Stereoselective divergent synthesis of 1,2-aminoalcohol-containing heterocycles from a common chiral nonracemic building block

Article abstract of DOI:10.1016/j.tetasy.2015.11.008

γ-N,N-Dibenzylamino-β-hydroxysulfoxide 1 proved to be an excellent chiral building block for the synthesis of a range of 1,2-amino alcohol-containing heterocycles. Thus, 1 was converted into 4,5-disubstuted oxazolidin-2-one 4 and aminoepoxides 2 and 3. Aminoepoxide 2 proved to be an excellent precursor to access oxazolidin-2-one 5 and azetidin-3-ol 6. Finally, 2 was used as a key intermediate that allowed the development of a divergent strategy to access cis-2-methyl-6-substituted piperidin-3-ol alkaloids. (+)-Deoxocassine 7 and a C-6 ethyl analogue 8 were prepared to illustrate this approach and to demonstrate that this strategy should be adaptable to the production of other members of this alkaloid family.

Full text of DOI:10.1016/j.tetasy.2015.11.008

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective divergent synthesis of 1,2-aminoalcohol-containing
heterocycles from a common chiral nonracemic building block
⇑
Pierre-Yves Géant, Erwann Grenet, Jean Martínez, Xavier J. Salom-Roig
Institut de Biomolécules Max Mousseron (IBMM), UMR 5247, Université de Montpellier, CNRS, Place Eugène Bataillon, 34095 Montpellier, France
a r t i c l e i n f o
a b s t r a c t
Article history:
c
-N,N-Dibenzylamino-b-hydroxysulfoxide 1 proved to be an excellent chiral building block for the synthe-
Received 6 November 2015
Accepted 26 November 2015
Available online xxxx
sis of a range of 1,2-amino alcohol-containing heterocycles. Thus, 1 was converted into 4,5-disubstuted
oxazolidin-2-one 4 and aminoepoxides 2 and 3. Aminoepoxide 2 proved to be an excellent precursor to
access oxazolidin-2-one 5 and azetidin-3-ol 6. Finally, 2 was used as a key intermediate that allowed
the development of a divergent strategy to access cis-2-methyl-6-substituted piperidin-3-ol alkaloids.
(+)-Deoxocassine 7 and a C-6 ethyl analogue 8 were prepared to illustrate this approach and to demon-
strate that this strategy should be adaptable to the production of other members of this alkaloid family.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
O
HO
HO
C19H40
NH
The advance of biology has revealed the imperative need of
developing structural diversity for a rapid and efficient lead gener-
ation in drug discovery. Analogously to biosynthetic pathways pro-
vided by Nature, and as an alternative to the traditional ‘single
target’ strategy, the design of divergent pathways to produce col-
lections of biologically active compounds from a single building
block presents significant challenges to synthetic chemists.1
Among the naturally occurring and synthetic cyclic amino alco-
hols, in which a 1,2-amino alcohol moiety is contained within the
ring,2 oxazolidin-2-ones are of special importance because of their
use as chiral auxiliaries3 and their occurrence in synthetic pharma-
ceuticals.4 Representatives of this class of compound include beflox-
atone, streptazolin, and cytoxazone (Fig. 1). Besides oxazolidinones,
azetidines are also an extraordinary class of azaheterocyclic com-
pounds. In particular, azetidin-3-ols can be found in natural prod-
ucts, as the sphingosine type alkaloids Penaresidines A and B and
Penazetidin A,5 and can be considered as potential building blocks
of diverse enantiopure bioactive nitrogen-containing compounds.
Therefore, the synthesis of optically active oxazolidin-2-ones and
azetidin-3-ols still remains challenging to synthetic chemists.
On the other hand, cis-2-methyl-6-substituted piperidin-3-ol
alkaloids, which have been isolated from leaves and twigs of the
plant genera Cassia and Prosopis,6 have as a common stereochemi-
cal feature an ‘all-cis’ relative configuration. The structural diver-
sity is due to a long side chain at C-6. Considerable effort has
HN
Ar
O
Me
N
H
C12H25
OH
HO
(-)-Cytoxazone
Ar = 4-MeOPh
Penazetidin A
(+)-Deoxocassine
Figure 1. Examples of 1,2-aminoalcohol containing heterocycles.
been invested in the development of syntheses based on a chiral
pool approach7 or the use of asymmetric synthesis.8 However,
most of the synthetic approaches disclosed to date, have the major
drawback that they do not allow adequate diversity and substitu-
tion. In light of this, short, efficient, and versatile strategies provid-
ing diverse access to C-6 analogues of ‘all-cis’ 2-methyl-6-
substituted piperidin-3-ols, continue to be a subject of importance
in synthetic organic chemistry.
As part of our ongoing efforts to develop the synthetic possibil-
ities of (2R,3S)-3-(dibenzylamino)-1-[(R)-p-tolylsulfinyl]butan-2-
ol 1 as a valuable chiral building block, we herein report a
divergent strategy allowing access to relevant chiral heterocycle
compounds containing a 1,2-amino alcohol moiety (Fig. 2). Thus,
1 has been further elaborated by taking advantage of the versatility
of the sulfoxide chemistry leading to oxirane 3 and oxazolidin-2-
one 4. We then transformed intermediate 1 into N,N-dibenzy-
laminoepoxide 2, and focussed our attention on the use of this sec-
ond synthetic intermediate as a common precursor to obtain
oxazolidin-2-one 5, azedidin-3-ol 6 and notably to access ‘all-cis’
2-methyl-6-substituted-3-piperidinols alkaloids as the natural
product (+)-deoxocassine 7 and its synthetic analogue 8.9
⇑
Corresponding author.
E-mail address: salom-roig@univ-montp2.fr (X.J. Salom-Roig).
http://dx.doi.org/10.1016/j.tetasy.2015.11.008
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Géant, P.-Y.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.008

2
P.-Y. Géant et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
O
HO
Me
(R = Me) as a model substrate to develop, as illustrated herein, fur-
ther applications of this dibenzylaminoketone synthon.
HO
Me
N
N
H
We next focused our attention on the preparation of
Bn
CH3
3
8
c
-N,N-dibenzylamino-b-hydroxysulfoxide 1 starting from enan-
N
H
C12H25
tiomerically pure
a
-N,N-dibenzylamino-a0-(R)-sulfinylketone 10a
(+)-Deoxocassine
by means of a sulfoxide-controlled highly stereoselective reduction
of the carbonyl group using diisobutylaluminium hydride (DIBAL-
H) as a reducing agent, in the presence of ZnI2 (Scheme 2).13 We
improved the yield of this two-step sequence by reacting crude
10a without previous isolation. Thus, starting from 9a (R = Me),
the desired derivative 1 was obtained in 94% yield in multigram
amounts and with an excellent stereoselectivity (>95:5). The rela-
tive syn-configuration of 1 was confirmed by chemical correlation
with the amino alcohol 12, obtained in 72% yield by cleavage of the
C–S bond of 10a with Raney nickel. The specific rotation observed
7
OH
O
S
O
:
pTol
NBn2
NBn2
2
1
Me
BnN
OH
O
O
6
O
BnN
Me
BnN
Me
O
OH
H
for 12 {[a]
25 = +71 (c 1.8 CHCl3)} was consistent with that reported
SpTol
H
D
in the literature14 {[
a]
D = +75 (c 2.3 CHCl3)}.
4
5
Figure 2. Our divergent strategy to access diverse 1,2-amino alcohol-containing
heterocycles.
OH
[α]D25 = +71 (c 1.8, CHCl3)
lit. +75 (c 2.3, CHCl3)
2. Results and discussion
NBn2
12
Recently,10 we put forward a novel and efficient strategy that
ii
allowed the recovery of enantiomerically pure
lamino-a0-(R)-sulfinylketones 10, starting from an epimeric mix-
ture of
-bromo-a0-(R)-sulfinylketones 9,11 through a combined
a-N,N-dibenzy-
MOMO
NHBn
O
S
OH
O
S
MOMO
NBn2
O
S
i
iv
iii
:
:
:
10a
pTol
pTol
pTol
a
NBn2
in situ substitution–epimerization process, a so-called dynamic
kinetic resolution (Scheme 1). Our approach involved a nucle-
ophilic displacement of the more reactive bromine epimer by
dibenzylamine and epimerization of the less reactive one. This is
a 1,4-stereoinduction process whereby the stereochemical infor-
mation of the sulfoxide group guides the generation of the new
stereocenter. Compound 10a was isolated as a single diastereoiso-
mer in 84% yield, after washing the crude solid material with
diethyl ether. The absolute configuration of the newly formed
stereogenic center was previously assigned as (S) by using X-ray
crystallographic analysis;10 herein we report a correlation with
the known dibenzylaminoketone 11, which was obtained in 60%
yield by cleavage of the C–S bond of 10a with Raney nickel. The
13
14
1
O
N
Bn
CH3
vi
3
OH
v
S
pTol
NHBn
O
vii
15
BnN
Me
O
SpTol
4
specific rotation observed for 11 {[
a
]
D
25 = ꢀ52.5 (c 2.95 CHCl3)}
was consistent with that reported in the literature12
Scheme 2. Reagents and conditions: (i) ZnI2, rt, 30 min, then DIBAL-H, THF, ꢀ78 °C,
94% from 9a; (ii) Raney Ni, EtOH, rt, 72%; (iii) MOMCl, EtNiPr2, CH2Cl2, reflux, 87%;
(iv) NIS (3 equiv), CH2Cl2, MS 4 Å, rt, 67%; (v) tBuBr, CHCl3, reflux, 87%; (vi) (a)
Me3OBF4, CH2Cl2; (b) K2CO3, H2O, 58%; (vii) CDI, NEt3, CH2Cl2, rt, 78%.
