A [3+3] cyclization strategy for asymmetric synthesis of alkyl substituted piperidine-2-ones using 1,2-cyclic sulfamidates: A formal synthesis of (S)-coniine from l-norvaline

Article abstract of DOI:10.1016/j.tet.2012.09.081

Regioselective ring-opening reactions of a set of representative 1,2-cyclic sulfamidates with lithium triethylorthopropiolate proceeded efficiently to deliver the corresponding δ-amino-α,β-unsaturated esters after acidic hydrolysis. Hydrogenation of the unsaturated esters and subsequent thermal cyclization afforded the related alkyl substituted piperidine-2-ones. This approach represents a novel [3+3] cyclization strategy for the asymmetric synthesis of alkyl substituted piperidin-2-ones. Efficiency of the cyclization process is illustrated by a formal asymmetric synthesis of (S)-coniine from l-norvaline.

Full text of DOI:10.1016/j.tet.2012.09.081

Tetrahedron 68 (2012) 10218e10229
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A [3þ3] cyclization strategy for asymmetric synthesis of alkyl substituted
piperidine-2-ones using 1,2-cyclic sulfamidates: a formal synthesis
of (S)-coniine from -norvaline
L
*
Abdullah Karanfil, Berrin Balta, Mustafa Eskici
Department of Chemistry, Faculty of Arts and Science, Celal Bayar University, 45016 Mansa, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2012
Received in revised form 29 August 2012
Accepted 17 September 2012
Available online 23 September 2012
Regioselective ring-opening reactions of a set of representative 1,2-cyclic sulfamidates with lithium
triethylorthopropiolate proceeded efficiently to deliver the corresponding d-amino-a,b-unsaturated es-
ters after acidic hydrolysis. Hydrogenation of the unsaturated esters and subsequent thermal cyclization
afforded the related alkyl substituted piperidine-2-ones. This approach represents a novel [3þ3] cycli-
zation strategy for the asymmetric synthesis of alkyl substituted piperidin-2-ones. Efficiency of the cy-
clization process is illustrated by a formal asymmetric synthesis of (S)-coniine from L-norvaline.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Cyclic sulfamidates
Lithium triethylorthopropiolate
Cyclization
Piperidines
1. Introduction
stereochemistry. These beneficial features make cyclic sulfamidates
synthetically potent electrophilic synthons for the synthesis of N-
containing compounds, and the reaction of cyclic sulfamidates with
a wide range of nucleophiles including, nitrogen,6 oxygen,7 sulfur,8
phosphorus,9 and halogene-based10 nucleophiles has been re-
ported in the literature.11
Activation of the hydroxyl group of readily available, often
enantiopure, 1,2- and 1,3-aminoalcohols for nucleophilic displace-
ment through formation of cyclic sulfamidates provides an effective
alternative to the reactivity profile of activated aziridines and
azetidines, respectively.1 Additionally there exist several advan-
tages in favor of the chemistry of cyclic sulfamidates.2 With cyclic
sulfamidates nucleophilic attack occurs regioselectively at the ox-
ygen bearing carbon, and attack at the CdN bond is not generally
observed. There is also no specific requirement for the presence and
subsequent removal of a strictly activating protecting group on the
nitrogen atom. Thus, the use of cyclic sulfamidates allows flexibility
concerning the protecting group employed, and a range of pro-
tecting groups including Ts, Bn, Cbz, and Boc can be used with
a very little effect on nucleophilic cleavage.3,4 Moving from 3- to 4-
ring systems, azetidines could lack the required reactivity to be
used as electrophiles.5 In the case of cyclic sulfamidates, on going
from five- to six-membered ring systems, a useful level of reactivity
is attainable as the reactivity of 1,2-cyclic sulfamidates is not largely
derived from the ring strain. Besides, cyclic sulfamidates with de-
fined stereochemistry at the CdO bond are generally accepted to
undergo nucleophilic displacement with a clean inversion of
Of particular interest is the ring-opening reaction with carbon-
based nucleophiles that enable the synthesis of functionalized
amines. In this context, the reactivity of cyclic sulfamidates toward
synthetically more versatile carbon-based nucleophiles other than
cyanide has been less widely exploited in synthesis. Over the last
decade, Gallagher and co-workers12 and others13 have shown that
cyclic sulfamidates could exhibit a high level of reactivity toward
stabilized carbon nucleophiles. Nucleophilic cleavage of a series of
1,2 and 1,3-cyclic sulfamidates by structurally functionalized and
stabilized-enolates followed by thermal lactamization of the sub-
stitution products constituted [3þ2] and [4þ2] cyclization strate-
gies to the syntheses of
a-functionalized pyrrolidone and
piperidone systems, respectively.12 Application of this sulfamidate-
based chemistry in the syntheses of a number of piperidine con-
taining natural products as well as industrially important mole-
cules, (ꢀ)-aphanorphine,12c,f (þ)-laccarin, and antidepressant
(ꢀ)-paroxetine12a largely contributes to the establishment of cyclic
sulfamidates as synthetically versatile emerging building blocks in
synthesis.
We have recently reported a synthetically useful level of re-
* Corresponding author. Tel.: þ90 2362412151; fax: þ90 2362412158; e-mail
address: mustafa.eskici@cbu.edu.tr (M. Eskici).
activity of cyclic sulfamidates toward acetylides (Scheme 1).14 Ring-
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.081

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229
10219
Scheme 1. Nucleophilic substitution of cyclic sulfamidates with acetylides.
opening reactions of a structurally diverse set of 1,2- and 1,3-cyclic
sulfamidates 1 with a range of lithium acetylides 2 proceeded
illustrated by a formal synthesis of the hemlock alkaloid (S)-coniine
from -norvaline.
L
smoothly in
a regioselective fashion to form N-sulfate in-
termediates 3. Acidic hydrolysis afforded the alkynylated amines 4
in yields ranging from 29% to 98%. The acetylenic displacement of
sulfamidates 1 provided an alternative route for the synthesis of
alkynylated amines.15 Primary carbon-centered 1,2-cyclic sulfami-
dates were found to be particularly effective in the alkylation re-
2. Results and discussion
2.1. Synthesis of cyclic sulfamidates
Although a number of elegant technologies have been de-
veloped over the last decade for the synthesis of cyclic sulfamidates
utilizing precursors other than aminoalcohols,16 the most direct
routes to relatively simple cyclic sulfamidates, as in the case of the
present work, involve the use of aminoalcohols and a two-step
cyclization approach (thionyl chloride and Ru-mediated oxida-
tion). A structurally representative set of 1,2-cyclic sulfamidates
7aeg was prepared from aminoalcohols using the two-step cycli-
zation procedure in order to examine briefly their structural effect
on the alkylation by triethylorthopropiolate (Scheme 2). The benzyl
group was used for N-protection due to the ease of installation and
subsequent removal by hydrogenation, as well as the stability un-
der basic conditions. Primary carbon-centered sulfamidates 7aed
were prepared in enantiomerically pure form. Among the second-
ary carbon-centered 1,2-cyclic sulfamidates, ephedrine-derived 7e
and lactic acid-derived 7f were optically pure, 7g was synthesized
in racemic form for convenience.11c The use of 7g is considered to
action furnishing the related
yields.
b-alkynylated amines in excellent
The high reactivity of 1,2-cyclic sulfamidates toward acetylides
prompted us to explore the formation of a piperidine skeleton from
the b-alkynylated amines through lactamization upon hydrogena-
tion, once the acetylide possesses a pendant ester functionality. In
this communication, we disclose the results of the efficient sub-
stitution of a structurally diverse set of 1,2-cyclic sulfamidates by
lithium triethylorthopropiolate to give
d-amino-a,b-unsaturated
esters after acidic hydrolysis that upon hydrogenation thermally
cyclize to the alkyl substituted piperidine lactams, in which
[NeCeC] fragment from the 1,2-cyclic sulfamidate and [CeCeC]
fragment from the propiolate anion are combined to form the pi-
peridine ring system. This approach represents a novel [3þ3] an-
nulation strategy for the asymmetric synthesis of the substituted
piperidin-2-ones. The efficiency of the cyclization process has been
Scheme 2. Synthesis of 1,2-cyclic sulfamidates 7aeg.

