D. Dissertation, Cornell University, 1995.
(7) For studies on electrophilic additions, see: De La Mare, P. B.
D.; Bolton, R. Electrophilic Additions to Unsaturated Systems; Elesevi-
er: Amsterdam, 1982. Fahey, R. C. Top. Stereochem. 1968, 3, 237-
342.
(8) Kahn, S. D.; Pau, C. F.; Chamberlin, A. R.; Hehre, W. J . J . Am.
Chem. Soc. 1987, 109, 650-663.
(11) Ratios were obtained by integration of 1H NMR spectra of
mixtures. Typically, one or more pairs of peaks were sufficiently well-
resolved to obtain accurate integration values with (10% precision.
Most reported yields are unoptimized. Because of the water-solubility
and/or volatility of many low-molecular weight target compounds, the
ratios of products, whenever appropriate, were measured using NMR
for in situ reaction monitoring and the results compared with the ratios
of isolated products.
(9) For seminal work on the stereochemistry of additions to substi-
tuted cyclohexenes, see (a) Barili, P. L.; Bellucci, G.; Marioni, F.;
Morelli, I.; Scartoni, V. J . Org. Chem. 1972, 37, 4353-4357. (b) Bellucci,
G.; Berti, G.; Ingrosso, G.; Mastrorilli, E. Tetrahedron Lett. 1973, 3911-
3914. (c) Bellucci, G.; Berti, G.; Bianchini, R.; Ingrosso, G.; Mastrorilli,
E. Gazz. Chim. Ital. 1976, 106, 955-966. (d) Bellucci, G.; Bianchini,
R.; Ingrosso, G.; Mastrorilli, E. Gazz. Chim. Ital. 1978, 108, 643-650.
(10) Finnegan, R. A.; Wepplo, P. J . Tetrahedron 1972, 28, 4267-
4271.
(12) Chmielowiec, U.; Uzarewicz, I.; Uzarewicz, A. Pol. J . Chem.
1990, 64, 613-619.

4060 J . Org. Chem., Vol. 65, No. 13, 2000
Clark et al.
Sch em e 5
Sch em e 6
31, and its structure was unambiguously established by
X-ray crystallography.
The formal addition of HOCl to substituted cyclo-
pentenes also favored products arising from syn-chloro-
nium ion formation. Reaction of N-chlorosuccinimide in
H2O-DMF with diol 28 furnished the halohydrin formate
34, although only in 20% yield. The structure of 34 was
confirmed by reaction with base to afford epoxide 30,
which was identical with an authentic sample. The
reaction of NCS-H2O with diacetate 351a gave better
results, producing 36 (65% yield), which also formed 30
upon treatment with base.In summary, the addition of
hypohalous acids to substituted cyclopentenes afforded
predominantly trans-1,2-halohydrins arising from syn-
addition of X+ to the allylic substituent. This preference
for 1,2-addition products derived from intermediate syn-
halonium ions appears to be independent of the nature
of the substituent (i.e., alkyl, OH, OR) and is most
pronounced with polysubstituted cyclopentenes.
MeSCl Ad d ition s. The stereochemistry of alkyl- and
arylsulfenyl chloride additions to substituted cyclo-
pentenes was first examined by Hartke et al. (Scheme
7).17 In contrast to HOBr and HOCl additions, no clear
stereochemical trend was apparent in this study. Addi-
tion of p-tolyl sulfenyl chloride to a solution of chloro-
sulfide 37 in CH2Cl2 afforded dichlorodisulfides 40 and
41 as a 9:1 ratio in high yield. The predominant product
40 apparently arose from the intermediate 38 in which
a putative thiiranium ion intemediate was oriented anti
to the allylic substituent. In contrast, the same addition
to the corresponding chlorosulfone 42 afforded products
44 and 45 apparently arising from the regioisomeric
opening of a common syn-thiiranium ion of structure 43.
The present study examined the addition of MeSCl to
2-cyclopenten-1-ol 13 in a variety of solvents (Scheme 8).
When CH3SCl was combined with 13 in CH2Cl2, a 1.4:1
ratio of products was obtained in 60% yield after acetyl-
ation. Since the two products were unstable to chroma-
tography, the mixture was immediately acetylated. The
product mixture displayed well-resolved NMR signals for
the two components, consistent with 1-chloro-2-thio-3-
acetoxycyclopentanes. However, pure samples of each
product could not be obtained by chromatography, and
nuclear Overhauser enhancement (NOE) measurements
on the mixture were unable to provide unambiguous
stereochemical assignments. Ultimately, the two addition
products were assigned structures 46 (major) and 47
(minor) on the basis of the following chemical correlation
of their derived acetates 48 and 49. After a number of
unsuccessful attempts using Bu3SnH, Na-NH3, and Na-
naphthalene, the dehalogenation-deacetylation of a
major and minor products were assigned structures 19
and 20, respectively, on the basis of the following
transformations. The product mixture was treated with
K2CO3 in methanol to furnish two epoxyazides, 21 and
22. Peracid epoxidation of 18 also afforded 21 and 22 in
a 1.3:1 ratio, and the two compounds were readily
separated by chromatography. The structure of the major
isomer was established as the trans-epoxyazide 21 by its
reaction with NaN3, which afforded the meso-hydroxy-
diazide 23. The structure of the minor cis-epoxyazide 22
was confirmed by reduction of the azide and acetylation
of the resulting amine to afford cis-epoxyacetamide 24,
which was spectroscopically indistinguishable from an
authentic sample prepared according to a literature
method.13 Thus, the addition of HOBr to 18 proceeded
predominantly via the syn-bromonium ion to afford 19
as the major addition product.
The formal addition of HOBr to several more highly
substituted cyclopentenes also favored products arising
from an initial syn-bromonium ion (Scheme 5). Reaction
of cis-cyclopentene-1,4-diol 2514 with NBS in H2O gave
bromotriol 26 as the only product in 44% yield. That 26
1
was the only product formed was confirmed by H NMR
monitoring of a parallel reaction performed in DMSO-d6
and D2O, which indicated <10% formation of other
stereoisomers. The structure of 26 was established by
cyclization in base to the meso-epoxydiol 27, whose
spectroscopic properties were distinct from those of the
isomeric meso-epoxydiol obtained by the syn-selective
peracid epoxidation of 25.15 Addition of HOBr in DMSO-
H2O to the protected triol 28 afforded bromohydrin 29
in 56% yield (Scheme 5).1b Reaction of 29 with K2CO3
furnished epoxide 30, whose spectral properties differed
from those of the corresponding epoxide arising from
peracid oxidation of 28.
The reaction of NBS-H2O with dimethoxyacetamide
31 (Scheme 5) was studied under similar conditions.
Compound 31 was prepared by the photolysis of pyri-
dinium perchlorate in methanol.16 A single bromohydrin
32 was isolated in 92% yield, which was transformed in
base to the corresponding epoxyacetamide 33. Compound
33 was identical with the product of peracid oxidation of
(13) Vince, R.; Daluge, S. J . Med. Chem. 1974, 17, 578-583.
(14) Kaneko, C.; Sugimoto, A.; Tanaka, S. Synthesis 1974, 876-877.
(15) (a) Sable, H. Z.; Adamson, T.; Tolbert, B.; Posternak, Th. Helv.
Chim. Acta 1963, 66, 1157-1165. (b) Theil, F.; Schick, H.; Winter, G.;
Reck, G. Tetrahedron 1991, 47, 7569-7582.
(16) Ling, R.; Yoshida, M.; Mariano, P. S. J . Org. Chem. 1996, 61,
4439-4449.
(17) Hartke, K.; J ung, M.-H.; Zerbe, H.; Kampchen, T. Liebigs Ann.
Chem. 1986, 1268-1280.

Electrophilic Additions to Substituted Cyclopentenes
J . Org. Chem., Vol. 65, No. 13, 2000 4061
Sch em e 7
Sch em e 9
which has been shown to increase the ionic character of
sulfenyl chloride additions.20
Sch em e 8
A similar study of the reaction of CH3SCl with 3-azido-
cyclopentene 18 was carried out to afford a mixture of
two addition products (Scheme 9). While NMR chemical
shifts and coupling constants indicated that each product
was a 1-chloro-2-(methylthio)-3-azidocyclopentane, no
clear-cut stereochemical assignments could be made. The
major product was ultimately assigned structure 52 by
hydrogenation over palladium on carbon, and condensa-
tion of the resulting amine with p-bromophenyl isocyan-
ate (2 equiv). That two-step process, which was intended
to prepare the corresponding crystalline N-arylurea for
X-ray diffraction analysis, afforded instead an unxpected
bicyclic urea in 38% yield, whose solid-state structure was
unambiguously shown to be 58 by X-ray analysis (Figure
2).
Given the regiochemistry assigned by NMR, the origin
of 58 was best rationalized from the all-trans-amino-
cyclopentane 54 as shown in Scheme 9. Following the
initial formation of urea 55, a formal 1,2-methylthio shift
via thiiranium 56 led to 57, which then reacted with a
second equiv of ArNCO. The structural assignment
established that CH3SCl additions to 18 afforded a major
product 52 formally arising from the anti-azidothi-
iranium ion intermediate predominated, with ratios of
52 to 53 ranging from 2.5:1 in THF to 5.5:1 in CDCl3.
The reaction of more highly substituted cyclopentenes
with CH3SCl was also investigated. In the case of cis-
1,4-diacetoxy-2-cyclopentene 59 (Scheme 10), reaction
with CH3SCl in CH2Cl2 or CCl4 produced a single
diacetoxychlorosulfide in 80-85% yield. The product was
assigned structure 60 based on its saponification and
sample enriched in 48 was achieved using potassium
triethylborohydride to afford trans-2-(methylthio)cyclo-
pentanol 50, which was identical with an authentic
sample18 prepared from epoxycyclopentane 51 by a
known method.19
The addition of CH3SCl to 13 was monitored by 1H
NMR, and the product mixture was studied as a function
of solvent (Scheme 8). No stereoselectivity was observed
when CH3SCl additions were performed in CDCl3 or
CD3CN, but a modest preference for 46, the product of
anti-thiiranium ion opening, was noted when the reaction
was conducted in THF-d8. The reaction in THF was little
affected when carried out in the presence of 1.5 M LiClO4,
(18) Goodman, L.; Benitez, A.; Baker, B. R. J . Am. Chem. Soc. 1958,
80, 1680-1686.
