Allenylzincs and tert-butylsulfinylimines: A fruitful marriage for synthesis

Article abstract of DOI:10.1016/j.tetasy.2010.04.044

The stereoselective synthesis of alkynyl 1,2-amino alcohols by the addition of 3-chloro-and 3-methoxymethoxy-allenylzincs to chiral tert- butylsulfinylimines is described. The methodology is applicable to the preparation of alkynyl 2-amino-1,3-diols (O,N,O stereotriads) using α-alkoxy tert-butylsulfinylimines as chiral starting materials. The scope and limitations of the methodology along with recent applications to the efficient asymmetric syntheses of natural and/or bioactive alkaloids and polyhydroxylated alkaloids are presented.

Full text of DOI:10.1016/j.tetasy.2010.04.044

Tetrahedron: Asymmetry 21 (2010) 1147–1153
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Tetrahedron: Asymmetry report number 133
Allenylzincs and tert-butylsulfinylimines: a fruitful marriage for synthesis
*
*
Candice Botuha, Fabrice Chemla , Franck Ferreira , Julien Louvel, Alejandro Pérez-Luna
UPMC–Univ Paris 6 and CNRS, UMR 7201, Institut Parisien de Chimie Moléculaire (FR 2769), case 183, 4 place Jussieu, F-75005 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of alkynyl 1,2-amino alcohols by the addition of 3-chloro- and 3-methoxy-
methoxy- allenylzincs to chiral tert-butylsulfinylimines is described. The methodology is applicable to
the preparation of alkynyl 2-amino-1,3-diols (O,N,O stereotriads) using a-alkoxy tert-butylsulfinylimines
as chiral starting materials. The scope and limitations of the methodology along with recent applications
to the efficient asymmetric syntheses of natural and/or bioactive alkaloids and polyhydroxylated alka-
loids are presented.
Received 2 April 2010
Accepted 19 April 2010
Available online 21 June 2010
Dedicated to Henri Kagan on the occassion
of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147
2. Synthesis of alkynyl 1,2-amino alcohols. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147
2.1. By ring-opening of alkynyl aziridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147
2.2. By direct addition to tert-butylsulfinylimines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149
3. Synthetic applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1150
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
1. Introduction
OH
H
X
S
BrZn
TMS
RL
RS
N
The 1,2-amino alcohol pattern is found in a number of naturally
occurring and/or biologically active molecules such as alkaloids,
antibiotics, aminosugars, and enzyme inhibitors. As a consequence,
methods for its stereoselective preparation have been the subject
of frequent publications.1 By contrast, despite their high synthetic
potential, little is reported on the stereoselective synthesis of
highly functionalized alkynyl 1,2-amino alcohols. Commonly,
these compounds are obtained by the addition of propargyl/alle-
O
•
+
RS
RL
TMS
NH2
( )-2a: X = Cl
( )-2b: X = OMOM
1
3
Scheme 1. Retrosynthetic scheme for alkynyl 1,2-amino alcohols.
Herein, we report our advances in this area and some recent
applications in natural product synthesis.
nylmetals to a
-amino aldehydes.2,3
Over the past 10 years, our group has been involved in the
development of new methods for the stereoselective preparation
of synthetically useful compounds.4 In a continuation of this work,
we reasoned that alkynyl 1,2-amino alcohols of structure 1 could
be obtained stereoselectively by the addition of 3-heterosubstitut-
ed allenylzincs ( )-2 to enantiopure tert-butylsulfinylimines 3
where RL is the large substituent and RS the small one (Scheme 1).
2. Synthesis of alkynyl 1,2-amino alcohols
2.1. By ring-opening of alkynyl aziridines
Aziridines are well documented to undergo in most cases regio-
and stereoselective nucleophile ring-opening reactions.5 We have
previously shown that racemic alkynyl aziridines6 could be easily
obtained by the stereoselective addition of 3-chloro allenylzinc
( )-2a to achiral imines.4c In our ongoing works, we then wished
to take advantage of the high electrophilicity of these aziridines
* Corresponding authors. Tel.: +33 (0)14 427 7567; fax: +33 (0)14 427 6436
(F.C.); tel.: +33 (0)14 427 5571; fax: +33 (0)14 427 7567 (F.F.)
