Cyclizations using selenium chemistry for substituted 3-hydroxypiperidines and 3-hydroxypyrrolidines

Article abstract of DOI:10.1071/CH11073

The development of new methods for the stereoselective synthesis of nitrogen heterocycles is of current interest because of increasing demands for the syntheses of biologically important alkaloids and related compounds. It is shown that selenium-induced c

Full text of DOI:10.1071/CH11073

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2011, 64, 1327–1338
Cyclizations using Selenium Chemistry for Substituted
3-Hydroxypiperidines and 3-Hydroxypyrrolidines
A B C
, ,
B
Matthew A. Cooper
and A. David Ward
A
Institute for Molecular Bioscience, The University of Queensland, St Lucia,
Qld 4072, Australia.
B
Department of Chemistry, University of Adelaide, Adelaide, SA 5005, Australia.
C
Corresponding author. Email: m.cooper@uq.edu.au
The development of new methods for the stereoselective synthesis of nitrogen heterocycles is of current interest because of
increasing demands for the syntheses of biologically important alkaloids and related compounds. It is shown that
selenium-induced cyclization of 4-hydroxy-5-pentenylamines occurs regio- and stereo-selectively to afford cis-3-
hydroxy-2-phenylselenomethylpyrrolidines, whereas 5-hydroxy-6-hexenylamines cyclize and give trans-3-hydroxy-
2-phenylselenomethylpiperidines, with some compounds forming stable hydrates. In all cases cyclization proceeds
regioselectively to give only the exo adducts with moderate to good diastereoselectivity. The reaction appeared to be under
kinetic control as product ratios did not alter with time and the separated diastereomers did not interconvert when
resubjected to the reaction conditions. These phenylseleno-substituted compounds could be transformed to diols by
substitution of the corresponding selenone with a hydroxide ion. Substituted pyrrolidines and piperidines were thus
afforded from unsaturated protected amines by electrophilic activation with SeII, followed by oxidation of the intermediate
to SeVI and substitution with nucleophiles.
Manuscript received: 14 February 2011.
Manuscript accepted: 27 April 2011.
Published online: 23 August 2011.
Introduction
stereoselective cyclization of these substrates, however, has
received comparatively little attention.[11] Ninoi et al.[12] have
reported that cyclization of an optically active pentenyl amide
with phenylselanyl chloride gave the pyrrolidine 1a with 25 %
enantiomeric excess and Clive et al.[13] have reported that
cyclization of a 5-hexenyl carbamate with phenylselanyl
chloride gave only the cis-2,6 disubstituted piperidine 1b
(Scheme 1).
The inherent versatility of selenium compounds lies in their
ability to act as both an electrophile and as a nucleophile. The
phenylselenide anion is a good nucleophile[2] and has been used
to displace halide and sulfonate anions[3] and cleave esters and
lactones.[4] The phenylselenide anion also undergoes conjugate
addition to a,b-unsaturated carbonyl compounds and, with tri-
butyl phosphine, converts alcohols directly into alkyl phenyl
selenides.[5] In marked contrast, organoselenium species con-
taining a good leaving group (e.g., Cl, Br, I, O2CCF3, and
phthaloyl (Phth)) can serve as extremely reactive, soft electro-
philes.[2,6,7] Organoselenium moieties can thus be introduced
into a variety of organic substrates as nucleophiles or as elec-
trophiles, using very mild conditions and usually in high yield.
Addition of selenium to an organic compound is usually carried
out using the phenylselanyl halides, phenylselanyl phthalimide,
phenylseleninic acid, or diphenyldiselenide. Phenylselenenyl
halides react instantaneously with double bonds to give anti-
Markovnikov adducts, which isomerize rapidly at room
temperature in polar solvents, or slowly at low temperatures
in non-polar solvents,[8] to the thermodynamically more stable
Markovnikov adducts.[9] This isomerization involves the revers-
ible formation of an episelenonium ion and is dependent upon
the solvent, temperature, and nature of the counter anion of the
selenium reagent used.
Diastereoselective intramolecular addition of heteronucleo-
philes directed by an allylic hydroxy group has been employed
in the syntheses of a variety of natural products and their
synthetic intermediates.[11,14–23] Accordingly, we wished to
determine if selenium induced cyclizations of unsaturated
N-protected amines possessing an allylic hydroxy group could
afford products with defined stereochemistry. We have reported
inprevious communications[24,25] that such reaction with hexenyl-
and pentenyl-N-protected amines proceeds regio- and stereo-
selectively to afford cyclized dihydroxyphenylselenated
adducts. The concomitant incorporation of the synthetically
useful phenylseleno group could then enable ready elaboration
of these products; for example, by substitution of a higher
oxidation state SeVI selenone derivative. More recently, it has
been reported that the selenone group can be exploited in the
conversion of allylic alcohols by dihydroxyselenides from
b-hydroxy epoxides,[26] stereoselective synthesis of substituted
cyclopropanes by organocatalytic Michael addition to vinyl
selenones,[27] and Michael additions to a-substituted cyanoace-
tates with a,b-unsaturated selenones in the presence of bifunc-
tional urea and thiourea organocatalysts to provide adducts with
The cyclofunctionalization[10] of unsaturated carbamates
and unsaturated amides using phenylselanyl halides has been
reported to afford pyrrolidine and piperidine derivatives in
high yield. The use of selenium reagents as mediators of
Ó CSIRO 2011
10.1071/CH11073

1328
M. A. Cooper and A. D. Ward
SePh
C11H23
PhSeCl
C11H23
PhSeCl
NH
N
SePh
NH
CO2Et
N
CO2Et
Ph
Ph
O
O
1a
1b
Scheme 1.
ORЈ
ORЈ
ORЈ
PhSeX
SePh
ϩ
SePh
NHR
N
R
N
R
3
4
5
a: R ϭ CO2Et, RЈ ϭ H
d: R ϭ Ac, RЈ ϭ H
b: R ϭ Boc, RЈ ϭ H
e: R ϭ Ac, RЈ ϭ Ac
c: R ϭ Ts, RЈ ϭ H
f: R ϭ CO2Et, RЈ ϭ Ac
g: R ϭ CO2Et, RЈ ϭ TBDPS h: R ϭ Ac, RЈ ϭ COCF3 i: R ϭ Boc, RЈ ϭ COCF3
Scheme 2.
all-carbon quaternary stereocenters.[28] We show herein that
substituted hydroxy-pyrrolidines and -piperidines can be readily
made from N-protected hydroxy-unsaturated amines by electro-
philic activation with SeII, followed by oxidation of the inter-
mediate to SeVI and subsequent displacement of this leaving
group.
separated diastereomers did not interconvert when resubjected
to the reaction conditions.
The rate and stereoselectivity of the reaction was enhanced
by the use of more polar solvents, which suggests that the rapid
formation[34] of an intermediate selenonium ion is responsible
for the fast, stereoselective reaction observed. Tiecco et al. have
reported[35] that the presence of nucleophilic halide ions is
sometimes responsible for a decrease in stereoselectivity of
selenium-induced cyclizations. Alkyl phenyl selenides may also
react with phenylselanyl halides[36] affording deselenation
products and complex mixtures. It was thought the reagents
phenylselanyl sulfate[35] and phenylselanyl phthalimide,[37]
which do not suffer from these complications, may provide a
greater stereoselectivity. However, when 3a was reacted with
phenylselanyl sulfate no increase in stereoselectivity was
observed. Reaction with phenylselanyl phthalimide gave only
starting materials, although HPLC and thin-layer chromato-
graphy (TLC) analysis indicated that selenium-containing inter-
mediates had formed. It is possible that the phthalimido group is
too bulky to allow the approach of the neighbouring phenylse-
leno moiety, thus formation of a selenonium ion is sterically
hindered and cyclization cannot occur (Scheme 3).
Results and Discussion
Cyclization of N-Protected 3-Hydroxy-4-pentenylamines
As unsaturated amines are known[3,29] to react directly upon
nitrogen with selenium electrophiles, it was necessary to synthesize
the N-protected analogues of 3-hydroxy-4-pentenylamine[30]
2 for cyclization studies. A variety of different N-protecting
groups, conferring differing degrees of nucleophilicity and dif-
fering steric environments to the nitrogen atom, were employed
in these studies (Scheme 2). The carbamates 3a and 3b and the
sulfonamide 3c were synthesized from 2 using standard techni-
ques.[31] Attempts to synthesise the amide 3d directly from 2
using a variety of methods always resulted in concomitant for-
mation of the acetate 3e, thus 3d was prepared by selective
hydrolysis[32] of the ester moiety of 3e with barium hydroxide.
Cyclizations were routinely carried out using a slight excess
of the phenylselanyl halide in the presence of dry silica gel
as catalyst,[13] and anhydrous potassium carbonate as a non-
nucleophilic acid scavenger. As addition of phenylselanyl
halides is a reversible process,[13,33] an acid trap was required
to prevent competing addition of acid formed as an adjunct to
cyclization to the free alkene. The orange colour of phenyl-
selanyl chloride was discharged immediately upon addition to a
solution of the alkenes 3a–3d in dichloromethane at ꢀ78 8C, and
the reaction mixtures were then warmed to room temperature.
Examination of the reaction mixtures by reverse phase high-
performance liquid chromatography (HPLC) revealed the rapid
conversion of starting material into distinct, UV-active products
and enabled accurate determination of reaction times and
product ratios. In all cases cyclization proceeds regioselectively
to give only the five membered ring adducts and with good
diastereoselectivity (Table 1). The reaction appears to be under
kinetic control as product ratios did not alter with time and the
Effect of Hydrogen Bonding and N-Protecting Group
The allylic hydroxy group plays an important role in the stereo-
selective cis cyclization of 3-hydroxy-4-pentenamides,[20,23,30]
3-hydroxy-4-pentenoic acids,[38] and 4-pentene-1,3-diols.[19] It
has been proposed[19,22] that a transition state characterized by
an intramolecular hydrogen bonded six-membered ring directs
attack of the electrophile to the syn face of the double bond.