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A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229
be a test of the triethylorthopropiolate anion for the elimination
pathway, as the potential of the sulfamidate 7g toward elimination
is already reported.11c
ester 14a was found to be not sufficiently stable; decomposition to
a varying extent on storage was observed, and therefore was
rapidly subjected to hydrogenation to effect both saturation and
debenzylation. A brief scanning of palladium catalysts (Pd(OH)/C
and Pd/C) and solvents (MeOH and THF) revealed that a combi-
nation of Pd(OH)/C and Pd/C in THF were effective hydrogenation
conditions for saturation and debenzylation.23 Exposure of 14a to
atmospheric hydrogenation conditions led to desired saturation
and deprotection forming amino ester 15a. Premature lactam-
ization was observed during hydrogenation (TLC). In order to
drive lactamization to completion, the crude reaction mixture was
filtered through a pad of CeliteÒ, followed by removal of volatiles
under reduced pressure, and the residue dissolved in toluene was
L-Phenylalanine, alanine and valine were esterified using thionyl
chloride and then converted into the benzamide derivatives 5aec
with benzoylchloride (Scheme 2). Global reduction with LiAlH4
gave the aminoalcohols 6aec in high yields. Cyclization of the
aminoalcohols 6aec to 1,2-cyclic sulfamidates 7aec was achieved
by the standard two-step cyclization protocol. In the synthesis of
alaninol cyclic sulfamidate 7b, exposure of the intermediate sulfa-
midite to the oxidation conditions longer than 10e15 min led to
extensive decomposition on a large scale preparation, therefore the
duration of the oxidation step kept short to obtain a high yield of
7b. Prolinol cyclic sulfamidate 7d was prepared directly from the
refluxed for
6
h. Chromatographic purification afforded
reaction of
a
L
-prolinol with sulfuryl chloride at ꢀ78 ꢁC in DCM in
phenylalanine-derived lactam 16a (½a D30
ꢀ55.3 (c 1, CHCl3)) in 87%
ꢂ
single operation.11i Ephedrine-derived 7e and elimination-
yield over two steps.
sensitive 7g sulfamidates were prepared according to literature.11c
(S)-Ethyl lactate 8 was converted into the benzylamide derivative
9 via an amidation reaction,17 which was reduced to the desired
aminoalcohol 10 with LiAlH4.18 The two-step sulfamidate formation
sequence produced lactic acid-derived sulfamidate 7f in 71% yield
under unoptimized conditions. In this way, multigram quantities of
sulfamidates 7aeg were readily available for ring-opening
reactions.
Using a similar set of reaction conditions, the results of nu-
cleophilic cleavage of the representative set of 1,2-cyclic sulfa-
midates 7aeg with 12 and thermal cyclization of the
substitution products 14aef, to the corresponding lactams 16aef
are shown in Table 1. With the exception of prolinol 7d, primary
carbon-centered 1,2-cyclic sulfamidates 7aec were particularly
suitable in the alkylation reaction with 12 delivering the related
d
-amino-a,b-unsaturated ester 14aec in high yields following
acidicebasic work-up. Cyclization of the amino esters 14aec was
equally efficient also, leading to the synthesis of the desired
lactams 16aec. Ring-opening of prolinol sulfamidate 7d oc-
curred readily under similar conditions, but we were unable to
hydrolyze the resulting intermediate using the standard 5 M HCl
conditions. Attempted hydrolysis of the intermediate under
various acidic conditions (concentrated HCl, 20% and 50% H2SO4)
failed to yield any success; heating usually resulted in degra-
dation of the intermediate.
The steric and/or electronic tolerance of the 1,2-cyclic sulfami-
dates toward 12 were examined with 7eeg. Sterically demanding
ephedrine-derived sulfamidate 7e was completely unreactive with
12 under the standard conditions. We previously observed that
inclusion of HMPA in the reaction mixture was found to enhance
both the reaction rates and yields significantly.14 In an attempt to
overcome the lack of reactivity of 7e for 12, the same reaction run in
the presence of 10% HMPA by volume at either ꢀ10 ꢁC or ꢀ78 ꢁC
gave a complex mixture. The reaction of sterically less demanding
lactic acid-derived 7f with 12 proceeded slowly without HMPA
(substitution product 14f was obtained in a 30% yield); a significant
amount of the sulfamidate 7f remained unreacted in the reaction
mixture (TLC). With the use of HMPA, the reaction seemed to be
more rapid and efficient; the corresponding amino ester 14f was
obtained in a good yield (76%). On exposure of the elimination
sensitive sulfamidate 7g to the propiolate 12, a smooth reaction
proceeded to form an intermediate (all sulfamidate 7g consumed
by TLC). Acidic hydrolysis of the intermediate produced N-benzyl
2.2. Substitution with 1,2-cyclic sulfamidates and cyclization
studies
Initially, we tried to generate the propiolate anion from the
reaction of n-BuLi on methylpropiolate directly in THF,19 and react
it with phenylalaninol sulfamidate 7a to obtain d-amino-a,b-un-
saturated methylester. These efforts produced no success in our
hands; the sulfamidate remained unreacted in the mixture. This
failure may be attributable to the instability of the propiolate
anion in solution through the inclination of the acetylenic moiety
and alkyl carboxylate group to react with each other.20 Accord-
ingly attention moved to known triethylorthopropiolate as a syn-
thetically more stable propiolate anion precursor. Thus
triethylorthopropiolate 11 was prepared from triethylorthopro-
pionate using double brominationeelimination reactions.21 Ac-
tion of n-BuLi on triethylorthopropiolate in THF at ꢀ10 ꢁC readily
generated lithium triethylorthopropiolate 12.22 Ring-opening of
sulfamidate 7a with 12 proceeded smoothly to form the in-
termediate N-sulfate 13a (Scheme 3). Hydrolysis of 13a with 5 M
HCl solution not only cleaved the N-sulfate but also led to con-
current hydrolysis orthoester to the corresponding ethylester
14a.21b Neutralization of the reaction mixture with aqueous sat-
urated NaHCO3 solution followed by chromatographic purification
furnished N-benzyl-d-amino-a,b-unsaturated ethylester 14a in
89% yield. A slight excess (2 equiv) of the nucleophilic component
12 was required for the complete consumption of 7a. The amino
Scheme 3. Reaction of phenylalaninol 1,2-cyclic sulfamidate 7a with triethylorthopropiolate 12.

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229
10221
Table 1
Reactions of lithium triethylorthopropiolate 12 with various 1,2-cyclic sulfamidates 7aeg
Entry
1
1,2-Cylic sulfamidates
Substitution products 14 (yield)a
Lactams 16 (yield)a
2
3
4
dsee text
d
d
5
6
dcomplex mixture
7
d
a
Yield of isolated product after chromatographic purification.
Reactions performed at ꢀ78 ꢁC (see text).
b
c
Reaction run in THF with the addition of 10% HMPA by volume.
cinnamylamine 17 as the major product by TLC analysis. During
chromatographic purification, significant decomposition of 17 was
observed causing to the isolation of 17 in a much reduced yield
35%.24 Efforts to achieve any observable degree of substitution by
running the reaction ꢀ78 ꢁC with or without HMPA did not produce
any success. These results suggest that sulfamidate 7g is not suit-
able for the present cyclization strategy.
literature value (½a D30
ꢂ
ꢀ89 (c 0.96, EtOH))27 indicate clean inversion
of the stereochemistry during the alkylation of 7f with 12.
Utilizing the high reactivity of the stereoelectronically suitable
1,2-cyclic sulfamidates toward lithium triethylorthopropiolate,
this novel and equally efficient [3þ3] cyclization strategy enables
the transformation of
a-aminoacids into the corresponding pi-
peridine lactams in a concise manner, and in this sense is com-
parable favorably with the existing strategy.28 It is also
appropriate to note here that the present [3þ3] annulation ap-
proach for the synthesis of the piperidine skeleton complements
to the [4þ2] cyclization strategy developed by Gallagher,12 which
relies upon the reactivity of 1,3-cyclic sulfamidates toward
stabilized-enolates. More readily availability of the precursor
vicinal aminoalcohols in optically pure form coupled with sig-
nificantly higher reactivity of the corresponding 1,2-cyclic sulfa-
midates could largely contribute to the wider synthetic
application of the [3þ3] cyclization strategy for the asymmetric
synthesis of substituted 2-piperidones.