{[
a
]
D = ꢀ55.4 (c 3.2 CHCl3)}. Moreover, since both enantiomers of
methyl-p-tolylsulfoxide are readily available, this simple and easy
methodology enabled the preparation of the corresponding (R)-
dibenzylaminoketones; for example we obtained ent-10a from
ent-9a by using the same reaction conditions. Having demon-
strated that the methodology could be adapted to several side
chains (R = Me, i-Bu, Bn and CH2-c-Hex), we selected 10a
With the chiral building block 10a in hand, we next investigated
its use as a synthetic intermediate to obtain both oxirane 3 and the
4,5-disubstituted oxazolidin-2-one 4. Thus, protection of the free
alcohol as methoxy methyl ether (MOM) was achieved upon
treatment of 1 with MOMCl in the presence of Hünig’s base to give
13 in 87% yield. Amine monodebenzylation using NIS15 to afford 14
in 67% yield was followed by sulfoxide reduction by exposure to an
excess amount of tert-butyl bromide in refluxing chloroform16 to
furnish the corresponding sulfide 15 in 87% yield. Concomitant
cleavage of the methoxy methyl ether occurred. To the best of
our knowledge, cleavage of MOM ethers with tBuBr had never been
described before and under neutral conditions could be an alterna-
tive to the diverse methodologies described in the literature, which
have the major drawback of employing acidic conditions.17 Deriva-
tive 15 was then reacted with Meerwein’s salt (Me3OBF4) and the
resulting sulfonium salt was treated with aqueous K2CO3 to afford
oxirane 3, which was isolated in 58% yield, along with methyl
p-tolylsulfide after this two-step procedure.13 Alternatively, in
the presence of Et3N, sulfide 15 was converted into oxazolidin-2-
one 4 using CDI in 78% yield. The anti-relationship between the
O
O
O
S
O
O
S
i
R
:
R
:
ii
pTol
pTol
NBn2
NBn2
Br
9a
R = Me , i-Bu, Bn
CH2-c-Hex
10a
[α]D25 = +13.6
11
R = Me
[α]D25 = -52.5
(c 1, Me2CO)
(c 2.95, CHCl )
3
lit. -55.4
(c 3.2, CHCl3)
O
O
O
O
S
S
pTol
pTol
iii
:
:
NBn2
Br
ent-9a
10a
ent-
[α]D25 = -13.7
(c 1.02, Me2CO)
Scheme 1. Reagents and conditions: (i) Bn2NH, THF, rt, 84% 10a; (ii) Raney Ni,
EtOH, 0 °C, 15 min, 60%; (iii) Bn2NH, THF, rt, 70%.
Please cite this article in press as: Géant, P.-Y.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.008

P.-Y. Géant et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
oxazolidin-2-one substituents was confirmed by NOESY
experiments.
dichloromethane15 and the crude of the resulting monobenzylated
product was heated in iPrOH at 100 °C under microwave irradia-
tion, giving rise, by ring expansion process, to the formation of
an 85:15 mixture of N-protected azetidin-3-ol 6 and aziridinol
17. The major product, enantiopure N-protected azetidin-3-ol 6,
was isolated in 48% yield from 2.21
Next, the chiral building block 1 was transformed into another
useful chiral synthon, oxirane 2 (Scheme 3). This conversion was
achieved following a similar protocol described for compound 14
(vide supra). Thus, a three-step sequence involving sulfinyl reduc-
tion with tBuBr in refluxing chloroform,16 subsequent sulfur
methylation by Me3OBF4 in anhydrous CH2Cl2, without further
purification of the resulting b-sulfenyl derivative, and treatment
of the corresponding sulfonium salt by aqueous K2CO3, furnished
epoxide 2 in 78% yield from 1, after purification by column chro-
matography on silicagel.
Finally, it was our expectation to develop a general divergent
strategy leading to the synthesis of ‘all-cis’ 2-methyl-6-substi-
tuted-3-piperidinol alkaloids by using syn-(2R,10S)-2-(1-dibenzy-
laminomethyl)epoxide 2 as common building block. Hence, we
decided to prepare (+)-deoxocassine 7 (R = C12H25) and a synthetic
analogue 8 (R = Et). In our retrosynthetic analysis depicted in
Figure 3, both target piperidinols would derive from a debenzyla-
tion and concomitant intramolecular reductive amination of
dibenzylamino ketone 18. To access dibenzylamino ketone 18,
two pathways (a and b in Fig. 3) were envisaged. Firstly, we
planned to prepare 18 by alkylation of methylketone 19, which
was obtained by oxirane ring opening of 2 with an allylic
organometallic. In a second approach, the key step leading to
dibenzylamino ketone 18 involved an oxirane ring opening of 2
by the nucleophilic lithiated anion of hydrazones 20a or 20b and
subsequent hydrazone hydrolysis.
OH
O
S
Me
BnN
OH
O
O
iii
iv
i
:
pTol
NBn2
NHBn
NBn2
2
1
16
6
ii
OH
O
BnN
Me
O
H
OH
N
Bn
5
17
O
O
Scheme 3. Reagents and conditions: (i) (a) tBuBr, CHCl3, reflux; (b) Me3OBF4,
CH2Cl2, rt, 5 h, then K2CO3, 78% (from 1); (ii) CAN, NaHCO3, 84%; (iii) NIS (3 equiv),
CH2Cl2, MS 4 Å, t.a.; (iv) iPrOH, MW, 100 °C, 1.5 h, 48% from 2.
HO
Me
NBn2
+
2
19
Me
NBn2
+
M
a
RX
We next focused our efforts in exploring new synthetic applica-
tions of vicinal syn-N,N-dibenzylamino oxirane 2. The latter could
be transformed in a straightforward manner into oxazolidin-2-
one 5 using a two-step procedure.18 Thus, 2 was reacted with
CAN and treatment of the subsequent monobenzylated amine19
reaction crude with a saturated solution of NaHCO3 resulted in a
regioselective intramolecular epoxide opening to afford oxazo-
lidin-2-one 5 in 84% yield. The cis-relationship between the oxazo-
lidin-2-one substituents was confirmed by NOESY experiments.
This cis-2,4-disubstituted oxazolidin-2-one can be considered a
pseudo epimer of the trans-oxazolidin-2-one 4.
O
HO
Me
HO
Me
R
R
N
H
b
NBn2
: R = CH3
NMe2
R
8: R = CH3
7
18a
18b: R = C11H23
N
O
: R = C11H23
+
NBn2
20a: R = CH3
20b
2
: R = C11H23
Figure 3. Retrosynthetic analysis for (+)-deoxocassine 7 and its synthetic analogue 8.
Epoxide ring expansion with nucleophiles has received only
limited attention in the literature.20 In this context, we envisioned
the use of oxirane 2 as a precursor of N-protected azetidin-3-ol 6.
Regarding the first approach, the oxirane ring opening of key
compound 2 depended on the treatment of the latter with an
excess of magnesium allyl chloride in the presence of CuI in THF
Compound
2
was treated with 3 equiv of NIS in dry
OCH3
O
OH
OH
O
i
ii
+
NBn2
NBn2
O
NBn2
NBn2
22
19
2:3
2
21
iii
OMOM
OMOM
OMOM
iv
R
NBn2
O
NBn2
O
NBn2
27
26
25
NMe2
OH
N
OH
OH
v
2
NBn2
O
23
NBn2
O
NBn2
24
19
Scheme 4. Reagents and conditions: (i) Magnesium allyl chloride, CuI, THF, ꢀ40 °C, 76%; (ii) PdCl2(CH3CN)2, CuCl2ꢁ2H2O, MeOH, O2, rt; (iii) MOMCl, DIPEA, CH2Cl2, reflux,
88%; (iv) PdCl2(CH3CN)2, CuCl2ꢁ2H2O, MeOH, O2, rt, 56%; (v) (a) BuLi, THF, 0 °C, then 2; (b) SiO2, THF, H2O, rt, 54%.
Please cite this article in press as: Géant, P.-Y.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.008

4
P.-Y. Géant et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
at ꢀ40 °C (Scheme 4). The corresponding amino alcohol 21 with a
syn-relative configuration was obtained in 76% yield. The reaction
was totally regioselective and no other regioisomer was observed
by 1H NMR analysis of the crude reaction. The anti-amino alcohols
of this type are normally obtained by addition of an organometallic
N,N-dimethylhydrazones has found a wide applicability.25 Indeed,
N,N-dialkylhydrazones offer many advantages such as the high
nucleophilicity of their organolithium derivatives, regioselectivity
and controlled
a-monoalkylation. Even though azaenolates can
react with quite a number of electrophiles, oxiranes have rarely
been employed.24,26 In this context, our initial efforts focused on
the preparation of dimethyl hydrazones 20a and 20b (Scheme 5).
