Development of efficient new methodology for generation, cyclization and functional trapping of iminyl and amidyl radicals

Article abstract of DOI:10.1016/S0040-4020(01)00878-X

New methodology has been devised for the generation and subsequent cyclization of iminyl and amidyl radicals under mild conditions. The process involves either the treatment of oximes with 2,6-dimethylbenzenesulfinyl chloride, or the treatment of hydroxamic acids with tert-butylsulfinyl chloride (-50°C to rt), to give the corresponding nitrogen radicals, followed by cyclization onto pendant olefins. Radical traps such as diphenyl diselenide, diphenyl disulfide, and TEMPO can be used to terminate the cyclizations, thus introducing functionality that provides multiple options for further manipulation. In a more convenient procedure, both iminyl and amidyl radical cyclizations can be initiated using commercially available diethyl chlorophosphite which generally provides similar (with diphenyl disulfide and TEMPO) or significantly higher (with diphenyl diselenide) yields of products.

Full text of DOI:10.1016/S0040-4020(01)00878-X

TETRAHEDRON
Pergamon
Tetrahedron 57 02001) 8779±8791
Development of ef®cient new methodology for generation,
cyclization and functional trapping of iminyl and amidyl radicals
Xichen Lin, Gerald D. Artman, III, Didier Stien and Steven M. Weinrebp
152 Davey Laboratory, Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA
Received 20 August 2001;accepted 23 August 2001
AbstractÐNew methodology has been devised for the generation and subsequent cyclization of iminyl and amidyl radicals under mild
conditions. The process involves either the treatment of oximes with 2,6-dimethylbenzenesul®nyl chloride, or the treatment of hydroxamic
acids with tert-butylsul®nyl chloride 02508C to rt), to give the corresponding nitrogen radicals, followed by cyclization onto pendant ole®ns.
Radical traps such as diphenyl diselenide, diphenyl disul®de, and TEMPO can be used to terminate the cyclizations, thus introducing
functionality that provides multiple options for further manipulation. In a more convenient procedure, both iminyl and amidyl radical
cyclizations can be initiated using commercially available diethyl chlorophosphite which generally provides similar 0with diphenyl disul®de
and TEMPO) or signi®cantly higher 0with diphenyl diselenide) yields of products. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction and background
a better understanding of the reactivity of these species.
However, this ®eld has not received nearly the attention
as have carbon-centered radicals. As part of our long-
standing research on the total synthesis of alkaloids and
other nitrogen-containing natural products, we became
interested in the prospect of utilizing nitrogen radical cycli-
zations to ef®ciently access highly functionalized inter-
mediates. A major goal of our research was to develop
¯exible, operationally simple new methodology to effect
nitrogen radical±ole®n cyclizations which would also
allow trapping of the resulting carbon radical with a variety
An attractive strategy for constructing nitrogen heterocycles
involves the cyclization of a nitrogen-centered radical onto
a pendant ole®n.1 During the past decade a considerable
amount of methodology has been developed to effect this
type of transformation in a synthetically useful manner, with
aminyl, iminyl2 and amidyl3 radicals receiving signi®cant
attention. In particular, the innovative studies of Newcomb
and of Zard have led to a variety of clever methods for
generating different types of nitrogen radicals, and also to
Scheme 1.
Scheme 2.
Keywords: iminyl radicals;amidyl radicals;cyclization.
Corresponding author. Tel.: 11-949-824-5392;fax: 11-949-824-8571;e-mail: smw@chem.psu.edu
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020001)00878-X

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X. Lin et al. / Tetrahedron 57 (2001) 8779±8791
of heteroatoms 0rather than a hydrogen), thereby leading to
products readily amenable to subsequent functional group
manipulations.4
Towards this goal, we were attracted by the report of
Hudson and coworkers that treatment of an oxime 1 with
a sul®nyl chloride at low temperature, followed by warming
to room temperature, leads to an N-sulfonylimine 4 0Scheme
1).5,6 In a series of mechanistic experiments based on NMR
and EPR spectroscopy, it was convincingly shown that this
process involves initial formation of sul®nate ester 2 which
upon warming undergoes spontaneous homolysis to an
iminyl/sulfonyl `caged' radical pair 3. Subsequent recombi-
nation of this radical pair then affords the observed product
4. A closely related reaction is also known for various
hydroxamic acid derivatives.7 Thus, a hydroxamic acid 5
reacts with a sul®nyl chloride to ultimately produce an
N-sulfonylamide 8 0Scheme 2). Once again, mechanistic
evidence indicated that this transformation occurs via
sul®nate 6 and amidyl/sulfonyl radical pair 7. It was also
shown by isotopic labelling experiments that radical pair
Scheme 3.
Table 1. Isolated yields of radical cyclization products of oxime ole®ns
Radical traps
PhSSPh
PhSeSePh
Oxime13
Product
XˆSePh
0EtO)2PCI
XˆSPh
XˆTEMPO
0EtO)2PCI
ArSOCI
ArSOCI
0EtO)2PCI
ArSOCI
61%
12a
86%
86%
70%
12b
69%
68%
61%
12c
41%
64%
58%
13a
67%
13b
58%
13c
49%
14a
72%
60%
14b
61%
49%
14c
58%
49%
15a
56%
15b
65%
16a
75%
16b
62%
16c

X. Lin et al. / Tetrahedron 57 (2001) 8779±8791
8781
Scheme 4.
recombination is intramolecular.7d However, despite the
apparent simplicity and mildness of generating iminyl and
amidyl radicals by these processes, to our knowledge no
attempt had ever been made to intercept these radicals
with an internal alkene. In this paper we describe the full
details of our exploratory work in this area.4
14% of tert-butyl phenyl selenide. The best reagent,
however, proved to be bulky 2,6-dimethylbenzenesul®nyl
chloride12 which provided 12a in 61% isolated yield. The
product yield was reduced, however, when the even more
sterically hindered compound 2,4,6-triisopropylbenzene-
sul®nyl chloride was used, perhaps due to dif®culties in
the initial oxime sul®nylation step.
2. Results and discussion
Using the optimum experimental conditions found for 12a,
a series of oxime ole®n substrates13 was examined and the
results are shown in Table 1. The reactions are best
performed by treating the oxime in methylene chloride
with 2,6-dimethylbenzenesul®nyl chloride 02 equiv.)
initially at 2508C in the presence of Hunig's base and a
radical trapping agent, and then slowly warming the mixture
to room temperature. With diphenyl diselenide or TEMPO
as the trapping agents, only a small excess was required to
provide the desired products in acceptable isolated yields.
However, with less reactive trapping reagents14,15 such as
diphenyl disul®de or 1,4-cyclohexadiene, a large excess
must be used or signi®cant amounts of side products are
produced. For example, exposure of oxime 16 to the
standard cyclization conditions in the presence of
100 equiv. of 1,4-cyclohexadiene as a hydrogen atom
source afforded the desired reduced product 17 in moderate
yield 0Eq. 01)), but if substantially smaller quantities of this
trap were used varying amounts of the sulfur-containing
by-product 18 were formed.16
2.1. Iminyl radical cyclizations
Preliminary feasibility experiments were conducted with
oxime 9 derived from commercially available 2-allylcyclo-
hexanone. The hope was that the initially formed iminyl
radical 0cf. 10) would cyclize more rapidly than recombi-
nation to the N-sulfonylimine, and that the resulting carbon
centered radical 11 would then react with a sulfonyl radical
to afford 12 0XˆTs) 0Scheme 3).8 In fact, treatment of
oxime 9 with p-toluenesul®nyl chloride9 did give bicyclic
imine sulfone 12, but only in low yield with the major by-
product in this reaction being the uncyclized N-sulfonyl-
imine. The cyclization could not be improved signi®cantly
by adding diphenyl diselenide as a radical trap, and only a
poor 22% yield of imine selenide 12a was obtained, with the
N-sulfonylimine once again being the major product.
It therefore became evident that in order to make this
approach viable it was necessary to interfere with or slow
the radical recombination step, and we considered two
sul®nyl chloride-based strategies. The ®rst was to generate
a sulfonyl radical which should be prone to rapid loss of SO2
by producing a stabilized alkyl radical, thereby preventing
N-sulfonylimine formation.9,10 The other was to use bulky
sul®nyl chlorides and slow radical recombination by steric
factors. Thus, treatment of oxime ole®n 9 with benzyl-
sul®nyl chloride/diphenyl diselenide indeed led to a
substantial improvement in the yield of cyclization product
12a to 41%. In support of the premise that loss of sulfur
dioxide from the benzylsulfonyl radical was atleast partially
occurring was the fact that we isolated benzyl phenyl
selenide in 24% yield. It might also be noted that use of
Hunig's base provided slightly better yields of product 12a
than did triethylamine, and was superior to DMAP, NaH,
tert-BuOK, pyridine or 2,6-di-tert-butylpyridine in explora-
tory reactions using benzylsul®nyl chloride. In addition,
methylene chloride was a far better solvent than THF,
toluene, acetonitrile, ether or chlorobenzene. Although
cinnamylsul®nyl chloride did not prove useful, tert-butyl-
sul®nyl chloride,11 which in principle can work via both of
the effects mentioned above, did lead to an improved 47%
yield of selenide 12a. This reaction also produced about
ꢀ1†
More recently we have investigated modi®cations of this
methodology with the intent of increasing the yields of
cyclization products and also ®nding an alternative,
commercially available initiating reagent. One possible
solution which occurred to us was to make use of a related
reaction of oximes 19 with trivalent phosphorus compounds
known to produce N-phosphinylimines 22 0Scheme 4).17,18
This transformation, as in the case of the corresponding
sul®nyl reaction in Scheme 1, has been shown in mecha-
nistic studies by Hudson and coworkers to proceed via a
radical pair 21 formed by homolytic dissociation of the
initial intermediate 20.17b,c An analogous reaction has also
been described for the conversion of hydroxamic acids to
N-phosphinylamides 0cf. Scheme 2, vide infra).19