The critical issue of the alkylation with 1,2-cyclic sulfamidates
described in this study that requires clarification is the SN2 nature
of the displacement with 7f. Attempts to derivatize N-benzyl-
amino-
d-
a,
b
-unsaturated ethylester 14f with (þ)-MTPA into the
corresponding Mosher amide was unsuccessful due to de-
composition.25 Instead lactam 16f was converted to the piperidine
hydrochloride salt 18, which was derivatized into the correspond-
ing Mosher amide 19 (Scheme 4). Observation of a pair of two
rotamers (approximately 2:1 ratio) of 19 by analysis of the 1H NMR
spectroscopic data26 and the specific rotation (½a 2D3
ꢀ82.5 (c 1,
ꢂ
CHCl3)) of the known lactam 16f in close agreement with the

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A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229
Scheme 4. Conversion of lactam 16f into Mosher amide derivative 19.
2.3. Asymmetric synthesis of (S)-coniine from
L
-norvaline
2.4. Substitution studies with 1,3-cyclic sulfamidate 31
We wished to demonstrate the effective implementation of the
1,2-cyclic sulfamidate mediated annulation strategy on a synthesis
of biologically active molecules containing an alkyl substituted pi-
peridine unit. The piperidine alkaloid (S)-coniine 27 [(S)-2-
propylpiperidine] was targeted. There are many routes available
for the synthesis of (S)-coniine as this simple alkaloid has fre-
quently provided a sound platform to rigorously test a new asym-
metric methodology.29 Our approach for the synthesis of (S)-
We were also interested in the reactivity of 1,3-cyclic sulfami-
dates in the alkylation reaction with 12. Methyl substituted 31 as
the only studied 1,3-cyclic sulfamidate was prepared from N-ben-
zyl-1,3-aminoalcohol 30, available from ethyl crotonate 29
(Scheme 6).11c Using the standard two-step sulfamidate formation
protocol, conversion of aminoalcohol 30 into 31 was low yielding
(less than 30%). Close monitoring of the reactions showed that the
formation of the intermediate cyclic sulfamidite was efficient. It is
the oxidation step of the sulfamidite to the sulfamidate responsible
for the observation of the low yield; extensive decomposition was
believed to take place during oxidation. Changing the oxidation
conditions to the biphasic solvent system (CHCl3/MeCN/H2O),
routinely used for the synthesis of cyclic sulfates as a closely related
class of electrophiles, significantly improved the yield of the oxi-
dation step to 73%. It appears that performing oxidation using the
biphasic solvent system could be milder conditions for sensitive
substrates.
Cyclic sulfamidate 31 exhibited considerably lower reactivity
toward 12 as compared with alanine-derived 7b (Scheme 6).
Without HMPA sulfamidate 31 failed to react with 12 even over
a longer reaction time (48 h). The use of HMPA led to an useful level
of reactivity, and the corresponding reaction of 31 with 12 gener-
ated N-sulfate intermediate 32. Acid-prompted hydrolysis of 32
was anticipated to cleave the N-sulfate along with concurrent hy-
drolysis of the orthoester to the ethylester 33. After neutralization
of the reaction mixture, chromatographic purification afforded
alkylidine pyrrolidine compound 34 in 80% yield. Facile formation
of 34 during the work-up conditions could be rationalized on the
conjugate addition of the amino group onto the activated triple
coniine 27 from
a regioselective ring-opening of norvalinol 1,2-cyclic sulfamidate
23 with 12 and thermal cyclization of -amino- -unsaturated
L
-norvaline 20 is shown in Scheme 5 and involves
d
a,b
ester 25 after saturation and debenzylation to form the piperidine
nucleus. Using the similar reagents and conditions for the synthesis
of 1,2-cyclic sulfamidates, -norvaline 20 was converted into the
L
benzamide derivative 21, which was reduced to the precursor
norvalinol 22. Preparation of the sulfamidate 23 was highly effi-
cient using the two-step cyclization procedure. Nucleophilic
cleavage of 23 with 12 proceeded smoothly to form the in-
termediate 24, which was hydrolyzed to d-amino-a,b-unsaturated
ester 25 in a high yield. Palladium catalyzed hydrogenation and
subsequent thermal cyclization afforded 6-n-propylpiperidin-2-
one 26 in 86% yield. Reduction of the carbonyl group with LiAlH4
readily generated (S)-coniine 27. Because of the volatility and tox-
icity, as well as for ease of comparison, (S)-coniine 27 was con-
verted to the known N-Boc coniine 28 (½a D30
þ32.6 (c 1, CHCl3))
ꢂ
whose specific rotation is in a close agreement with the literature
value (½a 2D0
ꢂ
þ33.5 (c 1, CHCl3)).29k Efficiency of the [3þ3] cyclization
strategy has been illustrated by a formal asymmetric synthesis of
(S)-coniine from -norvaline 20 in 46% overall yield.
L
Scheme 5. Asymmetric synthesis of (S)-coniine 27.

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229
10223
Scheme 6. Synthesis and reactivity of 1,3-cyclic sulfamidate 31 toward acetylide 12.
bond to form spontaneously the energetically favorable five-
membered pyrrolidine ring system. The stereochemistry of 34 was
determined by NOE NMR correlation between the benzylic and the
alkene protons, which is consistent with literature observations.12d
prolinol sulfamidate 7d are available in the literature.11c,i Synthesis
of the lactate derived sulfamidate 7f is presented separately.
4.2.1. General procedure for synthesis of ethyl 2-benzamidoalka-
noates. To a stirred suspension and/or solution of a L-amino acid
(100 mmol) in anhydrous ethanol (150 mL) cooled in an ice bath
was added dropwise thionyl chloride (190 mmol). The reaction
mixture was then refluxed for 4 h. On heating the solid hydro-
chloride salt gradually became solubilized to produce a clear so-
lution. After cooling, volatiles were removed in vacuo to give the
corresponding solid ethylester hydrochloride salt. This salt was
used in the benzoylation step directly without further purification.
To a stirred solution of the hydrochloride salt and triethylamine
(230 mmol) in DCM (250 mL) cooled in an ice-bath was added
dropwise a solution of benzoylchloride (112 mmol) in DCM (50 mL).
After stirring for 4 h, water (300 mL) was added to the resulting
mixture. The separated organic phase was sequentially washed
with 2 M HCl (200 mL), saturated NaHCO3 solution (200 mL), then
brine (200 mL), dried (Na2SO4) and concentrated under reduced
pressure. Purification of the crude product by recrystallization from
DCMehexane afforded the colorless benzamide derivative crystals.
3. Conclusions
In conclusion, we have developed an efficient [3þ3] cyclization
strategy for asymmetric synthesis of alkyl substituted piperidin-2-
ones using readily available 1,2-cyclic sulfamidates. Efficiency of
this novel cyclization process has been illustrated by a formal
asymmetric synthesis of (S)-coniine from L-norvaline. Extension of
this chemistry to more complicated 1,2-cyclic sulfamidates, and
application to synthesis of N-heterocycles containing alkyl
substituted piperidine units are currently underway and will be
reported elsewhere.