Reaction of the O-protected derivatives of 3a, i.e., the acetate 3f
and the silyl ether 3g, under the conditions described above
resulted in complete loss of stereoselectivity and necessitated
much greater reaction times (Table 1). The type of N-protecting
group employed also had a marked effect on the stereoselectivity
of the reaction. The carbamates 3a and 3b and the sulfonamide
3c were of comparable reactivity, however, when the amide
3d was subjected to reaction with phenylselanyl bromide in
chloroform, none of the trans isomer 5d could be detected by
1
HPLC or H NMR analysis. The diasteromeric purity of the

Using Se(II) Then Se(VI) to Cyclise Then Substitute Nitrogen Herterocycles
1329
Table 1. Selenium-induced cyclization of N-protected 3-hydroxy-4-pentenylamines
Substrate
PhSe(X)
Cl
X ¼ Reaction conditionsA
Product ratio (yield [%])B
3a
CH2Cl2, a, 4 h
CHCl3, b, 30 min
Dioxan, b, 40 min
CH2Cl2, a, 2 h
CHCl3, b, 20 min
CH2Cl2, a, 4 h
CH2Cl2, a, 4 h
CH2Cl2, a, 2 h
CHCl3, b, 20 min
CH2Cl2, a, 3 h
CH2Cl2, a, 2 h
CHCl3, b, 20 min
CH2Cl2, a, 24 h
CH2Cl2, a, 16 h
CHCl3, b, 1 h
4a/5a 75/25 (88)
85/15 (88)
76/24 (83)
Br
79/21 (95)
87/13 (95)
SO4
Cl
72/28 (84)
3b
3c
3d
4b/5b 74/26 (56)
80/20 (60)
Br
88/12 (70)
Cl
Br
4c/5c 64/36 (83)
66/34 (85)
72/28 (84)
Cl
Br
4d/5d 90/10 (21)C
.99/,1 (23)
.99/,1 (40)
4f/5f 50/50 (60)
4g/5g 60/40 (68)
3f
Br
Br
CHCl3, b, 48 h
CHCl3, b, 1 h
3g
Aa ¼ ꢀ78 8C 10 min to RT, b ¼ 0 8C 10 min to RT.
BYield refers to isolated yield, product ratios determined by HPLC analysis.
CDetermined by HPLC: none of the trans isomer could be isolated.
12
OH
ϩ
OH
C(1)–N bond
3a – COOEt
3b – COOtBu
3c – Ts
3d – Ac
PhSePhth
SePh
SePh
10
8
NH
CO2Et
NH
CO2Et
Phth
Scheme 3.
6
4
O
H
PhSe
HO
2
Ph
O
N
H
ϩ
Se
N
0
O
O
Ϫ180
Ϫ120
Ϫ60
0
60
120
180
R
H
Dihedral angle [°]
O
R
N
Fig. 1. Dihedral angle C–N bond energy calculation using the MM2 force
H
R
field for compounds in this study with variant N-protecting groups.
Scheme 4.
results in the protecting group on nitrogen shielding one face of
the double bond and directs the subsequent selective stereofacial
attack of selenium to this bond (Scheme 4).
product 4d was confirmed upon examination of the 19F NMR
spectrum of the trifluoroacetate derivative 4h, which showed
only one peak at ꢀ0.63 ppm. The trifluoroacetates 4i and 5i were
clearly resolvable by 19F NMR at ꢀ0.32 and 2.34 ppm.
The minimized energy profile from a dihedral drive about
the C–N bond for the N-protected 3-hydroxy-4-pentenylamines
shows that 3a, 3b, and 3c have a similar energy profile, however,
that of 3d is of much higher energy, reflecting the greater double
bond character of this bond.[39] There is also a significant local
minimum in which hydrogen bonding is seen between the
hydroxy proton and the oxygen atom of the amide further
restricting rotation about the C–N bond (Fig. 1).
The cis pyrrolidine 4b was converted[26] by the intermediacy
of a selenone into the cis diol 9 in good yield by reaction with
m-chloroperoxybenzoic acid (MCPBA) and sodium hydroxide.
The diol 9 was then protected as its disilyl ether 9a by
reaction[15] with t-butyldimethylsilyl chloride (Scheme 5).
Compounds such as 9 and 9a are useful templates for the
synthesis of a variety of alkaloids. The disilyl ether 9a has
been oxidized to b-hydroxyproline,[40] converted by an aldol
The observed reactivity towards selenium-induced cycliza-
tion of the sulfonamides, carbamates, and amides shows a
general tendency: the less acidic the NH the greater the yield
and the greater the double bond character of the C–N bond of
the protecting group, the greater the stereoselectivity. The quite
dramatic increase in stereoselectivity observed in the case of the
amide 3d may be attributed to the carbonyl group influencing
which face of the double bond is attacked by selenium. This
hypothesis is proposed on the basis of molecular modelling
studies using a MM2 force field on the substrates 3a, 3c, and 3d
and on their phenylseleno adducts. In all cases there is strong
hydrogen bonding depicted between the hydroxy proton and the
nitrogen atom to form a six-membered ring. This interaction

1330
M. A. Cooper and A. D. Ward
OH
OH
OTBDMS
OTBDMS
TBDMSCl
Imidazole
(i) MCPBA
iPrOH
SePh
OH
N
Boc
N
Boc
DMAP, DMF
N
(ii) KOH(aq)
Boc
4b
9
9a
Scheme 5.
OH
ORЈ
ORЈ
ORЈ
CO2Et
ϩ
SePh
SePh
N
N
R
N
R
NHR
H
H
6
7
8
O
a R ϭ CO2Et RЈ ϭ H
b R ϭ Boc RЈ ϭ H c R ϭ SO2C6H4CH3, RЈ ϭ H
d R ϭ COCH3, RЈ ϭ H e R ϭ SO2C6H4CH3, RЈ ϭ TBDPS
f R ϭ Ac, RЈ ϭ Ac
Se
Scheme 6.
Ph
Fig. 2. Structure proposed[1] for the hydrate 11 in which water is held
firmly in place by dipole–dipole interactions from the ring nitrogen (dþve
due to the carbamate) and selenium.
Table 2. Selenium-induced cyclization of N-protected 4-hydroxy-5-
hexenylamines
Substrate
Reaction conditionsA
Product ratio 7/8B (yield [%])
OH
OH
6a
a, 48 h
3/1 (57)
5/1 (61)
No reaction
3/1 (59)
5/1 (58)
3/1 (41)
3/1 (27)
PhSeCl
b, 18 h
SePh
6b
6c
a or b, 5 days
a, 48 h
NH
Boc
N
Boc
b, 18 h
6g
7g
6d
6e
a, 48 h
a, 5 days
Scheme 7.
Aa ¼ PhSeCl, CH2Cl2 ꢀ78 8C 10 min to RT, b ¼ PhSeBr, CHCl3 0 8C 10 min
to RT.
BYield refers to isolated yield, product ratios were determined by HPLC
thermodynamically unfavourable seven-membered ring. Simi-
lar selectivity has been described in the 6-exo selenoether-
ification of enantiomerically pure unsaturated diols, in which
case the presence of the oxygen atom close to the intermediate
seleniranium ring was reported to govern regio- and stereo-
selectivity, and reactions performed under kinetic and thermo-
dynamic control both led to the same products.[44]
ananlysis.
condensation of a chiral enolate ester into (ꢀ)-detoxinine,[41]
and elaborated[15,42] to 3-hydroxyglutamic acid,[43] an amino
acid component of the peptide antibiotic S-520.
Upon extended reaction times, or upon exposure of the
hydroxypiperidines 7a, 7d, and 7e to tetrahydrofuran (THF)/
water in the presence of a catalytic amount of silica gel, stable
hydrates (e.g., 11) could be isolated. The formation of a stable
hydrate was most facile with the amide 7d, slow with the
carbamate 7a and did not occur with the sulfonamide 7c. The
ability of these compounds to include water follows a general
trend in accordance with the rotational barrier about the C–N
and SO2–N bonds.[39] The more double bond character the C–N
bond of the protecting group possesses, the more likely it is that
the compound will include water. This observation supports the
hypothesis that the inclusion of water involves hydrogen bond-
ing to the carbonyl or sulfonyl moiety of the protecting group.
Unfortunately none of the hydrates were suitable for X-ray
crystallographic analysis, but all gave micro-analytical data[1]
consistent with the structures proposed (e.g., Fig. 2).
Cyclization of N-Protected 4-Hydroxy-5-hexenylamines
While there have been many examples of the cyclization of
N-substituted-3-hydroxy-4-pentenylamines using a variety of
electrophilic reagents,[15,20,21,23,30,42] 4-hydroxy-5-hexenyl-
amines have proved comparatively unreactive.[20,21] In the few
cases in which cyclization occurred,[21] product mixtures were
obtained or the reaction occurred non-stereoselectively. In fact
Tamaru et al.[20] have reported that N-protected 4-hydroxy-5-
hexenylamines are unreactive towards phenylselanyl chloride
and phenylselanyl phthalimide. We found, however, that sub-
strates such as the carbamate 6a, the sulfonamide 6b, and the
amide 6d, synthesized in an analogous manner to 3a–d, were
indeed cyclized upon treatment with phenylselanyl chloride in
dichloromethane (Scheme 6, Table 2). These reactions pro-
ceeded with trans-stereoselectivity and were considerably
slower than those of the 3-hydroxy-4-pentenylamines, with less
stereo-selectivity. Reaction in this case may be slow because no
hydrogen bonding between the hydroxy proton and the nitrogen
atom may occur as this would require the formation of a
Although the t-butylcarbamate 6b would not cyclize, the
4-hydroxy-4-methyl t-butylcarbamate 6g underwent clean
reaction to give a 3:1 mixture of diastereomers 7f and 8f in
good yield (Scheme 7). Substitution at the allylic position of

Using Se(II) Then Se(VI) to Cyclise Then Substitute Nitrogen Herterocycles
1331
OAc
OMe
HO
OH
OH
H
OH
H
N
CO2H
N
H
N
N
H
OH
OH
NH2
Slaframine
Detoxinine
Anisomycin
Retronecin
Fig. 3. Structures of slaframine, detoxinine, anisomycin, and retronecin.
OH
OH
OH
OH
HO
OH
OH
N
H
R
OH
N
Ac
N
H
8
9
10a R ϭ (CH2)9COEt
10b R ϭ (CH2)10CH(OH)Me
Fig. 4. Examples of polyhydroxylated piperidines with trans substituents at C2 and C3.
compounds such as 6g has been previously reported[30] to
increase the efficacy of cyclization reactions.
and the prosopis alkaloids prosopinine 10a and prosopine[54]
10b also possess potent biological activity (Fig. 4).
Conclusion
Assignation of Stereochemistry
Development of new methods for the stereoselective synthesis
of nitrogen heterocycles is of current interest because of
increasing demands for the syntheses of biologically important
alkaloids and related compounds. Polyhydroxylated nitrogen
heterocycles are found abundantly in nature and constitute a
major class of glucosidase inhibitors. Compounds such as
detoxinine, anisomycin, retronecin, slaframine, swainsonine,
and castanospermine effect highly specific inhibition of a
variety of trimming glucosidases and show little cytotoxicity
in vitro or in vivo.[55] They have been used, or implicated for use,
as antihyperglycemic compounds, inhibitors of tumour meta-
stasis, anti-obesity drugs, fungistatic compounds, insect anti-
feedants, and antivirals.[56] We have developed a novel route to
establish the core nitrogen heterocycle with moderate control
of stereochemistry to afford 3-hydroxypiperidines and 3-
hydroxypyrrolidines suitable for further elaboration.