(19) Conte, V.; DiFuria, F.; Modena, G.; Sbampato, G.; Valle, G.
Tetrahedron: Asymmetry 1991, 2, 257-276
(20) Smit, W. A.; Zefirov, N. S.; Bodrikov, I. V.; Krimer, M. Z. Acc.
Chem. Res. 1979, 12, 282-288.

4062 J . Org. Chem., Vol. 65, No. 13, 2000
Clark et al.
F igu r e 2. X-ray crystal structure of rearrangement product 58.
Sch em e 10
Sch em e 11
been utilized for methylsulfenylation reactions of alkenes
in conjunction with sources of cyanide, azide, or other
nucleophiles.21 The process results in trans-vicinal addi-
tion to the alkene by nucleophilic opening of a putative
thiiranium ion. Attempts to react DMTSF with cyclo-
pentenol 13 under a variety of conditions afforded
complex, oligomeric products. Alternatively, a solution
of cyclopentenyl acetate 67 (Scheme 11) was treated with
DMTSF in CH2Cl2, with subsequent addition of aqueous
NaN3, and afforded a 2:1 mixture of diastereomeric
products, identified as 68 and 69, in 48% overall yield.
Some deacetylation and oligomerization occurred, which
lowered the yield. After careful chromatography to
separate the two azidothioethers, the major isomer 68
was hydrogenated using excess Pd/C to the corresponding
amine 70, and directly aroylated using p-bromobenzoyl
chloride to give 71, whose structure was unambiguously
established by X-ray diffraction.
cyclization in K2CO3-CH3OH to form non-meso epoxide
62. The corresponding cis-cyclopentene-1,4-diol 25 re-
acted with CH3SCl to afford a 2:1 mixture of adducts in
81% yield. The isomeric products could be separated by
chromatography, and the major diol was shown to be 63
by acetylation and correlation with 60. Stereochemical
assignments were further secured by conversion of 63 to
the corresponding crystalline bis-p-bromobenzoate 65,
whose structure was solved by X-ray diffraction analysis.
Interestingly, the stereoselectivity of CH3SCl addition to
25 was reversed in d8-THF, giving a 1:1.5 ratio of 63 and
64. Addition of CH3SCl to diacetate 351a proceeded via
syn-episulfonium ion formation to afford chlorothioether
66 as the sole product (88% yield). The structure of 66
was confirmed by nuclear Overhauser enhancement
(NOE) spectroscopy, where NOE effects were observed
between H2 and H4, and between H1 and H3. No H1/
H4 or H3/H5 NOE effects were observed.
Similarly, reaction of 3-azidocyclopentene 18 with
DMTSF/CH2Cl2 and subsequently with aqueous NaN3
afforded a 2:1 mixture of isomeric diazidomethyl sulfides
72 and 73 (Scheme 12) in 60% yield. The minor isomer
(21) (a) Trost, B. M.; Shibata, T. J . Am. Chem. Soc. 1982, 104, 3225-
3228. (b) Trost, B. M.; Shibata, T.; Martin, S. J . J . Am. Chem. Soc.
1982, 104, 3228-3230. (c) Caserio, M. C.; Kim, J . K. J . Am. Chem.
Soc. 1982, 104, 3231-3233. (d) Trost, B. M.; Martin, S. J . J . Am. Chem.
Soc. 1984, 106, 4263-4265.
DMTSF Ad d ition s. Dimethyl(methylthio)sulfonium
tetrafluoroborate [DMTSF; CH3SS+ (CH3)2 BF4-] has

Electrophilic Additions to Substituted Cyclopentenes
J . Org. Chem., Vol. 65, No. 13, 2000 4063
Sch em e 12
electrophilic additions to cyclic and acyclic allylically
substituted alkenes,8,24 cite at least three factors that can
affect the overall reaction. These include the relative
abundance at equilibrium of each conformational isomer,
the relative reactivity of each conformer, and the regio-
and stereoselectivities observed in the reaction of each
conformer. Moreover, some electrophilic additions may
proceed stepwise via reversible, rapidly equilibrating
intermediates, from which stereoisomeric products may
be formed at different rates. Such intermediates may
differ widely in structure and net charge (e.g., cationic,
bridged halonium ions; neutral, 4-coordinate sulfuranes)
and may undergo subsequent nucleophilic addition via
stereochemically distinct mechanisms. While we hoped
to devise a general strategy for assembling a broad range
of functionalized cyclopentanes, it was evident that
variations in the nature of the allylic substituent (which
may coordinate, participate, or eliminate during addition)
could also influence the regio- and stereochemical out-
come.
Additions of NBS-H2O and NCS-H2O with 10, 13, 18,
25, 28, and 31 likely involve three-membered halonium
ions and were consistently syn-selective. Those results
were in agreement with the reactivity model developed
by Kahn et al. for conformers of acyclic allylic alcohols
and ethers most closely corresponding to the envelope
conformation of the cyclopentene ring.8 In that model,
the alkene face syn- to the oxygen substituent was made
more reactive by interaction of nonbonded n-electrons on
oxygen both with the alkene’s p-electron cloud and with
the incipient electrophile. Whereas such effects would be
expected to be less significant in the case of allylic azide
or alkyl substituents, both 3-azidocyclopentene and 3-
methylcyclopentene displayed syn selectivities compa-
rable to that observed with 2-cyclopentenol 13, suggesting
that other steric or stereoelectronic factors might also be
involved.
For formal 1,2-additions of HOBr and HOCl to alkenes,
additional stabilization of the intermediate syn-halonium
ions might be achieved by a hyperconjugative generalized
anomeric effect. In the original anomeric effect, electron
donation from the nonbonded n-electrons on the pyranose
oxygen into the adjacent C-O σ* orbital of an electro-
negative anomeric substituent results in preferential
stabilization of the less sterically favored axial (R) ste-
reoisomer.25 A related phenomenon, termed the “gauche
effect”, has been invoked to explain the preferred gauche-
conformations of certain 1,2-disubstituted ethanes,26 and
involves similar (C-H)σ-(C-X)σ* orbital interactions.
Allylically substituted cyclopentenes such as 10, 13, and
18 would be expected favor an envelope conformation
having an equatorial CH3 or N3 substituent, as shown
in Scheme 13. Addition of X+ may lead to two cyclic
halonium ions, 79 and 80 (Scheme 13). A generalized
anomeric effect may stabilize the syn-adduct 79, where
the axial allylic C-H σ-bond can serve as an electron-
releasing group to stabilize the strongly electronegative
halonium ion by back-donation into the C-X σ*-bond. For
cyclopentene-derived syn-halonium ions such as 79, mo-
lecular modeling studies indicate an almost perfect (180
was assigned the meso-diazide structure 73 by NMR. The
major product 72 formally arises from azidolysis of the
syn-azidothiiranium ion, suggesting that the stereochem-
istry of electrophilic DMTSF-promoted sulfenylations
more closely resembles NBS-H2O-DMSO than MeSCl
additions.
Application of the DMTSF-mediated trans-1,2-azido-
sulfenylation reaction to the known22 all-cis-cyclopen-
tenetriol 74 was of interest as a short, convergent route
to analogues of the potent R-mannosidase inhibitor,
mannostatin. Reaction of 74 with DMTSF in CH3CN
followed by NaN3 afforded 75 as the only isolable product
in 32% yield. The stereochemistry of 75 was established
by reduction of the azide group to the corresponding
amine using propane-1,3-dithiol.23 The resulting racemic
aminotriol was shown to be spectroscopically distinct
from synthetic (-)-mannostatin A,3a and assigned struc-
ture 76 corresponding to 1,5-bis-epi-mannostatin A. The
same reaction of DMTSF/NaN3 with tribenzyl ether 77
afforded 78 as the only addition product in 34% yield.
Both 75 and 78 result from methanesulfenylation syn to
the three oxygen substituents on the cyclopentene ring.
Discu ssion a n d Con clu sion s
The results of the present study indicate that additions
of NBS-H2O, NCS-H2O, and DMTSF/NaN3 to a range
of hydroxy, alkoxy, and azide-containing mono-, di-, and
trisubstituted cyclopentenes proceed with fair to good
stereoselectivities. With these electrophiles, the stereo-
chemistry of addition favors products derived from syn-
approach of the initial electrophile with respect to the
allylic substituent. In reactions of CH3SCl with cyclo-
pentenol 13 and cyclopentenyl azide 18, the major
products were derived from anti-addition of the electro-
phile, whereas the reaction of CH3SCl with cis-cyclopen-
tene-1,4-diol 25 and the corresponding diacetate 59 gave
products derived exclusively from syn-oriented electro-
philic approach.
Kahn et al., who have developed theoretical models to
better understand the regio- and stereochemistry of
(24) See ref 8 for a comprehensive review of additions of a variety
of electrophiles to a broad range of cyclic and acyclic alkenes.
(25) (a) Lemieux, R. U. Pure Appl. Chem. 1971, 25, 527-548. (b)
Kirby, A. J . The Anomeric Effect and Related Stereochemical Effects
at Oxygen; Springer: New York, 1983.
(22) Borcherding, D. R.; Scholtz, S. A.; Borchardt, R. T. J . Org.
Chem. 1987, 52, 5457-5461.
(23) Bayley, H.; Standring, D. N.; Knowles, J . R. Tetrahedron Lett.
1978, 3633-3634.
(26) Wolfe, S. Acc. Chem. Res. 1972, 5, 102-111.

4064 J . Org. Chem., Vol. 65, No. 13, 2000
Clark et al.