8782
X. Lin et al. / Tetrahedron 57 (2001) 8779±8791
Scheme 5.
Exploratory reactions were conducted using oxime ole®n 9
as the substrate and diphenyl diselenide as the radical trap
0Eq. 02)). Some commercially available phosphorus
reagents were tried, and we were pleased to ®nd that diethyl
chlorophosphite afforded a yield of product 12a which was
signi®cantly better than that obtained with the sul®nyl
reagent. Using diphenylchlorophosphine only led to the
uncyclized N-phosphinylimine. In addition, diisopropyl-
ethylamine was still the most effective base. Table 1
contains the results of several cyclizations using these
newly developed conditions. In general, cyclizations with
diphenyl diselenide 02 equiv.) as the trap proceeded in
superior yields compared to those done with 2,6-dimethyl-
benzenesul®nyl chloride. The reactions with diphenyl
disul®de 010±20 equiv.) and TEMPO 02 equiv.) could be
effected in yields comparable to those using the sul®nyl
reagent.
2.2. Amidyl radical cyclizations
In view of the successful results described above for the
iminyl radical cyclizations, we next turned to an exploration
of the feasibilty of effecting amidyl radical cyclizations via
the same strategy. Hydroxamic acid ole®n 23 was selected
as the test substrate, and diphenyl diselenide as the radical
trapping agent 0Scheme 5). Initial experiments were
conducted with various sul®nyl chlorides as the activating
reagent, and isolated yields of cyclization product 23a are
shown in Scheme 5. Inexplicably, 2,6-dimethylbenzene-
sul®nyl chloride, which is most effective in the iminyl
radical cases, did not work well in the amidyl system. Of
all the sul®nyl compounds tried, tert-butylsul®nyl chloride
01.5 equiv.) in fact proved best, with cyclization product 23a
isolated in 64% yield. In addition, the radical recombination
product 24 was formed in 14% yield along with 6% of
reduced amide 25, and 10% of the starting hydroxamic
acid 23.
Using the experimental conditions optimized for substrate
23, a series of cyclizations was investigated on the ole®nic
hydroxamic acids listed in Table 2. Once again, diphenyl
diselenide, diphenyl disul®de and TEMPO all proved to be
effective radical trapping agents. As with the iminyl radical
reactions, PhSSPh must be used in large excess.20 After
discovering that phosphorus reagents could be ef®ciently
employed in initiating the iminyl radical cyclizations 0vide
supra), we returned to the hydroxamic acid substrate 23 to
study this modi®cation in the amidyl radical series. Indeed,
diethyl chlorophosphite 01.5 equiv.) again proved to be very
effective in initiating the reaction and the yield of selenide
23a was substantially improved over that obtained with tert-
butylsul®nyl chloride 0Scheme 5). Some additional
examples of cyclizations with this reagent are shown in
Table 2. As can be seen, yields of selenide cyclization
products are signifcantly improved and those using the
other radical traps are similar to the sul®nyl chloride results.
It might also be noted that we have been unable to effect a
6-exo cyclization in the amidyl series.
ꢀ2†
An attempt was also made to effect a 6-exo iminyl radical
cyclization to produce a six-membered ring imine 0Eq. 03)).
However, none of the desired product was formed. It is
known that 6-exo iminyl radical cyclizations are about
two orders of magnitude slower than the corresponding 5-
exoclosures, and thus radical recombination and other side
processes evidently become favored in this system.15 It
might also be noted that there are few existing examples
of 6-exo cyclizations of nitrogen radicals.1±3
The feasibility of using the methodology in a tandem cycli-
zation was also tested as shown in Scheme 6.21 Thus,
exposure of hydroxamic acid diene 30 to tert-butylsul®nyl
chloride and PhSeSePh under our standard conditions
led to bicyclic lactam selenide 32 059%, 2:1 mixture of
ꢀ3†

X. Lin et al. / Tetrahedron 57 (2001) 8779±8791
Table 2. Isolated yields of radical cyclization products of ole®nic hydroxamic acids
8783
Radical traps
PhSeSePh
PhSSPh
Hydroxamic Acid
Product
XˆSePh
XˆSPh
XˆTEMPO
tert-BuSOCI
tert-BuSOCI
0EtO)2PCI
tert-BuSOCI
0EtO)2PCI
0EtO)2PCI
64%
23a
70%
26a
84%
58%
23b
74%
26b
58%
60%
23c
78%
26c
67%
65%
27a
83%
64%
27b
63%
62%
27c
59%
59%
28a
56%
28b
56%
28c
58%
29a
79%
61%
29b
75%
57%
29c
61%
diastereomers) via the intermediate monocyclic carbon-
centered radical 31. This cyclization was also effected
with diethyl chlorophosphite but a by-product, 0EtO)2P0O)-
SePh, could not be separated chromatographically from the
desired compound 32.
loid synthesis 0vide infra), we examined a further trans-
formation of the bicyclic selenide product 29a. As hoped,
treatment of this material with hydrogen peroxide cleanly
led to the desired bicyclic ole®n 33 0Eq. 04)).22
Prior to applying this cyclization methodology to an alka-
ꢀ4†
2.3. Formal total synthesis of ,1/2)-peduncularine via
an amidyl radical cyclization
The indole alkaloid peduncularine 034) is a major metabo-
lite of the Tasmanian shrub Aristotelia peduncularis.23 This
compound has an unusual 6-azabicyclo[3.2.1]-3-octene
skeleton not previously found in indole alkaloids. Plants
of the Aristotelia genus have long been used in folk
medicine in New Zealand and South America, and
peduncularine itself shows weak antitumor activity. Three
total syntheses of peduncularine have emanated from the
Scheme 6.

8784
X. Lin et al. / Tetrahedron 57 (2001) 8779±8791
Lactam selenide 40 was then oxidized with hydrogen
peroxide as was done in the model system 29a to afford
the desired bicyclic alkene 41 in high yield.22 Finally, the
methyl ether group of 41 could be cleaved with BBr3 to give
the alcohol 35. This compound had NMR spectra identical
to those of an authentic sample.25 Thus, alcohol 35 can be
synthesized in only four steps in good overall yield from
acrylate hydroxamic acid 38. Since Hiemstra and co-
workers24a have previously converted bicyclic lactam 35
to peduncularine 034), our synthesis of this intermediate
constitutes a formal racemic total synthesis of this interest-
ing alkaloid.
Scheme 7.
groups of Hiemstra,24a Rigby24b and Woerpel.24c The
Hiemstra synthesis, which was also enantioselective,
involved elaboration of the key bicyclic alcohol lactam 35,
whereas both the Rigby and Woerpel racemic approaches
proceeded via the epimeric alcohol 36 0Scheme 7).
3. Conclusion
In this paper we have reported ef®cient, experimentally
simple new methodology for effecting iminyl and amidyl
radical/ole®n cyclizations starting from readily available
oximes and hydroxamic acids, respectively. The cycli-
zations can be terminated with various radical traps such
as diphenyl diselenide, diphenyl disul®de and TEMPO,
thereby providing products which are more highly
functionalized than those produced by related tin hydride-
based methods.1±3 Cyclizations are initiated by 2,6-di-
methylbenzenesul®nyl chloride for the oxime substrates,
and tert-butylsul®nyl chloride for the hydroxamic acids
from 2508C to room temperature using diisopropylethyl-
amine as a base. More conveniently, both types of cycli-
zations can be initiated by diethyl chlorophosphite under the
same mild reaction conditions. This reagent generally
produces selenide-trapped products in substantially higher
yields than do the sul®nyl chlorides and gives similar yields
of products when using diphenyl disul®de and TEMPO as
the trapping reagents. Moreover, the chlorophosphite
initiator is also preferable since it is a commercially
available compound, and excess reagent can be easily
removed due to its hydrolytic lability and water solubility.
The reactions have been shown to work well for a wide
variety of substrates involving 5-exo processes, but have
been unsuccessful in analogous 6-exo cyclizations. We are
continuing to explore improvements and applications of this
methodolgy.
It occurred to us that the amidyl radical cyclization method-
ology described above might provide a short, direct and
ef®cient route to the pivotal Hiemstra peduncularine inter-
mediate 35. Our approach began with hydroxamic acid 38
which was easily prepared from acryloyl chloride and
commercially available N-isopropylhydroxylamine hydro-
chloride 0Scheme 8). Attempted Diels±Alder reaction of
this compound with 1-methoxybutadiene 037) by heating
in toluene, or using various Lewis acid catalysts led to
complex mixtures of products. However, the cycloaddition
proceeded smoothly at 12 Kbar at room temperature to
afford the desired adduct 39 as a single stereoisomer.
Exposure of this hydroxamic acid to tert-butylsul®nyl
chloride/PhSeSePh under the usual conditions provided
the requisite cyclization product 40 but only in a modest
30% yield. However, we were pleased to ®nd that using
diethyl chlorophosphite led to a dramatic increase in the
yield of bicyclic selenide 40 to 70%. Compound 40 is a
single isomer whose stereostructure has not been established.
4. Experimental
4.1. General experimental
Reactions were run under an atmosphere of argon. Flash
column chromatography was performed using E. Merck
Silica Gel 60 070±230 mesh). Preparative TLC was done
with EM Silica Gel 60 PF254. THF was distilled from
sodium/benzophenone ketyl. Methylene chloride was
distilled from calcium hydride. Reactions run under high
pressure were performed in a LECO model PG-200-HPC
apparatus.
4.1.1. 2-,3-Methylbut-2-enyl)-cyclohexanone oxime ,16).
To a solution of cyclohexanone oxime 01.24 g, 11.0 mmol)
in dry THF 040 mL) at 2788C was added n-BuLi 011.0 mL,
2 M solution in hexane) over 10 min. The resulting mixture
was stirred in an ice bath for 20 min, recooled to 2788C and
Scheme 8.