The stereochemistry of the isomers 4a–d was assigned as cis
initially on the basis of the 13C NMR spectra by analogy with
literature values[20] and by
a heteronuclear correlation
(HETCOR)[45] experiment. The CSe resonance of the cis iso-
mers were generally ,2 ppm further upfield than those of the
trans isomers as a result of a g-gauche effect.[46] A 4.15 %
nuclear Overhauser effect (nOe) enhancement was observed
between the protons H2 and H3 of 4c and a 0.5 % enhancement
for the same protons of 5c. The pyrrolidine 4c was obtained in
crystalline form suitable for X-ray analysis,[47] which clearly
depicts the cis relationship of the substituents at C2 and C3. This
configuration of the substituents at C2 and C3 of the pyrrolidine
ring is abundant in alkaloids possessing potent biological
activity such as slaframine,[42,48,49] detoxinine,[41] anisomycin,[50]
and retronecin[16] (Fig. 3).
The relative stereochemistry of the hydroxypiperidines was
assigned on the basis of the coupling constants between H2 and
H3. In the cis isomer 8c H2 appeared at 3.56 ppm (ddd) and H3 at
4.09 ppm (dt) with J2,3 3.7. In the trans isomer 7c H2 appeared
at 3.87 ppm (ddd) and H3 at 4.43 ppm (dt) with J2,3 9.5. These
coupling constants compare favourably with the values calcu-
lated by application of the Karplus equation[51] to the energy
minimized structures of 8c: H2H3 3.7 Hz and 7c: H2H3 8.7 Hz.
The stereochemistry was confirmed by a series of nOe experi-
ments in which a 13.7 % enhancement was seen between the H2
and H3 protons of 8c, and only a 2.6 % enhancement for the
same protons of 7c. The stereochemistry of 7f was elucidated
from a nOe enhancement observed between the acetate methyl
resonance and the two diastereotopic hydrogens adjacent to
selenium. No enhancement was observed to the proton adjacent
to nitrogen.
Experimental
1H NMR, 13C NMR, and all two-dimensional NMR spectra were
obtained on a Bruker ACP-300 (7.05T) spectrometer. Double-
quantum filtered correlation spectroscopy (DQF-COSY) spec-
tra were recorded at a constant 20 8C in phase sensitive mode
using time proportional phase incrementation[57] to give quad-
rature detection in f1. Routinely 2048 data points were recorded
in f1 and 512 in f2, with 64 transients at each value of t1. nOe
samples were degassed by freeze–pump–thawing (4 cycles) and
1
run at a constant 20 8C. H NMR spectra were recorded as
solutions in deuterochloroform, using tetramethylsilane as an
internal standard unless otherwise specified. 77Se NMR spectra
were obtained on the 300 MHz Bruker ACP-300 at 57.2 MHz
with a spectroscopic width of 100 kHz and a digital resolution of
6 Hz per point using diphenyldiselenide (d 463) as an external
standard. 19F NMR spectra were obtained at on the 300 Bruker
Polyhydroxylated piperidines with trans substituents at C2
and C3, such as the acetamide[52] 8 deoxymannojirimycin[53] 9,

1332
M. A. Cooper and A. D. Ward
ACP-300 at 282 MHz using trifluoroacetic acid (d 0) as an
external standard. NMR data are reported as follows: chemical
shift (d) (multiplicity, coupling constant(s) J [Hz], relative
integral) where multiplicity is defined as: s ¼ singlet, d ¼
doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet, or combinations
of the above.
Electron impact mass spectra were recorded at 70 eV on an
AEI 3074 mass spectrometer. Fast atom bombardment mass
spectra and collisional activation mass analyzed ion kinetic
energy spectroscopy (CA-MIKES) spectra were recorded on a
V.G. ZAB 2HF mass spectrometer. Melting points were
recorded on a Kofler hot-stage apparatus equipped with a
Reichert microscope, and are uncorrected. Microanalyses
were performed by the Australian Microanalytical Service,
Melbourne. Infrared spectra were recorded on a Jasco A-102
spectrometer as nujol mulls or liquid films, or as solutions where
indicated.
temperature for 4 h, diluted with ethyl acetate (40 mL), and
washed with 1 N hydrochloric acid (2 ꢁ 40 mL), followed by
10 % sodium bicarbonate (20 mL). The organic phase was sep-
arated, dried, the solvent removed under reduced pressure and
the residue recrystallized (ethyl acetate/ether/light petroleum) to
give the sulfonamide 3b (1.11 g, 88 %) as white needles, mp 70–
71.5 8C. Anal. Calc. for C12H17NO3S: C 56.45, H 6.71, N 5.49.
Found: C 56.38, H 6.68, N 5.46 %. dH 7.75 (d, J 8.2, 2H), 7.30 (d,
J 8.2, 2H), 6.91 (s, 1H, NH), 5.79 (ddd, J 17.1, 10.6, 6.6, 1H,
CH¼CH2), 5.18 (dd, J 1.8, 17.1, 1H, CHaHb¼CH), 5.08 (dd, J
1.8, 10.6, 1H, CHaHb¼CH), 4.24 (m, 1H, CHOH), 3.80 (br s,
1H, OH), 3.08 (m, 2H, CH2N), 2.42 (s, 3H, ArCH3), 1.71 (m, 2H,
CH2). nmax/cmꢀ1 3350, 3250, 1160, 815. m/z 256 (M þ H), 238
(M–OH), 184 (M–C4H6OH), 155 (M–SO2PhCH3).
t-Butyl N-(3-Hydroxy-4-pentenyl)carbamate (3c)
To an emusified mixture of the amine 2 (101 mg, 1 mmol) in
water (10 mL) at 0 8C was added portion-wise 2-(t-butoxy-
carbonyloxyimino)-2-phenylacetonitrile (BOC-ON, 271 mg,
1.1 mmol) followed by a solution of sodium hydroxide (44 mg,
1.1 mmol) in water (1 mL). The mixture was warmed to room
temperature and stirred for a further 6 h. The mixture was then
diluted with ethyl acetate (20 mL) and washed with hydrochloric
acid (2 ꢁ 10 mL), followed by 10 % sodium bicarbonate
(10 mL). The organic phase was separated, dried, the solvent
removed under reduced pressure, and the residue chromato-
graphed to give the carbamate 3c (133 mg, 68 %) as a colourless
oil, bp 108 8C, 0.01 mm (block). Anal. Calc. for C10H19NO3:
requires C 59.67, H 9.52, N 6.96. Found: C 59.36, H 9.59, N
6.79 %. dH 5.87 (ddd, J 17.1, 10.6, 6.6, 1H, CH¼CH2), 5.42 (br s,
1H, NH), 5.24 (dd, J 1.8, 17.1, 1H, CHaHb¼CH), 5.08 (dd, J 1.8,
10.6, 1H, CHaHb¼CH), 4.18 (m, 1H, CHOH), 4.03 (s, 1H, OH),
3.32 (m, 1H, CHaN), 3.15 (m, 1H, CHbN), 1.64 (m, 2H, CH2),
1.44 (s, 9H). nmax/cmꢀ1 3340, 1685, 1520. m/z 202 (M þ H), 145
(M–tBu), 101 (M–CO2tBu).
Preparative chromatography was performed using Merck
Kieselgel PF254 silica using, unless otherwise stated, a Chro-
matotron 7924T (Harrison Research, Palo Alto/TC Research,
California), eluting with a gradient of light petroleum/ethyl
acetate. Flash chromatography was performed using Merck
Kieselgel 60 (230–400 mesh) eluting with a gradient of light
petroleum/ethyl acetate. HPLC was carried out using a Waters
Model 501 solvent delivery system and a U6K injector with
a Waters Model 481 absorbance detector. Analyses were
performed using a Waters Z-module with a Waters Radial-
PAK C18 reverse phase cartridge (10 cm ꢁ 8 mm) eluting
with a methanol/water gradient. All organic extracts were dried
over anhydrous sodium sulfate unless otherwise specified.
Phenylselanyl phthalimide was synthesized according to
the method of Nicolaou et al.[37] MCPBA was recrystallized
from dichloromethane/light petroleum and was 85 % pure
as determined by epoxidation of a stoichiometric amount of
cyclohexene.
Ethyl N-(3-Hydroxy-4-pentenyl)carbamate (3a)
N-(3-Hydroxy-4-pentenyl)acetamide (3d)
To an emusified mixture of the amine 2 (1.01 g, 10 mmol) in
water (30 mL) at 0 8C was added ethyl chloroformate (0.65 g,
6 mmol). The emulsion was stirred at 0 8C for 5 min and then a
second portion of ethyl chloroformate (0.65 g, 6 mmol) was
added, followed immediately by a solution of sodium hydroxide
(0.5 g, 1.2 mmol) in water (5 mL). The mixture was stirred at
0 8C for a further 1.5 h, and extracted with ethyl acetate
(3 ꢁ 20 mL). The combined organic extracts were washed with
1 N hydrochloric acid (10 mL), and then 10 % sodium bicar-
bonate (10 mL). The organic phase was separated, dried, the
solvent removed under reduced pressure and the residue chro-
matographed to give the carbamate 3a (1.53 g, 89 %) as a light
yellow oil. bp 115–118 8C, 0.013 mm (block). Calc. for
C8H18NO3: C 55.47, H 8.73, N 8.09. Found: C 55.18, H 8.58, N
8.30 %. dH 5.87 (ddd, J 17.1, 10.6, 6.6, 1H, CH¼CH2), 5.79 (s,
1H, NH), 5.24 (dd, J 1.8, 17.1, 1H, CHaHb¼CH), 5.08 (dd, J 1.8,
10.6, 1H, CHaHb¼CH), 4.19 (s, 1H, OH), 4.17 (m, 1H, CHOH),
4.08 (q, J 6.9, 2H, CH2CH3), 3.29 (m, 2H, CH2N), 1.71 (m, 2H,
CH2), 1.22 (t, J 6.9, 3H, CH3). nmax/cmꢀ1 3600, 3450, 1705,
1510. m/z 174 (M þ H), 156 (M–OH), 102 (M–CO2Et).
A mixture of the acetate 3e (400 mg, 2.1 mmol) and barium
hydroxide (680 mg, 2.1 mmol) in methanol (20 mL) was stirred
at room temperature for 1 h. The solution was filtered through
celite, the celite washed with methanol (10 mL), and the solvent
removed under reduced pressure to give the amide 3d (300 mg,
100 %) as a colourless oil, bp 142 8C, 0.02 mm (block). Anal.