Sch em e 13
Sch em e 15
Sch em e 14
Such wide variations in selectivity may indicate that the
intermediates formed in electrophilic additions of MeSCl
are different in structure and/or reactivity from the cyclic
halonium ions implicated in NBS-H2O and NCS-H2O
additions.
While electrophilic additions of halogens and sulfenyl
chlorides to alkenes and alkynes both afford trans-
products, the intermediacy of discrete, three-membered,
cyclic thiiranium and thiirenium ions in RSCl additions
remains controversial.20 Whether such ions can form
reversibly is not known, and their subsequent reactivity
toward nucleophiles is not fully understood. In the case
of allylically substituted cyclopentenes such as 10, 13,
and 18, electrophilic addition of CH3SCl might proceed
via stereoisomeric thiiranium ions 84/85 (Scheme 15)
and/or a-sulfurane adducts 86/87. Moreover, nucleophiles
can attack 84/85 at one of the three-membered ring
carbons (to afford overall anti-addition) or at sulfur,
giving rise to R-sulfuranes 86/87, respectively. A recent
report documents both modes of reactivity in stereoiso-
meric thiiranium ions.28 The relative rates of formation
of such intermediates and of nucleophilic ring opening
likely determine the overall stereoselectivity of addition.
Earlier kinetic studies on MeSCl additions to alkenes
indicate that chloride is retained in the solvent cage, and
that the first-formed intermediate, thought to be the
R-sulfurane or thiiranium ion pair, undergoes rapid
nucleophilic attack.20 Under those conditions, the product
distribution would be determined solely by the relative
rates of electrophilic attack, which would explain the anti
selectivity observed for simple cyclopentenes 10, 13, and
18. Sterically demanding or electronegative substituents
on the cyclopentene would be expected retard nucleophilic
opening of the sulfurane or thiiranium ion,29 and reduce
the preference for anti-addition. Such a trend is evident
in comparing products derived from 13, cyclopentenediol
25, and the corresponding diacetate 59 (Scheme 10), as
well as products from chlorosulfide 37 and the corre-
( 5°) antiperiplanar orbital overlap between the C-H s
and C-X σ*-bonds. Models further established that
dihedral angles in substituted onium ions in the corre-
sponding cyclohexenyl and cycloheptenyl systems devi-
ated significantly ((15 to 25°) from antiperiplanarity.
Moreover, such a generalized anomeric effect should be
additive in the case of two bis-allylically substituted
cyclopentenes such as 25, 28, and 31, which would
further stabilize the corresponding diequatorial confor-
mation 81.
If the intermediate halonium ions such as 79-81 were
formed reversibly, as has been suggested for highly
substituted, bridged bromonium ions,27 then the product
distribution in HOX additions would be determined not
by the thermodynamically more stable halonium ion, but
by the rate of halonium ion opening. On the basis of steric
factors, the transition state for the opening of the syn-
halonium ion 79 to the observed products (11, 16, 19)
would be expected to be lower in energy than that for
the anti-halonium ion 80. Intermediate 80 must undergo
a conformational change to 82 (Scheme 14) in order for
nucleophilic attack at the distal carbon to proceed via
trans-diaxial opening. The incipient H2O or DMSO nu-
cleophile in 82 would experience a 1,3-diaxial interaction
with the substituent R. Additional steric repulsions would
result in 1,4-disubstituted cyclopentenes such as 25, 28,
and 31.
Unlike NBS-H2O additions, the reaction of MeSCl
with allylically substituted cyclopentenes displayed no
consistent stereochemical trend. In previously reported
studies on the reaction of methyl and p-tolylsulfenyl
chloride with 37 and 42, modest changes in the remote
(homoallylic) substituent led to a reversal in the overall
stereochemistry of addition.17 In the present study,
cyclopentenol 13 and cyclopentenyl azide 18 afforded
mostly anti products, whereas bis-allylically substituted
cyclopentenes give increasing proportions of syn products.
(28) Fachini, M.; Lucchini, V.; Modena, G.; Pasi, M.; Pasquato, L.
J . Am. Chem. Soc. 1999, 121, 3944-3950.
(29) Similar effects of inductively withdrawing substituents have
been observed in acid-catalyzed epoxide openings: (a) Bronsted, J . N.;
Kilpatrick, M.; Kilpatrick, M. J . Am. Chem. Soc. 1929, 51, 428-461.
(b) Caron, M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1557-1560,
and references therein; (c) Behrens, C. H.; Sharpless, K. B. J . Org.
Chem. 1985, 50, 5696-5704.
(27) Brown, R. S. Acc. Chem. Res. 1997, 30, 131-137.

Electrophilic Additions to Substituted Cyclopentenes
J . Org. Chem., Vol. 65, No. 13, 2000 4065
(film) 3400, 2950, 2850, 1350, 1190, 1040 cm-1; CIMS m/z 181
(M+), 163 (M-H2O), 100 (M - HBr), 83 (M - H2O - HBr).
Ad d ition of HOBr to 3-Azid ocyclop en ten e; Syn th esis
of 3-Azid o-2-br om ocyclop en ta n ols 19 a n d 20. N-Bromo-
succinimide (460 mg, 2.6 mmol) was added to a stirred solution
of 3-azidocyclopentene 18 (143 mg, 1.3 mmol) in DMSO (20
mL) containing H2O (1.2 mL). After 2 h, the solution was
diluted with H2O (75 mL) and extracted with EtOAc (2 × 50
mL). The combined organic layers were dried over MgSO4 and
evaporated to a yellow oil, which was chromatographed on SiO2
(3:1 hexanes:EtOAc) to afford a 3:1 mixture of 19 and 20 (247
mg, 91%; Rf 0.56 in 1:1 hexanes:EtOAc). For 19: 1H NMR (300
MHz, CDCl3) δ 4.45 (m, 1 H), 4.12 (m, 2 H), 2.4-1.6 (m, 5 H);
13C NMR (75 MHz, CDCl3) δ 78.1, 63.4, 60.2, 29.4, 27.1; 20:
1H NMR (300 MHz, CDCl3) δ 4.31 (m, 1 H), 4.03 (m, 1 H),
3.91 (t, 1 H, J ) 5.9 Hz), 2.4-1.6 (m, 5 H); 13C NMR (75 MHz,
CDCl3) δ 79.0, 67.7, 59.0, 30.4, 28.1; IR (mixture, neat) 3350
(b), 2950, 2100, 1260 cm-1; EIMS m/z 205/207 (M+, 1%), 162/
164 (M - HN3, 15%), 83 (M - HN3 - Br, 80%).
Con ver sion of 19 a n d 20 to cis- a n d tr a n s-3-Azid ocy-
clop en ten e Oxid es 21 a n d 22. Potassium carbonate (104 mg,
0.75 mmol) was added to a stirred solution of 19 and 20 (62
mg, 0.30 mmol) in dry CH3OH (6 mL). After stirring 20 h, the
solution was partitioned between H2O (30 mL) and CH2Cl2 (30
mL). The aqueous layer was then extracted with CH2Cl2 (15
mL). The combined organic extracts were dried (MgSO4) and
evaporated to give a yellow oil (35 mg, 92%) containing
epoxides 21 and 22.
sponding chlorosulfone 42 (Scheme 7). Alternatively, the
electron-deficient π-systems in 25 and 59 may be too
unreactive to form R-sulfuranes directly, reacting instead
via the corresponding syn-thiiranium ions, which can be
stabilized by the generalized anomeric effect noted
earlier. Unfortunately, no simple mechanistic picture
rationalizes the various solvent and dissolved electrolyte
effects on CH3SCl additions in the present study. For
example, THF gives higher amounts of anti product than
CH2Cl2 or CDCl3 in the case of cyclopentenol, yet the
situation is reversed in the case of azidocyclopentene.
Although not as thoroughly studied, additions of thio-
sulfonium salts such as DMTSF to substituted cyclo-
pentenes followed a more predictable and consistent
trend, exhibiting modest to excellent syn selectivity.
DMTSF and CH3SCl additions differ significantly in that
nucleophiles are only introduced into the former once the
initial electrophilic addition has been completed, and the
process of nucleophilic addition is slow. Thus, as with
NBS-H2O and NCS-H2O additions, the preferential syn-
stereoselectivity observed in DMTSF additions might be
the result of kinetically controlled opening of rapidly
interconverting thiiranium intermediates, formed in the
presence of a weak disulfide nucleophile. Consistent with
this rationale, a recent study demonstrated the rapid
interchange of S-alkyl thiiranium groups with alkyl
disulfides, likely involving a rapid alkene-thiiranium ion
equilibrium.28
Authentic samples of 21 and 22 were prepared as follows.
To a stirred solution of 18 (114 mg, 1.0 mmol) in CH2Cl2 (5
mL) was added m-chloroperoxybenzoic acid (350 mg, 2.0 mmol)
in CH2Cl2 (5 mL). The resulting solution was stirred for 1 h
at 40 °C, then at room temperature overnight. After diluting
with CH2Cl2 (20 mL), the solution was washed with 10%
NaHSO3 (2 × 10 mL), filtered through Celite, and washed with
2 N NaOH (2 × 10 mL). The organic phase was then dried
(Na2SO4) and concentrated in vacuo. The residue was chro-
matographed (SiO2, 4:1 hexanes:EtOAc) to afford 21 (58 mg,
46%) and 22 (44 mg, 35%), both as clear oils. For 21: Rf 0.49
The results reported here demonstrate that electro-
philic additions to cyclopentenes can be a useful and
stereoselective tool in organic synthesis. Additions of
NBS-H2O, NCS-H2O, and DMTSF to functionalized
substrates proceed with syn selectivity, giving predomi-
nantly or exclusively one product. MeSCl additions are
less predictable, but can be tuned by suitable alteration
of solvent and substrate. Such stereoselective electro-
philic additions have played an important role in prepar-
ing aminocyclopentitols and other densely functionalized
cyclopentanes, and will be of continuing utility as more
such substances are discovered and synthesized.