X. Lin et al. / Tetrahedron 57 (2001) 8779±8791
8785
4-bromo-2-methyl-2-butene 01.27 mL, 11 mmol) was
added. The mixture was warmed to rt slowly and stirred
for 1 h. The solution was washed with water, brine, dried
over MgSO4 and evaporated in vacuo. The residue was
puri®ed by ¯ash column chromatography 020% EtOAc/
hexanes) to afford the ketoxime ole®n 16 as a pale yellow
0hexanes-1/1 EtOAc/hexanes) to afford the desired cycli-
zation products. Isolated yields are listed in Table 1.
4.3.1. 2-Phenylselanylmethyl-3,3a,4,5,6,7-hexahydro-2H-
indole ,12a). 03:2 Mixture of diastereoisomers): H NMR
1
0360 MHz, CDCl3) d 7.58±7.54 0m, 2H), 7.29±7.24 0m,
3H), 4.38 0m, 0.4H), 4.10 0m, 0.6H), 3.44 0dd, Jˆ11.8,
5.4 Hz, 0.6H), 3.25 0dd, Jˆ12.2, 5.0 Hz, 0.4H), 3.05 0dd,
Jˆ11.8, 8.2 Hz, 0.6H), 2.94 0dd, Jˆ12.2, 7.8 Hz, 0.4H),
2.78±2.54 0m, 2H), 2.40 0ddd, Jˆ12.8, 9.1, 7.3 Hz, 0.6H),
2.21±1.97 0m, 3H), 1.88±1.78 0m, 1H), 1.68 0ddd, Jˆ13.2,
8.7, 6.8 Hz, 0.4H), 1.50±1.09 0m, 4H); 13C NMR 075 MHz,
CDCl3) d 180.5, 179.9, 132.3, 132.3, 130.6, 129.0, 126.6,
70.6, 70.5, 48.8, 48.0, 36.7, 34.9, 34.8, 34.6, 34.2, 31.9,
31.7, 27.0, 26.5, 25.3, 25.1;HRMS 0C 15H19NSe) calcd
292.0769 0MH1), found 292.0760.
1
solid 01.63 g, 82%): mp 68±698C; H NMR 0360 MHz,
CDCl3) d 5.12±5.07 0m, 1H), 2.85±2.81 0m, 1H), 2.38±
2.29 0m, 1H), 2.22±2.10 0m, 3H), 2.00±1.82 0m, 1H),
1.73±1.36 0m, 5H), 1.69 0s, 3H), 1.59 0s, 3H); 13C NMR
090 MHz, CDCl3) d 162.6, 132.8, 122.4, 42.5, 32.2, 29.3,
26.1, 25.7, 24.0, 23.5, 17.9;HRMS 0C 11H19NO) calcd
182.1545 0MH1), found 182.1550.
4.1.2. 2,6-Dimethylbenzenesul®nyl chloride. Excess
sulfur dioxide was bubbled through a solution of 2,6-
dimethylbenzenemagnesium bromide 020 mL, 1.0 M in
THF, Aldrich) at 08C in a fume hood allowing for adequate
venting of excess SO2. After 2±3 h, the reaction mixture
was diluted with ice-cold 5% HCl 020 mL) and the aqueous
layer was then extracted with 20 mL of methylene chloride.
The organic extract was dried over MgSO4, and concen-
trated in vacuo to afford 2,6-dimethylbenzenesul®nic acid
as a white solid 03.3 g, 95%) which was used without further
puri®cation.
4.3.2. 2-Phenylsulfanylmethyl-3,3a,4,5,6,7-hexahydro-
2H-indole ,12b). 03:2 Mixture of diastereoisomers): 1H
NMR 0360 MHz, CDCl3) d 7.32±7.28 0m, 2H), 7.21±7.16
0m 2H), 7.08 0br t, Jˆ7.3 Hz, 1H), 4.21 0m, 0.4H), 3.97 0m,
0.6H), 3.40 0dd, Jˆ12.6, 5.4 Hz, 0.6H), 3.20 0dd, Jˆ12.8,
4.7 Hz, 0.4H), 2.89 0dd, Jˆ12.6, 8.2 Hz, 0.6H), 2.76 0dd,
Jˆ12.8, 8.0 Hz, 0.4H), 2.65±2.45 0m, 2H), 2.30 0ddd, Jˆ
12.9, 8.6, 7.5 Hz, 0.6H), 2.12±1.87 0m, 3H), 1.78±1.69 0m,
1H), 1.58 0ddd, Jˆ13.3, 8.4, 6.6 Hz, 0.4H), 1.40±0.90 0m,
4H); 13C NMR 090 MHz, CDCl3) d 180.7, 180.1, 136.6,
136.6, 128.9, 128.8, 128.8, 125.7, 125.7, 69.8, 69.7, 48.6,
47.8, 40.3, 39.4, 36.1, 34.8, 34.7, 34.2, 31.8, 31.7, 26.9,
26.4, 25.2, 25.1;HRMS 0C 15H19NS) calcd 246.1316
0MH1), found 246.1318.
To a solution of 2,6-dimethylbenzenesul®nic acid 03.3 g,
19.0 mmol) in 7 mL of THF was added dropwise thionyl
chloride 01.70 mL, 22.8 mmol) at rt. After 3 h, the solvent
and excess thionyl chloride were evaporated in vacuo. The
resulting 2,6-dimethylbenzenesul®nyl chloride 03.4 g, 95%)
was used without further puri®cation 0dark green liquid). 1H
NMR 0200 MHz, CDCl3) d 7.35 0br t, Jˆ7.6 Hz, 1H), 7.13
0br d, Jˆ7.6 Hz, 2H), 2.66 0s, 6H).
4.3.3. 2-,2,2,6,6-Tetramethylpiperidin-1-yloxy)methyl-3,
3a,4,5,6,7-hexahydro-2H-indole ,12c). 03:2 Mixture of
diastereoisomers): H NMR 0360 MHz, CDCl3) d 4.15 0m,
1
0.4H), 4.03 0dd, Jˆ8.2, 4.6 Hz, 0.6H), 4.01 0m, 0.6H), 3.89±
3.82 0m, 1H), 3.76 0dd, Jˆ8.6, 4.6 Hz, 0.4H), 2.66±2.58 0m,
2H), 2.20±2.03 0m, 3H), 1.94±1.86 0m, 1H), 1.78±1.68 0m,
1H), 1.48±0.92 0m, 22H); 13C NMR 090 MHz, CDCl3) d
180.1, 179.4, 79.7, 78.7, 70.3, 69.9, 59.8, 59.7, 48.7, 48.0,
39.6, 39.5, 34.8, 34.7, 33.1, 33.0, 32.9, 31.8, 31.7, 26.8,
26.7, 25.4, 25.3, 20.3, 17.1, 17.0;HRMS 0C 18H32N2O)
calcd 293.2593 0MH1), found 293.2587. Anal. calcd for
C18H32N2O: C, 61.64;H, 6.55;N, 4.79.; Found: C, 61.42;
H, 6.41;N, 4.71.
4.2. General procedure for cyclization of oximes using
2,6-dimethylbenzenesul®nyl chloride
To a solution of the oxime 00.30 mmol)13 and radical trap
0TEMPO: 70 mg, 0.45 mmol;diphenyl diselenide: 187 mg,
0.60 mmol;diphenyl disul®de: 2.3 g, 6.0 mmol;cyclo-
hexadiene: 8.5 mL, 9.0 mmol) in methylene chloride 07.5
mL) at 2508C were added successively diisopropylethyl-
amine 00.105 mL, 0.60 mmol) and 2,6-dimethylbenzene-
sul®nyl chloride 0113 mg, 0.60 mmol). The mixture was
then warmed slowly to rt, and stirred for 5 h. The solution
was concentrated and the residue was puri®ed by ¯ash
column chromatography 020±100% EtOAc/hexanes gradi-
ent) to give the cyclization product as a yellow oil. Isolated
yields are listed in Table 1.
4.3.4. 5-Methyl-2-phenylselanyl-4-azatricyclo[4.2.1.00,0]-
non-4-ene ,13a). 1H NMR 0300 MHz, CDCl3) d 7.48±7.39
0m, 2H), 7.22±7.11 0m, 3H), 4.02 0d, Jˆ4.6 Hz, 1H), 3.05
0m, 1H), 2.99 0s, 1H), 2.41±2.38 0m, 2H), 2.22 0br d,
Jˆ10.9 Hz, 1H), 1.96 0s, 3H), 1.68±1.58 0m, 2H), 1.28 0br
d, Jˆ12.6 Hz, 1H); 13C NMR 075 MHz, CDCl3) d 184.2,
132.7, 130.5, 129.1, 126.8, 77.6, 52.3, 48.9, 48.0, 45.6, 37.4,
34.5, 19.4;HRMS 0C 15H17NSe) calcd 286.0664 0MH1),
found 286.0657.
4.3. General procedure for the cyclization of oximes
using diethyl chlorophosphite
The oxime 00.3 mmol) was dissolved in CH2Cl2 06 mL) with
either 0PhSe)2 00.6 mmol), 0PhS)2 03±6 mmol), or TEMPO
00.6 mmol) and cooled to 2508C. DIEA 00.8 mmol)
followed by 0EtO)2PCl 00.38 mmol, Aldrich, 98% purity)
were then slowly added. The solution was warmed to rt
over 1 h and stirred for an additional 1 h. The volatile
organics were removed under reduced pressure and the
residue was puri®ed by ¯ash silica gel chromatography
4.3.5. 5-Methyl-2-phenylsulfanyl-4-azatricyclo[4.2.1.00,0]-
non-4-ene ,13b). 1H NMR 0300 MHz, CDCl3) d 7.35±7.26
0m, 4H), 7.14 0br t, Jˆ7.2 Hz, 1H), 3.95 0d, Jˆ4.4 Hz, 1H),
3.09 0m, 1H), 2.93 0s, 1H), 2.48±2.41 0m, 2H), 2.28 0br d,
Jˆ5.5 Hz, 1H), 2.03 0s, 3H), 1.67 0ddd, Jˆ12.6, 10.3,
4.1 Hz, 1H), 1.62 0br d, Jˆ11.0 Hz, 1H), 1.35 0br d, Jˆ
12.6 Hz, 1H); 13C NMR 090 MHz, CDCl3) d 184.2, 136.1,

