Total diastereoselectivity in the one-pot multistep reaction of (RS)-(+)-{[(4-methylphenyl)sulfinyl]methyl}-1-oxa-4-azaspiro[4.5]dec-3-ene and E-methyl cinnamate. An approach to (2S,4S,5R,6R)-2-(hydroxymethyl)-4,6-diphenyl-1-azabicycle[3.3.1]nonane

Article abstract of DOI:10.1016/j.tetasy.2008.05.030

The base-mediated reaction of enantiomerically pure α-sulfinylketimine (+)-1 with (E)-methyl cinnamate afforded (+)-5a in a one-pot procedure with complete diastereoselectivity. A sole diastereomer of the eight possible ones was isolated which revealed the stereocontrol of the chiral sulfinyl group in the construction of the three new stereogenic centres. The absolute configuration of stereocentres introduced in (+)-5a was assigned on the basis of ¹H NMR data and a single X-ray structure.

Full text of DOI:10.1016/j.tetasy.2008.05.030

Tetrahedron: Asymmetry 19 (2008) 1411–1413
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total diastereoselectivity in the one-pot multistep reaction of
(RS)-(+)-{[(4-methylphenyl)sulfinyl]methyl}-1-oxa-4-azaspiro[4.5]dec-3-ene
and E-methyl cinnamate. An approach to (2S,4S,5R,6R)-2-(hydroxymethyl)-
4,6-diphenyl-1-azabicycle[3.3.1]nonane
a
a
b
Carlos Alvarez-Ibarra a, , Juan F. Collados Luján , Maria L. Quiroga-Feijóo , Gonzalo Rodríguez
*
a Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, Ciudad Universitaria, s/n, 28040 Madrid, Spain
b Departamento de Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 29049 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The base-mediated reaction of enantiomerically pure
a
-sulfinylketimine (+)-1 with (E)-methyl cinnamate
Received 6 May 2008
Accepted 29 May 2008
Available online 24 June 2008
afforded (+)-5a in a one-pot procedure with complete diastereoselectivity. A sole diastereomer of the
eight possible ones was isolated which revealed the stereocontrol of the chiral sulfinyl group in the con-
struction of the three new stereogenic centres. The absolute configuration of stereocentres introduced in
(+)-5a was assigned on the basis of 1H NMR data and a single X-ray structure.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
scopic data (NMR) of the crude reaction.5 The single crystal X-ray
analysis of 5a allows its relative configuration to be established;
We have reported several synthetic applications of compound 1
derived from rac-alaninol.1 Among the most important ones, there
is a method that leads to 4-alkyl/aryl-substituted 5-(p-tolylsulfin-
the absolute configuration takes into account the stereochemical
outcome of the reaction.
yl)-5,6-dehydropiperidine-2-ones
3
by reaction with alkyl
2. Results and discussion
ene-esters 2 in basic media. It implies the formation of an adduct
via a Michael reaction followed by transenolization and cyclization
of this intermediate in a one-pot procedure (Scheme 1).2
Since the diastereoselectivity was so high (>95:5), it seems that
the actual stereochemical substrate has to be the rigid intermedi-
ate 3a (R1 = Ph). In order to confirm this hypothesis, compound
3a was isolated from the reaction of 1 with E-methyl cinnamate
(1:1) using n-BuLi as a base (1:1) in a typical and well-established
procedure,6 yielding 61% of the (4S)-2-piperidone 3a. The following
reaction of 3a with E-methyl cinnamate (1:2), under the same con-
ditions that 3a was achieved, gave 5a with a high diastereoselectiv-
ity (>95:5) as determined by the analysis of the NMR spectroscopic
data.5 Compound 5a was purified by chromatography on deacti-
vated silica gel (hexane/ethyl acetate 4:1 v/v) to give white crystals
An important feature of this reaction is the diastereoselectivity
in being able to reach 100% of the stereoisomer 3 if isopropyl esters
are used. In addition it can be modulated in the reaction of 1 with
methyl esters by changing the nature of the metallic ion in the
reagent enolate.2b Compounds such as
3 are precursors of
N-substituted 4-alkyl/aryl-2-piperidinylmethanols 4, belonging to
a new heterocyclic series of the chiral b-amino alcohols.3 Our
current research is focused on the synthesis and evaluation of
these amino alcohols as chiral ligands in the catalytic dialkylzinc
addition to aldehydes and ketones.4
In particular, we have attempted to synthesize conformational-
ly restricted b-amino alcohols, such as 6, which are stereoana-
logues of compound 4. With these goals in mind, and since the
1-azabycicle[3.3.1]nonane building block can be achieved from
the glutaric amide-ester moiety of the compound 5, we herein re-
port the optimal conditions to obtain 5a (R1 = Ph; R2 = Me) in a
one-pot procedure starting from 1. Furthermore, it is accomplished
with an enantiomeric purity of >95:5, indicated from the spectro-
(59% yield) {mp 163–166 °C; [a]D = +188.4 (c 0.4, CHCl3)}. Its rela-
tive configuration was established from the single crystal X-ray
structure, which is shown in Figure 1.
The molecule has four stereogenic centres with the following
absolute configurations: S1 (S), C9 (S), C10 (R) and C26 (R). The
more significant angles around S1 are C8S1C1, 97.0(3); O1S1C8,
108.2(2), and O1S1C1, 106.5(2) near to the tetrahedrical geometry.
The atoms C8C9C11N1C12 in the cyclohexene ring are nearly
planar [N1, 0.0027(5) and C11, ꢀ0.023(5) Å at the maximum devi-
ation] with C10 deviating for ꢀ0.619(5) Å from the mean plane.
The oxazolidine ring exhibits an envelope conformation with
O4 at ꢀ0.366(5) Å, whereas N1C12C13C14 are practically in a
* Corresponding author. Tel.: +34 91 394 4223; fax: +34 91 394 4103.
E-mail address: caibarra@quim.ucm.es (C. Alvarez-Ibarra).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.030