1
(4:1 hexanes:EtOAc); H NMR (300 MHz, CDCl3) δ 4.03 (d, 1
H, J ) 4.8 Hz), 3.57 (d, 1 H, J ) 2.2 Hz), 3.49 (d, 1 H, J ) 1.9
Hz), 2.1-1.8 (m, 4 H); 13C NMR (75 Hz, CDCl3) δ 61.4, 57.5,
56.9, 26.2, 25.6; IR (neat) 2900, 2100, 1240, 850 cm -1; EIMS
125 (M+, 10%), 83 (M - N3, 20%). For 22: Rf 0.30 (4:1 hexanes:
EtOAc); 1H NMR (300 MHz, CDCl3) δ 3.72 (t, 1 H, J ) 8.0
Hz), 3.57 (m, 1 H), 3.48 (d, 1 H, J ) 2.7 Hz), 2.18 (dd, 1 H, J
) 14.2 Hz, 8.3 Hz), 1.92 (dt, 1 H, J ) 12.3 Hz, 8.1 Hz), 1.8-
1.6 (m, 1 H), 1.6-1.4 (m, 1 H); 13C NMR δ (75 MHz, CDCl3)
61.9, 57.7, 55.5, 26.4, 23.4; IR (neat) 2950, 2100, 1250, 850
cm-1, EIMS m/z 125 (M+, 25%), 83 (M - N3, 10%).
Exp er im en ta l Section 30
Ad d ition of HOBr to 2-Cyclop en ten ol 13; Syn th esis of
1-Br om o-2,5-d ih yd r oxycyclop en ta n es 16 a n d 17. To a
stirred solution of 13 (160 mg, 1.92 mmol) in H2O (11 mL) at
0 °C was added N-bromosuccinimide (380 mg, 2.10 mmol) in
one portion. After 1 h, the solution was warmed to room
temperature and then concentrated in vacuo. The solid residue
was triturated with cold ether (2 × 10 mL), and the combined
organic layers were then dried (MgSO4), filtered, and concen-
trated. The residue was purified by SiO2 flash chromatography
(4:1 toluene:CH3CN) to afford 273 mg of a 4:1 mixture of
bromohydrins 16 and 17 (78% yield). Analytically pure samples
of each isomer could be obtained by further chromatography
(SiO2, 1:1 EtOAc:hexanes). For 16: Rf ) 0.24 (1:1 EtOAc:
Syn th esis of m eso-2,5-Dia zid ocyclop en ta n ol 23. To a
stirred solution of trans-epoxyazide 21 (13 mg, 0.10 mmol) in
MeOH (1 mL) was added NaN3 (20 mg, 0.30 mmol). The
solution was heated at reflux for 5 h and then stirred for 20 h
at room temperature. The reaction was partitioned between
H2O (2 mL) and Et2O (2 mL). The aqueous layer was removed
and extracted with Et2O (2 × 2 mL). The combined ether layers
were dried (MgSO4) and concentrated in vacuo, and the residue
was chromatographed on SiO2 (4:1 hexanes:EtOAc) to afford
1
a colorless oil (7 mg, 41%): Rf 0.27 (4:1 hexanes:EtOAc); H
NMR (300 MHz, CDCl3) δ 3.87 (t, 1 H, J ) 7.6 Hz); 3.71 (m, 2
H), 2.25 (bs, 1 H), 2.11 (m, 2 H), 1.75 (m, 2 H); 13C NMR (75
MHz, CDCl3) δ 82.1, 65.6, 26.3; IR (neat) 3400 (b), 2100 1250
cm-1, EIMS m/z 168 (M+, 2%), 83 (M - HN3 - N3, 15%).
H yd r ogen a t ion of 22; Syn t h esis of cis-3-Acet a m id o-
cyclop en ten e Oxid e 24. A solution of 22 (28 mg, 0.22 mmol)
in dry MeOH (2 mL) containing Lindlar’s catalyst (10 mg) was
stirred at room temperature under 1 atm H2. After 4 h, TLC
showed complete disappearance of starting material. The
mixture was then cooled to 15 °C and purged with Ar.
Triethylamine (0.15 mL, 1.1 mmol) and acetic anhydride (0.10
mL, 1.1 mmol) were added, and after 20 h, catalyst was
removed by filtration through Celite. The solvents were
removed in vacuo, and the resulting residue was chromato-
graphed on SiO2 (12:1 CH2Cl2:MeOH) to afford 18 mg (58%)
1
hexanes); H NMR (300 MHz, D2O) δ 4.24 (m, 1 H), 4.11 (m,
1 H), 3.95 (dd, 1 H, J ) 6.5, 4.6), 2.15-1.98 (m, 2 H), 1.61 (m,
1 H), 1.38 (m, 1 H); 13C NMR (75 MHz, D2O) δ 77.2, 71.7, 61.0,
28.5, 28.3; IR (film) 3400, 2950, 2850, 1340, 1300, 1180, 1100,
1040 cm-1; CIMS m/z 262 (2M + 1 + CH4 - HBr - 2 H2O,
47%), 244 (2M + 1 + CH4 - HBr - 3H2O, 27%), 100 (100%).
1
For 17: Rf ) 0.28 (1:1 EtOAc:hexanes); H NMR (300 MHz,
D2O) δ 4.08 (m, 2 H), 3.69 (t, 1 H, J ) 7.9 Hz), 1.95 (m, 2 H),
1.57 (m, 2 H); 13C NMR (75 MHz, D2O) 76.4, 61.1, 28.4; IR
(30) General procedures: King, S. B.; Ganem, B. J . Am. Chem. Soc.
1994, 116, 562-570.

4066 J . Org. Chem., Vol. 65, No. 13, 2000
Clark et al.
of a low-melting solid whose spectral data matched those of
an authentic sample of 24 prepared by the literature method.13
Ad d ition of HOBr to cis-Cyclop en ten e-1,4-d iol 25;
Syn th esis of 1-Br om o-2,3,5-tr ih yd r oxycyclop en ta n e 26.
To a stirred solution of 25 (94 mg, 0.94 mmol) in H2O (2 mL)
at 0 °C was added NBS (333 mg, 1.87 mmol) in one portion.
After stirring for 1 h at room temperature, the mixture was
diluted with 5 mL of H2O and extracted with EtOAc (4 × 5
mL). The aqueous layer was then frozen and lyophilized to
give a white solid, which was purified by flash chromatography
over SiO2 (5% MeOH:EtOAc), affording pure 26 (80 mg, 44%)
as a colorless oil: Rf ) 0.36 (5% MeOH:EtOAc), 1H NMR (300
MHz, D2O) δ 3.96 (m, 2 H), 3.87 (m, 1 H), 3.75 (m, 1 H), 2.41
(m, 1 H), 1.54 (m, 1 H); 13C NMR (75 MHz, D2O) δ 85.3, 76.1,
71.4, 60.0, 40.7; IR (film) 3400, 2950, 1300, 1100 cm-1; CIMS
m/z 395 (2M + 1), 359 (2M + 1 - 2H2O), 295 (2M + 1 - H2O
- Br), 197 (M+), 179 (M - H2O), 99 (M - H2O - Br, 100%).
Con ver sion of 26 to tr a n s-1,4-Dih yd r oxycyclop en ten e
Oxid e 27. To a stirred solution of bromohydrin 26 (22 mg,
0.11 mmol) in MeOH (4 mL) at room temperature was added
anhydrous Na2CO3 (61 mg, 0.57 mmol) in one portion. The
heterogeneous mixture was then stirred at room temperature
for 10 h. After cooling to 0 °C, the reaction was quenched with
by the addition of NH4Cl (0.57 g) in H2O (1 mL). The methanol
was removed in vacuo, and the aqueous residue was frozen
and lyophilized to afford a white solid, which was triturated
several times with 1:9 MeOH:EtOAc. The triturates were then
concentrated in vacuo to furnish pure 27 (7.6 mg, 59%) as a
at room temperature for 8 h and then quenched by washing
with 10% sodium bisulfite (2 × 0.5 mL) and satd NaHCO3
(2 × 0.5 mL). The aqueous layers were pooled and extracted
with CH2Cl2 (2 × 2 mL). The combined organic layers were
dried over MgSO4 and concentrated to afford (10 mg, 62%)
cis-1,4-dihydroxy-2,3-oxido-5-(2’trimethylsilylethoxy)methyl-
cyclopentane as a clear oil: Rf 0.35 (9:1 CH2Cl2:MeOH); 1H
NMR (300 MHz, CDCl3) δ 3.93 (d, 2 H, J ) 7.8 Hz), 3.56 (m,
4 H), 3.51 (t, 2 H, J ) 8.3 Hz), 1.64 (m, 1 H), 0.89 (t, 2 H, J )
7.8 Hz), -0.02 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 73.2, 68.9,
68.8, 56.9, 47.5, 18.2, -1.3; IR (film) 3400, 2950, 2850, 1260,
1100, 1050 cm-1; CIMS m/z 245 (M + CH4 + 1 - H2O), 229
(M + 1 - H2O), 73 (100%).
Con ver sion of 28 to 1-Ch lor o-2,4-d ih yd r oxy-5-for m yl-
oxy-3-(2′-tr im eth ylsilyleth oxym eth yl)cyclop en ta n e 34.