4. Experimental
4.1. General
Melting points were determined on an Electrothermal 9200
apparatus and are uncorrected. IR spectra were recorded on a Per-
kineElmer Spectrum BX spectrometer as thin films on NaCl plates
or Nujol. 1H and 13C NMR spectra were recorded in CDCl3 on
a Varian AS 400 MHz NMR spectrometer with TMS as an internal
standard (Ege University, Izmir, Turkey). Chemical shifts are
4.2.1.1. (S)-Ethyl 2-benzamido-3-phenylpropanoate 5a.
expressed in
d (parts per million) units downfield from TMS. Cou-
pling constants (J) are quoted to the nearest 0.5 Hz. Mass Spectra
and Elemental analysis were taken from TUBITAK Marmara Re-
search Centre (MAM), Gebze, Istanbul, Turkey and University of
Toulouse, France. Optical rotations were measured with Rudolph
Research Analytical Autopol I Automatic Polarimeter. THF and ether
were freshly distilled from LiAlH4 before use. TLC was performed
using aluminum plates coated with silica gel (254 nm) and use of
the basic permanganate dying system. Flash column chromatog-
raphy was carried out using silica gel (0.063e0.2 mm). Removal of
solvents in vacuo was achieved using a IKA rotary evaporator at
room temperature unless otherwise stated. Yields refer to isolated
material, homogeneous by TLC and NMR spectroscopy, unless
otherwise stated.
Mp 102e103 ꢁC (DCM/hexane), lit.11c 102 ꢁC (DCM/petrol ether);
½
a 3D0
ꢂ
þ98.5 (c 1.06, CHCl3), lit.31
½
a 3D0
ꢂ
þ108.6 (c 0.76, CHCl3); TLC, Rf
0.56 [(EtOAc/hexane) 1:2]; IR (Nujol): 3366 (NH), 1748 (C]O, es-
ter), 1641 (C]O, amide); 1H NMR (400 MHz, CDCl3)
d 1.27 (3H, t,
J¼7.0), 3.23 (1H, dd, J¼5.5 and 13.5), 3.29 (1H, dd, J¼5.5 and 13.5),
4.21 (2H, q, J¼7.0), 5.07 (1H, dt, J¼5.5 and 7.5), 6.65 (1H, d, br, J¼7.0),
7.15e7.17 (2H, m, AreH), 7.22e7.31 (3H, m, AreH), 7.39e7.43 (2H,
m, AreH), 7.47e7.51 (1H, m, AreH), 7.71e7.74 (2H, m, AreH).
4.2.1.2. (S)-Ethyl 2-benzamidopropanoate 5b.
4.2. Synthesis of 1,2-cyclic sulfamidates 7aeg
1,2-Cyclic sulfamidates 7aeg were prepared according to the
literature protocols. Synthetic procedures for cyclic sulfamidates
7aec are given below as general procedures. Synthesis of ephed-
rine sulfamidate 7e, elimination sensitive sulfamidate 7g and

10224
A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229
substrate involved. Close monitoring of the reaction mixture was
Mp 98e99 ꢁC (DCM/hexane), lit.32a 95 ꢁC (Ether/petrol ether);
necessary in order to perform efficient oxidation without de-
composition. The reaction mixture was diluted with ether
(500 mL) and phases were separated. The aqueous phase was
extracted with ether (2ꢃ500 mL). Combined organic phases
were washed with NaHCO3 solution (300 mL), then brine
(300 mL), dried (MgSO4) concentrated in vacuo to give the crude
sulfamidate product. Colored ruthenium impurities were re-
moved by passing through a small pad of silica gel. Solid sulfa-
midates were further purified by recrystallization from DCM/
hexane to give colorless crystals 7a,b. Valine derived sulfamidate
7c is a pale yellow viscous oil, which is solidified on storage in
the fridge.
½
a 3D0
ꢂ
þ37.5 (c 1, CHCl3), lit.32b
½
a 1D9
ꢂ
þ33.4 (c 1, CHCl3); TLC, Rf 0.42
[(EtOAc/hexane) 1:2]; IR (Nujol): 3344 (NH), 1742 (C]O, ester),
1641 (C]O, amide); 1H NMR (400 MHz, CDCl3)
1.50 (3H, d, J¼7.0), 4.22 (2H, q, J¼7.0), 4.76 (1H, quintet, J¼7.0), 6.86
(1H, d, br, J¼6), 7.38e7.42 (2H, m, AreH), 7.45e7.49 (1H, m, AreH),
7.78e7.80 (2H, m, AreH).
d
1.28 (3H, t, J¼7.0),
4.2.1.3. (S)-Ethyl 2-benzamido-3-methylbutanoate 5c.
4.2.2.1.1. (S)-3,4-Dibenzyl-1,2,3-oxathiazolidine 2,2-dioxide 7a.
Mp 76e78 ꢁC (DCM/hexane), lit.33 77.5e78 ꢁC; ½a 3D0
þ40.2 (c 1,
ꢂ
CHCl3); TLC, Rf 0.59 [(EtOAc/hexane) 1:2]; IR (Nujol): 3333 (NH),
1731 (C]O, ester), 1639 (C]O, amide); 1H NMR (400 MHz, CDCl3)
d
0.98 (3H, d, J¼7.0), 1.00 (3H, d, J¼7.0), 1.29 (3H, td, J¼0.5 and 7.0),
Mp 65e66 ꢁC (DCM/hexane), lit.11c 64 ꢁC (DCM/petrol ether);
2.23e2.31 (1H, m), 4.16e4.29 (2H, m), 4.76 (1H, dd, J¼5.0 and 9.0),
6.67 (1H, d, br, J¼8), 7.40e7.51 (3H, m, AreH), 7.78e7.81 (2H, m
AreH).
½
a 3D0
ꢂ
ꢀ36.5 (c 1, CHCl3), lit.11c
½
a 2D0
ꢂ
ꢀ34 (c 0.76, CHCl3); TLC, Rf 0.33
[(EtOAc/hexane) 1:4]; IR (Nujol): 1376 and 1174 (SO2); 1H NMR
(400 MHz, CDCl3)
d
2.72 (1H, dd, J¼9.5 and 13.5), 3.00 (1H,dd, J¼5.0
4.2.2. General procedure for synthesis of 1,2-cyclic sulfamidates 7aec
and 13.5), 3.71e3.78 (1H, m), 4.21 (1H, dd, J¼5.0 and 8.5),
4.2.2.1. General procedure for the reduction of benzamide de-
rivatives 5aec and synthesis of 1,2-cyclic sulfamidates 7aec. To
a stirred suspension of LiAlH4 (321 mmol) in dry THF (500 mL)
cooled in an ice-bath was added dropwise a solution of the 2-
benzamidoalkanoate (178 mmol) in dry THF (100 mL). The
resulting mixture was then refluxed for 4 h. After cooling in an
ice-bath, excess LiAlH4 was quenched with sequential addition
of water (30 mL), 10% NaOH solution (30 mL), and water
(20 mL). The reaction mixture was stirred at room temperature
for 2 h for hydrolysis and the aluminum residues were removed
by filtration. It was observed that the crude aminoalcohol
product stuck to the aluminum residues on large scale prepa-
rations, and several washings with ether were not sufficient to
take all aminoalcohols into solutions. Therefore washings were
repeated until TLC showed no further aminoalcohols remained
in the residues. Combined organics were dried (Na2SO4) and
concentrated in vacuo to give the crude product. Aminoalcohols
6a,b were obtained as pale yellow solids, while 6c as a pale
yellow viscous oil. These crude aminoalcohols were used in the
4.28e4.34 (3H, m), 7.01 (2H, d, J¼7.0, AreH), 7.23e7.37 (8H, m,
AreH); 13C NMR (100 MHz, CDCl3)
d 38.66, 51.00, 60.28, 70.65,
127.58, 128.69, 129.09 (overlapping two peaks), 129.20, 129.29,
134.84, 135.45.
4.2.2.1.2. (S)-3-Benzyl-4-methyl-1,2,3-oxathiazolidine 2,2-dioxide
7b.
Mp 67e68 ꢁC (DCM/hexane), lit.10a 64.5e66 ꢁC (DCM/heptane);
½
a 3D0
ꢂ
þ21.7 (c 1, CHCl3), lit.10a
½
a 3D0
ꢂ
þ25 (c 0.8, MeOH); TLC, Rf: 0.39
[(EtOAc/hexane) 1:2]; IR (Nujol): 1334 and 1186 (SO2); 1H NMR
(400 MHz, CDCl3)
d
1.19 (3H, d, J¼6.5), 3.69e3.77 (1H, m), 4.10 (1H,
dd, J¼7.0 and 8.5), 4.20 (1H, d, J¼15.0), 4.38 (1H, d, J¼15.0), 4.55
(1H, dd, J¼6.5 and J¼8.5), 7.29e7.42 (5H, m, Ar-H): 13C NMR
(100 MHz, CDCl3)
135.08.
d 17.43, 49.84, 55.52, 72.51, 128.48, 128.80, 128.95,
next
step
directly
without
further
purification
or
characterization.