Thus, the reaction of 2-butanone with dimethyl hydrazine in
refluxing CH2Cl2 gave the corresponding dimethyl hydrazone 20a
in 82% yield. On the other hand, analogue 20b could be obtained
by a two step sequence starting from commercially available
alcohol 28, which was oxidized into the corresponding ketone 29
in 95% yield by using PCC. Dimethyl hydrazone 20b was obtained
in quantitative yield by using a procedure similar to that used
for 20a.
At this point, we proceeded to attempt an oxirane ring
opening of the common precursor 2 with the lithium aza-enolate
of dimethylhydrazones 20a or 20b (Scheme 6). Considerable
endeavors were necessary to optimize the reaction conditions.
The use of either BF3ꢁOEt2 as a catalyst or of an excess of anhydrous
LiCl as additive, according to a known literature procedure for eno-
late oxirane ring opening,26c,27 were unsuccessful. Finally, the
reaction was successfully implemented by adding oxirane 2 to an
excess of aza-enolate (11 equiv for 20a and 5.3 equiv for 20b),
generated from the corresponding hydrazones and butyllithium
at 0 °C, allowing the reaction mixture to warm to room
temperature. The corresponding hydrazones 30 were converted
in a one-pot procedure into the desired ketones 18a and 18b by
exposure of the crude to SiO2, in a 1:1 mixture of water and
tetrahydrofuran (THF) in a one-pot procedure in 63% and 79%
yield, respectively, after silica gel chromatography.
reagent to the corresponding a-aminoaldehyde under Felkin–Ahn
control, however the syn-diastereoisomers are difficult to access.22
We attempted to convert allylic alcohol 21 into methyl ketone 19
through a Wacker oxidation23 by exposure to PdCl2(CH3CN)2 and
CuCl2ꢁ2H2O as catalysts. We obtained a 2:3 inseparable mixture
composed of the desired methyl ketone 19 and ketal 22, which
consequently could not be isolated. Alternatively, methyl ketone
19 was obtained in 54% yield by alkylation of the lithium anion
of acetone dimethylhydrazone 23 with oxirane 2 and subsequent
in situ hydrazone hydrolysis. Concomitant formation of dimer 24
hampered the reaction yield. On the basis of the formation of the
ketal by-product 22 by the Wacker oxidation, we protected the
hydroxyl group of the allylic alcohol 21 as a MOM ether and 25
was obtained in 88% yield. Exposure of 25 to Wacker oxidation
conditions provided the desired methylketone 26 in a reasonable
56% yield. Nevertheless, attempts to obtain 27 by alkylating 26
with 1-iodoundecane (C11H23I) using LDA as base were unsuccess-
ful. Since ketone anions have proven to be quite unreactive toward
epoxides,24 we applied the procedure leading to N,N-dimethylhy-
drazone formation from 26 and subsequent alkylation of the corre-
sponding lithium anion. The procedure turned out to be very
troublesome and despite much experimentation, the formation of
27 was not observed.
The frustrating outcome for the first strategy aiming to
obtain ketones 18 turned our attention to the second approach,
which focused on the study of hydrazone 20a and 20b alkylations
with the common chiral building block 2. Among the
methodologies leading to the C–C bond formation, the use of
At this stage, completion of the targeted 2-methyl-6-substi-
tuted-3-piperidinols was conveniently and efficiently accom-
plished by in situ amine debenzylation and concomitant
reductive cyclization of the ensuing aminoketones. Thus, dibenzy-
laminoketones 18a and 18b afforded specifically, in a two-step
sequence, upon hydrogenation in the presence of 20% Pd(OH)2 on
carbon at room temperature and atmospheric pressure, (+)-deoxo-
cassine 728 and its C-6 ethyl analogue 8 in 75% and 61% yield, after
silica gel chromatography. From a mechanistic point of view, as
Me2N
N
O
i
20a
Me2N
O
described in the literature,7e the
was hydrogenated from the less hindered
leading to an ‘all-cis’ configuration with
D
1-piperidine intermediate 31
-face of the molecule
high degree of
OH
N
ii
iii
a
C12H25
C12H25
C12H25
20b
a
29
28
stereocontrol, since not even a trace of the C-6 epimer could be
detected by 1H NMR spectroscopic analysis of the crude reaction
mixture. The spectroscopic data (1H NMR, 13C NMR, and mass
Scheme 5. Reagents and conditions: (i) NH2Me2, CH2Cl2, reflux, 82%; (ii) PCC,
CH2Cl2, 95%; (iii) NH2NMe2, CH2Cl2, reflux, 100%.
O
NMe2
NMe2
O
N
N
NBn2
i
ii
2
HO
Me
R
HO
Me
R
R
20a: R = CH3, 11 eq.
20b
NBn2
18a,b
NBn2
30
: R = C11H23, 5.3 eq.
OH
O
3
HO
Me
H
N
H
H
H
H3C
iii
H3C
R
N
H
N
H
R
2
H
6
R
H
H
H
7
: R = C11H23
31
8: R = CH3
Scheme 6. Reagents and conditions: (i) BuLi, THF, 0 °C–rt then 2; (ii) SiO2, THF–H2O, 63% 18a and 79% 18b from 2; (iii) H2, Pd(OH)2/C, EtOH.
Please cite this article in press as: Géant, P.-Y.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.008

P.-Y. Géant et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
spectra), the melting point and the specific rotation of synthetic 7
were in complete agreement with those previously reported
{[ D = +11.8 (c 1.0, CHCl3)}.
25 = +11.6 (c 0.95, CHCl3); lit.7h {[
The deoxocassine C-6 ethyl analogue 8, which to our knowledge
4.2. Experimental procedures
a]
a]
4.2.1. (S)-3-(Dibenzylamino)butan-2-one 11
D
To a solution of 10a (240 mg, 0.592 mmol) in anhydrous EtOH
(8 mL) was added a large excess of activated Raney Ni in EtOH
(about 2 mL) at 0 °C. The suspension was stirred rapidly at 0 °C
for 15 min, then filtered through a Celite pad, and washed with
EtOH. The crude product was purified by column chromatography
on silica gel (cyclohexane/EtOAc 40:1) to afford 11 as a colorless oil
25
has never been described, exhibited a specific rotation of [
a]
=
D
+8.8 (c 1.1, CHCl3). The ‘all-cis’ relationship between the
substituents in compounds 7 and 8 was confirmed by the small
J2,3 value (1.3 Hz), typical for the axial–equatorial H-2 and H-3
protons in the major conformer of cis-2-methyl-6-substituted
piperidine-3-ols.7b,29 Moreover, the cis relationship between the
substituents at the 2,6-positions for compound 8 was confirmed
by NOESY experiments.
(94 mg, 60%). Rf = 0.63 (cyclohexane/EtOAc 4:1); [
a]
25 = ꢀ52.5
D
(c 2.95, CHCl3); 1H NMR (CDCl3, 300 MHz): d = 7.36–7.19
(m, 10H), 3.65 (d, J = 13.7 Hz, 2H), 3.41 (d, J = 13.7 Hz, 2H), 3.30
(q, J = 6.7 Hz, 1H), 2.19 (s, 3H), 1.11 (d, J = 6.7 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d = 211.1, 139.4, 128.9, 128.6, 127.3, 63.0, 54.7,
27.8, 7.1; ESIMS m/z 268.2 [M + H]+; HRMS (ES): m/z calcd for
3. Conclusion
C
18H22NO [M + H]+: 268.1701, found: 268.1707.
Among the four syn-N,N-dibenzylamino alcohols that we have
prepared in a previous study, we used compound 1 as a model
substrate to develop a divergent and efficient strategy allowing
4.2.2. (SS,3R)-3-(Dibenzylamino)-1-(p-tolylsulfinyl)butan-2-one
ent-10a
access to six different saturated heterocycles bearing
a 1,2
3-Bromo-1-[(S)-p-tolylsulfinyl]butan-2-one ent-9a (500 mg,
1.73 mmol) was dissolved in THF (10 mL) and dibenzylamine
(0.86 mL, 4.34 mmol) was added. The reaction mixture was stirred
for 5 h at room temperature and treated with saturated aqueous
KHCO3 (10 mL). The phases were separated and the aqueous one
was extracted with EtOAc (3 ꢂ 5 mL). The combined organic layers
were washed with a 10% KHSO4 aqueous solution (3 ꢂ 10 mL),
dried over MgSO4, and concentrated under reduced pressure. The
residue was washed with Et2O to afford ent-10a as a white solid
aminoalcohol moiety. This key chiral non-racemic building block
1 allowed the synthesis of oxirane 3 and oxazolidinone 4. Addi-
tionally, compound 1 furnished a second chiral building block,
oxirane 2. This precursor permitted access to both enantiopure
and synthetically useful oxazolidinone 5, a pseudo epimer of
oxazolidinone 4, and azetidin-3-ol 6. The synthetic potential of
oxirane 2 as precursor was further exemplified by the develop-
ment of a flexible total synthesis of (+)-deoxocassine 7 and its
C-6 ethyl analogue 8 by using a new, general, and efficient proto-
col. This approach involved as a key step, the coupling of aza-eno-
lates of hydrazones 20a and 20b with the key oxirane 2.