Calc. for C7H13NO2: C 58.89, H 9.15, N 9.78. Found: C 58.89,
H 9.11, N 10.15 %. dH 6.45 (s, 1H, NH), 5.87 (ddd, J 17.1, 10.6,
6.6, 1H, CH¼CH2), 5.24 (dd, J 1.8, 17.1, 1H, CHaHb¼CH), 5.08
(dd, J 1.8, 10.6, 1H, CHaHb¼CH), 4.17 (m, 1H, CHOH), 3.56
(s, 1H, OH), 3.24 (dt, J 8.3, 1.8, 1H, CHaN), 3.18 (dt, J 8.3, 1.8,
1H, CHbN), 1.99 (s, 3H, CH3), 1.72 (m, 1H), 1.62 (m, 1H).
n
(M–OH).
max/cmꢀ1 3250, 1630, 1540. m/z (FAB) 144 (M þ H), 126
N-(3-Acetoxy-4-pentenyl)acetamide (3e)
To a mixture of the amine 2 (101 mg, 1 mmol) and triethylamine
(404 mg, 4 mmol) in dry tetrahydrofuran (THF, 10 mL) under
nitrogen at 0 8C was added acetyl chloride (286 mL, 4 mmol)
dropwise over 2 min. The resultant solution was warmed to
room temperature and stirred overnight. The solvent was
then removed under reduced pressure, the residue diluted with
ethyl acetate (20 mL), washed with 1 N hydrochloric acid
(2 ꢁ 10 mL), followed by 10 % sodium bicarbonate (10 mL).
The organic phase was separated, dried, the the solvent removed
N-(3-Hydroxy-4-pentenyl)-4-toluenesulfonamide (3b)
To a stirred mixture of the amine 2 (505 mg, 5 mmol) in dry
pyridine (10 mL) under nitrogen at 0 8C was added portion-wise
tosyl chloride (1.05 g, 5.5 mmol). The mixture was stirred at this

Using Se(II) Then Se(VI) to Cyclise Then Substitute Nitrogen Herterocycles
1333
under reduced pressure and the residue chromatographed to give
the acetate 3e (142 mg, 77 %) as a colourless oil, bp 135 8C,
0.06 mm (block). Anal. Calc. for C9H15NO3: 185.1052; HRMS
found: 185.1056. dH 5.9 (s, 1H, NH), 5.80 (ddd, J 17.1, 10.6, 6.6,
1H, CH¼CH2), 5.32 (m, 1H), 5.25 (dd, J 1.8, 17.1, 1H,
CHaHb¼CH), 5.19 (dd, J 1.8, 10.6, 1H, CHaHb¼CH), 3.46
(m, 1H, CHaN), 3.08 (m, 1H, CHbN), 2.09 (s, 3H, OCOCH3),
1.98 (s, 3H, NCOCH3), 1.83 (m, 2H, CH2). nmax/cmꢀ1 3300,
reduced pressure, and the residue chromatographed to give the
cis pyrrolidine 4a as white crystals (272 mg, 83 %), mp 89–
90 8C. Anal. Calc. for C14H19NO3Se: C 51.22, H 5.83, N 4.27.
Found: C 51.17, H 5.64, N 4.25 %. dH (CDCl3, 50 8C) 7.57
(m, 2H), 7.28 (m, 3H), 4.54 (m, 1H, H3), 4.10 (q, J 6.9, 2H,
CH2CH3), 3.69–3.42 (m, 3H), 3.47 (dd, J 12.3, 3.6, 1H, H6a),
3.08 (dd, J 12.3, 10.9, 1H, H6b), 2.51 (br s, 1H, OH), 1.94 (m, 2H,
H4aH4b), 1.22 (t, J 6.9, 3H, CH3). dC (CDCl3, 50 8C) 155.4
(C¼O), 132.3, 131.6, 129.1, 126.6 (Ar), 72.1 (C3), 61.1 (CH2O),
44.6 (C6), 32.5 (C2), 32.0 (C5), 25.4 þ(C4), 14.6 (CH3). nmax/cmꢀ1
þ
0
1735, 1650, 1240. m/z 185 (M ), 126 (M–OCOCH3).
0
Ethyl N-(3-Acetoxy-4-pentenyl)carbamate (3f)
3420, 1670, 1580, 1480. m/z 329 (M ), 172 (M–SePh), 158 (M–
To a stirred mixture of the carbamate 3a (692 mg, 4 mmol)
and triethylamine (505 mg, 5 mmol) in dry THF (20 mL) under
nitrogen at 0 8C was added acetyl chloride (430 mL, 6 mmol)
dropwise over 2 min. The mixture was warmed to room tem-
perature and stirred for a further 24 h. The solvent was removed
under reduced pressure, and the residue redissolved in ethyl
acetate (50 mL), washed with 1 N hydrochloric acid
(2 ꢁ 10 mL), followed by 10 % sodium bicarbonate (10 mL).
The organic phase was separated, dried, the solvent removed
under reduced pressure, and the residue chromatographed to
give the acetate 3f (688 mg, 80 %) as a colourless oil, bp 101 8C,
0.02 mm (block). Anal. Calc. for C24H33NO3Si: C 71.03, H 8.08,
N 2.40. Found: C 71.15, H 8.18, N 2.40 %. dH 5.80 (ddd, J 17.1,
10.6, 6.6, 1H, CH¼CH2), 5.34 (m, 1H, CHOH), 5.22 (dd, J 1.8,
17.1, 1H, CHaHb), 5.19 (dd, J 1.8, 10.6, 1H, CHaHb¼CH), 5.06
(br s, 1H, NH), 4.10 (q, J 6.9, 2H, CH2CH3), 3.31 (m, 1H), 3.11
(m, 1H), 2.08 (s, 3H, COCH3), 1.83 (m, 2H), 1.23 (t, J 6.9, 3H,
CH3). nmax/cmꢀ1 3350, 1730, 1715, 1225. m/z 216 (M þ H), 156
(M–OAc), 102 (M–OAc–CO2Et).
CH2SePh). Further elution gave the trans pyrrolidine 5a as a
light yellow oil (41 mg, 12 %). dH (CDCl3, 50 8C) 7.54 (m, 2H),
7.24 (m, 3H), 4.35 (m, 1H, H3), 4.09 (q, J 6.9, 2H, CH2CH3),
3.85 (m, 1H, H2), 3.63–3.40 (m, 2H, H5aH5b), 3.30 (dd, J 12.3,
3.0, 1H, H6a), 2.63 (br s, 1H, OH), 2.55 (dd, J 12.3, 11.8, 1H,
H6b), 2.04 (m, 1H, H4a), 1.88 (m, 1H, H4b), 1.24 (t, J 6.9, 3H,
CH3). dC (CDCl3, 50 8C) 155.8 (C¼O), 134.9, 132.1, 130.5,
129.1 (Ar), 74.2 (C3), 61.1 (CH2O), 44.6 (C6), 31.4 (C2), 30.0
(C5), 27.9 (C4), 14.5 (CH3). nmax/cmꢀ1 3350, 1660, 1580, 1480.
þ
0
m/z 329 (M ), 172 (M–SePh), 158 (M–CH2SePh).
t-Butyl 2(R*)-Phenylselenomethyl-3(R*)-
hydroxypyrrolidine-1-carboxylate (4b) and t-Butyl
2(S*)-Phenylselenomethyl-3(R*)-hydroxypyrrolidine-
1-carboxylate (5b)
Using method B with the carbamate 3c (201 mg, 1 mmol), dry
silica (250 mg), anhydrous potassium carbonate (250 mg),
and phenylselanyl chloride (230 mg, 1.2 mmol) gave the cis
pyrolidine 4b as translucent needles (219 mg, 62 %), mp 101–
103 8C. Anal. Calc. for C16H23NO3Se: C 53.93, H 6.51, N 3.93.
Found: C 54.01, H 6.83, N 4.08 %. dH (CDCl3, 50 8C) 7.63 (m,
2H), 7.10 (m, 3H), 4.49 (m, 1H, H3), 3.96 (m, 1H, H2), 3.51 (m,
2H, H5aH5b), 3.38 (dd, J 12.3, 3.6, 1H, H6a), 3.02 (dd, J 12.3,
11.8, 1H, H6b), 2.09 (br s, 1H, OH), 1.88 (m, 2H, H4aH4b), 1.36
(s, 9H). dH (CDCl3, 50 8C) 154.6 (C¼O), 133.1, 131.5, 129.2,
127.5 (Ar), 88.1 (CMe3), 74.0 (C3), 43.3 (C6), 32.4 (C2), 30.6
(C5), 28.7 (C4), 28.4 (CH3). nmax/cmꢀ1 3410, 1660, 1460. m/z
Ethyl N-(3-t-Butyldiphenylsilyloxy-4-pentenyl)
carbamate (3g)
A mixture of the carbamate 3a (519 mg, 3 mmol), imidazole
(450mg, 7.5mmol), dimethylaminopyridine (80mg, 0.6mmol),
and t-butyldiphenylsilyl chloride (1.24 g, 4.5 mmol) in dry N,N-
dimethylformamide (DMF, 10 mL) was stirred at room tem-
perature for 24 h. The mixture was diluted with ether (10 mL),
washed with saturated sodium chloride (10 mL), 5 % hydro-
chloric acid (2 ꢁ 5 mL), 10 % sodium bicarbonate (5 mL), and
again with saturated sodium chloride (10 mL). The organic phase
was separated, dried, and the solvent removed under reduced
pressure to give the silyl ether 3g (1.22 g, 99 %) as a colourless
oil, bp 120 8C, 0.02 mm (block). Anal. Calc. for C24H33NO3Si:
C 71.01, H 8.08, N 2.40. Found: C 71.15, H 8.18, N 2.40 %. dH
7.7–7.2 (m, 10H), 5.80 (ddd, J 17.1, 10.6, 6.6, 1H, CH¼CH2),
5.19 (br s, 1H, NH), 5.01 (dd, J 1.8, 17.1, 1H, CHaHb¼CH), 4.98
(dd, J 1.8, 10.6, 1H, CHaHb¼CH), 4.27 (m, 1H, CHOH), 4.03 (q,
J 6.9, 2H, CH2CH3), 3.20 (m, 2H, CH2N), 1.60 (m, 2H), 1.26 (t, J
6.9, 3H, CH3), 1.06(s, 9H). nmax/cmꢀ1 3460, 1700, 1530. m/z 354
(M–tBu), 200 (M–Ph2tBu), 172 (M–SiPh2tBu).