E-mail addresses: fabrice.chemla@upmc.fr (F. Chemla), franck.ferreira@upmc.fr
(F. Ferreira).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.044

1148
C. Botuha et al. / Tetrahedron: Asymmetry 21 (2010) 1147–1153
to produce alkynyl 1,2-amino alcohols 1 by the regio- and stereo-
selective ring-opening reaction (at the propargylic position) of dia-
The high trans selectivity was assumed to result from the nucle-
ophilic attack of the (aS)-enantiomer of allenylzinc ( )-2a from the
less hindered si face of imine (R)-3 through the chelated transition
state model M1 (Scheme 3) wherein the zinc atom of the metallic
species is coordinated (in a four-membered metallacycle) by both
the nitrogen and the oxygen atoms of the sulfinyl auxiliary.
We further reasoned that using Lewis acids could have some
influence on the stereoselective outcome of the reaction by pre-
venting the coordination of the zinc atom. Unfortunately, pre-coor-
dination of imines with various Lewis acids afforded either
aziridines trans-4 (with ZnBr2, BF3ÁEt2O, or MAD12) or unidentified
by-products (with TiCl4). We then proceeded under the assump-
tion that HMPA13 would be able to coordinate the zinc atom of
( )-2a (Scheme 4).14 To our delight, when reacting imine 3a with
1 equiv of ( )-2a in Et2O in the presence of 8 equiv of HMPA, a
49:51 trans:cis ratio was obtained suggesting that, under these
conditions, allenylzinc ( )-2a is configurationally stable with re-
spect to the time scale defined by the reaction rate (Table 2, entry
1). Using larger amounts of HMPA allowed the stereoselectivity to
be improved. The best result was observed when 60 equiv of HMPA
were used leading to a 34:66 trans:cis mixture (Table 2, entry 2).
Everything then proceeded as if the rate of racemization of ( )-2a
were higher in the presence of 60 equiv of HMPA than in the pres-
ence of 8 equiv. As expected,10 employing 6 equiv of ( )-2a allowed
a high dynamic kinetic resolution to take place giving a 16:84
trans:cis mixture of aziridines (Table 2, entry 3). Under the best
conditions (6 equiv of ( )-2a, 60 equiv of HMPA, Et2O, from
À15 °C to rt), imines 3 possessing primary R substituents were eas-
ily converted into the corresponding aziridines with fair to high
selectivities in favor of the cis isomers (up to 89:11 dr). In all the
cases, the major aziridines cis-4 were isolated as diastereomerical-
ly (>98:02 dr) and enantiomerically (>99% ee) pure compounds in
stereo- and enantioenriched alkynyl aziridines
4 with O-
nucleophiles (Scheme 2).7
O-nucleophiles
P
OH
ring-opening reaction
N
R1
R2
R1
R2
TMS
NH2
1
4
TMS
>99% ee, >98:2 dr
Scheme 2. Alkynyl 1,2-amino alcohols from aziridines.
With the aim of synthesizing alkynyl aziridines 4 in diastereo-
and enantiopure form, we thus studied the stereoselective addition
of 3-chloro allenylzinc ( )-2a to enantiopure imines 3 (Scheme 3).8
Since allenylzinc ( )-2a could only be prepared in a racemic form
by the deprotonation (n-BuLi, 1 equiv of TMEDA, Et2O, À80 °C,
15 min) of 3-chloro-1-trimethylsilylprop-1-yne and subsequent
transmetallation of the intermediate allenyllithium (ZnBr2, Et2O,
À80 °C, 10 min), we investigated conditions for achieving a kinetic
resolution. We found that 6 equiv of ( )-2 in Et2O at room temper-
ature were necessary to obtain aziridines 4 with excellent trans:cis
ratios (up to 94:6) from enantiopure imines 3 (Table 1). In all cases,
the stereoselectivity was very close to that observed with racemic
imines9 (corresponding to the upper limit ratio according to Hoff-
mann’s studies on the configurational stability of organometallic
reagents10) which strongly suggests that ( )-2a could be regarded
as partially configurationally stable with respect to the time scale
defined by the reaction rate. Thus, under these conditions, trans
alkynyl aziridines 4 were isolated as diastereomerically (>98:02
dr) and enantiomerically (>99% ee) pure compounds in good iso-
lated yields (50–87%) after silica gel chromatography.11
H
BrZn
TMS
•
O
S
N
Cl
( )-2a
(6 equiv)
S
O
H
N
BrZn
•
2a
O
Et2O, HMPA (60 equiv)
S
N
H
R
TMS
Cl
R
( )-
S
—15 ºC then rt
(see Table 2)
(R)-3
>99% ee
O
RL
RS
N
(6 equiv)
TMS
cis-4, 50—64%
Et2O, rt
(see Table 1)
RL
RS
(R)-3
>99% ee
O
H
•
H
R
S
TMS
trans-4, 50—87%
N
Cl
via M2 :
RS
H
RL
Cl
•
S
TMS
BrZn
N
O
via M1 :
BrZn
Scheme 4. Synthesis of cis aziridines.