Compared to previous reported syntheses, our route avoids the
use of a protecting group for the 3-hydroxyl function. The obvious
synthetic potential of this short reaction sequence arises from its
convergent nature. Of great significance is the fact that the key
oxirane intermediate of this synthesis 2 should facilitate the syn-
thesis of other members of the ‘all-cis’ 2-methyl-6-substituted
piperidine-3-ol alkaloids by judicious choice of the ketone moiety.
Further applications of this divergent strategy to the synthesis of
other valuable chiral synthons and bioactive products are cur-
rently going on in our laboratory.
(489 mg, 70%). Rf = 0.60 (cyclohexane/EtOAc, 2:1); [
a]
D
25 = ꢀ13.7 (c
1.02, Me2CO); mp 89 °C; 1H NMR (CDCl3, 300 MHz): d = 7.37–7.12
(m, 14H), 4.20 (d, J = 13.2 Hz, 1H), 4.10 (d, J = 13.2 Hz, 1H), 3.62
(d, J = 13.4 Hz, 2H), 3.33 (d, J = 13.4 Hz, 2H), 2.83 (q, J = 6.6 Hz,
1H), 2.36 (s, 3H), 0.99 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d = 203.1, 142.1, 140.1, 138.7, 130.1, 127.2, 128.8,
127.8, 124.5, 66.3, 63.6, 55.0, 21.6, 6.0; ESIMS m/z 406.3 [M+H]+;
HRMS (ES): m/z calcd for C25H28NO2S [M+H]+: 406.1841; found
406.1850.
4.2.3. (2S,3S)-3-(Dibenzylamino)butan-2-ol 12
A
solution of aminohydroxysulfoxide syn-1 (100 mg,
0.245 mmol) in anhydrous EtOH (4 mL) was added to a large excess
of activated Ni Raney in EtOH (approx. 1 mL). The suspension was
stirred at room temperature for 4 h, then filtered through a Celite
pad, and washed with EtOH. The crude product was purified by
column chromatography on silica gel (cyclohexane/EtOAc 95:5)
to afford 12 as a colorless oil (47 mg, 72%). Rf = 0.15 (cyclohex-
4. Experimental
4.1. General
25 = +71 (c 1.8, CHCl3); 1H NMR (CDCl3,
All reagents and solvents were purchased from commercial
sources. THF was dried by distillation on sodium/benzophenone.
Diisopropylamine was distilled on KOH. Reactions were conducted
in flame dried glassware under an argon atmosphere. 1H NMR and
13C NMR spectra were recorded at 300 MHz and 75 MHz (or
400 MHz/100 MHz, or 600 MHz/150 MHz), respectively, either in
CDCl3 or MeOD using a Bruker Avance spectrometer. Chemical
shifts are given in ppm and reported to the residual solvent peak
(CHCl3 7.26 ppm and 77.16 ppm or MeOH 4.87, 3.31 ppm and
49.15 ppm). Data are reported as follows: chemical shift (d),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet), coupling constant(s) (J, Hz), and integration.
Analytical TLC was performed on silica gel 60F254 plates. Column
ane/EtOAc 95:5); [a]
D
300 MHz): d = 7.32–7.20 (m, 10H), 4.34 (br s, 1H), 3.80 (d,
J = 13.3 Hz, 2H), 3.60 (dq, J = 9.4, 6.0 Hz, 1H), 3.29 (d, J = 13.3 Hz,
2H), 2.45 (dq, J = 9.4, 6.7 Hz, 1H), 1.05 (d, J = 6.0 Hz, 3H), 0.99 (d,
J = 6.7 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d = 139.2, 129.2, 128.7,
127.4, 67.2, 60.5, 53.5, 19.6, 8.1; ESIMS m/z 270.0 [M+H]+; HRMS
(ES): m/z calcd for C18H24NO [M+H]+: 270.1858; found 270.1852.
4.2.4. (SR,2R,3S)-N,N-Dibenzyl-2-(methoxymethoxy)-1-(p-
tolylsulfinyl)butan-3-amine 13
To a solution of aminohydroxysulfoxide 1 (50 mg, 0.123 mmol)
in CH2Cl2 (2 mL) were added MOMCl (0.06 mL, 0.795 mmol) and
EtNiPr2 (0.13 mL, 0.746 mmol). The solution was heated at reflux
for 2 h, and then diluted with CH2Cl2 (3 mL), washed with water
(3 ꢂ 5 mL), dried over MgSO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
(cyclohexane/EtOAc 2:1) to afford 13 as a colorless oil (48 mg,
chromatography was carried out on silica gel 60 (63–200 lm).
High resolution mass spectra (HRMS) were measured on a Micro-
mass spectrometer using electrospray ionization (ESI) and Q-Tof
detection. Melting points were obtained with a Büchi apparatus
and are uncorrected. Optical rotations values were measured with
a Perkin–Elmer apparatus at 20 °C, 589 nm (sodium ray), and
concentrations are given in g/100 mL.
87%). Rf = 0.4 (cyclohexane/EtOAc 2:1); [a]
25 = +7.5 (c 1.05, CHCl3);
D
1H NMR (CDCl3, 400 MHz): d = 7.42 (d, J = 8.2 Hz, 2H), 7.33–7.25
(m, 12H), 4.64 (d, J = 6.9 Hz, 1H), 4.54 (d, J = 6.9 Hz, 1H),
Please cite this article in press as: Géant, P.-Y.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.008

6
P.-Y. Géant et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3.96 (d, J = 13.5 Hz, 2H), 3.74 (ddd, J = 5.8, 5.8, 3.5 Hz, 1H), 3.39 (s,
3H), 3.35 (d, J = 13.5 Hz, 2H), 3.25 (dd, J = 13.0, 6.0 Hz, 1H), 3.19
(dd, J = 13.0, 5.6 Hz, 1H), 2.94 (qd, J = 6.8, 3.5 Hz, 1H), 2.44 (s, 3H),
1.22 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d = 141.5,
141.2, 140.1, 129.9, 129.1, 128.3, 127.0, 124.5, 96.6, 77.3, 61.0,
56.1, 55.4, 55.0, 21.5, 9.2; ESIMS m/z 452.2 [M+H]+; HRMS (ES):
m/z calcd for C27H33NO3S [M+H]+: 452.2259; found 452.2241.
ESIMS m/z 192.2 [M+H]+; HRMS (ES): m/z calcd for C12H18NO [M
+H]+: 192.1388; found 192.1382.
4.2.8. (4S,5R)-3-Benzyl-4-methyl-5-((p-tolylthio)methyl)
oxazolidin-2-one 4
To a solution of 15 (54 mg, 0.179 mmol) in CH2Cl2 (1 mL) were
added NEt3 (0.03 mL, 0.212 mmol) and DIC (49 mg, 0.302 mmol).
The reaction mixture was stirred at room temperature for 3 h,
and diluted with CH2Cl2 (4 mL). The solution was washed with a
0.5 M HCl aqueous solution (3 ꢂ 5 mL), dried over MgSO4 and con-
centrated under reduced pressure. Purification of the crude pro-
duct by column chromatography on silica gel using cyclohexane/
EtOAc 4:1 as eluent 4 as a colorless oil (46 mg, 78%). Rf = 0.32
4.2.5. (SR,2R,3S)-N-Benzyl-2-(methoxymethoxy)-1-(p-
tolylsulfinyl)butan-3-amine 14
Powdered molecular sieves 4 Å (605 mg) were flame-dried and
cooled under argon. Next, N-iodosuccinimide (603 mg, 2.68 mmol)
was added. To this solid mixture was added a solution of 13
(405 mg, 0.897 mmol) in anhydrous CH2Cl2 (15 mL). The suspen-
sion was stirred at room temperature for 2 h, and then the mixture
was filtered and washed with CH2Cl2 (10 mL). The organic layer
was washed with aqueous saturated Na2S2O3 (3 ꢂ 10 mL), H2O
(10 mL), and brine (10 mL), dried over MgSO4 and concentrated
under reduced pressure. The crude material was purified by col-
umn chromatography on silica gel (cyclohexane/EtOAc 2:1 + 2%
NEt3) to afford 14 as a colorless oil (215 mg, 66%). Rf = 0.2 (cyclo-
(cyclohexane/EtOAc 4:1); [a]
25 = +20.6 (c 0.97, CHCl3); 1H NMR
D
(CDCl3, 400 MHz): d = 7.37–7.22 (m, 7H), 7.08 (d, J = 8.0 Hz, 2H),
4.76 (d, J = 15.2 Hz, 1H), 4.08–40.5 (m, 2H), 3.45 (pent, J = 6.2 Hz,
1H), 3.22 (dd, J = 13.9, 4.4 Hz, 1H), 2.85 (dd, J = 13.9, 8.5 Hz, 1H),
2.31 (s, 3H), 1.21 (d, J = 6.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d = 157.1, 137.4, 135.9, 131.0, 130.4, 130.0, 128.9, 128.1, 127.9,
78.8, 54.9, 45.7, 38.0, 21.1, 18.6; ESIMS m/z 328.1 [M+H]+, 655.3
[2M+H]+; HRMS (ES): m/z calcd for C19H22NO2S [M+H]+:
328.1371; found 328.1367.