4.2.2.1.3. (S)-3-Benzyl-4-isopropyl-1,2,3-oxathiazolidine 2,2-di-
To a stirred solution of the aminoalcohol (87.8 mmol), imidazole
(370 mmol), and triethylamine (200 mmol) in DCM (750 mL)
cooled in an ice-bath was added dropwise a solution of thionyl
chloride (99 mmol) in DCM (50 mL). The resulting mixture was
stirred until TLC indicated complete conversion of the amino-
alcohol into the intermediate sulfamidite and then quenched by the
addition of water (400 mL). The aqueous phase was separated and
extracted with DCM (2ꢃ250 mL). Combined organics were washed
with water (200 mL) and then brine (200 mL), dried (Na2SO4) and
concentrated in vacuo to give the crude product. Colored basic
impurities were removed by passing through a small pad of silica
gel. The intermediate sulfamidites were used directly in the oxi-
dation step.
oxide 7c.13c
Pale yellow viscous oil; ½a D30
ꢀ35.4 (c 1, CHCl3); TLC, Rf 0.33
ꢂ
[(EtOAc/hexane) 1:4]; IR (film): 1348 and 1186 (SO2); 1H NMR
(400 MHz, CDCl3)
d
0.85 (3H, d, J¼7.0), 0.89 (3H, d, J¼7.0), 1.83e1.93
To a stirred cooled (0 ꢁC) solution of the intermediate sulfa-
midite (47.8 mmol) in MeCN (400 mL) was added RuCl3 (70 mg),
followed by NaIO4 (72.76 mmol) and then water (300 mL). The
reaction mixture was stirred for 15 min to 5 h depending on the
(1H, m), 3.43 (1H, dt, J¼5.5 and 7.0), 4.22e4.28 (2H, m), 4.39e4.44
(2H, m), 7.30e7.42 (5H, m, AreH); 13C NMR (100 MHz, CDCl3)
d
16.11, 18.35, 29.77, 52.26, 64.74, 67.30, 128.53, 128.94, 129.10,
135.10.

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229
10225
4.2.2.2. Synthesis of 1,2-cyclic sulfamidate 7f.
4.2.2.2.1. (S)-N-Benzyl-2-hydroxypropanamide 9.
(benzylamino)-alky-2-ynoate 14aef as a pale yellow oil. The un-
saturated amino esters 14aef were found to be prone to de-
composition during column chromatography and/or storage.
Amino ester 14b and lactate-derived 14f were particularly sensi-
tive to decomposition; analytical pure samples of 14b and 14f
could not be obtained. Thus analytical and spectroscopic data of
14aef should be treated with caution. The unsaturated amino es-
ters 14aef were swiftly subjected to hydrogenation conditions to
transform them into stable lactam derivatives 16aef.
Also, using the same stoichiometry as above, the reaction
was carried out in freshly distilled THF (20 mL) containing HMPA
(1 mL) cooled at ꢀ10 ꢁC (ice-salt bath) or at ꢀ78 ꢁC (dry ice-acetone
bath).
A mixture of (S)-ethyl lactate (20.9 g, 177 mmol) and benzyl-
amine (59.5 g, 556 mmol) was refluxed overnight. The reaction
mixture was dissolved in DCM (250 mL), washed with 5 M HCl until
TLC showed that all benzylamine was removed, then brine
(200 mL), dried (Na2SO4) and concentrated in vacuo. Purification of
the crude product by flash column chromatography eluting
((EtOAc/hexane) 1:1 to 1:0 gradient) afforded the title compound as
4.3.1.1.1. (S)-Ethyl 5-(benzylamino)-6-phenylhex-2-ynoate 14a.
a pale yellow oil (23.50 g, 74%); ½a D30
ꢂ
ꢀ6.5 (c 1, CHCl3), lit.34
½ ꢂ
a 3D0
ꢀ6.8 (c 6.9, CHCl3); TLC, Rf 0.58 [EtOAc]; 1H NMR (400 MHz, CDCl3)
d
1.42 (3H, d, J¼7), 3.47 (1H, s, br), 4.24 (1H, q, J¼7), 4.42 (2H, d,
J¼6), 7.01 (1H, s, br), 7.23e7.34 (5H, m, AreH).
4.2.2.2.2. (S)-3-Benzyl-5-methyl-1,2,3-oxathiazolidine 2,2-
dioxide 7f.
½
a 3D1
(film): 3481, 3338 (NH), 2337 (C^C), 1706 (C]O ester); 1H NMR
(400 MHz, CDCl3)
1.32 (3H, t, J¼7.0), 2.40e2.51 (2H, m), 2.83
ꢂ
ꢀ6.4 (c 1.95, CHCl3); TLC, Rf 0.53 [(EtOAc/hexane) 1:3]; IR
d
(1H, dd, J¼7.0 and 13.5), 2.88 (1H, dd, J¼7.0 and 13.5), 3.02e3.08
(1H, m), 3.77 (1H, d, J¼13.5), 3.86 (1H, d, J¼13.5), 4.23 (2H, q,
J¼7.0), 7.16e7.31 (10H, m, AreH); 13C NMR (100 MHz, CDCl3)
14.27, 23.73, 40.61, 51.27, 56.74, 62.07, 75.52, 85.59, 126.76,
127.24, 128.22, 128.64, 128.77, 129.53, 138.41, 140.08, 153.84; MS
(ESI-ToF) m/z: [MþH]þ found 322.1809, C21H24NO2 requires
322.1807.
Using the general reduction procedure with LiAlH4, benzyla-
mide 9 (14.93 g, 83 mmol) was reduced to the aminoalcohol 10
(10.46 g, 76%) as a pale yellow viscous oil. The crude aminoalcohol
was used in the next step directly.
4.3.1.1.2. (S)-Ethyl 5-(benzylamino)hex-2-ynoate 14b.
Using the general sulfamidate formation procedure, the ami-
noalcohol 10 (14.95 g, 90.47 mmol) was converted into the lactate
derived sulfamidate 7f (14.6 g, 71%) as a pale yellow oil (It is worth
mentioning that duration of the oxidation step was kept short
(5e10 min) in order to avoid decomposition). ½a D20
ꢀ15.2 (c 1,
ꢂ
CHCl3); TLC, Rf 0.44 [(EtOAc/hexane) 1:3]; IR (film): 1605, 1344 and
1185 (SO2); 1H NMR (400 MHz, CDCl3)
d
1.50 (3H, d, J¼6.4), 3.04
½
a 3D1
IR (film): 3394, 3327(NH), 2235 (C^C), 1709 (C]O ester); 1H
NMR (400 MHz, CDCl3)
and 7.0), 2.47 (1H, d, J¼3.0), 2.48 (1H, d, J¼3.0), 2.94e3.01 (1H,
m), 3.80 (2H, s), 4.21 (2H, q, J¼7.0), 7.20e7.33 (5H, m, AreH);
13C NMR (100 MHz, CDCl3) 14.26, 20.69, 26.53, 51.07, 51.29,
62.06, 75.10, 85.76, 127.29, 128.28, 128.68, 140.28, 153.86; MS
(ESI-ToF) m/z: [MþNa]þ found 268.1325, C15H19NNaO2 requires
268.1313.
ꢂ
ꢀ14.8 (c 1.65, CHCl3); TLC, Rf 0.6 [(EtOAc/hexane) 1:3];
(1H, dd, J¼8.0 and 9.5), 3.42 (1H, dd, J¼6.0 and 9.5), 4.11 (1H, d,
J¼14), 4.32 (1H, d, J¼14), 4.83e4.92 (1H, m), 7.31e7.40 (5H, m, Ar-
H); 13C NMR (100 MHz, CDCl3)
d 19.56, 51.47, 53.98, 77.51, 128.67,
d
1.21 (3H, d, J¼6.5), 1.30 (3H, td, J¼1.0
128.85, 129.10, 134.70; MS (MALDI-ToF) m/z: [MþNa]þ found
250.0537, C10H13NNaO3S requires 250.0514.