þ
0
355 (M ), 138 (M–SePh), 124 (M–CH2SePh). Further elution
gave the trans pyrrolidine 5b as a light yellow oil (39 mg, 8 %).
dH (CDCl3, 50 8C) 7.63 (m, 2H), 7.14 (m, 3H), 4.31 (m, 1H, H3),
3.73 (m, 1H, H2), 3.50 (m, 1H, H5a), 3.32 (m, 1H, H5b), 3.19 (dd,
J 12.3, 3.2, 1H, H6a), 2.85 (br s, 1H, OH), 2.51 (dd, J 12.3, 11.6,
1H, H6b), 1.95 (m, 1H, H4a), 1.76 (m, 1H, H4b), 1.37 (s, 9H). dC
(CDCl3, 50 8C) 154.4 (C¼O), 132.9, 131.9, 129.0, 127.1 (Ar),
87.8 (CMe3), 75.1 (C3), 65.3 (CMe3O), 44.6 (C6), 30.9 (C2),
30.2 (C5), 2þ9.6 (C4), 28.5 (CH3). nmax/cmꢀ1 3400, 1660, 1460.
0
m/z 355 (M ), 138 (M–SePh), 124 (M–CH2SePh).
2-(R*)-Phenylselenomethy-3(R*)-hydroxypyrrolidine-
1-tosylate (4c) and 2-(S*)-Phenylselenomethy-3(R*)-
hydroxypyrrolidine-1-tosylate (5c)
Ethyl 2(R*)-Phenylselenomethyl-3(R*)-hydroxypyrrolidine-
1-carboxylate (4a) and Ethyl 2(S*)-phenylselenomethyl-
3(R*)-hydroxypyrrolidine-1-carboxylate (5a)
Method A: To a stirred mixture of the sulfonamide 3b (254 mg,
1 mmol), dry silica (250 mg), and anhydrous potassium car-
bonate (250 mg) in dry dichloromethane (10 mL) under nitrogen
at ꢀ78 8C was added a solution of phenylselanyl chloride
(230 mg, 1.2 mmol) in dry dichloromethane (3 mL) dropwise
over 5 min. The mixture was stirred at ꢀ78 8C for 10 min, and
then at room temperature for 3 h. The solution was fitered
through celite, the celite washed with ethyl acetate, the filtrate
concentrated under reduced pressure and the residue chroma-
tographed to give a mixture of the cis and trans pyrrolidines 4c
Method B: To a solution of the carbamate 3a (173 mg, 1 mmol),
dry silica (250 mg), and anhydrous potassium carbonate
(250 mg) in dry chloroform (10 mL) under nitrogen at 0 8C was
added a solution of phenylselanyl chloride (230 mg, 1.2 mmol)
in dry chloroform (3 mL) dropwise over 5 min. The mixture
was stirred at 0 8C for 10 min, and then at room temperature
for 30 min. The solution was filtered through celite, the celite
washed with ethyl acetate, the filtrate concentrated under

1334
M. A. Cooper and A. D. Ward
and 5c which was fractionally recrystallized (ethyl acetate/
ether/light petroleum) to give 4c as translucent needles, mp 110–
112 8C. Anal. Calc. for C18H21NO3SSe: C 52.68, H 5.16, N 3.41.
Found: C 52.36, H 5.15, N 3.47 %. dH 7.62 (m, 2H), 7.37 (m,
3H), 7.44 and 7.37 (d, J 8.2, 4H, C6H4), 4.37 (m, 1H, H3), 3.71
(dd, J 12.3, 3.6, 1H, H6a), 3.56 (dt, J 5.8, 10.8, 1H, H5a), 3.46
(ddd, J 11.8, 3.6, 4.0, 1H, H2), 3.44 (dt, J 5.8, 10.8, 1H, H5b), 3.20
(dd, J 12.3, 11.8, 1H, H6b), 2.38 (s, 3H, ArCH3), 2.34 (br s, 1H,
OH), 1.66 (m, 1H, H4a), 1.17 (m, 1H, H4b). dC 144.1, 133.9,
129.4, 127.2 (Ar), 71.8 (C3), 63.7 (C7), 47.7 (C2), 32.6 (C5),
26.7 (C4), 20.6 (MePh). nOe ( % enhancement): H2H3 (4.1),
H2H6a (1.6), H2H6b (0.8), H3OH (2.4), H3H4a (3.0), H3H4b
(1.8), H4aH4b (11.0), H6aH6b (17.5). nmax/cmꢀ1 3400, 1660,
Ethyl 20(R*)-(Phenylselenomethyl)-30(R*)-
(t-butyldiphenylsilyloxy)pyrrolidine-1-carboxylate (4g)
and Ethyl 20(S*)-(Phenylselenomethyl)-30(R*)-
(t-butyldiphenylsilyloxy)pyrrolidine-1-carboxylate (5g)
Using method B with the carbamate 3g (205 mg, 0.5 mmol), dry
silica (250 mg), anhydrous potassium carbonate (250 mg), and
phenylselanyl bromide (130 mg, 0.55 mmol) gave a 3:2 mixture
of the pyrrolidines 4g and 5g as a viscous yellow oil (192 mg,
68 %). HRMS: 567.1707; C30H37NO3SeSi requires 567.1708.
þ
max/cmꢀ1 1690, 1580, 1480, 1420, 1100. m/z 567 (M ), 490
0
n
(M–Ph), 434 (M–tBuPh), 411 (M–SePh). dH (CDCl3, 50 8C) 4g:
7.70 and 7.32 (m, 10H), 7.57 (m, 2H), 7.28 (m, 3H), 4.41 (m,
H3), 4.10 (q, J 6.9, 2H, CH2CH3), 3.69–3.42 (m, 3H), 3.47 (dd, J
12.3, 3.6, 1H, H6a), 3.08 (dd, J 12.3, 10.9, 1H, H6b), 1.94 (m, 2H,
H4aH4b), 1.22 (t, J 6.9, 3H, CH3), 1.11 (s, 9H). 5g: 7.70 and 7.32
(m, 10H), 7.54 (m, 2H), 7.24 (m, 3H), 4.30 (m, 1H, H3), 4.09 (q,
J 6.9, 2H, CH2CH3), 3.85 (m, 1H, H2), 3.63–3.40 (m, 2H,
H5aH5b), 3.30 (dd, J 12.3, 3.0, 1H, H6a), 2.55 (dd, J 12.3, 11.8,
1H, H6b), 2.04 (m, 1H, H4a), 1.88 (m, 1H, H4b), 1.24 (t, J 6.9, 3H,
CH3), 1.06 (s, 9H).
þ
0
1580, 1480. m/z 411 (M ), 255 (M–SePh), 241 (M–CH2SePh).
The supernatant of the recrystallization was then concentrated
and the residue recrystallized to give 5c as white crystals, mp
139–141 8C. dH 7.80 (m, 2H), 7.63 (m, 3H), 7.37 and 7.24 (d, J
8.2, 4H, C6H4), 4.04 (dt, J 6.4, 12.9, 1H, H3), 3.73 (dd, J 12.3,
8.9, 1H, H6a), 3.63 (dt, J 6.5, 10.6, 1H, H5a), 3.51 (ddd, J 6.4, 1.8,
8.9, 1H, H2), 3.43 (dd, J 12.3, 1.8, 1H, H6b), 3.06 (dt, J 6.5, 10.6,
1H, H5b), 2.41 (s, 3H, ArCH3), 2.30 (br s, 1H, OH), 1.91 (m, 1H,
H4a), 1.61 (m, H4b). dC 147.2, 131.4, 129.8, 127.4 (Ar), 71.1
(C3), 59.7 (C7), 46.9 (C2), 32.4 (C5), 27.7 (C4), 22.0 (MePh). nOe
( % enhancement): H2H3 (0.5), H2H6a (1.5), H2H6b (0.8), H3OH
(2.3), H3H4a (3.0), H3H4b (1.5), H4aH4b (10.1), H6aH6þb (17.0).
2(R*)-Phenylselenomethyl-3(R*)-
trifluoroacetoxypyrrolidine-1-acetate (4h)
To a stirred mixture of the alcohol 4d (18 mg, 0.06 mmol) and
triethylamine (9 mg, 0.09 mmol) in dry dichloromethane (2 mL)
under nitrogen was added trifluoroacetic anhydride (15 mg,
0.072 mmol) and the mixture stirred at room temperature for
24 h. The solution was washed with 10 % hydrochloric acid
(5 mL), 10 % sodium bicarbonate (5 mL), dried, and the solvent
removed under reduced pressure to give the trifluoroacetate
4h as a colourless oil (15 mg, 63 %). HRMS: 395.0249;
C15H16NO3F3Se requires 395.0247. dH 7.59 (m, 2H), 7.24 (m,
3H), 5.68 (dt, J 5.0, 4.7, 1H, H3), 4.44 (ddd, J 5.0, 10.3, 3.7, 1H,
H2), 3.89 (dd, J 12.8, 3.7, 1H, H6a), 3.65 (m, 2H, H5aH5b), 2.93
(dd, J 12.8, 10.3, 1H, H6b), 2.2–2.0 (m, 2H), 2.03 (s, 3H, CH3).
n
max/cmꢀ1 3400, 1660, 1580, 1480. m/z 411 (M ), 255
0
(M–SePh), 241 (M–CH2SePh).
N-Acetyl-2(R*)-phenylselenomethyl-3(R*)-
hydroxypyrrolidine (4d)
Using method B with the amide 3d (143 mg, 1 mmol), dry
silica (250 mg), anhydrous potassium carbonate (250 mg), and
phenylselanyl chloride (230 mg, 1.2 mmol) gave the cis pyrro-
lidine 4d as white crystals, mp 150–151 8C. Anal. Calc. for
C13H17NO2Se: C 52.35, H 5.75, N 4.70. Found: C 52.18, H 5.68,
N 4.62 %. dH 7.63 (m, 2H), 7.22 (m, 3H), 4.50 (dt, J 5.1, 5.6, 1H,
H3), 3.70 (dd, J 12.2, 3.5, 1H, H6a), 3.61 (m, 3H), 3.09 (dd, J
12.2, 9.9, 1H, H6b), 3.08 (br s, 1H, OH), 2.05 (m, 2H, H4aH4b),
1.99 (s, 3H, COCH3). dC 206.5 (C¼O), 132.2, 130.0, 128.4,
dF ꢀ0.63. nmax/cmꢀ1 1770, 1685, 1400, 1150. m/z 395 (M ),
þ
0
298 (M–COCF3).
125.1 (Ar), 69.6 (C3), 60.1 (C6), 45.2 (C2), 32.0 (C5), 28.7 (C4),
þ
0
21.8 (CH3). nmax/cmꢀ1 3400, 1630, 1060. m/z 299 (M ), 142
t-Butyl 2(R*)-Phenylselenomethyl-3(R*)-
trifluoroacetoxypyrrolidine-1-carboxylate (4i)
and t-Butyl 2(S*)-Phenylselenomethyl-3(R*)-
trifluoroacetoxypyrrolidine-1-carboxylate (5i)
(M–SePh), 128 (M–CH2SePh).