8786
X. Lin et al. / Tetrahedron 57 (2001) 8779±8791
129.0, 129.0, 125.7, 77.2, 52.3, 52.2, 48.1, 44.9, 36.7, 34.2,
19.5;HRMS 0C 15H17NS) calcd 244.1160 0MH1), found
244.1150.
4.3.12. 2-,1-Methyl-1-phenylselanylethyl)-3,3a,4,5,6,7-
hexahydro-2H-indole ,16a). 03:2 Mixture of diastereo-
1
isomers): H NMR 0300 MHz, CDCl3) d 7.58 0br t, Jˆ
7.8 Hz, 2H), 7.29±7.18 0m, 3H), 4.10±4.03 0m, 0.4H),
3.88±3.80 0m, 0.6H), 2.60±2.45 0m, 2H), 2.20±2.02 0m,
3H), 1.96±1.87 0m, 1H), 1.76±1.68 0m, 1H), 1.58±1.14
0m, 10H); 13C NMR 075 MHz, CDCl3) d 181.7, 180.3,
168.5, 138.6, 133.3, 128.5, 128.5, 128.5, 128.4, 80.2, 80.0,
51.6, 50.5, 48.7, 48.2, 35.2, 34.3, 32.6, 32.0, 31.7, 27.9,
27.7, 27.1, 26.9, 26.7, 26.6, 26.5, 25.7, 25.3, 25.1;HRMS
0C17H23NSe) calcd 318.1101 0MH1), found 318.1080.
4.3.6. 5-Methyl-2-,2,2,6,6-tetramethylpiperidin-1-yloxy)-
4-azatricyclo[4.2.1.00,0]non-4-ene ,13c). 1H NMR 0300
MHz, CDCl3) d 4.03 0d, Jˆ4.6 Hz, 1H), 3.39 0s, 1H), 2.99
0m, 1H), 2.72 0m, 1H), 2.30 0m, 1H), 1.99 0m, 1H), 1.95 0s,
3H), 1.43 0s, 6H), 1.13 0s, 6H), 1.57±1.13 0m, 9H); 13C
NMR 075 MHz, CDCl3) d 183.3, 89.0, 79.4, 59.2, 50.8,
47.7, 44.9, 40.1, 34.9, 34.8, 32.7, 20.2, 19.2, 17.2;HRMS
0C18H30N2O) calcd 291.2436 0MH1), found 291.2436.
4.3.13. 2-,1-Methyl-1-phenylsulfanylethyl)-3,3a,4,5,6,7-
hexahydro-2H-indole ,16b). 03:2 Mixture of diastereo-
4.3.7. 5-Methyl-2-,1-methyl-1-phenylselanylethyl)-3,4-
1
1
isomers): H NMR 0300 MHz, CDCl3) d 7.48 0br t, Jˆ
dihydro-2H-pyrrole ,14a). H NMR 0360 MHz, CDCl3)
7.2 Hz, 2H), 7.29±7.22 0m, 3H), 3.98±3.92 0m, 0.4H),
3.81±3.73 0m, 0.6H), 2.60±2.42 0m, 2H), 2.24 0m, 0.6H),
2.18±2.00 0m, 2.4H), 1.97±1.85 0m, 1H), 1.76±1.65 0m,
1H), 1.53±1.02 0m, 10H); 13C NMR 090 MHz, CDCl3) d
181.2, 180.1, 137.7, 137.6, 131.8, 131.6, 128.6, 128.6,
128.4, 128.3, 79.2, 79.0, 53.1, 51.9, 48.7, 48.2, 35.2, 34.3,
32.0, 31.8, 31.7, 31.5, 27.3, 27.1, 27.0, 26.6, 25.3, 25.1,
24.9, 23.8;HRMS 0C 17H23NS) calcd 274.1629 0MH1),
found 274.1651.
d 7.66±7.64 0m, 2H), 7.36±7.25 0m, 3H), 4.04±4.00 0m
1H), 2.60±2.40 0m, 2H), 2.04 0s, 3H), 2.04±1.85 0m, 2H),
1.39 0s, 3H), 1.35 0s, 3H); 13C NMR 090 MHz, CDCl3) d
175.4, 138.4, 128.5, 128.3, 127.5, 82.1, 51.2, 39.4, 27.7,
26.4, 25.6, 19.8;HRMS 0C 14H19NSe) calcd 282.0760
0MH1), found 282.0753.
4.3.8. 5-Methyl-2-,1-methyl-1-phenylsulfanylethyl)-3,4-
dihydro-2H-pyrrole ,14b). H NMR 0360 MHz, CDCl3)
1
d 7.56±7.54 0m, 2H), 7.34±7.29 0m, 3H), 3.99±3.94 0m,
1H), 2.55±2.41 0m, 2H), 2.04 0d, Jˆ4.0 Hz, 3H), 1.90±
2.05 0m, 2H), 1.30 0s, 3H), 1.18 0s, 3H); 13C NMR
090 MHz, CDCl3) d 175.5, 137.7, 131.7, 128.6, 128.4,
81.0, 52.5, 39.4, 27.0, 24.9, 24.6, 19.8;HRMS 0C 14H19NS)
calcd 234.1316 0MH1), found 234.1321. Anal. calcd for
C14H19NS: C, 72.05;H, 8.21;N, 6.00. Found: C, 71.78;H,
8.15;N, 5.95.
4.3.14. 2-[1-Methyl-1-,2,2,6,6-tetramethylpiperidin-1-yl-
oxy)ethyl]-3,3a,4,5,6,7-hexahydro-dole ,16c). 03:2 Mix-
ture of diastereoisomers): H NMR 0300 MHz, CDCl3) d
1
4.37 0m, 0.4H), 4.14 0m, 0.6H), 2.68±2.62 0m, 1H), 2.56±
2.47 0m, 1H), 2.33 0m, 0.6H), 2.22±2.06 0m, 2.4H), 2.02±
1.97 0m, 1H), 1.84±1.76 0m, 1H), 1.58±0.92 0m, 28H); 13C
NMR 090 MHz, CDCl3) d 180.2, 178.8, 80.6, 80.3, 80.1,
80.0, 59.3, 59.2, 48.7, 48.0, 40.9, 40.9, 35.4, 34.8, 34.8,
34.7, 34.6, 34.4, 32.0, 31.8, 31.1, 30.0, 27.2, 26.6, 25.5,
25.2, 24.5, 23.8, 22.7, 22.0, 20.8, 20.7, 20.4, 20.4, 17.1;
HRMS 0C20H36N2O) calcd 321.2906 0MH1), found
321.2924.
4.3.9. 5-Methyl-2-[1-methyl-1-,2,2,6,6-tetramethylpiperi-
din-1-yloxy)ethyl]-3,4-dihydro-2H-pyrrole ,14c). 1H
NMR 0360 MHz, CDCl3) d 4.30±4.25 0m, 1H), 2.49±2.44
0m, 2H), 2.01 0d, Jˆ1.7 Hz, 3H), 2.04±1.92 0m, 2H), 1.51
0s, 3H), 1.50±1.42 0m, 4H), 1.31±1.24 0m, 2H), 1.15 0s, 3H),
1.13 0s, 3H), 1.07 02, 3H), 1.06 0s, 3H), 1.01 0s, 3H); 13C
NMR 090 MHz, CDCl3) d 174.5, 82.1, 80.5, 59.3, 40.9,
40.9, 39.3, 34.7, 24.4, 23.7, 22.3, 20.8, 20.4, 19.8, 17.1;
HRMS 0C17H32N2O) calcd 281.2593 0MH1), found
281.2599.
4.3.15. 2-Isopropyl-3,3a,4,5,6,7-hexahydro-2H-indole ,17).
03:2 Mixture of diastereoisomers): 1H NMR 0300 MHz,
CDCl3) d 3.90±3.80 0m, 0.4H), 3.55±3.49 0m, 0.6H),
2.70±2.45 0m, 3H), 2.18±2.04 0m, 3H), 2.00±1.89 0m,
1H), 1.82±1.71 0m, 2H), 1.50±1.08 0m, 3H), 1.04 0d, Jˆ
6.7 Hz, 1.8H), 0.93 0d, Jˆ6.8 Hz, 1.2H), 0.85 0d, Jˆ6.7 Hz,
1.8H), 0.79 0d, Jˆ6.8 Hz, 1.2H); 13C NMR 075 MHz,
CDCl3) d 178.7, 178.4, 77.2, 76.8, 48.4, 48.1, 35.1, 34.7,
33.4 02), 33.1, 31.8, 31.8, 31.5, 27.2, 26.6, 25.5, 25.2, 20.3,
19.5, 18.7, 18.2;HRMS 0C 11H19N) calcd 166.1596 0MH1),
found 166.1584.
4.3.10. 4,4-Dimethyl-2-phenylselanylmethyl-3,4-dihydro-
2H-pyrrole ,15a). H NMR 0360 MHz, CDCl3) d 7.58±
1
7.49 0m, 2H), 7.32±7.16 0m, 4H), 4.31 0m, 1H), 3.35 0dd,
Jˆ11.9, 5.9 Hz, 1H), 3.01 0dd, Jˆ11.9, 7.8 Hz, 1H), 1.96
0dd, Jˆ12.9, 7.3 Hz, 1H), 1.40 0dd, Jˆ12.9, 7.7 Hz, 1H),
1.19 0s, 3H), 1.07 0s, 3H); 13C NMR 090 MHz, CDCl3) d
175.3, 132.5, 130.4, 129.0, 126.8, 72.2, 49.9, 43.6, 34.3,
26.2, 24.8;HRMS 0C 13H17NSe) calcd 262.0664 0MH1),
found 262.0646.
4.4. General procedure for preparation of hydroxamic
acids
To a solution of the alkenoic acid 01.0 mmol) in methylene
chloride 02.50 mL) was added oxalyl chloride 00.174 mL,
2.0 mmol) and DMF 01 drop) at 08C. The reaction mixture
was stirred for 10 min at 08C and for 1 h at rt. The solvent
and excess reagents were removed by evaporation under
reduced pressure, and the crude acid chloride obtained
was added to an ice cooled suspension of N-substituted
hydroxylamine hydrochloride 02.0 mmol), anhydrous
Na2CO3 00.33 g, 4.0 mmol) in dry ether 014 mL), containing
3 drops of pyridine. The reaction mixture was stirred
4.3.11. 4,4-Dimethyl-2-phenylsulfanylmethyl-3,4-dihydro-
2H-pyrrole ,15b). H NMR 0360 MHz, CDCl3) d 7.34 0br
1
d, Jˆ8.0 Hz, 2H), 7.25±7.20 0m, 3H), 7.10 0br t, Jˆ7.3 Hz,
1H), 4.22 0m, 1H), 3.38 0dd, Jˆ12.7, 5.6 Hz, 1H), 2.91 0dd,
Jˆ12.7, 8.1 Hz, 1H), 1.92 0dd, Jˆ12.9, 7.4 Hz, 1H), 1.43
0dd, Jˆ12.9, 7.7 Hz, 1H), 1.16 0s, 3H), 1.03 0s, 3H); 13C
NMR 090 MHz, CDCl3) d 175.5, 136.4, 129.2, 128.9,
125.9, 71.5, 49.9, 42.9, 40.0, 26.2, 24.8;HRMS
0C13H17NS) calcd 220.1160 0MH1), found 220.1170.