hexane/EtOAc 1:1 + 1% Et3N); [a]
25 = +83 (c 0.96, CHCl3); 1H NMR
D
(CDCl3, 300 MHz): d = 7.57 (d, J = 8.2 Hz, 2H), 7.33–7.24 (m, 7H),
4.64 (d, J = 7.0 Hz, 1H), 4.59 (d, J = 7.0 Hz), 3.83–3.78 (m, 1H),
3.74 (d, J = 13.0 Hz, 1H), 3.56 (d, J = 13.0 Hz), 3.40 (s, 3H), 3.32
(dd, J = 13.2, 5.0 Hz, 1H), 3.11 (dd, J = 13.2, 6.5 Hz, 1H), 3.02 (qd,
J = 6.5, 4.0 Hz, 1H), 2.40 (s, 3H), 1.13 (d, J = 6.5 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d = 141.7, 141.3, 140.5, 130.1, 128.4, 128.2,
127.1, 124.5, 96.5, 75.5, 59.6, 56.1, 54.2, 51.3, 21.5, 15.8; ESIMS
m/z 362.1 [M+H]+; HRMS (ES): m/z calcd for C20H28NO3S [M+H]+:
362.1790; found 362.1799.
4.2.9. (4S,5S)-3-Benzyl-5-(hydroxymethyl)-4-methyloxazolidin-
2-one 5
To a solution of 2 (0.127 g, 0.48 mmol) in 8 mL AcCN:H2O 5:1
was added CAN (0.55 g, 1 mmol). After 3 h of stirring at room tem-
perature, the reaction mixture was treated with a saturated solu-
tion of NaHCO3 (15 ml). After 30 min, water (15 mL) and EtOAc
(15 ml) were added. The phases were separated and the organic
one was extracted with EtOAc (3 ꢂ 25 ml). The beige solid 5 was
obtained in 84% yield (89 mg). Rf = 0.24 (cyclohexane/EtOAc 3:2);
4.2.6. (2R,3S)-3-(Benzylamino)-1-(p-tolylthio)butan-2-ol 15
A solution of 14 (101 mg, 0.279 mmol) and tBuBr (0.64 mL,
5.52 mmol) in CHCl3 (5 mL) was heated at reflux for 9 h and then
cooled to room temperature. The solvents were then evaporated
in vacuo and the crude material was purified by column chro-
matography on silica gel (cyclohexane/EtOAc 1:2 + 2% NEt3) to
afford 15 as a colorless oil (73 mg, 87%). Rf = 0.25 (cyclohexane/
[a]
25 = +30 (c 1.05, Me2CO); mp 79–80 °C; 1H NMR (CDCl3,
D
400 MHz): d = 7.30–7.19 (m, 5H), 4.72 (d, J = 15.3 Hz, 1H),
4.48–4.41 (m, 1H), 3.99 (d, J = 15.3 Hz, 1H), 3.81–3.67 (m, 3H),
2.61 (s, large, 1H), 1.12 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl3,
100 MHz): d = 157.9, 135.9, 128.9, 128.1, 128.0, 77.1, 60.8, 52.0,
45.7, 12.6; ESIMS m/z 222.1 [M+H]+; HRMS (ES): m/z calcd for
C
12H16NO3 [M+H]+: 222.1117; found 222.1146.
EtOAc 1:2 + 2% Et3N); [
a
]
25 = ꢀ6.3 (c 0.95, CHCl3); 1H NMR (CDCl3,
D
600 MHz): d = 7.32–7.25 (m, 7H), 7.09 (d, J = 8.0 Hz, 2H), 3.90 (d,
J = 13.0 Hz, 1H), 3.70 (d, J = 13.0 Hz, 1H), 3.46 (ddd, J = 7.8, 6.9,
3.8 Hz, 1H), 3.17 (dd, J = 13.5, 3.8 Hz, 1H), 2.95 (dd, J = 13.5,
7.8 Hz, 1H), 2.76 (d, J = 6.5 Hz, 1H), 2.32 (s, 3H), 1.12 (d,
J = 6.5 Hz, 3H); 13C NMR (CDCl3, 150 MHz): d = 140.3, 136.7,
132.3, 130.7, 129.9, 128.6, 128.3, 127.2, 73.1, 56.2, 51.6, 39.6,
4.2.10. (2S,3S)-1-Benzyl-2-methylazetidin-3-ol 6
Powdered molecular sieves 4 Å (150 mg) were flame-dried and
cooled under argon and mixed with N-iodosuccinimide (248 mg,
1.10 mmol). To this solid mixture was added a solution of epoxide
2 (100 mg, 0.374 mmol) in anhydrous CH2Cl2 (7 mL). The suspen-
sion was stirred at room temperature for 1.5 h and then the mix-
ture was filtered and washed with CH2Cl2 (5 mL). The organic
layer was washed with aqueous saturated Na2S2O3 (2 ꢂ 5 mL)
and H2O (5 mL), dried over MgSO4 and concentrated under reduced
pressure. The crude material was dissolved in iPrOH (4 mL) and
this solution was heated under microwave irradiation (400 W,
10 °C) for 1.5 h. The solvent was evaporated, and the crude product
was purified by column chromatography on silica gel (EtOAc + 2%
NEt3) to afford 6 as a colorless oil (32 mg, 48%). Rf = 0.19 (EtOAc);
21.1, 16.9; ESIMS m/z 302.2 [M+H]+; HRMS (ES): m/z calcd for C18
24NOS [M+H]+: 302.1579; found 302.1573.
-
H
4.2.7. (2R,10S)-2-[1-(N-Benzyl-N-methylamino)ethyl]oxirane 3
To a solution of 15 (65 mg, 0.217 mmol) in CH2Cl2 (2 mL) was
added trimethyloxonium tetrafluoroborate (37 mg, 0.25 mmol)
and the reaction mixture was stirred at room temperature for
4 h, after which additional Me3OBF4 (37 mg, 0.25 mmol) was added
and the stirring was continued for 2 h. The resulting heterogeneous
mixture was treated with saturated aqueous K2CO3 (2 mL) and stir-
red overnight. The aqueous phase was recovered and extracted
with CH2Cl2 (3 ꢂ 5 mL). The combined organic layers were dried
over MgSO4 and concentrated to dryness. The crude product was
purified by column chromatography on silica gel (cyclohexane/
EtOAc, 4:1) to afford 3 as a colorless oil (24 mg, 58%). Rf = 0.2
[a]
25 = +44.6 (c 0.83, CHCl3); 1H NMR (CDCl3, 400 MHz): d = 7.27–
D
7.15 (m, 5H), 4.18 (td, J = 5.7, 5.7, 1.5 Hz, 1H), 3.60 (d, J = 12.7 Hz,
1H), 3.45 (d, J = 12.7 Hz, 1H), 3.32–3.25 (m, 1H), 3.13 (dd, J = 8.9,
1.3 Hz, 1H), 3.06 (dd, J = 8.9, 5.6 Hz, 1H), 0.97 (d, J = 6.5 Hz, 3H);
13C NMR (CDCl3, 100 MHz): d = 137.9, 129.0, 128.3, 127.2, 66.8,
66.2, 61.3, 61.0, 13.2; ESIMS m/z 178.1 [M+H]+; HRMS (ES): m/z
calcd for C11H16NO [M+H]+: 178.1232; found 178.1229.
(cyclohexane/EtOAc 4:1); [a]
25 = +12 (c 1, CHCl3); 1H NMR (CDCl3,
D
400 MHz): d = 7.37–7.23 (m, 5H), 3.74–3.67 (m, 2H), 3.09 (ddd,
J = 6.8, 4.1, 2.8 Hz, 1H), 2.78–2.76 (m, 1H), 2.55–2.48 (m, 2H),
2.29 (s, 3H), 1.12 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d = 139.2, 128.4, 127.7, 126.3, 59.9, 58.3, 53.5, 43.6, 37.6, 12.2;
4.2.11. ((2R,3S)-1-Benzyl-3-methylaziridin-2-yl)methanol 17
Obtained as a by-product with 6 as a pale yellow oil. [a]
25 = +13
D
(c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d = 7.27–7.16 (m, 5H),
3.66 (dd, J = 11.4, 5.0 Hz, 1H), 3.47 (dd, J = 11.4, 6.1 Hz, 1H), 3.46
Please cite this article in press as: Géant, P.-Y.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.008

P.-Y. Géant et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
(s, 2H), 2.06 (s large, 1H), 1.76–1.69 (m, 2H), 1.14 (d, J = 5.6 Hz, 3H);
4.2.15. (2S,3S,9S,10S)-2,10-Bis-(dibenzylamino)-3,9-
dihydroxyundecan-6-one 24
13C NMR (CDCl3, 100 MHz): d = 139.5, 128.8, 128.3, 127.5, 64.6,
60.4, 44.5, 39.7, 13.7. ESIMS m/z 355.24 [2M+H]+; HRMS (ES): m/
z calcd for C11H16NO [M+H]+: 178.1232; found 178.1233.