Ethyl 20(R*)-Phenylselenomethyl-30(R*)-acetoxypyrrolidine-
1-carboxylate (4f) and Ethyl 2’(S*)-(Phenylselenomethyl)-
30(R*)-O-acetoxypyrrolidine-1-carboxylate (5f)
To a stirred 1:1 mixture of the alcohols 4b and 5b (62 mg,
0.26 mmol) and triethylamine (26 mg, 0.26 mmol) in dry
dichloromethane (2 mL) under nitrogen was added tri-
fluoroacetic anhydride (555 mg, 0.26 mmol) and the mixture
stirred at room temperature for 24 h. The solution was washed
with 10 % hydrochloric acid (5 mL), 10 % sodium bicarbonate
(5 mL), dried, and the solvent removed under reduced pressure
to give a 1:1 mixture of the trifluoroacetates 4i and 5i as a col-
ourless oil (73 mg, 89 %). HRMS: 453.0649; C18H22NO4F3Se
reqþuires 453.0666. nmax/cmꢀ1 1775, 1685, 1390, 1160. m/z 453
Using method B with the carbamate 3f (215 mg, 1 mmol), dry
silica (500 mg), anhydrous potassium carbonate (500 mg), and
phenylselanyl bromide (283 mg, 1.2 mmol) gave a 1:1 mixture
of the cis and trans pyrrolidines as a viscous yellow oil (220 mg,
60 %). HRMS: 371.0616; C16H21NO4Se requires 3þ71.0636.
n
max/cmꢀ1 1720, 1690, 1520, 1240. m/z 371 (M ), 328
0
(M-COCH3), 200 (M-CH2SePh). dH (CDCl3, 50 8C) 4f: 7.57
(m, 2H), 7.28 (m, 3H), 5.03 (m, 1H, H3), 4.10 (q, J 6.9, 2H,
CH2CH3), 3.69–3.42 (m, 3H), 3.47 (dd, J 12.3, 3.6, 1H, H6a),
3.08 (dd, J 12.3, 10.9, 1H, H6b), 2.02 (s, 3H, COCH3), 1.94 (m,
2H, H4aH4b), 1.22 (t, J 6.9, 3H, CH3). 5f: 7.54 (m, 2H), 7.24 (m,
3H), 4.96 (m, 1H, H3), 4.09 (q, J 6.9, 2H, CH2CH3), 3.85 (m, 1H,
H2), 3.63–3.40 (m, 2H, H5aH5b), 3.30 (dd, J 12.3, 3.0, 1H, H6a),
2.55 (dd, J 12.3, 11.8, 1H, H6b), 2.10 (s, 3H, COCH3), 2.04
(m, 1H, H4a), 1.88 (m, 1H, H4b), 1.24 (t, J 6.9, 3H, CH3).
0
(M ), 396 (M–tBu), 380 (M–tBuO), 356 (M–COCF3), 240
(M–tBu–SePh). dH 4i: 7.56 (m, 2H), 7.26 (m, 3H), 5.51 (m, 1H,
H3), 4.02 (m, 1H, H2), 3.56 (m, 2H, H5aH5b), 3.28 (dd, J 3.2,
12.8, 1H, H6a), 2.69 (dd, J 11.6, 12.8, 1H, H6b), 2.3–1.8 (m, 2H),
1.37 (s, 9H). 5i: 7.56 (m, 2H), 7.26 (m, 3H), 4.40 (m, 1H, H3),
3.80 (m, 1H, H2), 3.6–3.4 (m, 2H, H5aH5b), 3.30 (dd, J 3.2, 12.8,
1H, H6a), 2.60 (dd, J 11.6, 12.8, 1H, H6b), 2.3–1.8 (m, 2H), 1.36
(s, 9H). dF 4i: ꢀ0.32, 5i: 2.14.

Using Se(II) Then Se(VI) to Cyclise Then Substitute Nitrogen Herterocycles
1335
Ethyl N-(4-Hydroxy-5-hexenyl)carbamate (6a)
room temperature for 1 h. The solution was filtered through
celite, the celite washed with methanol (10 mL), and the solvent
removed under reduced pressure to give the amide 6d (0.72 g,
100 %) as a colourless oil. bp 145 8C, 0.02 mm (block). HRMS:
157.1098; C8H15NO2 requires 157.1102. dH 6.41 (s, 1H, NH),
5.80 (ddd, J 17.1, 10.6, 6.6, 1H, CH¼CH2), 5.17 (dd, J 1.8, 17.1,
1H, CHaHb¼CH), 5.12 (dd, J 1.8, 10.6, 1H, CHaHb¼CH), 4.14
(m, 1H, CHOH), 3.54 (m, 1H, OH), 3.28 (m, 2H, CH2N), 1.98
(s, 3H, CH3), 1.7–1.5 (m, 4H). nmax/cmꢀ1 3320, 1640, 1570. m/z
To an emulsified mixture of 6-amino-3-methylhex-1-ene-3-ol
(690 mg, 6 mmol) in water (50 mL) at 0 8C was added ethyl
chloroformate (450 mg, 4.5 mmol). The mixture was stirred at
this temperature for 5 min and then 30 % sodium hydroxide
(1.08 g, 9 mmol) was added followed immediately by a second
portion of ethyl chloroformate (450 mg, 4.5 mmol). The mixture
was stirred at room temperature for 2 h and then extracted with
ethyl acetate (30 mL). The organic extracts were washed with
1 N hydrochloric acid (10 mL), 10 % sodium bicarbonate
(10 mL), dried, the solvent removed under reduced pressure, and
the residue chromatographed to give the carbamate 6a as a
yellow oil (765 mg, 68 %). bp 108 8C, 0.1 mm (block). Anal.
Calc. for C9H17NO3: C 57.93, H 9.15, N 8.48. Found: C 57.97, H
9.36, N 8.66 %. dH 5.87 (ddd, J 17.1, 10.6, 6.6, 1H, CH¼CH2),
5.79 (s, 1H), 5.24 (dd, J 1.8, 17.1, 1H, CHaHb¼CH), 5.08 (dd,
J 1.8, 10.6, 1H, CHaHb¼CH), 4.82 (s, 1H, NH), 4.11 (q, J 6.9,
2H, CH2), 3.21 (m, 2H, CH2N), 1.91 (m, 2H), 1.58 (m, 2H), 1.23
(t, J 6.9, 3H, CH3). nmax/cmꢀ1 3340, 1690, 1550, 1260. m/z 188
(M þ H), 170 (M–OH).
þ
0
157 (M ), 140 (M–OH).
N-(4-t-Butyldiphenylsilyloxy-5-hexenylsulfonamide)-
4-toluenesulfonamide (6e)
A mixture of the alcohol 6c (269 mg, 1 mmol), imidazole
(150mg, 2.5mmol), dimethylaminopyridine (27 mg, 0.2 mmol),
and t-butyldiphenylsilyl chloride (413 mg, 1.5 mmol) in dry DMF
(5mL) was stirred at room temperature for 24 h. The solution was
diluted with ether (5mL), washed with saturated sodium chloride
(3mL), 10 % hydrochloric acid (5mL), 10 % sodium bicarbonate
(5mL), and again with saturated sodium chloride (3mL). The
organic phase was separated, dried, the solvent removed under
reduced pressure, and the residue chromatographed to give the
silyl ether 6e as a colourless oil (504mg, 99%). dH 7.72 and 7.36
(m, 10H), 7.61 and 7.21 (d, J 8.2, 4H), 5.64 (ddd, Jax 17.1, Jbx
10.6, Jay 6.6, 1H, CH¼CH2), 4.95 (dd, Jab 1.8, Jax 17.1, 1H,
CHaHb¼CH), 4.92 (s, 1H, NH), 4.90 (dd, Jab 1.8, Jbx 10.6, 1H,
CHaHb¼CH), 4.08 (m, 1H, CHOSi), 3.46 (m, 2H, CH2N),
t-Butyl N-(4-Hydroxy-5-hexenyl)carbamate (6b)
A
mixture of 6-amino-3-methylhex-1-ene-3-ol (0.92 g,
8 mmol), triethylamine (1.21 g, 12 mmol), and BOC-ON
(2.21 g, 9 mmol) in dioxan (20 mL) and water (20 mL) was
stirred at room temperature for 24 h. The solution was diluted
with ethyl acetate (40 mL) and the organic phase separated,
washed with 10 % sodium hydroxide solution, the solvent
removed under reduced pressure, and the residue distilled to
give the carbamate 6b as a yellow oil (0.92 g, 53 %). bp 105 8C,
0.02 mm (block). Anal. Calc. for C11H21NO3: C 59.71, H 9.83,
N 7.51. Found: C 59.66, H 10.01, N 7.22 %. dH 5.82 (ddd,
J 17.1, 10.6, 6.6, 1H, CH¼CH2), 5.18 (dd, J 1.4, 17.1, 1H,
CHaHb¼CH), 5.02 (dd, J 1.4, 10.6, 1H, CHaHb¼CH), 4.80 (br s,
1H, NH), 4.11 (m, 1H, CHOH), 3.15 (m, 2H, CH2N), 2.69 (br s,
1H, OH), 1.6–1.4 (m, 4Hþ), 1.43 (s, 9H). nmax/cmꢀ1 3340, 1690,
2.73 (m, 2H), 2.36 (s, 3H, ArCH3), 1.35 (m, 2H), 1.04 (s, 9þH).
0
n
max/cmꢀ1 1740, 1600, 1500, 1160. m/z (FAB) 507 (weak M ),
450 (M–tBu), 374 (M–tBu–Ph), 296 (M–(Ph)2tBu).
N-(4-Acetoxy-5-hexenyl)acetamide (6f)
To a mixture of 6-amino-3-methylhex-1-ene-3-ol (0.69 g,
6 mmol) and triethylamine (1.82 g, 4 mmol) in dry THF (20 mL)
under nitrogen at 0 8C was added acetyl chloride (1.28 mL,
18 mmol) dropwise over 2 min. The resultant solution was
warmed to room temperature and stirred overnight. The solvent
was then removed under reduced pressure, the residue diluted
with ethyl acetate (40 mL), and washed with 1 N hydrochloric
acid (2 ꢁ 10 mL) and 10 % sodium bicarbonate (10 mL). The
organic was phase separated, dried, the solvent removed under
reduced pressure, and the residue chromatographed to give the
acetate 6f (0.926 g, 77 %) as a colourless oil. HRMS: 199.1208;
C10H17NO3 requires 199.1190. dH 5.72 (s, 1H, NH), 5.80 (ddd,
J 17.1, 10.6, 6.6, 1H, CH¼CH2), 5.17 (dd, J 1.8, 17.1, 1H,
CHaHb¼CH), 5.12 (dd, J 1.8, 10.6, 1H, CHaHb¼CH), 4.20
(m, 1H, CHOAc), 3.65 (m, 2H, CH2N), 2.40 (s, 3H, CH3), 2.10
(s, 3H, CH3), 1.9–1.7 (m, 2H), 1.6–1.5 (m, 2H). nmax/cmꢀ1 1725,
0
1525. m/z (FAB) 215 (M ), 159 (M–tBu), 142 (M–tBuO).