1412
C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 19 (2008) 1411–1413
C15C16C18C19 are practically planar with C14 and C17 atoms
deviating from the mean plane in 0.605(5) and ꢀ0.671(5) Å in a
nearly chair conformation. The phenyl rings are planar within
experimental error while the benzyl atoms C9 and C26 are practi-
cally in the same plane as their respective phenyl rings. It is inter-
esting to note that the phenyl ring joined to the C9 atom is
proximately parallel to that joined to the sulfinyl group but no
intramolecular contacts are observed because the distance within
the centroids reaches 3.515(5) Å.7,8
The structure of the 3,4-syn adduct 5a is in accordance with a
Re-facial diastereoselectivity of the lithium enolate 3a (anti versus
the phenyl group joined to the C9 atom), and a Si-facial one of the
E-methyl cinnamate (Fig. 2). This approach appears to be favoured
because it allows the complexation of the lithium ion by the O5
atom and the C27 carbanionic one in the transition state. Further-
more, it avoids the 1,3-quasi axial interactions involving the
phenyl group of the ester to be developed as shown in Figure 2.
It should be noted that an eight-membered cyclic transition state
seems to be too flexible for effective transfer of the chirality of
the enolate and in turn, a six-membered ring involving the lithium
ion has been proposed.
O
N
S
O
p
-Tol
1
1.
2.
n-BuLi (-78ºC to -30ºC)
R1
OR2
/-30ºC to rt
O
2
O
N
O
R1
R1
O
O
H
O
R1
N
OR2
O
S
O
p
-Tol
S
3
p-Tol
5
O5 Ph
H
O
O
H
OMe
26
O
28
S
H
27
11
28
26
N
OMe
O 14
13
O
10
p
-Tol
N
27
Ph
Li
12
9
H
11 O
R
9
8
5 H
10
N
H
Ph
Ph
S
H
R1
H
HO
p
-Tol
O
R1
5a
N
4
HO
Figure 2. Re-Facial and simple diastereoselectivities in the reaction of Li+-3a
enolate and E-methyl cinnamate 2.
R1
H
6
Scheme 1.
In order to achieve the synthesis of 5a in a one-pot procedure,
the reaction was carried out by starting from 1 (0.5 mmol in
1.5 mL of THF), n-BuLi (1.1 mmol) and E-methyl cinnamate
(1.2 mmol; 0.6 M solution in THF) following the general procedure
described herein.6 After the addition of the ene-ester, the reaction
mixture was allowed to reach room temperature and was monitor-
plane (N1, 0.018 in the maximum deviation). Moreover, a steric ef-
fect around the spiranic centre was observed for C15–C16,
1.561(7) Å and C14–N1, 1.493(5) Å. On the other side, atoms
Figure 1. ORTEP drawing of (+)-5a showing the atom-numbering scheme. Atoms of hydrogen at non-chiral centres are omitted for the sake of simplicity.8