Obtained as a by-product with 19 as a pale yellow oil (4 mg, 7%).
Rf = 0.08 (cyclohexane/EtOAc 4:1); [
a
]
25 = ꢀ37.5 (c 0.39, CHCl3); 1H
D
NMR (CDCl3, 400 MHz): d = 7.31–7.22 (m, 20H), 4.42 (br s, 2H),
3.80 (d, J = 13.3 Hz, 4H), 3.41 (td, J = 9.2, 2.4 Hz, 2H), 3.29 (d,
J = 13.3 Hz, 4H), 2.58–2.40 (m, 6H), 1.83–1.79 (m, 2H), 1.28–1.22
(m, 2H), 1.02 (d, J = 6.6 Hz, 6H); 13C NMR (CDCl3, 100 MHz):
d = 211.3, 139.0, 129.2, 128.6, 127.4, 70.0, 58.4, 53.4, 38.9, 27.6,
8.2; ESIMS m/z 593.3 [M+H]+.
4.2.12. (2S,3S)-2-(Dibenzylamino)hept-6-en-3-ol 21
At first, CuI (110 mg, 0.579 mmol) was flame-dried and cooled
under argon. Next, THF (1 mL) was added, and the suspension
was cooled at ꢀ40 °C. Allylmagnesium chloride (2 M in THF,
0.56 mL, 1.12 mmol) was added, and the solution was stirred at
ꢀ40 °C for 45 min. A solution of epoxide 2 (51 mg, 0.191 mmol)
in THF (2 mL) was added, and the stirring was continued at
ꢀ40 °C for 13 h. Saturated aqueous NH4Cl (5 mL) was added, the
aqueous phase was recovered and was extracted with EtOAc
(3 ꢂ 5 mL). The combined organic layers were dried over MgSO4
and concentrated in vacuo. The crude material was purified by col-
umn chromatography on silica gel (EtOAc/cyclohexane 20:1) to
afford 21 as a colorless oil (45 mg, 76%). Rf = 0.38 (cyclohexane/
4.2.16. (2S,3S)-N,N-Dibenzyl-3-(methoxymethoxy)hept-6-en-2-
amine 25
To a solution of 21 (28 mg, 0.090 mmol) in CH2Cl2 (2 mL) were
added MOMCl (0.04 mL, 0.530 mmol) and EtNiPr2 (0.09 mL,
0.517 mmol). The solution was heated at reflux for 16 h, and then
diluted with CH2Cl2 (10 mL), washed with water (3 ꢂ 5 mL), dried
over MgSO4 and concentrated. The crude product was purified by
column chromatography on silica gel (cyclohexane/EtOAc 10:1)
to afford 25 as a colorless oil (28 mg, 88%). Rf = 0.35 (cyclohex-
EtOAc 8:1);
[a]
25 = +52.5 (c 0.80, CHCl3); 1H NMR (CDCl3,
D
400 MHz): d = 7.35–7.24 (m, 10H), 5.88–5.78 (m, 1H), 5.03–4.93
(m, 2H), 4.51 (s, 1H), 3.85 (d, J = 13.3 Hz, 2H), 3.51 (td, J = 9.5,
2.4 Hz, 1H), 3.33 (d, J = 13.3 Hz, 2H), 2.58 (dq, J = 9.5, 6.7 Hz, 1H),
2.32–2.23 (m, 1H), 2.17–2.08 (m, 1H), 1.61–1.53 (m, 1H), 1.29–
1.19 (m, 1H), 1.04 (d, J = 6.7 Hz, 3H); 13C NMR (CDCl3, 100 MHz):
d = 139.1, 139.0, 129.2, 128.7, 127.4, 114.6, 70.3, 58.5, 53.4, 33.3,
30.2, 8.2; ESIMS m/z 310.2 [M+H]+; HRMS (ES): m/z calcd for
ane/EtOAc 10:1); [a]
25 = +19 (c 0.58, CHCl3); 1H NMR (CDCl3,
D
400 MHz): d = 7.43–7.24 (m, 10H), 5.75 (ddt, J = 16.9, 10.5, 6.4 Hz,
1H), 5.00–4.85 (m, 2H), 4.66 (d, J = 6.8 Hz, 1H), 4.62 (d, J = 6.8 Hz,
1H), 4.03 (d, J = 13.7 Hz, 2H), 3.57–3.35 (m, 6H), 2.98–2.76 (m,
1H), 2.06–1.59 (m, 4H), 1.18 (d, J = 6.9 Hz, 3H); 13C NMR (CDCl3,
100 MHz): d = 140.7, 138.8, 129.0, 128.1, 126.7, 114.3, 96.7, 82.2,
55.8, 55.1, 54.2, 30.8, 29.7, 9.4; ESIMS m/z 353.24 [M+H]+;
HRMS (ES): m/z calcd for C23H32 NO2 [M+H]+: 354.2433; found
354.2421.
C
21H28NO [M+H]+: 310.2171; found 310.2177.
4.2.13. 2-(Propan-2-ylidene)-1,1-dimethylhydrazine 23
A mixture of acetone (2 mL, 27.2 mmol) and N,N-dimethylhy-
drazine (2 mL, 26.2 mmol) was treated with MgSO4 (2 g). The mix-
ture was heated at reflux for 6 h and then allowed to cool to room
temperature and filtered. The excess acetone was removed under
reduced pressure, to give 23 as a colorless liquid (2.5 g, 95%). 1H
NMR (CDCl3, 400 MHz): d = 2.43 (s, 6H), 1.96 (s, 3H), 1.93 (s, 3H);
13C NMR (CDCl3, 100 MHz): d = 165.0, 47.2, 25.4, 18.3; ESIMS m/z
101.1 [M+H]+; HRMS (ES): m/z calcd for C5H12N2 [M+H]+:
101.1079; found 101.1072.
4.2.17. (5S,6S)-6-(Dibenzylamino)-5-(methoxymethoxy)heptan-
2-one 26
To a solution of 25 (72 mg, 0.204 mmol) in MeOH (2.5 mL) were
added PdCl2(CH3CN)2 (8 mg, 0.031 mmol) and CuCl2ꢁ2H2O (51 mg,
0.299 mmol). Next, O2 was bubbled through this suspension for
2.5 h at room temperature. The mixture was then filtered off and
concentrated in vacuo. The residue was dissolved in EtOAc
(5 mL), and H2O (5 mL) and ammonia (60% in water, 1 mL) were
added. The aqueous phase was recovered and extracted with EtOAc
(3 ꢂ 5 mL). The combined organic layers were dried over MgSO4
and concentrated. The crude material was purified by column
chromatography on silica gel (CH2Cl2/MeOH, 99:1) to give 26 as
a colorless oil (42 mg, 56%). Rf = 0.20 (cyclohexane/EtOAc 9:1);
4.2.14. (5S,6S)-6-(Dibenzylamino)-5-hydroxyheptan-2-one 19
n-Butyllithium (2.5 M in hexane, 0.4 mL, 1 mmol) was slowly
added to a solution of 23 (97 mg, 0.97 mmol) in THF (2 mL) at
0 °C. The solution was stirred at 0 °C for 1 h. A white precipitate
was formed. The solution was then warmed to room temperature,
and stirred for 10 min. A solution of epoxide 2 (49 mg, 0.183 mmol)
in THF (5 mL) was added, the mixture was stirred 6 h at room tem-
perature, and then quenched with saturated aqueous NH4Cl
(10 mL). The aqueous layer was recovered and extracted with
EtOAc (3 ꢂ 5 mL). The combined extracts were dried (MgSO4),
and concentrated under reduced pressure. The residue was dis-
solved in THF (2 mL), H2O (2 mL), and SiO2 (1 g) was added. The
mixture was stirred overnight, filtered off, and the phases were
separated. The aqueous layer was extracted with EtOAc
(3 ꢂ 2 mL). The combined organic layers were dried over MgSO4
and concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (cyclohexane/
EtOAc, 9:1) to give 19 as a colorless oil (32 mg, 54%). Rf = 0.28
[a]
25 = +14 (c 0.96, CHCl3); 1H NMR (CDCl3, 300 MHz): d = 7.37–
D
7.18 (m, 10H), 4.61 (d, J = 6.8 Hz, 1H), 4.55 (d, J = 6.8 Hz, 1H),
3.97 (d, J = 13.6 Hz, 2H), 3.40–3.31 (m, 6H), 2.73 (qd, J = 6.9,
4.1 Hz, 1H), 2.11–1.72 (m, 7H), 1.15 (d, J = 6.9 Hz, 2H); 13C NMR
(CDCl3, 75 MHz): d = 208.6, 140.7, 129.1, 128.2, 126.8, 96.7, 81.9,
55.8, 55.1, 53.9, 39.4, 29.8, 25.1, 9.3; ESIMS m/z 370.3 [M+H]+;
HRMS (ES): m/z calcd for C23H32NO3 [M+H]+: 370.2382; found
370.2379.
4.2.18. 2-(Butan-2-ylidene)-1,1-dimethylhydrazine 20a
A solution of 2-butanone (5 mL, 55.9 mmol) and N,N-dimethyl-
hydrazine (5 mL, 65.8 mmol) in CH2Cl2 (20 mL) was heated at
reflux for 6 h, and then allowed to cool to room temperature.