N-(4-Hydroxy-5-hexenyl)-4-toluenesulfonamide (6c)
To a stirred mixture of 6-amino-3-methylhex-1-ene-3-ol
(690 mg, 6 mmol) in dry pyridine (40 mL) under nitrogen at 0 8C
was added tosyl chloride (1.33 g, 7 mmol) portion-wise. The
mixture was stirred at this temperature for 4 h, diluted with
ethyl acetate (40 mL), and washed with 1 N hydrochloric acid
(2 ꢁ 40 mL), followed by 10 % sodium bicarbonate (20 mL).
The organic phase was separated, dried, the solvent removed
under reduced pressure, and the residue recrystallized (ethyl
acetate/ether/light petroleum) to give the sulfonamide 6c as a
white solid (1.15 g, 71 %). mp 51–53 8C. Anal. Calc. for
C13H19NO3S: C 57.97, H 7.11, N 5.20. Found: C 61.24, H 7.16,
N 5.33 %. dH 7.75 (d, J 8.2, 2H), 7.30 (d, J 8.2, 2H), 5.79 (ddd,
J 17.1, 10.6, 6.6, 1H, CH¼CH2), 5.18 (dd, J 1.8, 17.1, 1H,
CHaHb¼CH), 5.08 (dd, J 1.8, 10.6, 1H, CHaHb¼CH), 4.85
(s, 1H, NH), 4.08 (m, 1H, CHOH), 2.97 (m, 2H, CH2N), 2.90
(s, 1H, OH), 2.43 (s, 3H, ArCH3), 1.59 (m, 2H), 1.57 (m, 2H).
þ
0
1700, 1230. m/z 199 (M ), 140 (M–OCOCH3).
t-Butyl-(4-methylhex-5-en-4-ol)carbamate (6g)
A mixtureof 6-amino-3-methylhex-1-ene-3-ol (1.29 g, 10mmol),
triethylamine (1.52g, 15 mmol), and BOC-ON (2.71g, 11mmol)
in dioxan (20 mL) and water (20 mL) was stirred at room
temperature for 24h. The solution was washed with 10 %
aqueous sodium hydroxide (2ꢁ 20 mL) and the organic phase
separated, dried, the solvent removed under reduced pressure, and
the residue chromatographed to give the carbamate 6g as a yellow
oil (1.47 g, 63%). bp 128–130 8C, 0.20 mm. Anal. Calc. for
C12H23NO3: C 62.85, H 9.93, N 6.26. Found: C 62.29, H 9.93,
N 6.26 %. dH 5.85 (dd, J 12.1, 17.4, 1H, CH¼CH2), 5.19 (dd, J
n
(M–OH), 155 (M–SO2C6H4CH3).
max/cmꢀ1 1640, 1600, 1500, 1320, 1155. m/z 270 (M þ H), 252
Compound 6d
N-4-(Hydroxy-5-hexenyl)acetamide
A mixture of the acetate 6f (0.92 g, 4.6 mmol) and barium
hydroxide (1.47 g, 4.6 mmol) in methanol (20 mL) was stirred at

1336
M. A. Cooper and A. D. Ward
16.0, 1.6, 1H, CHa¼CH2), 5.07 (dd, J 12.1, 1.6, 1H, CHb¼CH2),
3.47 (s, 1H, OH), 3.08 (m, 2H, CH2N), 1.53 (m, 4H), 1.42 (s, 9H),
1.26 (s, 3H, CH3). dC 156.06 (C¼O), 144.67 (CH¼CH2), 111.69
(CH¼CH2), 78.99 (CO2C), 72.79 (C(OH)), 40.72 (CH2N),
38.96 (C(OH)CH2), 28.53 ((CH3)3), 27.63 (CH3), 24.60
(CH2CH2N). nmax (CCl4)/cmꢀ1 3640, 3500, 3430, 1735, 1650,
1180. m/z 230 (Mþ H), 212 (M–H2O), 173 (M–tBu), 129
(M–CO2tBu).
2(S*)-Phenylselenomethyl-3(R*)-hydroxypiperidine-
1-acetate Mono Hydrate (7d) and 2(R*)-Phenylselenomethyl-
3(R*)-hydroxypiperidine-1-acetate Mono Hydrate (8d)
Using method A with the amide 6d (157 mg, 1 mmol), potassium
carbonate (500 mg), dry silica (500 mg), and phenylselanyl
chloride (210 mg, 1.1 mmol) gave a 3:1 mixture of 7d and 8d as a
white solid which was recrystallized from ether/light petroleum
to give 7d as white needles (127 mg, 41 %). mp 130–132 8C.
Anal. Calc. for C14H21NO3Se: C 50.01, H 6.41, N 4.24. Found:
C 49.93, H 5.93, N 3.96 %. dH 7.58 (m, 2H), 7.27 (m, 3H), 4.80
(m, 1H, H3), 3.95 (m, 1H, H2), 3.87 (dd, J 5.0, 4.8, 1H, H7a), 3.23
(dd, J 5.0, 2.6, 1H, H7b), 3.18 (m, 2H, H6aH6b), 1.97 (s, 3H, CH3),
1.78 (m, 2H, H4aH4b), 1.62 (m, 2H, H5aH5b). dC 206.4 (C¼O),
141.4, 134.6, 129.3, 127.9 (Ar), 72.9 (C3), 64.6 (C7), 56.9 (C2),
39.2 (C6), 32.4 (C4), 26.1 (CH3C¼CO), 20.1 (C5). nmax/cmꢀ1
Ethyl 2(S*)-Phenylselenomethyl-3(R*)-hydroxypiperidine-
1-carboxylate (7a) and Ethyl 2(R*)-Phenylselenomethyl-
3(R*)-hydroxypiperidine-1-carboxylate (8a)
Using method A with the carbamate 6a (187 mg, 1 mmol),
potassium carbonate (500 mg), dry silica (500 mg), and phe-
nylselanyl chloride (210 mg, 1.1 mmol) gave an inseparable 3:1
mixture of the piperidines 7a and 8a (196 mg, 57 %) as a light
yellow oil. Anal. Calc. for C15H21NO3Se: C 52.63, H 6.18, N
4.09. Found: C 52.40, H 5.97, N 3.89 %. nmax/cmꢀ1 3450, 1705,
þ
0
3280, 1655, 1475. m/z (FAB) 333 (M ), 315 (M–H2O), 297
(M–OH–OH2).
2(S*)-Phenylselenomethyl-3(R*)-(t-butyldiphenylsilyloxy)-
pyrrolidine-1-p-toluenesulfonate Mono Hydrate (7e) and
2(R*)-Phenylselenomethyl-3(R*)-(t-butyldiphenylsilyloxy)-
pyrrolidine-1-p-toluenesulfonate Mono Hydrate (8e)
þ
0
1295. m/z 343 (M ), 326 (M–OH), 187 (M–SePh), 173
(M–CH2SePh). 7a: dH 7.52 (m, 2H), 7.22 (m, 2H), 4.88 (dt, J 9.6,
5.4, 1H, H3), 4.10 (q, J 6.9, 2H, CH2), 4.02 (ddd, J 9.6, 9.2, 5.5,
1H, H2), 3.44 (dd, J 12.8, 9.2, 1H, H7a), 3.31 (dd, J 12.8, 5.5, 1H,
H7b), 3.16 (m, 2H, H6aH6b), 2.40 (s, 1H, OH), 1.67 (m, 2H,
H4aH4b), 1.58 (m, 2H, H5aH5b), 1.23 (t, J 6.9, 3H, CH3). dC 209.1
(C¼O), 156.8, 133.3, 129.3, 127.6 (Ar), 70.8 (C3), 66.3 (CH2O),
61.5 (C7), 60.7 (C2), 40.4 (C6), 31.7 (C4), 27.4 (C5), 14.6 (CH3).
Using method A with the sulfonamide (507 mg, 1 mmol),
potassium carbonate (500 mg), dry silica (500 mg), and phe-
nylselanyl chloride (210 mg, 1.1 mmol) gave the a 3:1 mixture
of the hydrates 7e and 8e as white crystals (216 mg, 32 %). mp
108–113 8C. Anal. Calc. for C35H41NO3SSeSi: C 61.74, H 6.37,
N 2.00. Found: C 61.36, H 6.55, N 1.70 %. 7e: dH 7.7–7.2 (m,
19H), 4.44 (t, J 6.2, 1H, OHa), 4.00 (dt, J 1.9, 6.4, 1H, H3), 3.90
(dd, J 11.4, 8.4, 1H, H7a), 3.82 (dd, J 11.4, 6.2, 1H, H7b), 3.27
(ddd, J 1.9, 6.2, 8.4, 1H, H2), 2.55 (dt, J 6.2, 6.9, 2H, H6aH6b),
2.39 (s, 3H, ArCH3), 2.03 (s, 1H, OHb), 1.82 (m, 1H, H4a), 1.47
(m, 1H, H4b), 1.20 (m, 2H, H5aH5b), 1.03 (s, 9H). dC 143.2,
136.0, 135.8, 129.9, 129.4, 127.7, 127.6, 126.9 (Ar), 72.5 (C3),
63.0 (C7), 54.6 (C2), 42.5 (C6), 31.9 (C4), 26.8 (CH3), 25.9
(CMe3), 21.4 (ArCH3), 19.4 (C5). dHSe 281. nmax/cmꢀ1 1760,
d
Se 306.6. 8a: dH 7.52 (m, 2H), 7.22 (m, 3H), 4.68 (m, 1H, H3),
4.10, q (6.9, 2H, CH2), 3.89 (m, 1H, H2), 3.29 (dd, J 13.3, 3.5,
1H, H7a), 2.64 (dd, J 13.3, 12.7, 1H, H7b), 3.16 (m, 2H, H6aH6b),
2.40 (s, 1H, OH), 1.67 (m, 2H, H4aH4b), 1.58 (m, 2H, H5aH5b),
1.23 (t, J 6.9, 3H, CH3). dC 210.3 (C¼O), 156.8, 133.3, 129.3,
127.6 (Ar), 73.4 (C3), 66.6 (C7), 60.8 (CH2O), 37.4 (C2), 32.0
(C6), 27.5 (C5), 24.1 (C4), 14.5 (CH3). dSe 306.8.