X. Lin et al. / Tetrahedron 57 (2001) 8779±8791
8787
overnight at rt. Water was then added and the organic layer
was separated, dried over MgSO4 and concentrated in
vacuo. The residue was puri®ed by ¯ash column chroma-
tography 040% EtOAc/hexanes) to give the hydroxamic
acid.
12.0 mmol) in methylene chloride 015 mL) at 2508C was
added successively diisopropylethylamine 00.131 mL, 0.75
mmol) and tert-butylsul®nyl chloride 063 mg, 0.45 mmol).
The mixture was then warmed slowly to rt and stirred for
about 5 h. The solution was concentrated and the residue
was puri®ed by ¯ash column chromatography 020±50%
EtOAc/hexanes gradient) to give the cyclization product
as a yellow oil. Isolated yields are listed in Table 2.
4.4.1. 2,2-Dimethylpent-4-enoic acid N-hydroxy-N-methyl
amide ,23). Colorless oil, 74%: 1H NMR 0360 MHz,
CDCl3) d 9.15 0br s, 1H), 5.67 0ddt, Jˆ17.3, 10.0, 7.3 Hz,
1H), 5.04 0br s, 1H), 4.98 0br d, Jˆ10.0 Hz, 1H), 3.23 0s,
3H), 2.40 0d, Jˆ7.3 Hz, 2H), 1.20 0s, 6H); 13C NMR 090
MHz, CDCl3) d 176.5, 134.7, 117.5, 43.5, 42.2, 37.9, 25.1;
HRMS 0C8H15NO2) calcd 158.1181 0MH1), found
158.1183.
4.6. General procedure for cyclization of hydroxamic
acids using diethyl chlorophosphite
The hydroxamic acid 00.3 mmol) was dissolved in CH2Cl2
010 mL) with either 0PhSe)2 00.6 mmol), 0PhS)2 03±6
mmol), or TEMPO 00.6 mmol) and cooled to 2508C.
DIEA 00.8 mmol) followed by 0EtO)2PCl 00.45 mmol,
Aldrich, 98% purity) were then slowly added. The solution
was warmed to rt over 1 h and stirred for an additional 1 h.
The volatile organics were removed under reduced pressure
and the residue was puri®ed by ¯ash column chroma-
tography 020/80 EtOAc/hexanes-1/1 EtOAc/hexanes) to
afford the desired g-lactam. Isolated yields are listed in
Table 2.
4.4.2. 2,2-Dimethylpent-4-enoic acid N-benzyl-N-hydroxy
amide ,26). White solid, 71%: mp 69±708C; H NMR
1
0360 MHz, CDCl3) d 7.25±7.01 0m, 5H), 5.66 0ddt, Jˆ
17.3, 10.0, 7.2 Hz, 1H), 4.96±4.91 0m, 2H), 4.74 0s, 2H),
2.34 0d, Jˆ7.2 Hz, 2H), 1.19 0s, 3H); 13C NMR 090 MHz,
CDCl3) d 176.1, 135.8, 134.7, 128.6, 128.1, 127.7, 117.6,
53.4, 44.1, 42.2, 25.5;HRMS 0C 14H19NO2) calcd 234.1494
0MH1), found 234.1477.
4.4.3. Bicyclo[2.2.1]hept-5-ene-2-carboxylic acid N-
hydroxy-N-methyl amide ,27). White solid, 66%: mp
65±668C; 1H NMR 0360 MHz, CDCl3) d 6.23 0dd, Jˆ5.5,
3.2 Hz, 1H), 5.98 0dd, Jˆ5.5, 2.8 Hz, 1H), 3.40 0s, 3H), 3.15
0br s, 1H), 3.10±2.92 0m, 1H), 2.94 0br s, 1H), 2.00±1.90 0m,
1H), 1.50±1.30 0m, 3H).13d
4.6.1. 1,3,3-Trimethyl-5-phenylselanylmethylpyrrolidin-
2-one ,23a). H NMR 0360 MHz, CDCl3) d 7.53±7.50 0m,
1
2H), 7.30±7.26 0m, 3H), 3.64 0m, 1H), 3.26 0dd, Jˆ12.2,
3.2 Hz, 1H), 2.91 0dd, Jˆ12.2, 8.5 Hz, 1H), 2.75 0s, 3H),
2.10 0dd, Jˆ12.2, 7.3 Hz, 1H), 2.91 0dd, Jˆ12.2, 7.3 Hz,
1H), 1.20 0s, 3H), 1.09 0s, 3H); 13C NMR 090 MHz,
CDCl3) d 180.0, 133.2, 129.3, 129.3, 127.5, 76.6, 56.3,
40.7, 40.2, 32.4, 28.0, 25.8, 25.5;HRMS 0C 14H19NOSe)
calcd 294.0737 0MH1), found 294.0716.
4.4.4. 2-Cyclohex-2-enyl-N-hydroxy-N-methyl aceta-
mide ,28). Pale yellow oil, 67%: 1H NMR 0360 MHz,
CDCl3) d 9.21 0br s, 1H), 5.75±5.72 0m, 1H), 5.55 0br d,
Jˆ9.4 Hz, 1H), 3.37 0s, 3H), 2.67 0br s, 1H), 2.30 0br s, 2H),
1.98±1.25 0m, 6H); 13C NMR 090 MHz, CDCl3) d 173.5,
130.5, 127.5, 38.2, 35.9, 31.8, 28.8, 24.9, 20.9;HRMS
0C9H15NO2) calcd 170.1181 0MH1), found 170.1191.
4.6.2. 1,3,3-Trimethyl-5-phenylsulfanylmethylpyrrolidin-
2-one ,23b). 1H NMR 0360 MHz, CDCl3) d 7.38±7.22 0m,
5H), 3.64±3.59 0m, 1H), 3.31 0dd, Jˆ12.9, 3.5 Hz, 1H), 2.93
0dd, Jˆ12.9, 8.1 Hz, 1H), 2.79 0s, 3H), 2.10 0dd, Jˆ13.0,
7.5 Hz, 1H), 1.75 0dd, Jˆ13.0, 7.5 Hz, 1H), 1.21 0s, 3H),
1.10 0s, 3H); 13C NMR 090 MHz, CDCl3) d 180.0, 135.5,
130.1, 129.1, 126.7, 77.8, 55.9, 40.1, 39.9, 38.4, 28.2, 25.9,
25.5;HRMS 0C 14H19NOS) calcd 250.1266 0MH1), found
250.1289.
4.4.5. Cyclohex-3-enecarboxylic acid N-hydroxy-N-
methyl amide ,29). Colorless oil, 84%: H NMR 0360
1
MHz, CDCl3) d 5.70 0s, 2H), 3.39 0s, 3H), 2.65 0br s, 1H),
2.33±1.80 0m, 6H); 13C NMR 075 MHz, CDCl3) d 177.1,
170.1, 126.5, 125.6, 125.0, 36.2, 35.9, 35.6, 27.2, 24.9, 24.7;
HRMS 0C8H13NO2) calcd 156.1025 0MH1), found
156.1025.
4.6.3. 1,3,3-Trimethyl-5-,2,2,6,6-tetramethylpiperidin-1-
yloxy)methyl-pyrrolidin-2-one ,23c). 1H NMR 0360 MHz,
CDCl3) d 3.79 0ABq Jˆ9.8 Hz, each peak further split, d,
Jˆ6.9, 3.7 Hz, 2H), 3.64±3.57 0m, 1H), 2.92 0s, 3H), 1.96
0dd, Jˆ12.8, 7.9 Hz, 1H), 1.55 0dd, Jˆ12.8, 7.0 Hz, 1H),
1.46±1.41 0m, 4H), 1.34±1.28 0m, 2H), 1.18 0s, 3H), 1.14 0s,
6H), 1.11 0s, 3H), 1.09 0s, 6H); 13C NMR 090 MHz, CDCl3)
d 180.0, 79.7, 59.9, 55.9, 39.9, 39.6, 37.3, 33.1, 32.9, 29.3,
25.9, 25.4, 20.3, 20.1, 16.9;HRMS 0C 17H32N2O2) calcd
297.2542 0MH1), found 297.2563.
4.4.6. 2,2-Dimethylpent-4-enoic acid N-hydroxy-N-
,3-methylbut-2-enyl) amide ,30). Colorless oil, 60%: H
1
NMR 0360 MHz, CDCl3) d 5.75 0ddt, Jˆ18.0, 9.1, 7.3 Hz,
1H), 5.23 0br t, Jˆ6.8 Hz, 1H), 5.08±5.03 0m, 2H), 4.29 0d,
Jˆ6.8 Hz, 2H), 2.39 0d, Jˆ7.3 Hz, 2H), 1.75 0s, 3H), 1.71
0s, 3H), 1.26 0s, 6H); 13C NMR 090 MHz, CDCl3) d 174.6,
137.8, 134.7, 117.9, 117.6, 47.8, 44.4, 41.7, 25.7, 25.6,
22.45, 18.0;HRMS 0C 12H21NO2) calcd 212.1651 0MH1),
found 212.1641.
4.6.4. N-,2,2-Dimethylpent-4-enoyl)-N-methyl-t-butyl-
sulfonamide ,24). Mixture of rotamers: 1H NMR
0360 MHz, CDCl3) d 5.77 0ddt, Jˆ17.3, 10.1, 7.1 Hz, 1H),
5.13 0br s, 1H), 5.08 0m, 1H), 3.82 0s, 0.7H), 3.41 0s, 2.3H),
2.44±2.39 0m, 2H), 1.56 0s, 2.1H), 1.49 0s, 6.9H), 1.33 0s,
1.4H), 1.29 0s, 4.6H);HRMS 0C 12H23NO3S) calcd 262.1477
0MH1), found 262.1495.
4.5. General procedure for cyclization of hydroxamic
acids using tert-butylsul®nyl chloride
To a solution of the hydroxamic acid 00.30 mmol) and
radical trap 0TEMPO: 70 mg, 0.45 mmol;diphenyl di-
selenide: 187 mg, 0.60 mmol;diphenyl disul®de: 4.6 g,