To a stirred solution of 28 (52 mg, 0.23 mmol) in DMF
containing 0.1% water (2.4 mL) at 0 °C was added N-
chlorosuccinimide (90 mg, 0.68 mmol) in one portion. The
resulting solution was allowed to stand at room temperature
for 48 h and then diluted with H2O (5 mL) and extracted with
Et2O (8 × 10 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo to an oil. Puri-
fication by flash chromatography (1:1 hexanes:EtOAc) afforded
pure 34 (14 mg, 20%): Rf 0.43 (1:3 hexanes:EtOAc); 1H NMR
(300 MHz) δ 8.14 (s, 1 H), 5.16 (t, 1 H, J ) 5.9 Hz), 4.31 (dd,
1 H, J ) 6.5, 4.8 Hz), 4.07 (dd, 1 H, J ) 9.0, 4.5 Hz), 3.98 (dd,
1 H, J ) 8.4, 5.4 Hz), 3.57 (d, 2 H, J ) 4.4 Hz), 3.52 (t, 2 H, J
) 8.8 Hz), 3.52 (t, 2 H, J ) 8.8 Hz), 2.35 (m, 1 H), 0.91 (t, 2 H,
J ) 8.2 Hz), 0.01 (s, 9 H); 131C NMR (75 MHz CDCl3) δ 161.2,
86.8, 76.3, 72.8, 69.1, 68.8, 63.4, 51.3, 18.1, -1.3; IR (film) 3400,
2950, 2850, 1740 cm-1; FABMS m/z 311 (M + 1, 8%), 283 (M
+ 1 - CO), 97%), 119 (100%).
Con ver sion of 29 to 1,4-Dih yd r oxy-2,3-oxid o-5-(2′-tr i-
m eth ylsilyleth oxy)m eth ylcyclop en ta n e 30. To a solution
of bromohydrin 29 (1.72 g, 5.3 mmol) in MeOH (150 mL) at 0
°C under Ar was added anhydrous Na2CO3 (2.8 g, 26.5 mmol).
The mixture was then stirred at room temperature for 22 h
and then cooled to 0 °C and quenched with NH4Cl (2.8 g, 53
mmol) in H2O (50 mL). The bulk of MeOH was then removed
in vacuo, and the aqueous residue was extracted with EtOAc
(3 × 75 mL). The combined EtOAc layers were washed with
brine (15 mL) and dried over MgSO4. Concentration gave a
crude solid, which was chromatographed over SiO2 (14:1
CH2Cl2:MeOH) to afford epoxide 30 (0.84 g, 65%) as a white
crystalline solid: mp 76-81 °C; Rf 0.20 (14:1 CH2Cl2:MeOH);
1H NMR (300 MHz, CDCl3) δ 4.10 (d, 2 H, J ) 6.2 Hz), 3.60
(d, 2 H, J ) 0.5 Hz), 3.47 (t, 2 H, J ) 8.2 Hz), 3.25 (d, 2 H, J
) 8.1 Hz), 2.19 (t, 1 H, J ) 8.1 Hz), 0.92 (t, 2 H, J ) 8.3 Hz),
0.01 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 73.2, 70.7, 68.3,
58.9, 57.6, 18.1, -1.4; IR (film) 3400, 2950, 2850,1450, 1350,
1250 cm-1; CIMS m/z 245 (M + 1 + CH4 - H2O, 2%), 73
(100%).
1
white solid: Rf 0.53 (1:9 MeOH:EtOAc); H NMR (300 MHz,
D2O) δ 4.15 (d, 2 H, J ) 5.9 Hz), 3.49 (s, 2 H), 1.76 (dt, 1 H, J
) 15.8, 4.6 Hz), 1.43 (d, 1 H, J ) 15.8 Hz); 13C NMR (75 MHz,
D2O) δ 72.2, 61.3, 41.1; IR (film) 3300, 2950, 1350, 1100, 1020,
860 cm-1; CIMS m/z 117 (M + 1), 99 (M + 1 - H2O), 81 (M +
1 - 2H2O), 69 (100%).
P er a cid Ep oxid a tion of 25; Syn th esis of cis-1,4-Dih y-
d r oxycyclop en ten e Oxid e. To a stirred solution of cyclo-
pentene-1,4-diol (81.8 mg, 0.81 mmol) in THF (4 mL) at 0 °C
was added MCPBA (154 mg, 0.90 mmol). The resulting
solution was stirred at room temperature for 20 h. The THF
was then removed in vacuo and replaced with H2O (2 mL).
The H2O layer was extracted with EtOAc (2 × 2 mL); the
aqueous layer was then frozen and lyophilized to give a crude
solid which was chromatographed over SiO2 (19:1 EtOAc:
MeOH) to afford pure cis-1,4-dihydroxycyclopentene oxide (64
1
mg, 68%) as a colorless oil: Rf 0.20 (19:1 EtOAc:MeOH); H
NMR (300 MHz, D2O) δ 4.04 (t, 2 H, J ) 8.4 Hz), 3.41 (s, 2 H),
2.08 (dt, 1 H, J ) 12.4, 7.3 Hz), 1.05 (dt, 1 H, J ) 12.3, 8.6
Hz); 13C NMR (75 MHz, D2O) δ 71.6, 60.6, 34.4; IR (film) 3300,
2950, 1350, 1100, 1020, 860 cm-1; CIMS m/z 117 (M + 1), 99
(M + 1 - H2O, 100%).
Ad d ition of HOBr to Diol 28; 1-Br om o-2,3,5-tr ih y-
d r oxy-4-(2′-tr im eth ylsilyleth oxy)m eth ylcyclop en ta n e 29.
To a stirred solution of diol 28 (1.70 g, 7.4 mmol) under Ar at
10 °C in DMSO (10 mL) were added H2O (0.27 mL, 14.8 mmol)
and N-bromosuccinimide (2.63 g, 14.8 mmol). The resulting
homogeneous solution was stirred for 30 min, and the reaction
was allowed to warm to room temperature. The reaction was
then quenched by the slow addition of 5% aqueous NaHCO3
(35 mL) and extracted with Et2O (4 × 30 mL). The combined
ether extracts were washed with brine (30 mL), dried over
MgSO4, and concentrated. The resulting brown oil was chro-
matographed on a column of SiO2 (3:1 EtOAc:hexanes) to
afford bromohydrin 29 (1.4 g, 56%) as a white solid: mp 89-
90 °C; Rf 0.41 (3:1 EtOAc:hexanes); 1H NMR (300 MHz, CDCl3)
δ 4.29 (dd, 1 H, J ) 8.5, 6.5 Hz), 4.06 (dd, 1 H, J ) 8.6, 5.1
Hz), 3.92 (t, 1 H, J ) 3.5 Hz), 3.79 (t, 1 H, J ) 6.5 Hz), 3.53-
3.48 (m, 4 H), 2.24 (m, 1 H), 0.91, (t, 2 H, J ) 8.2 Hz), -0.01
(s, 9 H); 13C NMR (75 MHz, CDCl3) δ 82.5, 71.9, 69.6, 68.8,
59.3, 51.8, 29.6, 18.1, 1.4; IR (film) 3360, 2900, 1400, 1350,
1250, 1100, 1040 cm-1; CIMS m/z 327 (M+, 2%), 73 (100%).
P er a cid E p oxid a t ion of 28; Syn t h esis of cis-1,4-Di-
h yd r oxy-2,3-oxid o-5-(2’t r im e t h ylsilyle t h oxy)m e t h yl-
cyclop en ta n e. To a solution of diol 28 (15 mg, 0.072 mmol)
in CH2Cl2 (0.5 mL) at room temperature under Ar was added
MCPBA (12 mg, 0.07 mmol). The resulting mixture was stirred
Ad d ition of HOBr to 4-Aceta m id o-3,5-d im eth oxycyclo-
p en ten e 31; Syn th esis of Aceta m id o-1-br om o-2-h yd r oxy-
3,5-d im eth oxycyclop en ta n e 32. To a solution of 31 (20 mg,
0.11 mmol) in water (2 mL) was added N-bromosuccinimide
(58 mg, 0.32 mmol). After stirring for 2 d, the solution was
evaporated and the residue chromatographed on SiO2 (20:1
CH2Cl2:MeOH) to afford 32 (30 mg, 92%) as a colorless oil: Rf
) 0.31 (9:1 CH2Cl2:MeOH); 1H NMR (300 MHz, CDCl3) δ 6.50
(bs, 1 H, J ) 7.0 Hz), 4.33 (m, 2 H), 4.16 (m, 1 H), 3.82 (m, 1
H), 3.66 (m, 1 H), 3.40 (s, 3 H), 3.39 (s, 3 H), 2.04 (s, 3 H); 13
C
NMR (75 MHz, CDCl3) δ 171.6, 89.1, 81.6, 78.8, 62.3, 58.1,
58.0, 54.1, 23.9; IR (film) 3250, 1650, 1390, 1100 cm-1; FIMS
m/z 283, 281 (M+, 100%), 202 (M - Br, 51%).
Con ver sion of 32 to 4-Aceta m id o-3,5-d im eth oxycyclo-
p en ten e oxid e 33. To a stirred solution of 32 (26 mg, 0.092
mmol) in MeOH (1 mL) was added K2CO3 (32 mg, 0.23 mmol).
After 20 h, the mixture was diluted with H2O (2 mL) and then
saturated with K2CO3 and extracted with EtOAc (2 × 2 mL).
The combined organic layers were evaporated to afford 33 (15
mg, 83%) as a white solid: mp 89-91°C; Rf ) 0.56 (9:1 CH2Cl2:
1
MeOH); H NMR (300 MHz, CDCl3) δ 5.48 (bd, 1 H, J ) 9.7
Hz), 4.38 (d, 1 H, J ) 9.6 Hz), 3.64 (s, 2 H), 3.57 (s, 2 H), 3.45
(s, 6 H), 1.92 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 168.6, 85.9,

Electrophilic Additions to Substituted Cyclopentenes
J . Org. Chem., Vol. 65, No. 13, 2000 4067
58.4, 57.7, 55.0, 23.5; IR (film) 3400, 2900, 1660, 1540, 1370,
1100 cm-1; FDMS m/z 202 (M + 1, 87%). Crystals of 33 suitable
for X-ray analysis were obtained by recrystallization from
CH2Cl2:hexanes.
in dry MeOH (10 mL). The resulting solution was heated at
reflux for 4 h and then cooled and diluted with 5% NaOH (25
mL). The reaction mixture was extracted with CH2Cl2 (5 × 2
0 mL), and the combined extracts were dried (MgSO4) and
concentrated in vacuo to afford a yellow oil (135 mg, 79%): Rf
0.17 (4:1 hexanes:EtOAc): 1H NMR (300 MHz, CDCl3) δ 4.1
(m, 1 H), 2.82 (m, 1 H), 2.2-1.5 (m, 6 H), 2.14 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 78.3, 53.4, 33.4, 30.5, 21.6, 14.3; IR
(neat) 3400 (b), 2950, 1400, 975 cm-1; EIMS m/z 132 (M+, 45%).