4.3. Synthesis of alkyl substituted piperidin-2-ones
4.3.1. Synthesis of (S)-ethyl 5-(benzylamino)-alky-2-ynoates
4.3.1.1. General procedure for ring-opening reactions of 1,2-cyclic
sulfamidates 7aeh with lithium triethylorthopropiolate. To a stirred
solution of triethylorthopropiolate (1.35 g, 7.85 mmol, 2 equiv) in
freshly distilled THF (20 mL) cooled to ꢀ10 ꢁC (salt-ice bath) under
argon atmosphere was added n-butyllithium (5.2 mL, 8.3 mmol,
15% solution in hexane), and the solution was stirred at this tem-
perature for 1 h. A solution of a cyclic sulfamidate (1.2 g,
3.93 mmol) in dry THF (2e3 mL) was then added to the acetylide
solution via a syringe. After stirring at ꢀ10 ꢁC for 5e6 h, the
resulting mixture was allowed to warm up to room temperature
gradually with stirring for 24 h. The reaction mixture was then
treated with 4 mL 5 M HCl solution to hydrolyze the N-sulfate
4.3.1.1.3. (R)-Ethyl 5-(benzylamino)-6-methylhept-2-ynoate 14c.
½
a 3D1
(film): 3400 (NH), 2235 (C^C), 1711 (C]O ester); 1H NMR
(400 MHz, CDCl3)
ꢂ
ꢀ38.4 (c 0.98, CHCl3); TLC, Rf 0.67 [(EtOAc/hexane) 1:3]; IR
d
0.93 (3H, d, J¼7.0), 0.95 (3H, d, J¼7.0),1.31 (3H, t,
intermediate for 2-3
h
before neutralization with saturated
J¼7.0), 1.85e1.94 (1H, m), 2.43e2.26 (3H, m), 3.75 (1H, d, J¼13.0),
3.89 (1H, d, J¼13.0), 4.22 (2H, q, J¼7.0), 7.22e7.37 (5H, m, AreH);
13C NMR (100 MHz, CDCl3) 14.27, 18.70, 19.04, 21.44, 31.10, 51.82,
60.95, 62.02, 74.81, 87.93, 127.18, 128.38, 128.57, 140.67, 153.91; MS
(ESI-ToF) m/z: [MþNa]þ found 296.1648, C17H23NNaO2 requires
296.1626.
NaHCO3 solution. Extraction with ether (2ꢃ100 mL) and drying
over anhydrous Na2SO4 followed by evaporation of volatiles in
vacuo gave the crude product. Purification by flash column chro-
matography eluting with the ((EtOAc/hexane) 1:8 to 1:3 gradient)
solvent system (containing 0.5% triethylamine) afforded ethyl 5-

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A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229
4.3.1.1.4. (S)-Ethyl 5-(benzylamino)-4-methylpent-2-ynoate 14f.
127.17, 129.05, 129.40, 137.06, 172.37. MS (ESI-ToF) m/z: [MþNa]þ
found 212.1092, C12H15NNaO requires 212.1051; Anal. Calcd for
C12H15NO: C, 76.16; H, 7.99; N, 7.40%. Found: C, 76.19; H, 8.03; N, 7.45.
4.3.2.1.2. (S)-6-Methylpiperidin-2-one 16b.
Using the general procedure, the reaction of lactate derived
sulfamidate 7f (2 g, 8.81 mmol) with 12 in dry THF (30 mL) con-
taining HMPA (1.5 mL) cooled at ꢀ10 ꢁC (salt-ice bath) under argon
atmosphere afforded (S)-ethyl5-(benzylamino)-4-methylpent-2-
ynoate (14f) (1610 mg, 74%) as a pale yellow oil. It is worth noting
that with inclusion of HMPA as a polar cosolvent, the reaction was
Mp 82e84 ꢁC (hexane), lit.29e 79e81 ꢁC; ½a 3D0
þ32.5 (c 1, CHCl3),
ꢂ
lit.29e
½
a 2D5
ꢂ
þ22.7 (c 0.3, CHCl3); TLC, Rf 0.3 [(DCM/acetone) 7:3]; IR
(Nujol); 3198 (NH), 1672 (C]O amide); 1H NMR (400 MHz, CDCl3)
1.20 (3H, dd, J¼1.0 and 6.5), 1.29e1.37 (1H, m), 1.64e1.75 (1H, m),
complete less than 2e3 h. ½a D31
ꢀ56.2 (c 1.0, CHCl3); TLC, Rf 0.26
ꢂ
d
[(EtOAc/hexane) 1:3]; IR (film): 3394, 3338 (NH), 2238 (C^C), 1708
1.85e1.92 (2H, m), 2.22e2.40 (2H, m) 3.47e3.55 (1H, m), 6.88 (1H,
(C]O ester); 1H NMR (400 MHz, CDCl3)
d
1.23 (3H, d, J¼7.0), 1.30
s, br); 13C NMR (100 MHz, CDCl3)
172.29.
d 20.03, 22.92, 30.62, 31.20, 48.90,
(3H, t, J¼7.0), 2.66e2.85 (3H, m), 3.82 (2H, d, J¼3.5), 4.21 (2H, q,
J¼7.0), 7.22e7.34 (5H, m, AreH); 13C NMR (100 MHz, CDCl3)
d 14.25,
4.3.2.1.3. (R)-6-Isopropylpiperidin-2-one 16c.
17.74, 27.03, 53.64, 53.83, 62.02, 74.29, 91.65, 127.21, 128.25, 128.62,
140.28, 153.93; MS (ESI-ToF) m/z: [MþNa]þ found 268.1324,
C15H19NNaO2 requires 268.1313.
4.3.1.1.5. N-Benzyl cinnamylamine17.11c
Using the general procedure, the reaction of the sulfamidate 7g
(1.0 g, 6.6 mmol) with 12 in dry THF (20 mL) cooled to ꢀ10 ꢁC (salt-
ice bath) under argon atmosphere for 48 h afforded N-benzyl cin-
namylamine 17 (258 mg, 35%) as a pale yellow oil. TLC, Rf 0.5 1H
Mp 79e80 ꢁC (hexane), lit.29e 75e77 ꢁC; ½a 3D0
þ62.3 (c 1, CHCl3),
ꢂ
lit.29e
½
a 3D0
ꢂ
þ68.9 (c 0.4, CHCl3); TLC, Rf 0.45 [(DCM/acetone) 7:3]; IR
(Nujol); 3232 (NH), 1667 (C]O amide); 1H NMR (400 MHz, CDCl3)
0.91e0.95 (6H, m), 1.32e1.43 (1H, m), 1.60e1.73 (2H, m),
d
NMR (400 MHz, CDCl3)
6.31 (1H, dt, J¼6.0 and 16), 6.54 (1H, d, J¼16), 7.19e7.38 (10H, m,
d
3.44 (2H, dd, J¼1.0 and 6.5), 3.84 (2H, s),
1.79e1.96 (2H, m), 2.18e2.29 (1H, m), 2.35e2.42 (1H, m), 3.16e3.21
(1H, m), 6.17 (1H, s, br); 13C NMR (100 MHz, CDCl3)
20.24, 24.95, 31.63, 33.00, 58.89, 173.00.
d 17.92, 18.25,
AreH).
4.3.2.1.4. (S)-5-Methylpiperidin-2-one 16f.
4.3.2. Synthesis of alky substituted piperidin-2ones 16aef
4.3.2.1. General procedure of cyclization of ethyl 5-(benzylamino)-
alky-2-ynoates. To a solution of the ethyl 5-(benzylamino)-alkyl-2-
ynoate (3.47 mmol) in THF (25 mL) was added Pd/C (140 mg) and
Pd(OH)/C (140 mg) at room temperature. The resulting solution was
flushed with argon several times and then hydrogenated for 24 h.