TMS
Scheme 3. Synthesis of trans aziridines.
Table 2
Synthesis of aziridines cis-4 produced via Scheme 4
Entry
Imine
R
trans:cisa
Yieldb (%)
49:51c
34:66d
16:84
16:84
11:89
22:78
29:71
13:87
29:71
27:73
nd
nd
54
55
64
56
62
56
50
60
Table 1
Synthesis of aziridines trans-4 produced via Scheme 3
1
2
3
4
5
6
7
8
9
3a
3a
3a
3b
3h
3i
3j
3k
3l
n-Pr
n-Pr
n-Pr
(E)-Crotyl
Me
Entry
Imine
RL
RS
trans:cisa
Yieldb (%)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
n-Pr
(E)-Crotyl
i-Pr
c-Hexyl
Ph
Ph
H
H
H
H
89:11 (90:10)
90:10 (94:06)
94:06 (96:04)
90:10 (90:10)
86:14 (91:09)
90:10 (91:09)
—
61
64
69
58
50
69
87
n-Hept
(E)-nC5H11CH@CH
(E)-PhCH@CH
Ph(CH2)2
(E)-nC5H11C„C
H
Me
n-Pent
10
3m
3g
n-Pent
Selectivities measured by 1H NMR on the crude reaction mixtures. Dr values of
a
Selectivities were measured by 1H NMR on the crude reaction mixtures.
the major cis isomers measured by 1H NMR were >98:02.
a
b
Selectivities obtained with racemic imines 3 are indicated in parentheses. Dr values
Isolated yields in purified major cis isomers.
Reaction run with 1 equiv of ( )-2a in the presence of 8 equiv of HMPA.
Reaction run with 1 equiv of ( )-2a in the presence of 60 equiv of HMPA.
of the major trans isomers measured by 1H NMR were >98:02.
c
b
d
Isolated yields in purified major trans isomers.

C. Botuha et al. / Tetrahedron: Asymmetry 21 (2010) 1147–1153
1149
good yields (50–64%) after silica gel chromatography.15 It is worth
noting that no reaction occurred with secondary R substituents un-
der these conditions (Scheme 4).
The formation of the major cis isomers under the above-men-
tioned conditions has been explained by the synclinal transition
state model M2 in which the imine adopts its most stable confor-
mation due to an important nN?rÃS—O hyperconjugative interaction
(Scheme 4). In such a situation, the (aS)-enantiomer of allenylzinc
( )-2a approaches from the re face of imine (R)-3 by minimizing
the steric interaction between the chlorine atom and the sulfinyl
auxiliary.
Having in hands a general method for the stereoselective prep-
aration of either trans or cis alkynyl aziridines, we then undertook
studies on their ring-opening reactions with oxygen nucleophiles.
Running the reaction with TFA/H2O,16 BF3ÁEt2O then H2O, or
HClO4/H2O17 failed to produce the desired alkynyl 1,2-amino alco-
hols. By contrast, treating alkynyl aziridines ent-4 overnight with
1 equiv of PTSA in a refluxing 7:1 MeCN/H2O mixture18 directly
afforded the corresponding alkynyl 1,2-amino alcohols 1 as the re-
sult of the aziridine-ring opening with H2O and concomitant nitro-
gen deprotection (Scheme 5).