C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 19 (2008) 1411–1413
1413
ized by TLC (silica gel; hexane/ethyl acetate 4:1, v/v). Thus, it was
References
observed that the formation of 3a was complete after 1 h while its
disappearance, related to the appearance of compound 5a, was
complete after 2 h. The workup of the reaction mixture required
the addition of methanol (0.1 mL) and, then, the evaporation of sol-
vent to avoid hydrolysis of the ester product. The residue was di-
luted with ethyl acetate and then filtered through a pad of
Celite; the filtrate was concentrated at reduced pressure at rt.
The residue was purified by flash chromatography on deactivated
silica gel (hexane/ethyl acetate: 4:1, v/v). The isolated product
(244 mg, 0.4 mmol) was obtained as a white solid (83% yield; Mp
1. Compound 1 was prepared as described in: Khiar, N.; Fernádez, I.; Alcudia, F.;
Hua, D. M. Tetrahedron Lett. 1993, 34, 699–702; See also: Hua, D. H.; Khiar, N.;
Zhang, F.; Lambs, L. Tetrahedron Lett. 1992, 33, 7751.
2. (a) Acherki, H.; Alvarez-Ibarra, C.; Barrasa, A.; de Dios, A. Tetrahedron Lett. 1999,
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Tetrahedron: Asymmetry 2004, 15, 693–697; (e) Acherki, H.; Alvarez-Ibarra, C.;
Collados Luján, J. F.; Quiroga-Feijóo, M. L. Tetrahedron: Asymmetry 2005, 16,
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3. Alvarez-Ibarra, C.; Collados Luján, J. F.; García Martínez, A.; Quiroga-Feijóo, M. L.;
Teso Vilar, E., unpublished results.
4. For some leading references, see: (a) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–
824; (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons:
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163–166 °C, [a]D = +188.4 (c 0.4, CHCl3)). Its structure was deter-
mined from the spectroscopic NMR data and it was identical to
the previous ones recorded for the sole product accomplished from
3a in the two-step procedure.
5. Compound 5a [83% from (S)-(+)-3]. Mp 163–166 °C (from ethanol). [
a]D +188.4
(c 0.4, CHCl3). IR (CHCl3)
m
max/cmꢀ1 1739.7, 1689.5, 1654.8. 1H NMR dH
:
(500 MHz; CDCl3; Me4Si) 7.60–6.30 (m, 14H, ArH), 5.25 (s, 2H, H13), 3.46 (s, 3H,
OMe), 3.37 (s, 1H, H9), 3.30 (ddd, 1H, J1,3 = 11.0, 9.2, 6.2 Hz, H26), 2.69
(subsystem AB, 1H, JAB = 15.8, J1,3 = 9.2 Hz, H27 or H270), 2.67 (subsystem AB,
1H, JAB = 15.8, J1,3 = 6.2 Hz, H270 or H27), 2.61 (d, 1H, J = 11.4 Hz, H10), 2.5–2.3
(m, 2H, cyclohexyl), 2.18 (s, 3H, Me (Tol)), 1.9–1.6 (m, 7H, cyclohexyl), 1.31 (m,
1H, cyclohexyl). 13C NMR dC (125 MHz; CDCl3; Me4Si) 172.1 (C11), 167.1 (C28),
143.6, 141.6, 140.7, 140.5, 138.0 (C1, C4,C12, C20, C30), 129.6, 129.1, 129.0,
128.8, 127.8, 126.8, 126.5, 125.1 (C–H Ar), 112.7 (C8), 99.7 (C14), 65.4 (C13),
58.2 (C10), 51.9 (C29), 42.3 (C26), 39.6 (C9), 39.5 (C27), 33.7, 32.3, 24.8, 23.3,
23.2 (cyclohexyl), 21.6 (Me-Tol). Anal. Calcd for C35H37NO5S: C, 72.01; H, 6.39;
N, 2.40. Found: C, 72.17; H, 6.22; N, 2.51.
3. Conclusion
In conclusion, a key intermediate in the route to enantiomeri-
cally pure and conformationally restricted 2-piperidinyl methanols
such as 6 has been accomplished from the chiral
mine 1 and E-methyl cinnamate in a one-pot procedure using n-
BuLi as a base (83% yield). We are currently exploring the chemis-
try of this multifunctional heterocycle to give 6a (R1 = Ph) as well
as trying to extend the scope of this route to introduce different
functionality in the adducts such as 5.
a-sulfinyl keti-
6. General procedure: To a cold (ꢀ78 °C) solution of sulfinyl ketimine 1 (0.9 mmol)
in dry THF (5 mL), was added a solution of n-BuLi (1.6 M in hexane, 0.67 mL,
1.07 mmol). The solution was stirred at ꢀ78 °C for 0.5 h, after which the
temperature was raised to ꢀ30 °C and the E-ene ester 2 (1.2 mmol, 0.6 M
solution in THF) was added. The reaction mixture was warmed to rt and was
stirred for 2 h. The mixture was diluted with saturated aqueous NH4Cl solution
(5 mL) and extracted with EtOAc (3 ꢁ 15 mL). The combined organic layers were
washed with brine, dried over Na2SO4, concentrated at reduced pressure and
chromatographied on deactivated silica gel to isolate 230 mg of 3a as a pure
Acknowledgements
We gratefully acknowledge the Spanish DGES (MEC) (Projects
CTQ2004-07244-C02-01/BQU and CTQ2007-67103-C02-01) and
Proyecto Santander-UCM (Project PR34/07-15782) for the support
of this research. We also thank UCM for its facilities for NMR spec-
tra and also C. Pastor and Dr. M. Medina of the SIDI in the Univers-
idad Autónoma de Madrid for the X-ray data collection of
compound 5a.
diastereomer (61% yield). Compound 3a was identified by its [a]D = +29.7 (c 0.2,
CHCl3) and its NMR spectroscopic data in accordance with that reported.2b
7. (a) Rodríguez, J. G.; Temprano, F.; Esteban-Calderón, C.; Martínez-Ripoll, M.;
García-Blanco, S. Tetrahedron 1985, 41, 3813; (b) Rodríguez, J. G.; Vilches, J.;
Smith-Verdier, P.; García-Blanco, S. Tetrahedron 1983, 39, 199.
8. The crystallographic data for compound 5a have been deposited in the
Cambridge Crystallographic Data Centre No. CCDC 237968.