8788
X. Lin et al. / Tetrahedron 57 (2001) 8779±8791
4.6.5.
1-Benzyl-3,3-dimethyl-5-phenylselanylmethyl-
4.6.11. 1-Methyl-7-phenylselanyloctahydroindol-2-one
,28a). H NMR 0360 MHz, CDCl3) d 7.60±7.58 0m, 2H),
1
1
pyrrolidin-2-one ,26a). H NMR 0360 MHz, CDCl3) d
7.28±7.12 0m, 10H), 4.93 0d, Jˆ15.0 Hz, 1H), 3.78 0d, Jˆ
15.0 Hz, 1H) 3.48±3.38 0m, 1H), 3.31 0dd, Jˆ12.3, 3.1 Hz,
1H), 2.72 0dd, Jˆ12.3, 9.0 Hz, 1H), 1.99 0dd, Jˆ12.9,
7.2 Hz, 1H), 1.59 0dd, Jˆ12.9, 7.7 Hz, 1H), 1.18 0s, 3H),
1.04 0s, 3H); 13C NMR 090 MHz, CDCl3) d 180.1, 136.3,
132.6, 129.3, 129.2, 128.7, 127.9, 127.5, 127.1, 53.1, 44.2,
40.6, 40.2, 31.7, 25.5, 25.3;HRMS 0C 20H23NOSe) calcd
374.1023 0MH1), found 374.1027.
7.36±7.28 0m, 3H), 3.56±3.49 0m, 2H), 2.86 0s, 3H), 2.59±
2.52 0m, 1H), 2.31 0dd, Jˆ16.2, 7.1 Hz, 1H), 2.13 0dd, Jˆ
16.2, 4.9 Hz, 1H), 1.81±1.72 0m, 2H), 1.64±1.52 0m, 2H),
1.48±1.32 0m, 2H); 13C NMR 090 MHz, CDCl3) d 175.8,
134.6, 129.3, 128.8, 128.0, 63.1, 43.0, 37.4, 31.8, 28.7, 28.4,
27.2, 20.5;HRMS 0C 15H19NOSe) calcd 308.0722 0MH1),
found 308.0737.
4.6.12. 1-Methyl-7-phenylsulfanyloctahydroindol-2-one
,28b). H NMR 0300 MHz, CDCl3) d 7.36±7.34 0m, 2H),
1
4.6.6.
1-Benzyl-3,3-dimethyl-5-phenylsulfanylmethyl-
1
pyrrolidin-2-one ,26b). H NMR 0360 MHz, CDCl3) d
7.28±7.02 0m, 10H)), 4.98 0d, Jˆ15.1 Hz, 1H), 3.81 0d,
Jˆ15.1 Hz, 1H) 3.50±3.39 0m, 1H), 3.17 0dd, Jˆ13.1,
3.2 Hz, 1H), 2.70 0dd, Jˆ13.1, 8.7 Hz, 1H), 1.96 0dd, Jˆ
12.9, 7.3 Hz, 1H), 1.59 0dd, Jˆ12.9, 7.5 Hz, 1H), 1.19 0s,
3H), 1.05 0s, 3H); 13C NMR 090 MHz, CDCl3) d 180.2,
136.4, 135.4, 129.3, 129.0, 128.8, 128.0, 127.7, 126.4,
52.6, 44.4, 40.2, 39.9, 37.5, 25.6, 25.3;HRMS
0C20H23NOS) calcd 326.1579 0MH1), found 326.1605.
7.24±7.12 0m, 3H), 3.380dd, Jˆ5.8, 5.7 Hz, 1H), 3.32±3.28
0m, 1H), 2.89 0s, 3H), 2.53±2.49 0m, 1H), 2.23 0dd, Jˆ16.0,
7.2 Hz, 1H), 2.10 0dd, Jˆ16.0, 6.5 Hz, 1H), 1.72±1.49 0m,
4H), 1.41±1.32 0m, 2H); 13C NMR 090 MHz, CDCl3) d
175.5, 134.1, 132.1, 129.1, 127.4, 62.6, 47.5, 36.7, 32.1,
29.4, 28.5, 26.9, 19.5;HRMS 0C 15H19NOS) calcd
262.1266 0MH1), found 262.1242.
4.6.13. 1-Methyl-7-,2,2,6,6-tetramethylpiperidin-1-yl-
oxy)octahydroindol-2-one ,28c). 1H NMR 0360 MHz,
CDCl3) d 3.82 0ddd, Jˆ7.3, 7.2, 3.5 Hz, 1H), 3.28 0dd, Jˆ
7.2, 7.1 Hz, 1H), 2.97 0s, 3H), 2.55±2.51 0m, 1H), 2.16±2.06
0m, 2H), 1.61±0.96 0m, 24H); 13C NMR 090 MHz, CDCl3) d
174.8, 83.0, 64.3, 58.7, 40.1 0br), 35.7, 34.2, 33.8, 33.6,
30.2, 27.2, 26.5, 20.8, 20.5, 18.9, 17.1;HRMS
0C18H32N2O2) calcd 309.2542 0MH1), found 309.2559.
4.6.7. 1-Benzyl-3,3-dimethyl-5-,2,2,6,6-tetramethylpiperi-
din-1-yloxy)methylpyrrolidin-2-one ,26c). H NMR 0360
1
MHz, CDCl3) d 7.32±7.22 0m, 5H), 5.15 0d, Jˆ14.7 Hz,
1H), 4.10 0d, Jˆ14.7 Hz, 1H), 3.92 0dd, Jˆ9.6, 6.5 Hz,
1H), 3.78 0dd, Jˆ9.6, 4.3 Hz, 1H), 3.55 0m, 1H), 1.93 0dd,
Jˆ12.9, 7.9 Hz, 1H), 1.62 0dd, Jˆ12.9, 6.9 Hz, 1H), 1.48±
1.33 0m, 6H), 1.25 0s, 3H), 1.25±1.09 0m, 12H), 1.13 0s,
3H); 13C NMR 090 MHz, CDCl3) d 180.1, 136.9, 128.4,
128.1, 127.2, 79.6, 59.9, 52.5, 44.9, 39.9, 39.6, 37.5, 33.0,
32.9, 25.7, 25.4, 20.4, 20.2, 16.9;HRMS 0C 23H36N2O2)
calcd 373.2855 0MH1), found 373.2852.
4.6.14. 6-Methyl-4-phenylselanyl-6-azabicyclo[3.2.1]-
octan-7-one ,29a). 02:1 Mixture of exo/endo isomers):
1
Exo isomer: H NMR 0360 MHz, CDCl3) d 7.58±7.53 0m,
2H), 7.32±7.28 0m, 2H), 3.76±3.74 0m, 1H), 3.57±3.55 0m,
1H), 2.82 0s, 3H), 2.47 0br s, 1H), 2.10±2.03 0m, 2H), 1.97±
1.75 0m, 4H); 13C NMR 090 MHz, CDCl3) d 177.1, 134.1,
129.3, 127.9, 61.6, 40.3, 39.7, 33.3, 27.4, 25.5, 22.7. endo
Isomer: 1H NMR 0360 MHz, CDCl3) d 7.60±7.53 0m, 2H),
7.40±7.32 0m, 3H), 3.76 0d, Jˆ5.7 Hz, 1H), 3.44 0dd, Jˆ
11.9, 5.3 Hz, 1H), 3.12 0s, 3H), 2.47 0br s, 1H), 2.30±2.12
0m, 2H), 1.85±1.54 0m, 4H); 13C NMR 090 MHz, CDCl3) d
176.8, 134.3, 129.3, 129.3, 127.8, 62.0, 43.6, 40.2, 39.5,
30.6, 27.1, 27.1;HRMS 0C 14H17NOSe) calcd 292.0581
0MH1), found 292.0574.
4.6.8. 4-Methyl-2-phenylselanyl-4-azatricyclo[4.2.1.00,0]-
nonan-5-one ,27a). H NMR 0360 MHz, CDCl3) d 7.59±
1
7.58 0m, 2H), 7.32±7.28 0m, 3H), 3.52 0d, Jˆ4.7 Hz, 1H),
3.02 0br s, 2H), 2.52±2.49 0m, 1H), 2.36 0s, 3H), 2.34±2.37
0m, 1H), 2.12 0br, d, Jˆ10.9 Hz, 1H), 1.90±2.00 0m, 1H),
1.00±1.10 0m, 2H); 13C NMR 090 MHz, CDCl3) d 179.0,
135.2, 129.3, 128.5, 128.2, 68.7, 49.7, 45.0, 43.5, 41.4, 35.8,
35.6, 28.1;HRMS 0C 15H17NOSe) calcd 308.0554 0MH1),
found 308.0561.
4.6.9. 4-Methyl-2-phenylsulfanyl-4-azatricyclo[4.2.1.00,0]-
nonan-5-one ,27b). H NMR 0360 MHz, CDCl3) d 7.39±
4.6.15. 6-Methyl-4-phenylsulfanyl-6-azabicyclo[3.2.1]-
octan-7-one ,29b). 01:1 Mixture of diastereoisomers): Exo
isomer: 1H NMR 0360 MHz, CDCl3) d 7.43±7.40 0m, 2H),
7.34±7.28 0m, 3H), 3.68±3.66 0m, 1H), 3.54 0br s, 1H), 2.85
0s, 3H), 2.48±2.46 0m, 1H), 2.21±1.71 0m, 6H); 13C NMR
090 MHz, CDCl3) d 177.2, 135.2, 131.5, 129.4, 127.3, 61.0,
1
7.36 0m, 2H), 7.29±7.20 0m, 3H), 3.30 0d, Jˆ4.8 Hz, 1H),
2.96 0br t, Jˆ4.6 Hz, 1H), 2.88 0br s, 1H), 2.46±2.440m,
1H), 2.40 0s, 3H), 2.35±2.31 0m, 1H), 2.21 0br, d, Jˆ
11.0 Hz, 1H), 1.94±1.85 0m, 1H), 1.55±1.45 0m, 2H); 13C
NMR 090 MHz, CDCl3) d 179.0, 133.9, 132.8, 129.1, 127.7,
68.1, 54.5, 44.8, 43.0, 41.6, 35.1, 34.9, 28.3;HRMS
0C15H17NOS) calcd 260.1109 0MH1), found 260.1106.
1
42.8, 40.3, 32.0, 27.5, 24.7, 22.3. endo Isomer: H NMR
0360 MHz, CDCl3) d 7.43±7.41 0m, 2H), 7.35±7.27 0m,
3H), 3.70 0d, Jˆ5.8 Hz, 1H), 3.41±3.38 0m, 1H), 3.12 0s,
3H), 2.46 0br s, 1H), 2.30±1.92 0m, 3H), 1.64±1.50 0m, 3H);
13C NMR 090 MHz, CDCl3) d 176.7, 134.6, 131.7, 129.2,
127.3, 61.0, 48.2, 40.1, 38.4, 30.7, 26.3, 26.1;HRMS
0C14H17NOS) calcd 248.1109 0MH1), found 248.1104.
4.6.10. 4-Methyl-2-,2,2,6,6-tetramethylpiperidin-1-yloxy)-
1
4-azatricyclo[4.2.1.00,0]nonan-5-one ,27c). H NMR 0360
MHz, CDCl3) d 3.58 0d, Jˆ4.0 Hz, 1H), 3.54 0s, 1H), 2.92±
2.86 0m, 1H), 2.82 0s, 3H), 2.68 0s, 1H), 2.28 0br d, Jˆ
10.4 Hz, 1H), 1.90±1.80 0m, 2H), 1.48±1.32 0m, 7H),
1.20±1.10 0m, 13H); 13C NMR 090 MHz, CDCl3) d 179.4,
87.9, 68.3, 59.7, 43.7, 43.3, 41.6, 40.1, 35.1, 34.7, 33.7,
32.8, 28.9, 20.2, 17.1;HRMS 0C 18H30N2O2) calcd
307.2386 0MH1), found 307.2388.
4.6.16. 6-Methyl-4-,2,2,6,6-tetramethylpiperidin-1-yloxy)-
6-azabicyclo[3.2.1]octan-7-one ,29c). 01:1 Mixture of
diastereoisomers): H NMR 0360 MHz, CDCl3) d 4.05±
1
4.00 0m, 0.5H), 3.89±3.81 0m, 1H), 3.78±3.71 0m, 0.5H),
2.97 0s, 1.5H), 2.80 0s, 1.5H), 2.40 0br s, 0.5H), 2.38 0br s,