Water was then removed by the addition of MgSO4. After filtration,
the solvent and excess N,N-dimethylhydrazine were removed
under reduced pressure, to give 20a as a colorless liquid (5.2 g,
82%). Rf = 0.4 (cyclohexane/EtOAc 15: 1); 1H NMR (CDCl3,
300 MHz): d = 2.40–2.38 (m, 6H), 2.20–2.14 (m, 2H), 1.92–1.88
(m, 3H), 1.08–1.02 (m, 3H); 13C NMR (CDCl3, 75 MHz): d = 170.6,
169.0, 47.7, 47.2, 32.4, 24.7, 22.3, 16.2, 11.7, 11.2; ESIMS: m/
z = 115.1 [M+H]+; HRMS (ES): m/z calcd for C6H15N2 [M+H]+:
115.1235, found 115.1226.
(cyclohexane/EtOAc 4:1); [a]
25 = +26 (c 1, CHCl3); 1H NMR (CDCl3,
D
400 MHz): d = 7.33–7.22 (m, 10H), 4.46 (br s, 1H), 3.81 (d,
J = 13.2 Hz, 2H), 3.44 (td, J = 9.2, 2.6 Hz, 1H), 3.30 (d, J = 13.2 Hz,
2H), 2.62–2.46 (m, 3H), 2.08 (s, 3H), 1.86–1.82 (m, 1H), 1.33–
1.25 (m, 1H), 1.33–1.25 (m, 1H), 1.04 (d, J = 6.7 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): d = 209.1, 138.8, 129.1, 128.5, 127.3, 69.8, 58.2,
53.3, 39.6, 30.0, 27.4, 8.0; ESIMS m/z 326.2 [M+H]+; HRMS (ES):
m/z calcd for C21H28NO2 [M+H]+: 326.2120; found 326.2134.
Please cite this article in press as: Géant, P.-Y.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.008

8
P.-Y. Géant et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
4.2.19. (6S,7S)-7-(Dibenzylamino)-6-hydroxyoctan-3-one 18a
Oxirane opening: At first, nBuLi (2.5 M in hexane, 0.8 mL,
2 mmol) was slowly added to a solution of hydrazone 20a
(224 mg, 1.96 mmol) in THF (2 mL) at 0 °C. The mixture was stirred
at 0 °C for 1 h. A white precipitate was formed. The system was
then warmed to room temperature, and stirred for 10 min. A solu-
tion of epoxide 2 (48 mg, 0.179 mmol) in THF (5 mL) was added,
the mixture was stirred overnight at room temperature and then
quenched with saturated aqueous NH4Cl (10 mL). The aqueous
layer was recovered and extracted with EtOAc (3 ꢂ 5 mL). The
combined organic layers were dried over MgSO4, and concentrated
under reduced pressure.
concentrated under reduced pressure to afford pure 10 as a color-
less oil (13 mg, 75%). Rf = 0.12 (CH2Cl2/MeOH, 8:2 + 5% NEt3);
[a]
25 = +8.8 (c 1.1, CHCl3); 1H NMR (MeOD, 600 MHz): d = 3.81
D
(m, 1H), 3.21 (qd, J = 6.7, 1.3 Hz, 1H), 2.99–2.94 (m, 1H),
1.95–1.92 (m, 1H), 1.80–1.63 (m, 4H), 1.59–1.51 (m, 1H), 1.30 (d,
J = 6.7 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H); 13C NMR (MeOD,
150 MHz): d = 65.9, 60.0, 57.6, 31.0, 27.7, 23.1, 15.9, 10.0; ESIMS:
m/z = 144.1 [M+H]+; HRMS (ES): m/z calcd for C8H18NO [M+H]+:
144.1388, found 144.1389.
4.2.23. (2S,3S,6R)-6-Dodecyl-2-methylpiperidin-3-ol 7 [(+)-
deoxocassine]
Hydrolysis of hydrazone: the residue was dissolved in THF
(5 mL), H2O (5 mL), and then SiO2 (1 g) was added. The mixture
was stirred overnight, filtered off, and the aqueous layer was
recovered and extracted with EtOAc (3 ꢂ 5 mL). The combined
organic layers were dried over MgSO4 and concentrated under
reduced pressure. The crude product was purified by column chro-
matography on silica gel (cyclohexane/EtOAc, 9: 1) to give 18a as a
colorless oil (38 mg, 63%). Rf = 0.31 (cyclohexane/EtOAc, 9:1);
To a solution of 11b (36 mg, 0.075 mmol) in EtOH (1.5 mL) was
added Pd(OH)2/C (20%, 20 mg, 0.029 mmol), and the mixture was
placed under an atmosphere of H2. After 3 h at room temperature,
the mixture was filtered on short pad of silica and Celite, washed
with EtOH, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel
(EtOAc/MeOH 9:1 + 2% NEt3) to afford (+)-deoxocassine 1 as a
white solid (13 mg, 61%). Rf = 0.15 (EtOAc/MeOH, 9:1 + 2% NEt3);
[a
]
D
25 = +30.4 (c 0.92, CHCl3); 1H NMR (CDCl3, 300 MHz): d = 7.26–
[a]
25 = +11.6 (c 0.95, CHCl3); mp 49–51 °C; 1H NMR (CDCl3, 400 -
D
7.14 (m, 10H), 3.74 (d, J = 13.2 Hz, 2H), 3.32 (td, J = 2.5, 9.2 Hz,
1H), 3.23 (d, J = 13.3 Hz, 2H), 2.57–2.33 (m, 3H), 2.28 (qd, J = 1.7,
7.3 Hz, 2H), 1.84–1.73 (m, 1H), 1.28–1.16 (m, 1H), 0.98–0.91 (m,
6H); 13C NMR (CDCl3, 75 MHz): d = 211.8, 138.8, 129.0, 128.5,
127.3, 69.9, 58.2, 53.3, 38.2, 36.0, 27.5, 8.0, 7.8; ESIMS:
m/z = 340.2 [M+H]+; HRMS (ES): m/z calcd for C22H30NO2 [M+H]+:
340.2277, found: 340.2281.
MHz): d = 3.48–3.62 (m, 1H), 2.79 (qd, J = 6.5, 1.3 Hz, 1H), 2.60–
2.54 (m, 1H), 1.95–1.91 (m, 1H), 1.57–1.47 (m, 2H), 1.41–1.30
(m, 23H), 1.14 (d, J = 6.5 Hz, 3H), 0.82 (t, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): d = 68.1, 57.2, 55.8, 37.1, 32.1, 31.9, 29.8, 29.7,
29.7, 29.6, 29.4, 26.2, 25.9, 22.7, 18.8, 14.1; ESIMS: m/z = 284.2
[M+H]+; HRMS (ES): m/z calcd for C18H38NO [M+H]+ 284.2953,
found 284.2945.
Acknowledgments
4.2.20. Tetradecan-2-one 29
To
a
solution of pyridinium chlorochromate (765 mg,
Thanks are expressed to Mr. Pierre Sánchez for his help in
mass spectrometry analysis and to Aurélien Lebrun and
Karine Parra for recording some NMR spectra. We thank the
Ministère de l’Enseignement Supérieur et de la Recherche for
3.55 mmol) in CH2Cl2 (5 mL) was added tetradecan-2-ol (512 mg,
2.39 mmol) in CH2Cl2 (5 mL), at room temperature. The mixture
was stirred for 7 h, and then Et2O (10 mL) was added. The system
was stirred vigorously and filtered on a Celite and florisil pad.
The crude product was purified by column chromatography on
silica gel (cyclohexane/EtOAc 10:1) to give pure ketone 21 as a
colorless oil (482 mg, 95%). Rf = 0.7 (cyclohexane/EtOAc, 10:1);
1H NMR (CDCl3, 300 MHz): d = 2.35 (t, J = 2.75 Hz, 2H), 2.06
(s, 3H), 1.55–1.47 (m, 2H), 1.19 (br s, 18H), 0.81 (t, J = 6.6 Hz);
13C NMR (CDCl3, 75 MHz): d = 209.6, 44.1, 32.1, 30.1, 29.9, 29.8,
29.8, 29.7, 29.6, 29.6, 29.4, 24.1, 22.9, 14.3; ESIMS: m/z = 213.3
[M+H]+; HRMS (ES): m/z calcd for C14H28O [M+H]+: 213.2218,
found 213.2222.
providing
a research grant for the PhD thesis project of
P.Y.G and E.G.
References
1. (a) Serba, C.; Winssinger, N. Eur. J. Org. Chem. 2013, 4195–4214; (b) Shimokawa,
J. Tetrahedron Lett. 2014, 55, 6156.
2. Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
3. Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835.
4. Zappia, G.; Menendez, P.; Delle Monache, G.; Misiti, D.; Nevola, L.; Botta, B.
Mini-Rev. Med. Chem. 2007, 7, 389.
5. Salgado, A.; Boeykens, M.; Gauthier, C.; Declercq, J.-P.; De Kimpe, N.
Tetrahedron 2002, 58, 2763.