2(S*)-Phenylselenomethyl-3(R*)-hydroxypiperidine-1-
p-toluenesulfonate (7c) and 2(R*)-Phenylselenomethyl-
3(R*)-hydroxypiperidine-1-p-toluenesulfonate (8c)
þ
0
1600, 1500, 1175. m/z 663 (M ), 607 (M–tBu), 450 (M–
(Ph)2tBu). 8e: dH 7.7–7.2 (m, 19H), 4.40 (t, J 6.2, 1H, OHa), 4.09
(dt, J 4.8, 7.2, 1H, H3), 3.84 (dd, J 4.5, 5.4, 1H, H7a), 3.83 (dd, J
4.5, 5.6, 1H, H7b), 3.35 (ddd, J 4.8, 5.4, 5.6, 1H, H2), 2.41 (dt, J
6.2, 6.8, 2H, H6aH6b), 2.40 (s, 3H, ArCH3), 2.61 (s, 1H, OHb),
1.82 (m, 1H, H4a), 1.47 (m, 1H, H4b), 1.20 (m, 2H, H5aH5b), 1.03
(s, 9H). dH 143.2, 136.0, 135.8, 129.9, 129.4, 127.7, 127.6, 126.9
(Ar), 74.1 (C3), 62.4 (C7), 53.6 (C2), 42.2 (C6), 31.4 (C4), 26.9
(CH3), 25.9 (CMe3), 21.4 (ArCH3), 19.4 (C5). dSe 305.
Using method A with the sulfonamide 6c (269 mg, 1 mmol),
potassium carbonate (500 mg), dry silica (500 mg), and phe-
nylselanyl chloride (210 mg, 1.1 mmol) gave the cis piperidine
8c as a colourless oil (63 mg, 15 %). Anal. Calc. for
C19H23NO3SSe: C 53.64, H 5.45, N 3.29. Found: C 53.62, H
5.35, Nþ3.16 %. nmax/cmꢀ1 3450, 1600, 1580, 1500, 1150. m/z
0
425 (M ), 408 (M–OH), 268 (M–SePh), 254 (M–CH2SePh). dH
7.62 and 7.22 (d, J 8.3, C6H4), 7.45 (m, 2H), 7.24 (m, 3H), 4.09
(dt, J 3.7, 5.6, 1H, H3), 3.78 (dd, J 3.4, 14.4, 1H, H7a), 3.58 (m,
1H, H6a), 3.56 (ddd, J 11.2, 3.4, 3.7, 1H, H2), 3.10 (dd, J 11.2,
14.4, 1H, H7b), 2.95 (m, 1H, H6b), 2.41 (s, 3H, ArCH3), 2.29 (s,
1H, OH), 2.05 (m, 2H), 1.75 (m, 2H). dC 143.2, 133.5, 132.9,
130.0, 129.6, 129.0, 127.6, 127.0 (Ar), 68.8 (C3), 52.6 (C7),
47.5 (C2), 25.4 (C6), 23.3 (C4), 21.4 (C5), 19.6 (ArCH3). nOe
(% enhancement): H2H3 (13.7) Further elution gave the trans
piperidine (7c) as a colourless oil (196 mg, 46 %). dH 7.62 and
7.22 (d, J 8.3, 4H, C6H4), 7.45 (m, 2H), 7.24 (m, 3H), 4.43 (dt, J
9.5, 4.8, 1H, H3), 4.13 (s, 1H, OH), 3.87 (dt, J 9.5, 5.0, 1H, H2),
3.65 (m, 1H, H6a), 3.23 (dd, J 12.3, 5.1, 1H, H7a), 2.98 (dd, J
12.3, 9.6, 1H, H7b), 2.92 (m, 1H, H6b), 2.42 (s, 3H, ArCH3), 1.8–
1.4 (m, 4H). dH 143.2, 133.5, 132.9, 130.0, 129.6, 129.0, 127.6,
127.0 (Ar), 68.9 (C3), 57.3 (C7), 39.5 (C2), 27.2 (C6), 23.9 (C4),
23.3 (C5), 21.5 (ArCH3). nOe (% enhancement): H2H3 (2.6).
Other spectroscopic data as for 8c.
t-Butyl 3(R*)-Hydroxy-3-methyl-2(S*)-
phenylselenomethylpiperidine-1-carboxylate (7g)
Using method A with the carbamate 6g (229 mg, 1 mmol),
potassium carbonate (500 mg), dry silica (500 mg), and
phenylselanyl chloride (210 mg, 1.1 mmol) gave 7g as a white
solid that was recrystallized (light petroleum/ether) to give
white needles (289 mg, 75 %), mp 116–117 8C. Anal. Calc. for
C18H27NO3Se: C 56.24, H 7.08, N 3.64. Found: C 56.24, H 7.05,
N 3.70 %. nmax (CDCl3)/cmꢀ1 3420, 1680, 1575, 1510. m/z 385
þ
0
(M ), 170 (M–CH3), 367 (M–OH), 308 (M–Ph). dH (CDCl3,
50 8C) 7.62 (m, 2H), 7.26 (m, 3H), 3.99 (dd, J 14.3, 2.5, 1H, H2),
3.77 (m, 1H, H6a), 3.31 (dd, J 11.5, 14.3, 1H, H7a), 3.15 (dd, J
11.5, 2.5, 1H, H7b), 3.02 (m, 1H, H6b), 2.22 (br s, 1H, OH), 2.02
(m, 1H, H5a), 1.94 (m, 1H, H5b), 1.67 (m, 1H, H4a), 1.23 (m, 1H,
H4b), 1.46 (s, 3H, CH3), 1.25 (s, 9H). dC (CDCl3, 50 8C) 210.1
(C¼O), 155.6, 134.25, 129.08, 127.65 (Ar), 79.59 (CO2C),

Using Se(II) Then Se(VI) to Cyclise Then Substitute Nitrogen Herterocycles
1337
72.48 (C3), 58.90 (C7), 47.30 (C2), 45.02 (C6), 37.86 (C4), 32.10
(CH3), 28.29 ((CH3)3), 19.55 (C5). nOe ( % enhancement):
H2CH3 (,0.5), H7aCH3 (5.2), H7bCH3 (5.6).
11.3, 9.3, 1H, H7a), 3.77 (dd, J 11.3, 5.0, 1H, H7b), 3.19 (ddd, J
1.9, 5.0, 9.3, 1H, H2), 3.10 (t, J 6.9, 2H, H6aH6b), 1.8–1.4
(m, 4H), 1.21 (t, J 7.0, 3H, CH3). dC (CDCl3) 218.6 (C¼O),
156.9, 134.5, 129.3, 127.8 (Ar), 72.4 (C3), 64.4 (OCH2), 60.8
(C7), 56.3 (C2), 40.5 (C6), 32.5 (C4), 26.5 (C5), 14.6 (CH3). dC
(CD3OD) 216.4 (C¼O), 157.0, 135.1, 130.1, 128.3 (Ar), 70.7
(C3), 64.1 (C7), 61.6 (CH2O), 56.6 (C2), 41.5 (C6), 34.0 (C4),
27.6 (C5), 15.0 (CH3). dSe (CDCl3) 260. nmax (nujol)/cm–1 3350,
t-Butyl 2(R*)-(Hydroxymethyl)-3(R*)-hydroxypyrrolidine-
1-carboxylate (9)
To the selenide 4b (178 mg, 0.5 mmol) in isopropyl alcohol
(40 mL) was added MCPBA (407 mg, 2 mmol) and the mixture
stirred at room temperature for 1 h. A 10 % solution of sodium
hydroxide (5 mL) was then added and the mixture stirred at
room temperature for a further 4 h. The solution was diluted
with saturated sodium bicarbonate (10 mL) and extracted with
chloroform (2 ꢁ 20 mL). The combined organic extracts were
washed with saturated sodium chloride (10 mL), dried, the sol-
vent removed under reduced pressure and the residue chroma-
tographed to give the diol 9 as a light yellow oil (64 mg, 59 %).
dH 3.85 (br s, 1H), 3.75 (br s, 1H), 3.6–3.4 (m, 3H), 3.29 (m, 1H),
3.05 (br s, 1H), 1.95 (m, 1H), 1.63 (m, 1H), 1.46 (s, 9H). dC 156.3
(C¼O), 80.3 (OCMe3), 72.6 (C3), 67.9 (C6), 63.8 (C2), 44.9 (C5),
31.5 (C4), 28.3 (CH3). nmax/cm–1 3400, 1695, 1670. m/z (FAB)
219 (M þ H2), 217 (Mþ), 186 (M–CH2OH), 162 (M þ H2–tBu),
144 (M–tBuO).
þ
0
1705, 1515, 1210. m/z 361 (M ), 343 (M–H2O).
Molecular Modeling
The dihedral angle profiles were calculated using the MM2
force field.[48] The investigation into the putative transition state
of the reaction was done by ab initio calculations, using the
program Gamess.[49] All energy calculations, structure optimi-
zations, and transition state optimizations were done using the
RHF/6-31G basis set. The starting point of the transition state
investigation was the cyclic product (5d), by building both
stereoisomers (cis and trans) of the S-hydroxy isomer. For both
stereoisomers, both ring conformations (hydroxy in axial and
equatorial orientation) were built. All four structures were pre-
optimized by molecular mechanics calculations before opti-
mizing the structure with the RHF/6-13G basis set. The search of
the putative transition state was done in three steps: (a) constrain
t-Butyl 2(R*)-(t-Butyldimethylsilyoxymethyl)-
3(R*)-(t-butyldimethylsilyoxymethyl)pyrrolidine-
1-carboxylate (9a)
˚
the distance between the Se and the C to 2.1 A to form a cyclic Se
and optimize the structure, (b) protonate the nitrogen and opti-
mize the structure, and (c) use the final structure for transition
state optimization (RUNTYP ¼ SADPOINT). The final transi-
tion state structures were checked for virtual frequencies, before
calculating the free energies.
A mixture of the diol 9 (44 mg, 0.2 mmol), imidazole (86 mg,
1.4 mmol), t-butyldimethylsilyl chloride (80 mg, 0.5 mmol), and
DMAP (6 mg, 0.05 mmol) in dry DMF (2 mL) under nitrogen
was stirred at room temperature for 24 h. The mixture was
diluted with ether (3 mL), washed with saturated sodium chlo-
ride (2 mL), 10 % hydrochloric acid, 10 % sodium bicarbonate
(2 mL), and again with saturated sodium chloride (2 mL). The
organic phase was separated, dried, the solvent removed under
reduced pressure, and the residue chromatographed to give the
silyl ether 9a as a light yellow oil (50 mg, 76 %). dH 4.34 (br m,
1H, H3), 3.70 (m, 1H, H6a), 3.66 (m, 1H, H6b), 3.54–3.26
(m, 3H), 2.15–1.94 (m, 1H, H4a), 1.70–1.80 (m, 1H, H4b), 1.43
(s, 9H), 0.88 (s, 9H), 0.06–0.01 (m, 12H). nmax/cm–1 1695. m/z
Acknowledgements
The authors thank Johannes Zuegg for assistance with modelling work and
an NHMRC Australia Fellowship: AF 511105 for funding.
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