However, this methodology failed when applied to imines substi-
tuted with vinylic or aromatic side chains, or bearing a quaternary
carbon at the propargylic position. We then investigated an alter-
native method applicable to such unsaturated and hindered imines
using 3-methoxymethoxy allenylzinc ( )-2b (Scheme 6, 1st step).20
In all the cases, the reaction was run with 4 equiv of ( )-2b gener-
ated in situ in racemic form by the deprotonation of the corre-
sponding alkynyl ether (s-BuLi, TMEDA, Et2O, À80 °C, 1 h) and
subsequent transmetallation (ZnBr2, Et2O, À80 °C, 15 min). This
afforded 1,2-sulfinamido alkyl ethers 5 with high stereoselectivity
(>98:02) in favor of the anti isomers from imines 3 (Table 4). Under
these conditions, TMEDA used for the deprotonation step was
demonstrated to have a great influence on both the kinetics and
the stereoselectivity of the reaction. Indeed, when performing the
reaction in the presence of 4 equiv of TMEDA (Method A), only a
conversion of 47% was reached within 3 h at À80 °C from imine
3a, albeit with a >98:02 dr (Table 4, entry 1). Conversely, the use
H
BrZn
TMS
•
OMOM
OMOM
RL
( )-2b
(4 equiv)
S
O
N
RS
(S)-3
>99% ee
Et2O, TMEDA
—80 ºC, 1 h
(see Table 4)
TMS
RS
HN
RL
O
OH
PTSA (1equiv)
MeCN, H2O
S
S
N
TMS
R1
R2
O
R2
R1
anti-5, 41—94%
reflux, overnight
(see Table 3)
TMS
H2N
Br
Li
ent-4
1, 60–73%
O
O
HCl, MeOH
reflux, 1 h
>99% ee, >98:02 dr
RS
O
S
Scheme 5. Aziridine ring-opening reaction.
via M3 :
N
H
OH
RL
•
RL
BrZn
TMS
The reaction occurred in a highly regio- and stereoselective man-
ner (P95:05) in the case of 2,3-disubtituted aziridines which pos-
sess only saturated R1 or R2 = H substituents (Table 3). In all these
cases, 1,2-amino alcohols 1 were formed through the nucleophilic
attack of H2O at the propargylic carbon (which is the more electro-
philic center) of the aziridines. Thus, under these conditions, isomers
anti-1 and syn-1 were obtained selectively from trans-4 and cis-4
aziridines, respectively, in good isolated yields (60–73%). On the
other hand, with 2,3,3-trisubstituted aziridines (R1 and R2 – H)
low regioselectivity was observed, whereas aziridines bearing
unsaturated R1 or R2 substituents only led to unidentified
products.19
TMS
RS
H2N
anti-ent-1, 66—87%
Scheme 6. Synthesis of anti-1,2-amino alcohols.
Table 4
Synthesis of 1,2-amino alcohols ent-1 produced via Scheme 6
Entry
Imine
RL
RS
Methoda
Yieldsb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
3a
3a
3a
3b
3c
3d
3e
3f
3h
3l
3n
3o
3p
n-Pr
n-Pr
n-Pr
(E)-crotyl
i-Pr
c-Hexyl
Ph
Ph
H
H
H
H
H
H
H
Me
H
H
H
H
H
A
B
C
B
B
B
B
B
C
C
C
B
B
47c
100d
82 (78)
77 (73)
83 (81)
81 (86)
94 (86)
41 (87)
94e
Table 3
Synthesis of 1,2-amino alcohols 1 produced via Scheme 5
Entry
ent-4
R1
R2
1a
Yieldb (%)
1
2
3
4
5
6
7
8
trans-3a
cis-3a
trans-3c
trans-3d
trans-3h
cis-3h
n-Pr
H
H
anti-1a
syn-1a
anti-1c
anti-1d
anti-1h
syn-1h
anti-1i
syn-1i
66
71
70
73
64
66
60
66
n-Pr
H
H
Me
i-Pr
c-Hexyl
Me
Ph(CH2)2
TBSOCH2
MeO2C(CH2)3
Cl(CH2)4
78 (66)
84 (81)f
88
H
90g
H
Me
H
n-Hept
trans-3i
cis-3i
n-Hept
H
a
Method for the first step. Method A: reaction run in the presence of 4 equiv of
TMEDA with rapid (<2 min) addition of imine 3. Method B: reaction run in the
presence of 0.4 equiv of TMEDA with rapid (<2 min) addition of imine 3. Method C:
reaction run in the presence of 0.4 equiv of TMEDA with slow addition of imine 3
over a period of 45 min.
a
Regio- and stereoselectivities measured by 1H NMR on the crude reaction
mixtures were P95:05.
b
Isolated yields in purified products 1.
b
Isolated yields in purified products 5 from 3. In parentheses are given the iso-
lated yields in 1 from 5. Stereoselectivities measured by 1H NMR on the crude
reaction mixtures were >98:02 unless otherwise stated.