X. Lin et al. / Tetrahedron 57 (2001) 8779±8791
8789
0.5H), 2.35±1.12 0m, 24H); 13C NMR 090 MHz, CDCl3) d
177.7, 177.1, 82.8, 75.7, 62.2, 60.0, 59.9, 40.2, 40.2, 35.9,
34.1, 31.0, 29.2, 27.8, 27.4, 25.1, 24.1, 22.7, 20.2, 17.1,
17.0;HRMS 0C 17H30N2O2) calcd 295.2386 0MH1), found
295.2411.
amic acid 38 00.32 g, 2.5 mmol) and 1-methoxybutadiene
037, Aldrich, 0.30 mL, 3.0 mmol) in 5 mL of methylene
chloride was kept at rt and 12 Kbar pressure for 2 days.
The solution was then evaporated and the residue was
puri®ed by ¯ash column chromatography 050% EtOAc/
hexanes) to yield the adduct 39 00.35 g, 65%) as a pale
1
4.6.17. 2,2-Dimethyl-6-,1-methyl-1-methylselanylethyl)-
hexahydropyrrolizin-3-one ,32). 02:1 Mixture of dia-
stereoisomers): Major isomer: 1H NMR 0300 MHz,
CDCl3) d 7.61 0br d, Jˆ7.9 Hz, 2H), 7.38±7.28 0m, 3H),
3.96±3.88 0m, 1H), 3.89 0dd, Jˆ12.2, 8.3 Hz, 1H), 2.91 0dd,
Jˆ12.2, 8.3 Hz, 1H), 2.39 0dddd, Jˆ9.7, 8.3, 8.3, 7.1 Hz,
1H), 2.21±2.07 0m, 1H), 2.17 0dd, Jˆ12.3, 6.5 Hz, 1H), 1.59
0ddd, Jˆ13.3, 9.7, 6.6 Hz, 1H), 1.47 0dd, Jˆ12.3, 8.6 Hz,
1H), 1.34 0s, 6H), 1.21 0s, 3H), 1.14 0s, 3H); 13C NMR
075 MHz, CDCl3) d 179.5, 138.4, 128.8, 126.8, 56.4, 50.4,
48.7, 45.2, 44.1, 34.6, 28.3, 27.7, 25.1, 24.6. Minor isomer:
1H NMR 0300 MHz, CDCl3) d 7.62 0br d, Jˆ6.9 Hz, 2H),
7.38±7.28 0m, 3H), 3.88-3.80 0m, 1H), 3.45 0dd, Jˆ11.7,
9.1 Hz, 1H), 3.20 0dd, Jˆ11.7, 9.1 Hz, 1H), 2.65 0dddd, Jˆ
11.7, 9.1, 9.1, 6.3 Hz, 1H), 2.15±2.09 0m, 1H), 2.12 0dd,
Jˆ12.3, 6.1 Hz, 1H), 1.65±1.57 0m, 1H), 1.61 0dd, Jˆ
12.3, 8.1 Hz, 1H), 1.35 0s, 3H), 1.34 0s, 3H), 1.20 0s, 3H),
1.18 0s, 3H); 13C NMR 075 MHz, CDCl3) d 178.5, 138.4,
128.8, 127.0, 58.0, 52.4, 47.6, 45.6, 43.5, 43.1, 35.6, 27.7,
27.4, 25.2, 24.9;HRMS 0C 18H25NOSe) calcd 352.1180
0MH1), found 352.1170.
yellow oil. H NMR 0360 MHz, CDCl3) d 8.83 0br s, 1H),
5.84 0s, 2H), 4.62 0br s, 1H), 4.17 0br s, 1H), 3.26 0s, 3H),
3.10±3.05 0m, 1H), 2.10±1.52 0m, 4H), 1.10 0d, Jˆ6.8 Hz,
3H), 1.09 0d, Jˆ6.8 Hz, 3H); 13C NMR 090 MHz, CDCl3) d
173.5, 131.4, 124.9, 72.2, 56.9, 47.2, 42.5, 24.9, 19.2, 18.7,
18.5;HRMS 0C 11H19NO3) calcd 214.1443 0MH1), found
214.1426.
4.6.21. 6-Isopropyl-8-methoxy-4-phenylselanyl-6-aza-
bicyclo[3.2.1]octan-7-one ,40). Method A: To a solution
of the hydroxamic acid 39 063 mg, 0.30 mmol) and diphenyl
diselenide 00.19 g, 0.60 mmol) in methylene chloride
015 mL) at 2508C was added diisopropylethylamine 00.13
mL, 0.75 mmol) and tert-butylsul®nyl chloride 063 mg,
0.45 mmol). The mixture was then warmed slowly to rt,
and stirred for 5 h. The solution was evaporated in vacuo
and the residue was puri®ed by ¯ash column chroma-
tography 020±50% EtOAc/hexanes gradient) to give the
1
cyclization product 40 032 mg, 30%) as a yellow oil. H
NMR 0360 MHz, CDCl3) d 7.58±7.55 0m, 2H), 7.32±7.30
0m, 3H), 4.33 0septet, Jˆ6.8 Hz, 1H), 3.90 0br d, Jˆ3.6 Hz,
1H), 3.88 0s, 1H), 3.64±3.61 0m, 1H), 3.30 0s, 3H), 2.55 0br
s, 1H), 2.12±1.75 0m, 4H), 1.15 0d, Jˆ6.8 Hz, 3H), 1.09 0d,
Jˆ6.8 Hz, 3H); 13C NMR 090 MHz, CDCl3) d 173.6, 134.1,
129.4, 129.3, 128.0, 83.4, 59.6, 55.6, 46.6, 42.9, 42.8, 24.5,
21.7, 21.5, 20.3;HRMS 0C 17H23NO2Se) calcd 354.0972
0MH1), found 354.0986. Method B: To a solution of the
hydroxamic acid 39 053 mg, 0.25 mmol) and diphenyl
diselenide 0156 mg, 0.50 mmol) in CH2Cl2 08 mL) at
2508C was added diisopropylethylamine 0115 mL, 0.66
mmol) followed by diethyl chlorophosphite 056 mL,
0.39 mmol). The solution was stirred and slowly warmed
to rt over 2 h. The volatile organics were removed in vacuo
and the residue was puri®ed by ¯ash column chroma-
tography 020% EtOAc: hexanes to 50% EtOAc: hexanes)
to afford the bicyclic lactam 40 062 mg, 70%) as a yellow oil.
4.6.18. 6-Methyl-6-azabicyclo[3.2.1]oct-3-en-7-one ,33).
To a solution of the selenide 29a 060 mg, 0.20 mmol) in
methylene chloride 010 mL) at 08C was added 30% H2O2
00.18 mL) dropwise. The solution was slowly warmed to rt
and 3 drops of pyridine were added. After stirring for 3 h,
the mixture was washed with brine, dried over MgSO4 and
evaporated. The residue was puri®ed by ¯ash column
chromatography 060% EtOAc/hexanes) to provide alkene
1
33 025 mg, 90%). H NMR 0360 MHz, CDCl3) d 6.25±
6.18 0m, 1H), 5.70±5.64 0m, 1H), 3.55 0t, Jˆ4.9 Hz, 1H),
2.78 0s, 3H), 2.63 0s, 1H), 2.29 0s, 2H), 2.26 0ddd, Jˆ10.0,
5.0, 5.0 Hz, 1H), 1.89 0d, Jˆ10.3 Hz, 1H); 13C NMR
090 MHz, CDCl3) d 178.0, 130.3, 129.1, 54.9, 39.8, 33.6,
28.4, 28.1;HRMS 0C 8H11NO) calcd 138.0919 0MH1),
found 138.0918.
4.6.22. 6-Isopropyl-8-methoxy-6-azabicyclo[3.2.1]oct-3-
en-7-one ,41). To a solution of the selenide 40 070 mg,
0.20 mmol) in 10 mL of methylene chloride at 08C was
added 30% H2O2 00.18 mL) dropwise. The solution was
warmed to rt slowly and anhydrous pyridine 03 drops)
was added. After stirring for 3 h, the mixture was washed
with brine, dried over MgSO4 and evaporated. The residue
was puri®ed by ¯ash column chromatography 050±100%
EtOAc/hexanes gradient) to provide ole®n 41 053 mg,
4.6.19. N-Hydroxy-N-isopropylacrylamide ,38). To a
solution of N-isopropyl hydroxylamine hydrochloride
01.75 g, 15.7 mmol) and anhydrous sodium carbonate
03.00 g, 36.1 mmol) in dry ether 0150 mL) at 08C was
added acryloyl chloride 01.00 mL, 12.3 mmol) and anhy-
drous pyridine 03 drops). The reaction mixture was stirred
overnight at rt. Water was then added and the organic layer
was washed with brine, dried over MgSO4 and concentrated.
The residue was puri®ed by ¯ash column chromatography
040% EtOAc/hexanes) to give hydroxamic acid 38 as a pale
1
90%) as a colorless oil. H NMR 0360 MHz, CDCl3) d
6.10 0ddt, Jˆ9.4, 5.4, 2.0 Hz, 1H), 5.63 0dt, Jˆ9.4,
3.2 Hz, 1H), 4.32 0septet, Jˆ6.8 Hz, 1H), 3.79 0s, 1H),
3.77 0d, Jˆ5.4 Hz, 1H), 3.36 0s, 3H), 2.69±2.67 0m, 1H),
2.52±2.36 0m, 2H), 1.12 0d, Jˆ6.8 Hz, 3H), 1.11 0d, Jˆ
6.8 Hz, 3H); 13C NMR 090 MHz, CDCl3) d 173.9, 131.0,
128.4, 83.2, 55.8, 51.4, 45.4, 42.2, 28.3, 22.2, 20.5;HRMS
0C11H17NO2) calcd 196.1338 0MH1), found 196.1334.
1
yellow oil 01.25 g, 80%). H NMR 0360 MHz, CDCl3) d
8.76 0br s, 1H), 6.85±6.37 0m, 2H), 5.67 0br s, 1H), 4.70±
4.27 0m, 1H), 1.30±1.17 0m, 6H); 13C NMR 090 MHz,
CDCl3) d 165.9, 160.5, 128.5, 127.9, 127.1, 123.8, 50.7,
47.4, 19.9, 18.8;HRMS 0C 6H11NO2) calcd 130.0868
0MH1), found 130.0867.
4.6.20. 2-Methoxycyclohex-3-enecarboxylic acid N-
hydroxy-N-isopropyl amide ,39). A solution of hydrox-
4.6.23. 8-Hydroxy-6-isopropyl-6-azabicyclo[3.2.1]oct-3-
en-7-one ,35). To a solution of methyl ether 41 020 mg,