6. Viegas, C., Jr.; Bolzani, V. da. S.; Furlan, M.; Barreiro, E. J.; Young, M. C. M.;
Tomazela, D.; Eberlin, M. N. J. Nat. Prod. 2004, 67, 908. and references cited
therein.
4.2.21. 2-(Tetradecan-2-ylidene)-1,1-dimethyl-hydrazine 20b
To a solution of ketone 21 (455 mg, 2.14 mmol) and N,N-
dimethylhydrazine (0.25 mL, 3.29 mg) in CH2Cl2 (10 mL) was
added MgSO4 (500 mg). The mixture was heated at reflux over-
night, and then allowed to cool to room temperature. Water was
removed by addition of MgSO4. After filtration, the solvent and
excess N,N-dimethylhydrazine were removed under reduced pres-
sure, to give 20b as a colorless liquid (540 mg, 100%). Rf = 0.7
(cyclohexane); 1H NMR (CDCl3, 300 MHz): d = 2.40–2.36 (m, 6H),
2.18–2.10 (m, 2H), 1.91–1.88 (m, 3H), 1.49–1.44 (m, 2H), 1.23 (br
s, 18H), 0.85 (t, J = 6.7 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d = 169.9, 168.3, 47.7, 47.2, 44.0, 39.3, 32.1, 31.7, 30.0, 29.8, 29.8,
29.7, 29.7, 29.6, 29.5, 29.5, 29.4, 27.2, 26.7, 24.1, 22.9, 16.6, 14.3;
ESIMS: m/z = 255.3 [M+H]+; HRMS (ES): m/z calcd for C16H35N2
[M+H]+: 255.2800, found 255.2796.
7. For examples of chiral pool approaches in the synthesis of ‘all-cis’ 2-methyl-6-
substituted piperidin-3-ol alkaloids, see: (a) Hanessian, S.; Frenette, R.
Tetrahedron Lett. 1979, 20, 3391; (b) Kurihara, K.; Sugimoto, T.; Saitoh, Y.;
Igarashi, Y.; Hirota, H.; Moriyama, Y.; Tsuyuki, T.; Takahashi, T.; Khuong-Huu,
Q. Bull. Chem. Soc. Jpn. 1985, 58, 3337; (c) Kiguchi, T.; Shirakawa, M.; Ninomiya,
I.; Naito, T. Chem. Pharm. Bull. 1996, 44, 1282; (d) Kiguchi, T.; Shirakawa, M.;
Honda, R.; Ninomiya, I.; Naito, T. Tetrahedron 1998, 54, 15589; (e) Kumar, K. K.;
Datta, A. Tetrahedron 1999, 55, 13899; (f) Herdeis, C.; Schiffer, T. Tetrahedron
1999, 55, 1043; (g) Lee, H. K.; Chun, J. S.; Pak, C. S. Tetrahedron 2003, 59, 6445;
(h) Andrés, J. M.; Pedrosa, R.; Pérez-Encabo, A. Eur. J. Org. Chem. 2007, 1803.
8. For examples of asymmetric syntheses of ‘all-cis’ 2-methyl-6-substituted
piperidin-3-ol alkaloids, see: (a) Momose, T.; Toyooka, N. Tetrahedron Lett.
1993, 34, 5785; (b) Toyooka, N.; Yoshida, Y.; Momose, T. Tetrahedron Lett. 1995,
36, 3715; (c) Oetting, J.; Holzkamp, J.; Meyer, H. H.; Pahl, A. Tetrahedron:
Asymmetry 1997, 8, 477; (d) Momose, T.; Toyooka, N.; Jin, M. J. Chem. Soc.,
Perkin Trans. 1 1997, 2005; (e) Enders, D.; Kirchhoff, J. H. Synthesis 2000, 2099;
(f) Ma, D.; Ma, N. Tetrahedron Lett. 2003, 44, 3963; (g) Kandula, S. R. V.; Kumar,
P. Tetrahedron 2006, 62, 9942; (h) Leverett, C. A.; Cassidy, M. P.; Padwa, A. J. Org.
Chem. 2006, 71, 8591; (i) Kim, G.; Kim, N. Tetrahedron Lett. 2007, 48, 4481; (j)
Noël, R.; Vanucci-Bacqué, C.; Fargeau-Bellassoued, M.-C.; Lhommet, G. Eur. J.
Org. Chem. 2007, 476; (k) Raghavan, S.; Mustafa, S. Tetrahedron 2008, 64, 10055.
9. We have already described 7 and 8 in a short communication: Géant, P.-Y.;
Martínez, J.; Salom-Roig, X. J. Eur. J. Org. Chem. 2012, 62.
4.2.22. (2S,3S,6R)-6-Ethyl-2-methylpiperidin-3-ol 8
To a solution of 11a (37 mg, 0.109 mmol) in EtOH (1.5 mL) was
added Pd(OH)2/C (20%, 11 mg, 0.016 mmol), and the mixture was
placed under an atmosphere of H2. After 3 h at room temperature,
the mixture was filtered on Celite, washed with EtOH, and
Please cite this article in press as: Géant, P.-Y.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.008

P.-Y. Géant et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
9
10. Géant, P.-Y.; Martínez, J.; Salom-Roig, X. J. Eur. J. Org. Chem. 2011, 1300.
11.
-Bromo-a0-(R)-sulfinylketones 9 were prepared by condensation between the
19. Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, S.; Smith, A. D. J.
Chem. Soc., Perkin Trans. 1 2000, 3765.
20. (a) Thi ngoc Tam, N.; Magueur, G.; Ourévitch, M.; Crousse, B.; Bégué, J.-P.;
Bonnet-Delpon, D. J. Org. Chem. 2005, 70, 699; (b) Ho Oh, C.; Yun Rhim, C.; Ho
You, C.; Rai Cho, J. Synth. Commun. 2003, 4297.
21. An analytical sample of aziridinol 17 could be isolated (see Experimental part).
22. For a recent example of this type of additions, see: Silveira-Dorta, G.; Donadel,
O. J.; Martín, V. S.; Padrón, J. M. J. Org. Chem. 2014, 79, 6775.
a
corresponding racemic methylester and the lithium anion of (R)-methyl-p-
tolylsulfoxide (see Ref. 10).
12. (a) Bushnev, A. S.; Baillie, M. T.; Holt, J. J.; Menaldino, D. S.; Merrill, A. H., Jr.;
Liotta, D. C. Arkivoc 2010, 263; (b) Lagu, B. R.; Crane, H. M.; Liotta, D. C. J. Org.
Chem. 1993, 58, 4191; (c) Lagu, B. R.; Liotta, D. C. Tetrahedron Lett. 1994, 35,
4485.
13. (a) Solladié, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985, 25, 435; (b)
Kosugi, H.; Konta, H.; Uda, H. J. Chem. Soc., Chem. Commun. 1985, 211.
14. Concellón, J. M.; Bernad, P. L.; del Solar, V.; Suárez, J. R.; García-Granada, S.;
Díaz, M. R. J. Org. Chem. 2006, 71, 6420.
23. Andrés, J. M.; Pedrosa, R.; Pérez-Encabo Eur. J. Org. Chem. 2007, 1803; For a
review concerning Wacker reaction and related alkene oxidation reactions,
see: Takacs, J. M.; Jiang, X. Curr. Org. Chem. 2003, 7, 369.
24. Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506.
25. Lazny, R.; Nodzewska, A. Chem. Rev. 2010, 110, 1386.
15. Grayson, E. J.; Davis, B. G. Org. Lett. 2005, 7, 2361.
16. Tenca, C.; Dossena, A.; Marchelli, R.; Casnati, G. Synthesis 1981, 141.
17. The scope of this reaction is under investigation in our laboratories. For a
reference of the deprotection of MOM moiety under neutral conditions, see:
Miyake, H.; Tsumara, T.; Sasaki, M. Tetrahedron Lett. 2004, 45, 7213.
18. (a) Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. Tetrahedron 1985, 41, 163; (b)
Prévost, S.; Phansavath, P.; Haddad, M. Tetrahedron: Asymmetry 2010, 21, 16;
(c) Ayad, T.; Faugeroux, V.; Génisson, Y.; André, C.; Baltas, M.; Gorrichon, L. J.
Org. Chem. 2004, 69, 8775; (d) Vargas, G. E.; Afonso, M. M.; Palenzuela, J. A.
Synlett 2009, 1471.
26. For other examples of hydrazone alkylation by oxiranes, see: (a) Nishiyama, T.;
Woodhall, J. F.; Lawson, E. N.; Kitching, W. J. Org. Chem. 1989, 54, 2183; (b)
Taber, D. F.; Song, Y. J. Org. Chem. 1997, 62, 6603; (c) Enders, D.; Breuer, I.;
Nühring, A. Eur. J. Org. Chem. 2005, 2677.
27. Myers, A. G.; McKinstry, A. L. J. Org. Chem. 1996, 61, 2428.
28. For other synthesis of (+)- and (ꢀ)-deoxocassine, see Refs. 7b,8h and 8f–h,j,k.
29. Paterne, M.; Dhal, R.; Brown, E. Bull. Chem. Soc. Jpn. 1989, 62, 1321.
Please cite this article in press as: Géant, P.-Y.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.008