Ad d ition of Meth a n esu lfen yl Ch lor id e to Cyclop en -
ten yl Azid e 18; Syn th esis of 3-Ch lor o-2-m eth ylth iocy-
clop en tyl Azid es 52 a n d 53. To a solution of 18 (200 mg,
1.8 mmol) in CH2Cl2 (20 mL) at 0 °C was added methane-
sulfenyl chloride (170 mg, 2.1 mmol) in one portion. After 1 h,
the solvent was removed in vacuo, and the resulting residue
was filtered through a plug of SiO2 (1:19 EtOAc:hexanes) to
afford an orange oil (275 mg, 79%) containing a 3.5:1 mixture
of 52 and 53 together with minor amounts of a regioisomer.
Chromatography on SiO2 afforded samples enriched in the
major product 52: Rf 0.25 (1:19 EtOAc: hexanes); 1H NMR
(300 MHz, CDCl3) δ 4.08 (m, 1 H), 3.67 (m, 1 H), 3.09 (m, 1
H), 2.4-1.9 (m, 4 H), 2.25 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 66.9, 63.0, 60.8, 34.4, 29.9, 15.7.
Ad d ition of HOCl to Dia ceta te 35; Syn th esis of 1-Ch lo-
r o-3,5-d ia cetoxy-2-for m yloxy-4-(2′-tr im eth ylsilyleth oxy)-
m eth ylcyclop en ta n e 36. To a solution of diacetate 35 (15
mg, 0.05 mmol) in DMF (0.5 mL) containing 0.1% H2O at 0 °C
was added N-chlorosuccinimide (19 mg, 0.14 mmol). The
solution was stirred for 30 s at 0 °C and then sealed in a
Kimble vial for 24 h at room temperature. The reaction was
then diluted with H2O (1 mL) and extracted with Et2O (5 × 1
mL). The combined ether layers were washed with brine (1
mL) and dried over MgSO4. Filtration and concentration
afforded a crude oil, which was purified by flash chromatog-
raphy over SiO2 (4:1 hexanes:EtOAc) to give pure 36 (12 mg,
65%) as a colorless oil: Rf 0.35 (4:1 hexanes:EtOAc); 1H NMR
(300 MHz, CDCl3) δ 8.1 (s, 1 H), 5.58 (m, 1 H), 5.18 (t, 1 H, J
) 5.5 Hz), 5.14 (t, 1 H, J ) 4.6 Hz), 4.39 (dd, 1 H, J ) 7.9, 4.9
Hz), 3.56 (d, 2 H, J ) 3.0 Hz), 3.52 (t, 2 H, J ) 8.5 Hz), 2.33
(m, 1 H), 2.15 (m, 3 H), 2.08 (s, 3 H), 0.92 (t, 1 H, J ) 8.5 Hz),
0.01 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 170.5, 170.1, 159.7,
80.5, 75.6, 74.0, 68.8, 67.7, 58.9, 48.8, 20.9, 20.8, 17.9, -1.4;
IR (film) 2950, 2850, 1745, 1740, 1225, 1150, 1100, 1070 cm-1
;
For 53: 1H NMR (300 MHz, CDCl3) δ 4.39 (m, 1 H), 4.25
(m, 1 H), 3.27 (m, 1 H), 2.5-1.8 (m, 4 H), 2.21 (s, 3 H); 13C
NMR (75 MHz, CDCl3 mixture) δ 69.4, 68.4, 64.3, 63.2, 61.0,
52.3, 33.5, 29.4, 29.1, 29.0, 16.0, 15.0; IR (neat, mixture) 2970,
2100, 1255 cm-1; EIMS m/z 191 (M+, 20%), 149 (M - N3, 20%).
R ed u ct ion of 52; Syn t h esis of Met h ylt h io-4-b r om o-
p h en yl Oxa zolin e 58. A solution of 52 and 53 (>4:1, 31 mg,
0.16 mmol) in MeOH (1.5 mL) was treated with 10% palladium
on carbon (40 mg) and stirred under 1 atm H2 for 2 h. The
catalyst was removed by filtration through Celite, and solvent
was removed in vacuo to afford impure amine 54 (21 mg, 80%)
as a colorless oil. To a solution of 54 in CH2Cl2 (1.5 mL) were
added triethylamine (22 µL, 0.16 mmol) and 4-bromophenyl
isocyanate (95 mg, 0.48 mmol). After stirring 20 h, the
resulting white precipitate was filtered through Celite and the
filtrate evaporated. The resulting residue was chromato-
graphed (SiO2, 4:1 hexanes:EtOAc) to afford 58 as a white solid
(32 mg, 38%). mp 199-200 °C; Rf 0.33 (4:1 hexanes: EtOAc);
1H NMR (300 MHz, CDCl3) δ 11.74 (s,1 H), 7.43 (m, 6 H), 6.99
(m, 2 H), 5.10 (m, 1 H), 4.93 (d, 1 H, J ) 7.5 Hz), 3.31 (m, 1
H), 2.4-1.8 (m, 4 H), 2.17 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 149.7, 137.2, 132.2, 132.17, 125.4, 121.5, 118.5, 117.6, 116.7,
86.3, 59.9, 51.5, 32.1, 28.8, 15.3; IR (neat) 2977, 1668, 1699,
1592, 1487, 1384, 1307, 1236 cm-1; FDMS m/z 525 (M+, 100%)
Crystals of 58 suitable for crystallographic analysis were
obtained by recrystallization from CH2Cl2:hexanes.
Ad d ition of CH3SCl to cis-1,4-Dia cetoxy-2-cyclop en -
ten e 59; Syn th esis of 1-Meth ylth io-2-ch lor o-3,5-diacetoxy-
cyclop en ta n e 60. To a stirred solution of diacetate 59 (50
mg, 0.27 mmol) in CCl4 (0.5 mL) at 0 °C was added a 1.6 M
solution of MeSCl in CCl4 (0.51 mL) dropwise. After stirring
8 h at room temperature, the solution was concentrated in
vacuo and the resulting yellow oil was purified by flash
chromatography (3:1 hexanes:EtOAc) to afford pure 60 (61 mg,
84%) as a clear oil: Rf ) 0.28 (3:1 hexanes: EtOAc); 1H NMR
(300 MHz, CDCl3) δ 5.36 (m, 1 H), 5.13 (ddd, 1 H, J ) 10.0,
6.2, 4.9 Hz), 4.19 (dd, 1 H, J ) 10.0, 6.2 Hz), 3.10 (dd, 1 H, J
) 10.0, 5.2), 2.71 (ddd, 1 H, J ) 15.5, 8.9, 6.5 Hz), 2.22 (s, 3
H), 2.11 (s, 3 H) 2.10 (s, 3 H), 1.81 (ddd, 1 H, J ) 15.6, 4.8, 2.5
Hz); 13C NMR (75 MHz, CDCl3) δ 170.0, 169.7, 78.8, 72.4, 64.9,
56.9, 36.6, 21.0, 20.8, 15.8; IR (film) 2950, 2850, 1750, 1440,
1370, 1240, 1050 cm-1, FABMS m/z 267 (M + 1, 11%), 154
(100%).
CIMS m/z 412 (M + H2O), 384 (M + H2O - CO), 367 (M +
H2O - OCHO, 100%).
Ad d ition of Meth a n esu lfen yl Ch lor id e to 2-Cyclop en -
ten ol 13 in CH2Cl2; Syn th esis of 48 a n d 49. To a stirred
solution of 2-cyclopentenol 13 (130 mg, 1.55 mmol) in dry
CH2Cl2 (30 mL) was added methanesulfenyl chloride (140 mg,
1.7 mmol) in CH2Cl2 (10 mL). After 1 h, the solution was
evaporated to afford a brown oil (213 mg) consisting of 46 and
47. The 46/47 mixture was dissolved in pyridine (5 mL) and
stirred overnight with acetic anhydride (60 µL, 6.4 mmol). The
solution was then diluted with Et2O (50 mL) and washed with
satd NaHCO3 (3 × 30 mL). The combined aqueous layers were
back-extracted with Et2O (2 × 30 mL), and the combined ether
extracts were dried over MgSO4 and evaporated. The resulting
orange oil was filtered through a short column of neutral
alumina (4:1 hexanes:EtOAc) to afford a 1.4:1 mixture of 48
and 49 (191 mg, 60%), contaminated with traces of a regio-
isomeric impurity; Rf 0.36 (5:1 hexanes:EtOAc). For 48: 1H
NMR (300 MHz, CDCl3) δ 4.97 (m, 1 H), 4.06 (m, 1 H), 3.21 (t,
1 H, J ) 4.0 Hz), 2.6-1.7 (m, 4 H), 2.18 (s, 3 H), 2.07 (s, 3 H);
for 49: 1H NMR (300 MHz, CDCl3) δ 5.44 (m, 1 H), 4.23 (q, 1
H, J ) 5.4 Hz), 3.27 (t, 1 H, J ) 6.3 Hz), 2.6-1.7 (m, 4 H),
2.22 (s, 3 H), 2.06 (s, 3 H). 13C NMR (75 MHz, CDCl3, mixture)
δ 81.7, 79.4, 74.9, 67.2, 63.3, 62.6, 60.0, 59.9, 52.5, 34.5, 33.30,
30.32, 29.8, 29.6, 29.5, 21.4, 21.3, 21.2, 16.1, 15.5, 15.2; IR
(neat) 2976, 1742, 1230 cm-1; EIMS m/z 208 (M+, 35%).