The reaction mixture was filtered through CeliteÒ in vacuo to give
the crude product. The resulting products mixture was dissolved in
toluene (15 mL) and then refluxed for 4e10 h. After cooling,
evaporation of the volatiles in vacuo gave the crude lactam. Puri-
fication by flash column chromatography eluting with the ((DCM/
acetone) 7:3) solvent system afforded the alkyl substituted lactam
as a viscous oil. Analytical pure samples were obtained by re-
crystallization from hexane.
Mp 69e70 ꢁC (hexane); ½a 2D3
ꢂ
ꢀ82.5 (c 1, CHCl3), lit.27
½ ꢂ
a 3D0
ꢀ89 (c 0.96, EtOH); TLC, Rf 0.45 [(DCM/acetone) 7:3]; IR (Nujol);
3232 (NH), 1667 (C]O amide); 1H NMR (400 MHz, CDCl3)
d 1.01
(3H, d, J¼6.5), 1.42e1.52 (1H, m), 1.87e1.96 (2H, m), 2.28e2.44
(2H, m), 2.91 (1H, t, J¼11.0), 3.32e3.27 (1H, m), 7.18 (1H, s, br);
4.3.2.1.1. (R)-6-Benzylpiperidin-2-one 16a.35
13C NMR (100 MHz, CDCl3)
172.82.
d 18.52, 28.32, 29.20, 30.88, 49.15,
4.3.2.1.5. Mosher amide derivative (19): (R)-3,3,3-trifluoro-2-
methoxy-1-((S)-3-methylpiperidin-1-yl)-2-phenylpropan-1-one.26
Mp 141e142 ꢁC (hexane); ½a 3D0
ꢀ55.3 (c 1, CHCl3); TLC, Rf 0.6
ꢂ
[(DCM/acetone) 7:3]; IR (Nujol); 3182 (NH), 1658 (C]O amide); 1H
NMR (400 MHz, CDCl3)
d 1.41e1.51 (1H, m), 1.64e1.76 (1H, m),
1.88e2.00 (2H, m), 2.26e2.43 (2H, m), 2.62 (1H, dd, J¼9.0 and 13.5),
2.87 (1H, dd, J¼5.0 and 13.0), 3.61 (1H, septet, J¼5.0), 5.65 (1H, s, br),
7.16e7.18 (2H, m, ArH), 7.23e7.27 (1H, m, ArH), 7.30e7.34 (2H, m,
To a stirred suspension of LiAlH4 (250 mg, 6.59 mmol) in
dry ether (20 mL) cooled in an ice-bath was added dropwise
a solution of the lactam 16f (340 mg, 3.01 mmol) in dry ether
ArH); 13C NMR (100 MHz, CDCl3)
d 19.97, 28.89, 31.64, 43.57, 54.51,

A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229
10227
(2e3 mL). The reaction mixture was then refluxed for 3e4 h.
4.4.2. (S)-3-Benzyl-4-propyl-1,2,3-oxathiazolidine 2,2-dioxide 23.
After cooling in an ice-bath, excess LiAlH4 was quenched with
sequential addition of water (0.5 mL), 10% NaOH solution
(0.5 mL). The reaction mixture was stirred at room temperature
for 2 h for hydrolysis and the aluminum residues were re-
moved by filtration. The filtrate was dried over anhydrous
Na2SO4, then anhydrous HCl solution (3e5 mL) in ether was
added. Evaporation of volatiles in vacuo gave the solid hydro-
chloride salt. The crude salt was recrystallization from ether
(280 mg, 69%).
To a stirred solution of (þ)-MTPA (83 mg, 0.35 mmol) and
DMF (26 mg, 0.35 mmol) in hexane (15 mL) was added dropwise
oxalyl chloride (0.15 mL, 1.68 mmol). The reaction mixture was
stirred at room temperature for 1 h, and then filtered. Evapora-
tion of volatiles in vacuo gave the corresponding MTPA-Cl. To
a stirred solution of the hydrochloride salt (40 mg, 0.29 mmol)
and DMAP (90 mg, 0.74 mmol) in DCM (3 mL) cooled in an ice-
bath was added a solution of the prepared MTPA-Cl solution in
DCM (1 mL). The resulting mixture was stirred at room temper-
ature overnight and then sequentially washed with 2 M HCl
(5 mL), saturated NaHCO3 solution (5 mL), then brine (5 mL), and
dried (Na2SO4). Evaporation of volatiles in vacuo and purification
by flash column chromatography eluting with the ((EtOAc/hex-
ane) 1:10 to 1:6 gradient) solvent system afforded Mosher lactam
19 (48 mg, 55%) as a clear oil and a pair of rotamers (approxi-
mately 2:1). TLC, Rf 0.71 [(EtOAc/hexane) 1:4]; 1H NMR (400 MHz,
Using the general procedure, benzamide derivative 21
(9 g, 36.15 mmol) was reduced to the aminoalcohol 22 (6.2 g,
88%). The aminoalcohol (6.2 g, 32.1 mmol) was then con-
verted into cyclic sulfamidate 23 (7.9 g, 90%) as a pale yellow
viscous oil. ½a 3D0
þ18.0 (c 1, CHCl3); TLC, Rf 0.60 [(EtOAc/
ꢂ
hexane) 1:2]; IR (film); 1342 and 1186 (SO2); 1H NMR
(400 MHz, CDCl3)
d
0.82 (3H, t, J¼7.0), 1.15e1.30 (2H, m),
1.42e1.51 (1H, m), 1.58e1.66 (1H, m), 3.57e3.64 (1H, m),
4.16e4.22 (2H, m, unresolved signals due to overlapping with
signals at 4.20 ppm), 4.41 (1H, d, J¼15.0), 4.52 (1H, dd, J¼7.0
and 9.0), 7.29e7.42 (5H, m AreH); 13C NMR (100 MHz, CDCl3)
d
13.95, 17.87, 34.08, 50.94, 59.52, 70.99, 128.48, 128.88,
128.93, 135.17; MS (ESI-ToF) m/z: [MþNa]þ found 278.0811,
C12H17NNaO3S requires 278.0827.
4.4.3. (S)-Ethyl 5-(benzylamino)oct-2-ynoate 25.
CDCl3)
d
0.31e0.42 (1H, m, major), 0.65 (3H, d, J¼7.0, minor), 0.89
(3H, d, J¼7.0, major), 0.92e1.08 (H, series of multiplet), 1.34e1.61
(H, series of multiplet), 1.71e1.85 (H, series of multiplet), 2.25
(1H, dd, J¼11.0 and 12.5, major), 2.54 (1H, td, J¼3.0 and 13.0,
minor), 2.74 (1H, ddd, J¼3.0, 12.5 and 13.5, major), 3.67 (3H, q,
J¼1.5, major), 3.73 (3H, q, J¼1.5, minor), 3.69e3.74 (H, m, signals
overlapping with peaks at 3.73 ppm), 3.87 (1H, m, major), 4.54
(1H, m, major), 4.60 (1H, m, minor), 7.35e7.39 (H, m, AreH),
7.45e7.49 (H, m, AreH), 7.54e7.56 (H, m, AreH); 13C NMR
Using the general procedure, the reaction of norvalinol sulfa-
midate 23 (700 mg, 2.74 mmol) with 12 afforded (S)-ethyl 5-
(benzylamino)oct-2-ynoate 25 (660 mg, 92%) as a pale yellow oil.
(100 MHz, CDCl3)
d 18.98, 19.26, 23.96, 25.35, 27.15, 31.14, 31.69,
½
a 3D1
ꢂ
ꢀ25.5 (c 1.95, CHCl3); TLC, Rf 0.7 [(EtOAc/hexane) 1:3]; IR
(film): 3394e3338 (NH), 2235 (C^C), 1711 (C]O ester); 1H NMR
(400 MHz, CDCl3)
32.95, 33.11, 43.17, 45.42, 50.04, 52.92, 55.60, 55.63, 56.28, 84.92,
85.16, 126.74, 126.92, 128.34, 128.48, 129.29, 129.32, 134.48,
163.89, 164.13.
d
0.91 (3H, t, J¼7.0), 1.31 (3H, t, J¼7.0),
1.26e1.55 (4H, m), 2.47 (1H, dd, J¼5.0 and 17.0), 2.56 (1H, dd, J¼6
and 17.0), 2.79e2.85 (1H, m), 3.75 (1H, d, J¼13.0), 3.81 (1H, d,
J¼13.0), 4.22 (2H, q, J¼7.0), 7.22e7.36 (5H, m, Ar-H); 13C NMR
4.4. Asymmetric synthesis of (S)-coniine from
4.4.1. (S)-Ethyl 2-benzamidopentanoate 21.