8790
X. Lin et al. / Tetrahedron 57 (2001) 8779±8791
M. R.;Hudson, R. F. J. Chem. Soc., Perkin Trans. 2 1986,
1211.
0.10 mmol) in 2 mL of methylene chloride was added BBr3
01.00 mL, 1 M solution in CH2Cl2) at 2788C. After 1 h the
mixture was warmed to 2208C, and monitored by TLC.
After completion of the reaction 03 h), the mixture was
diluted with saturated NaHCO3 solution. The organic
layer was washed with brine, dried over MgSO4 and concen-
trated. The residue was puri®ed by ¯ash column chroma-
tography 050±100% EtOAc/hexanes gradient) to afford the
alcohol 35 015 mg, 83%) as a white solid: mp 86±888C; 1H
NMR 0360 MHz, CDCl3) d 6.10 0ddt, Jˆ9.2, 5.5, 2.2 Hz,
1H), 5.60 0dt, Jˆ9.2, 3.2 Hz, 1H), 4.32 0septet, Jˆ6.9 Hz,
1H), 4.22 0s, 1H), 3.64 0d, Jˆ5.5 Hz, 1H), 2.63 0s, 1H),
2.45±2.43 0m, 2H), 1.16 0d, Jˆ6.9 Hz, 3H), 1.14 0d, Jˆ
6.9 Hz, 3H); 13C NMR 090 MHz, CDCl3) d 174.4, 131.0,
127.9, 74.7, 56.4, 48.4, 42.6, 28.4, 22.1, 20.4;HRMS
0C10H15NO2) calcd 182.1181 0MH1), found 182.1199.
8. In all cases cyclization products 12 were inseparable 3:2
mixtures of diastereoisomers 0Section 4).
9. 0a) Kurzer, F. Organic Syntheses, Collect. Vol. 4;Wiley: New
York, 1967;p 937. For a review of sul®nyl chlorides see:
0b) Schwan, A. L.;Strickler, R. R. Org. Prep. Proc. Int.
1999, 31, 579.
10. Bertrand, M. P. Org. Prep. Proc. Int. 1994, 26, 257 and
references cited.
11. Richey, Jr., H. G.;Farkas, Jr, J. J. Org. Chem. 1987, 52, 479.
Sun, P.;Weinreb, S. M.;Shang, M. J. Org. Chem. 1997, 62,
8604. An alternative preparation of this sul®nyl chloride has
been reported: Cogan, D. A.;Liu, G.;Kim, K.;Backes, B. J.;
Ellman, J. A. J. Am. Chem. Soc. 1998, 120, 8011. Gontcharov,
A. V.;Liu, H.;Sharpless, K. B. Org. Lett. 1999, 1, 783 and
references cited.
12. 2,6-Dimethylbenzenesul®nyl chloride was synthesized as
described in Section 4. The compound has also been prepared
by a less ef®cient method: Cevasco, G.;Novi, M.;Petrillo, G.;
Thea, S. Gazz. Chim. Ital. 1990, 120, 131.
Acknowledgements
We are grateful to the National Institutes of Health 0CA-
34303) for ®nancial support of this research and the
Ministry of Foreign Affairs 0France) for a Lavoisier Post-
doctoral Fellowship to D. S.
13. Oximes 9, 13, 14, and 15 0Table 1) have been previously
prepared: 0a) Kawada, K.;Tsushima, T. Heterocycles 1989,
28, 573. 0b) Armstrong, P.;Grigg, R.;Heany, F.;Surendraku-
mar, S.;Warnock, W. J. Tetrahedron 1991, 47, 4495.
0c) Wagner-Jauregg, T.;Roth, M. Helv. Chim. Acta 1962,
45, 771. 0d) Boivin, J.;Callier-Dublanchet, A.-C.;Quiclet-
Sire, B.;Schiano, A.-M.;Zard, S. Z. Tetrahedron 1995, 51,
6517.
References
1. For reviews of nitrogen radical-ole®n cyclizations see:
0a) Esker, J. L.;Newcomb, M. Adv. Hetercycl. Chem. 1993,
58, 1. 0b) Zard, S. Z. Synlett 1996, 1148. 0c) Fallis, A. G.;
Brinza, I. M. Tetrahedron 1997, 53, 17543.
14. For rate constants of radical reactions with various trapping
Â
reagents see: Claridge, R. F. C., Ed.; Landolt Bornstein, New
Series II, Springer: Berlin, 1994;Vol. 18-A, p. 4 also see p 57.
Newcomb, M. Tetrahedron 1993, 49, 1151.
2. For more recent examples of iminyl radical cyclizations, see:
0a) Le Tadic-Biadatti, M.-H.;Callier-Dublanchet, A.-C.;
Horner, J. H.;Quiclet-Sire, B.;Zard, S. Z.;Newcomb, M.
J. Org. Chem. 1997, 62, 559. 0b) Boivin, J.;Schiano, A.-M.;
Zard, S. Z.;Zhang, H. Tetrahedron Lett. 1999, 40, 4531.
0c) Uchiyama, K.;Hayashi, Y.;Narasaka, K. Tetrahedron
1999, 55, 8915. 0d) Gagosz, F.;Zard, S. Z. Synlett 1999,
1978. 0e) Leardini, R.;McNab, H.;Minozzi, M.;Nanni, D.
J. Chem. Soc., Perkin Trans. 1 2001, 1072. 0f) Guindon, Y.;
Guerin, B.;Landry, S. R. Org. Lett. 2001, 3, 2293.
15. For rates of iminyl radical/ole®n cyclizations see Ref. 2a.
16. Compound 18 might be formed via some type of dispro-
portionation process. Cf. Davis, F. A.;Jenkins, Jr., R. H.;
Rizvi, S. Q. A.;Yocklovich, S. G. J. Org. Chem. 1981, 46,
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25. We are grateful to Professor Henk Hiemstra for NMR spectra
of authentic alcohol 35 and the corresponding acetate which
con®rmed the structure and stereochemistry of our material.
We also thank Professor James Rigby for providing copies of
spectra of the alcohol epimer 36 for comparison purposes.
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