Ad d ition of Meth a n esu lfen yl Ch lor id e to 2-Cyclop en -
ten ol 13 in THF -LiClO4; Syn th esis of 48 a n d 49. To a
solution of 13 (40 mg, 0.47 mmol) in 6 mL of 2 N LiClO4 in
dry THF at 0 °C was added MeSCl (43 mg, 0.52 mmol) neat.
After 2 h, the solution was diluted with Et2O (15 mL) and
washed with H2O (3 × 10 mL). The aqueous layers were
combined and back-extracted with Et2O (2 × 15 mL). The
combined ether extracts were dried and evaporated to afford
a
colorless liquid. This crude product was acetylated as
described above to afford 74 mg (71%) of 48 and 49 as a 5:1
mixture.
Red u ctive Dech lor in a tion of 48; Cor r ela tion w ith a n
Au th en tic Sa m p le of tr a n s-2-Meth ylth iocyclop en ta n ol
50. To a solution of 48 and 49 (∼5:1, 17 mg, 0.082 mmol) in
dry THF (1 mL) was added 1 M Super Hydride-THF (0.12
mL). After stirring 20 h, more Super Hydride solution (0.25
mL) was added. Three hours later, the solution was partitioned
between Et2O (6 mL) and H2O (6 mL). The aqueous layer was
extracted with more Et2O (5 mL), and the combined ether
layers were dried over MgSO4. Evaporation afforded a colorless
residue, which was purified by SiO2 chromatography (5:2
hexanes:EtOAc) to afford pure 50 (45%) whose spectral data
matched those of an authentic sample prepared as follows.
Cyclopentene oxide (0.11 mL, 1.3 mmol) was added to a
stirred solution of sodium thiomethoxide (91 mg, 1.3 mmol)
Sa p on ifica tion of 60; a ll-cis-1-Hyd r oxy-2-m eth ylth io-
3,4-oxid ocyclop en ta n e 62. To a stirred solution of diacetate
60 (56 mg, 0.21 mmol) methanol (7 mL) at 0 °C was added
K2CO3 (115 mg, 0.83 mmol) in one portion. The resulting
heterogeneous mixture was stirred at room temperature for 4
h. The reaction was then cooled to 0 °C and quenched by the
addition of NH4Cl (90 mg, 1.68 mmol) in H2O (5 mL). Acid (2
N HCl) was added dropwise to pH 7. The mixture was then
concentrated in vacuo, and the remaining aqueous portion was

4068 J . Org. Chem., Vol. 65, No. 13, 2000
Clark et al.
extracted with Et2O (5 × 10 mL). The combined Et2O layers
were washed with brine (5 mL) and then dried over MgSO4.
Filtration and concentration provided an oil. Purification by
flash chromatography (3:1 EtOAc:hexanes) gave pure 62 (10
mg, 60%) as a clear oil: Rf 0.41 (3:1 EtOAc:hexanes); 1H NMR
(300 MHz, CDCl3) 4.05 (m, 1H, 3.69 (s, 2H), 3.24 (d, 1H, J )
5.7 Hz), 2.32 (d, 1H, J ) 15.2 Hz), 2.23 (s, 3H), 2.07 (dd, 1H,
J ) 15.2, 5.9 Hz); 13C-NMR (75 MHz, CDCl3) 69.0, 58.9, 57.2,
53.4, 37.3, 14.8; IR (film) 3400, 2850, 1550, 1400, 1100, 1060
cm-1; FABMS m/z 147 (M + 1, 6%), 119 (100%).
ta n es 68 a n d 69. To a stirred solution under Ar of 67 (64 mg,
0.51 mmol) in CH2Cl2 (2 mL) containing Me2S (20 µL) was
added DMTSF (199 mg, 1.0 mmol). The mixture was stirred
for 4 h and then concentrated in vacuo to dryness. The residue
was cooled to 0 °C and dissolved in water (2 mL) containing
NaN3 (98 mg, 1.5 mmol). The solution was stirred for 4 d and
then extracted with EtOAc (3 × 2 mL). The combined organic
layers were dried (Na2SO4) and concentrated, and the residue
was filtered through SiO2 (6:1 hexanes:EtOAc) to afford a 2:1
mixture of 68 and 69 (52 mg, 48%). Careful chromatography
afforded pure samples of each isomer. For 68: Rf 0.44 (4:1
Ad d ition of CH3SCl to cis-Cyclop en ten e-1,4-d iol 25;
Syn th esis of 2-Ch lor o-3-m eth ylth io-1,4-cyclopen tan ediols
63 a n d 64. To a solution of diol 25 (96 mg, 0.96 mmol) in
CH2Cl2 (25 mL) at 0 °C was added MeSCl (103 mg, 1.2 mmol).
After 3 h, the solution was evaporated, and the orange residue
was chromatographed on SiO2 with 5:1 CH2Cl2:acetone to
afford a colorless oil (150 mg, 81% yield): Rf 0.37 (9:1 CH2Cl2:
MeOH). Diastereomers 63 and 64 (2:1 ratio) could be partially
separated by the above chromatography procedure. For 63: 1H
NMR (300 MHz, CDCl3) δ 4.26 (m, 2 H), 3.95 (m, 1 H), 3.12
(dd, 1 H, J ) 9.0 Hz, 4.3 Hz), 2.67 (bs, 2 H), 2.4-2.2 (m, 1 H),
2.20 (s, 3 H), 2.1-2.0 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ
77.6, 73.8, 67.9, 60.4, 39.2, 15.2. For 64: 1H NMR (300 MHz,
CDCl3) δ 4.25 (m, 1 H), 4.06 (m, 1 H), 3.94 (m, 1 H), 3.22 (m,
1 H), 2.4-2.1 (m, 2 H), 2.27 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 80.2, 71.1, 61.8, 39.2, 15.3; IR of mixture (neat) 3300, 2900,
1100 cm-1; EIMS m/z 185 (M+, 17%), 146 (M - HCl, 50%).
A sample of diol 63 (25 mg, 0.13 mmol) in distilled pyridine
(0.4 mL) at room temperature was acetylated by dropwise
addition of Ac2O (82 mg, 0.80 mmol) and stirring of the
resulting solution at room temperature for 4 h. The solvent
was then removed in vacuo (<2 mm Hg) to give a crude oil.
Purification by flash chromatography (3:1 hexanes:EtOAc)
provided pure 60 (31 mg, 90%) as a clear oil, which was
1
hexanes:EtOAc); H NMR (300 MHz, CDCl3) δ 5.35 (m, 1 H),
3.86 (m, 1 H), 2.90 (m, 1 H), 2.2-1.6 (m, 4 H), 2.18 (s, 3 H),
2.05 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 170.4, 74.8, 66.5,
57.1, 29.5, 28.8, 21.2, 16.1; IR (film) 2950, 2100, 1740, 1240
cm-1; GC/MS m/z 215 (M+, 20%), 155 (M+ - HOAc, 20%). For
1
69: Rf 0.44 (4:1 hexanes:EtOAc); H NMR (300 MHz, CDCl3)
δ 4.98 (m, 1 H), 3.66 (m, 1 H), 2,96 (m, 1 H), 2.2-1.6 (m, 4 H),
2.21 (s, 3 H), 2.03 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 170.7,
79.1, 66.4, 56.3, 29.9, 29.7, 21.4, 15.3; IR (film) 2950, 2100,
1740, 1240 cm-1; GC/MS m/z 215 (M+, 25%), 155 (M+ - HOAc,
30%).
Red u ction a n d Acyla tion of 68; Syn th esis of 1-Acet-
oxy-3-(p-br om oben zoylam in o)-2-m eth ylth iocyclopen tan e
71. A solution of 68 (26 mg, 0.12 mmol) in CH3OH (1.5 mL)
was stirred with 10% Pd/C (25 mg) under a hydrogen atmo-
sphere for 2.5 h. The catalyst was removed by filtration
through Celite, and the filtrate was concentrated in vacuo. The
residue was dissolved in CH2Cl2 (1 mL), and then triethyl-
amine (67 µL, 0.48 mmol) and p-bromobenzoyl chloride (40 mg,
0.18 mmol) were added. After stirring 10 h, the reaction
mixture was washed with satd NaHCO3 solution (2 mL) and
brine (2 mL). The organic layer was dried (Na2SO4) and
concentrated, and the residue was purified over SiO2 (8:1
toluene:CH3CN) to afford 35 mg (78%) of 71 as a white solid:
1
identical by H NMR with the sample of 60 prepared from 59
1
using MeSCl.
Rf 0.39 (5:1 toluene:CH3CN); mp 175 °C; H NMR (300 MHz,
The corresponding bis(4-bromobenzoate) ester 65 of 63 was
prepared by adding 4-bromobenzoyl chloride (77 mg, 0.35
mmol) to a stirred solution of 63 (25 mg, 0.14 mmol) in CH2Cl2
(2 mL) and pyridine (0.2 mL). After stirring 20 h, H2O (1 mL)
was added, and the resulting mixture was stirred for 45 min.
The aqueous layer was separated, and organic layer was
washed with 0.2 N HCl (2 × 2 mL) and satd NaHCO3 (2 × 2
mL). The combined aqueous layers were back-extracted with
CH2Cl2 (2 mL) and the combined organic layers then dried over
Na2SO4 and concentrated in vacuo. Chromatography on SiO2
(1:1 CH2Cl2:hexanes) afforded a white solid (59 mg, 79%). For
CDCl3) δ 7.64, 7.56 (2d, 2 H each, J ) 8.6 Hz), 6.21 (br. d, 1
H, J ) 6.4 Hz), 5.40 (m, 1 H), 4.31 (m, 1 H), 3.04 (m, 1 H),
2.51 (m, 1 H), 2.15 (m, 1 H), 2.14 (s, 3 H), 2.11 (s, 3 H), 1.85
(m, 1 H), 1.62 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 172.2,
169.2, 135.0, 132.9, 130.3, 127.2,76.1, 56.9, 55.4, 30.2, 29.9,
21.1, 15.6; IR 3290, 1735, 1640, 1545, 1245 cm-1; FIMS m/z
371, 373 (M+, 100%).