L-norvaline
(100 MHz, CDCl3)
d 14.27, 14.29, 19.32, 24.15, 36.76, 51.16, 55.08,
62.04, 75.07, 85.97, 127.22, 128.33, 128.54, 140.48, 153.83. MS (ESI-
ToF) m/z: [MþNa]þ found 296.1683, C17H23NNaO2 requires
296.1626.
4.4.4. (S)-6-Propylpiperidin-2-one 26.
Using the general procedure, L-norvaline (5 g, 42.7 mmol) was
converted into (S)-ethyl 2-benzamidopentanoate 21 (9.4 g, 88%)
as colorless crystals. Mp 60e61 ꢁC (DCM/hexane), lit.36 58e59 ꢁC;
½
a 3D0
ꢂ
þ35.7 (c 1, CHCl3), lit.36
½
a 3D0
ꢂ
þ15.9 (c 0.0014, EtOH, for R-
21); TLC, Rf 0.46 [(EtOAc/hexane) 1:2]; IR (Nujol); 3310 (NH), 1753
Using the general procedure, (S)-ethyl 5-(benzylamino)oct-2-
ynoate 25 (660 mg) was converted into the lactam 26 (260 mg,
87%) as light pale yellow crystals. Mp 57e60 ꢁC (Hexane), lit.29e
(C]O, ester), 1641 (C]O, amide); 1H NMR (400 MHz, CDCl3)
d
0.96 (3H, t, J¼7.5), 1.31 (3H, t, J¼7.0), 1.34e1.5 (2H, m), 1.70e1.80
(1H, m), 1.88e1.97 (1H, m), 4.22 (2H, q, J¼7.0), 4.75e4.80 (1H, m),
6.70 (1H, d, br, J¼7.0), 7.38e7.42 (2H, m, AreH), 7.45e7.49 (1H, m,
AreH), 7.77e7.79 (2H, m, AreH); 13C NMR (100 MHz, CDCl3)
58e60 ꢁC; ½a 3D0
ꢂ
þ23.8 (c 1, CHCl3), lit.29e
½
a 2D5
ꢂ
þ18.1 (c 0.6,
CHCl3), TLC, Rf 0.45 [(DCM/acetone) 7:3]; IR (Nujol); 3210 (NH),
1667 (C]O, amide); 1H NMR (400 MHz, CDCl3)
d 0.90 (3H, t,
d
13.95, 14.40, 18.83, 35.03, 52.69, 61.66, 127.25, 128.76, 131.84,
J¼7.0), 1.26e1.47 (5H, m), 1.58e1.69 (1H, m), 1.81e1.88 (2H, m),
134.33, 167.20 (C]O, amide), 173.03 (C]O, ester); Anal. Calcd
for C14H19NO3: C, 67.45; H, 7.68; N, 5.62%. Found: C, 67.79; H,
7.75; N, 5.66.
2.19e2.38 (2H, m), 3.29e3.35 (1H, m), 6.32 (1H, s, br); 13C NMR
(100 MHz, CDCl3)
172.68.
d 14.13, 18.70, 19.98, 28.55, 31.58, 39.26, 53.09,

10228
A. Karanfil et al. / Tetrahedron 68 (2012) 10218e10229
4.4.5. (S)-tert-Butyl 2-propylpiperidine-1-carboxylate (28) (N-Boc
4.5.2. (E)-Ethyl
2-(1-benzyl-5-methylpyrrolidin-2-ylidene)acetate
coniine).
34.
To a stirred suspension of LiAlH4 (500 mg, 166 mmol) in dry
ether (20 mL) cooled in an ice-bath was added dropwise a solu-
tion of the lactam 26 (500 mg, 3.54 mmol) in dry ether (2e3 mL).
The reaction mixture was then refluxed for 4 h. After cooling in
an ice-bath, excess LiAlH4 was quenched with sequential addition
of water (3 mL), 10% NaOH solution (3 mL). The reaction mixture
was stirred at room temperature for 2e3 h for hydrolysis and the
aluminum residues were removed by filtration. The filtrate was
dried over anhydrous Na2SO4, then anhydrous HCl solution
(3e5 mL) in ether was added dropwise. Evaporation of volatiles
in vacuo gave the crude solid hydrochloride salt (550 mg, 97%). To
a solution of the coniine hydrochloride salt (500 mg, 3.16 mmol)
in H2O (15 mL) was added solid NaHCO3 (1.86 g, 22.1 mmol), then
(Boc)2O (850 mg, 3.9 mmol). After stirring the reaction mixture at
room temperature overnight, %10 NaOH solution (3 mL) was
added and stirring continued for additional 2 h. The product was
extracted with ether (2ꢃ50 mL), then washed brine (2ꢃ50 mL)
and dried (Na2SO4). Evaporation of volatiles in vacuo and purifi-
cation by flash column chromatography eluting with the ((ether/
hexane) 1:20) solvent system afforded N-Boc coniine (560 mg,
Using the general procedure for the ring-opening studies, the
reaction of 1,3-cyclic sulfamidate 30 with 12 (1 g, 4.15 mmol) in THF
(20 mL) containing HMPA (2 mL) afforded (E)-ethyl 2-(1-benzyl-5-
methylpyrrolidin-2-ylidene)acetate 34 (860 mg, 80%) as a pale
yellow oil. TLC, Rf 0,67 [(EtOAc/hexane) 1:3]; IR (Nujol); 1682 (C]O,
ester), 1594, 1491, 1454 (aromatic); 1H NMR (400 MHz, CDCl3)
d 1.15
(3H, d, J¼6.0), 1.22 (3H, t, J¼7.0), 1.56e1.66 (1H, m), 2.12e2.21 (1H,
m), 3.11e3.19 (1H, m), 3.23e3.31 (1H, m), 3.61e3.69 (1H, sextet,
J¼6.5), 4.07 (2H, qd, J¼1.0 and 7.0), 4.26 (1H, d, J¼16.5), 4.45 (1H, d,
J¼16.5), 4.58 (1H, s, br), 7.16e7.18 (2H, m, AreH), 7.23e7.26 (1H, m,
AreH), 7.29e7.33 (2H, m, AreH); dC (100 MHz, CDCl3) d 14.91, 19.45,
29.83, 31.16, 47.94, 58.44, 59.02, 79.15, 126.99, 127.42, 128.84,
136.72, 165.72, 169.76. HRMS m/z: [MþH]þ found 260.1652,
C16H22NO2 requires 260.1651.
Acknowledgements
The authors gratefully acknowledge Celal Bayar University for
82) as a clear oil. ½a D30
ꢂ
þ32.6 (c 1, CHCl3), lit.29k
½
a 2D5
ꢂ
þ33.5 (c 0.6,
financial support through projects (FEF-2006-57 and FEF-2009-
CHCl3), TLC, Rf 0.18 [(ether/hexane) 1:20]; 1H NMR (400 MHz,
€
101) and Pelin SOZEN AKTAS¸ for obtaining HRMS.
CDCl3)
d
0.92 (3H, t, J¼7.0), 1.22e1.41 (4H, m), 1.45 (9H, s),
1.51e1.70 (6H, m), 2.71e2.78 (1H, m), 3.96 (1H, d, br, J¼13.0), 4.21
Supplementary data
(1H, m).
These data include1H NMR, 13C NMR and MOL files of the most
important compounds described in this article. Supplementary
data associated with this article can be found in the online version,
at http://dx.doi.org/10.1016/j.tet.2012.09.081.
4.5. Synthesis and reactivity of 1,3-cyclic sulfamidate 31
4.5.1. 3-Benzyl-4-methyl-1,2,3-oxathiazinane 2,2-dioxide 31.
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