Crystals of 71 suitable for X-ray analysis were obtained by
recrystallization from EtOH:H2O:CH3OH.
Ad d ition of DMTSF to Azid ocyclop en ten e 18; Syn th e-
sis of 2,5-Azid o-1-m eth ylth iocyclop en ta n es 72 a n d 73. To
a solution of 18 (36 mg, 0.33 mmol) in CH2Cl2 (2 mL) at 0 °C
under Ar was added DMTSF (130 mg, 0.66 mmol) in one
portion. After stirring 6 h, solvent was evaporated, and the
resulting residue was taken up in a solution of NaN3 (64 mg,
0.99 mmol) in H2O (2 mL). The solution was stirred for 4 d
and then extracted with ether (2 × 2 mL). The combined
organic layers were evaporated to a residue that was chro-
matographed on SiO2 (4:1 hexanes:EtOAc) to afford 39 mg
(60%) of 72 and 73 as a 2:1 mixture: Rf ) 0.50 (4:1 hexanes:
EtOAc). For 72: 1H NMR (300 MHz, CDCl3) δ 4.16 (m, 1 H),
3.75 (m, 1 H), 2.95 (m, 1 H), 2.25 (s, 3 H), 2.2-1.6 (m, 4 H);
13C NMR (75 MHz, CDCl3) δ 66.8, 66.5, 57.9, 29.1, 28.9, 15.9;
EIMS m/z 198 (M+, 15%). For 73: 1H NMR (300 MHz, CDCl3)
δ 3.89 (m, 2 H), 2.82 (t, 1 H, J ) 6.4 Hz), 2.25 (s, 3 H), 2.2-1.6
(m, 4 H): 13C NMR (75 MHz, CDCl3) 64.7, 57.6, 29.6, 15.4;
EIMS m/z 198 (M+, 20%); IR (film) (mixture) 2900, 2100, 1275
1
65: mp 108-111 °C; Rf 0.17 (1:1 CH2Cl2:hexanes); H NMR
(300 MHz, CDCl3) δ 7.87 (m, 4 H), 7.65 (m, 4 H), 5.65 (m, 1
H), 5.47 (dd, 1 H, J ) 5.3 Hz, 8.8 Hz), 3.39 (dd, 1 H, J ) 5.1
Hz, J ) 8.9 Hz), 2.90 (m, 1 H), 2.27 (s, 3 H), 2.18 (m, 1 H); 13
C
NMR (75 MHz, CDCl3) δ 165.3, 165.1, 132.1, 132.1, 131.5,
131.5, 129.0, 128.9, 128.8, 128.5, 80.5, 74.4, 66.2, 58.3, 37.2,
16.4; IR (neat) 1720, 1270, 1095 cm-1; FDMS m/z 547.8 (M -
1, 100%).
Crystals of 65 suitable for X-ray analysis were obtained by
recrystallization from CH2Cl2.
Ad d ition of Meth a n esu lfen yl Ch lor id e to Dia ceta te 35;
Syn t h esis of 1-Met h ylt h io-2-ch lor o-3,5-d ia cet oxy-4-(2′
tr im eth ylsilyleth oxy)m eth ylcyclop en ta n e 66. To a stirred
solution of 35 (34 mg, 0.11 mmol) was added a 1.6 M solution
of MeSCl in CCl4 (0.14 mL, 0.22 mmol) at 0 °C. After stirring
for 3 h at 0 °C, the solvent was removed in vacuo to afford a
crude oil. Chromatography over SiO2 (4:1 hexanes:EtOAc) gave
pure 66 (39 mg, 88%) as a colorless oil: Rf 0.45 (4:1 hexanes:
cm-1
.
Ad d ition of DMTSF to a ll-cis-Cyclop en ten etr iol 74;
Syn th esis of 5-Azid o-2,3,4-tr ih yd r oxy-1-m eth ylth iocy-
clop en ta n e 75. To a stirred 0 °C solution of cyclopentenetriol
74 (150 mg, 1.29 mmol) in CH3CN (7.5 mL) was added DMTSF
(304 mg, 1.55 mmol) under Ar. After 6 h at 0 °C, a solution of
NaN3 (252 mg, 3.88 mmol) in water (3 mL) was added. The
reaction was warmed to room temperature and stirred for 7
d. Solvent was then removed and the residue triturated with
1:1 CH2Cl2:MeOH (3 mL). The triturate was filtered through
Celite, rinsing with 10:1 CH2Cl2:MeOH (20 mL). The combined
organic layers were evaporated, and the residue was chro-
1
EtOAc); H NMR (300 MHz, CDCl3) δ 5.25 (dd, 1 H, J ) 7.4,
5.5 Hz), 5.20 (dd, 1 H, J ) 5.2, 2.2 Hz), 4.18 (dd, 1 H, J )
11.3, 7.7 Hz), 3.59 (m,2 H), 3.53 (t, 2 H, J ) 8.0 Hz), 3.20 (dd,
1 H J ) 11.3, 5.9 Hz), 2.20 (s, 3 H), 2.10 (s, 6 H), 2.10 (m, 1
H), 0.90 (m, 2 H), 0.01 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ
170.4, 170.1, 80.0, 75.9, 68.8, 68.7, 65.0, 55.5, 50.7, 20.9, 17.9,
15.9, -1.3; IR (film) 2950, 2850, 1750, 1375, 1220, 1090, 1030,
850 cm-1; CIMS m/z 397 (M + 1), 369 (100%).
Ad d ition of DMTSF to Cyclop en ten yl Aceta te 67;
Syn th esis of 1-Acetoxy-3-a zid o-2-m eth ylth iocyclop en -

Electrophilic Additions to Substituted Cyclopentenes
J . Org. Chem., Vol. 65, No. 13, 2000 4069
matographed on SiO2 (10:1 CH2Cl2:MeOH) to afford 85 mg
(32%) of pure 75 as well as 28 mg of a 1:1 mixture of 74 and
75: Rf ) 0.35 (10:1 CH2Cl2:MeOH); 1H NMR (300 MHz, CDCl3)
δ 4.07 (m, 1 H), 3.88 (m, 1 H), 3.79 (m, 1 H), 3.63 (m, 1 H)
2.85 (m, 1 H), 2.01 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 74.8,
71.8, 71.3, 70.8, 51.8, 14.8; IR (film) 3400, 2100, 1500, 1220,
1190 cm-1; FABMS m/z 205 (M+, 55%).
mmol) in water (1 mL) was added, and the solution was stirred
4 d at room temperature. The reaction mixture was diluted
with EtOAc (20 mL) and washed with brine (5 mL). The
aqueous layer was back-extracted with EtOAc (3 mL), and the
combined organic layers were dried (MgSO4) and concentrated
in vacuo. The residue was purified by prep TLC to afford 78
(83 mg, 34%) as a colorless oil: Rf 0.31 (4:1 hexanes:EtOAc);
1H NMR (300 MHz, D2O) δ 7.42-7.25 (m,15 H), 4.84-4.50 (m,
6 H), 4.33 (m, 1 H), 4.01-3.93 (m, 2 H), 3.60 (m,1 H), 2.94 (m,
1 H), 2.22 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 138.6, 138.4,
137.9, 128.7, 128.65, 128.60, 128.23, 128.18, 128.1, 127.95,
127.90, 81.2, 78.3, 76.4, 73.2, 73.1, 72.4,71.5, 51.0, 15.2; IR
(film) 2900, 2100, 1350, 1100 cm-1; FDMS m/z 479 (M+,100%).
Syn th esis of 2-Am in o-3,4,5-tr ih yd r oxy-1-m eth ylth io-
cyclop en ta n e (bis-ep i-m a n n osta tin A) 76. To a solution of
azide 75 (95 mg, 0.46 mmol) in MeOH (5 mL) was added
triethylamine (388 µL, 2.78 mmol) followed by propane-1,3-
dithiol (280 µL, 2.78 mmol). The solution was stirred 72 h at
room temperature, during which time a white solid precipi-
tated. The supernatant was then filtered and the filtrate
concentrated to a residue that was chromatographed on SiO2
(50:20:1 CH2Cl2:MeOH:NH4OH) to furnish 39 mg (48%) of 76
as an oil: 1H NMR (300 MHz, D2O) δ 4.03 (m,1 H), 3.87 (m, 1
Ack n ow led gm en t. Financial support from the U.
S. National Institutes of Health (GM 35712, to B.G.; GM
08500 training grant support for M.A.C.) is gratefully
acknowledged. We also thank Emil Lobkovsky of the
Departmental X-ray Facility for X-ray crystallographic
analyses, and Mr. Ryan Schoenfeld for valuable experi-
mental assistance.
H), 3.61 (m, 1 H), 2.91 (m, 1 H), 2.61 (m,1 H), 1.96 (s, 3 H); 13
C
NMR (75 MHz, D2O) δ 76.3, 71.6, 71.4, 62.0, 53.6, 15.0; IR
(film) 3350, 2900, 1590, 1425, 1125 cm-1; FABMS m/z 180 (M
1
+ 1, 60%), 163 (100%). The H NMR spectrum of 76‚HCl was
distinctly different from a spectrum of authentic mannostatin
A HCl salt.
Ad d ition of DMTSF to a ll-cis-3,4,5-Tr iben zyloxycyclo-
p en ten e 77; Syn th esis of 5-Azid o-2,3,4-tr iben zyloxy-1-
m eth ylth iocyclop en ta n e 78. To a stirred 0 °C solution of
cyclopentene 77 (200 mg, 0.52 mmol) in CH3CN (4 mL) was
added DMTSF (122 mg, 0.62 mmol). The solution was stirred
under argon for 2 h at 0 °C and then warmed to room
temperature. After 1.5 h, a solution of NaN3 (101 mg, 1.55
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra for all new compounds, as well as ORTEP diagrams
and tables of crystallographic data for compounds 33, 58, 65,
and 71. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O000101F