2.2. By direct addition to tert-butylsulfinylimines
c
Converion based on recovered starting imine 3 after 3 h of stirring at À80 °C.
d
The stereoselectivity was 89:11.
The stereoselective preparation of alkynyl 1,2-amino alcohols 1
through the addition of 3-chloro allenylzinc ( )-2a to imines 3 and
subsequent ring opening of the resulting aziridines 4 thus ap-
peared to be synthetically useful with a wide range of imines.
e
The stereoselectivity was 93:07.
The second reaction was run for 2 h at reflux. The TBS–ether was concomitantly
f
deprotected giving the free primary alcohol.
g
The stereoselectivity was 96:4.

1150
C. Botuha et al. / Tetrahedron: Asymmetry 21 (2010) 1147–1153
of 0.4 equiv of TMEDA (Method B) allowed complete conversion to
be attained within 1 h at –80 °C, but with a lower 89:11 stereose-
lectivity (Table 4, entry 2).
Finally, the best results were obtained when imine 3a was
slowly added at –80 °C over a period of 45 min (Method C) to an
etheral solution of allenylzinc ( )-2b. Thus, both complete conver-
sion and high stereoselectivity were observed within 1 h at –80 °C
(Table 4, entry 3).
All of these observations suggest that allenylzinc ( )-2b is not
completely configurationally stable in the time scale defined by
the rate of its reaction with imine 3a under these conditions.10
The same process (Method C) was applied to other primary imines
in order to produce the corresponding anti isomers 5 with high ste-
reoselectivity (Table 4, entries 9–11). By contrast, with all other
less reactive imines, no slow addition was necessary to reach an
excellent anti stereoselectivity (Table 4, entries 4–8, 12, and 13).
In all the cases, alkynyl 1,2-sulfinamido alkyl ethers anti-5 were
isolated in good to excellent yields (41–94%) with high stereoselec-
tivity (P 93:7 dr: >99% ee) after silica gel chromatography (>98:02
dr and >99% ee).
In all the cases, the stereoselectivity of the addition was excel-
lent and independent of the stereocenter configuration, whatever
a
the protecting group (TBS or Bn) on the oxygen atom. With imines
6a and 6b, the stereoselectivity (explained by a transition state
model analogous to M3) is consistent with the inherent selectivity
provided both by the sulfinyl group and the Felkin–Ahn model
which furnishes Felkin adducts anti,syn-7a and 7b through the
nucleophilic attack of ( )-2b from the si face of the imine. Interest-
ingly, under the same conditions, the si face of diastereoisomeric
imine 6c is also attacked by ( )-2b giving the anti-Felkin product
anti,anti-7c with a high selectivity, which indicates that the inher-
ent diastereofacial selectivity of the chiral auxiliary overrides the
selectivity provided by Felkin–Anh control.
3. Synthetic applications
Having in hands an efficient method for the stereoselective syn-
thesis of highly functionalized alkynyl 1,2-amino alcohols, we
investigated the synthesis of natural and/or bioactive products in
which the 1,2-amino alcohol motif can be found. The first synthesis
The stereoselectivity of the reaction was assumed to arise from
transition state model M3 wherein the imine adopts its less ener-
getic conformation. In M3, because of the possible chelation of a lith-
ium cation by both the oxygen atoms of the MOM-ether moiety and
thesulfinyl auxiliary, the (aS)-enantiomer of( )-2b approaches from
the si face of imine (S)-3 which corresponds to an anti relationship
between the RL substituent of the imine and the MOM-ether moiety
(Scheme 6). Surprisingly, and opposite to what we had previously
observed with ( )-2a, using HMPA in the reaction of ( )-2b with imi-
nes 3 did not allow the stereoselectivityto be switched in favor of the
isomeric syn-1,2-sulfinamido alkyl ethers.
that we reported was that of (À)-
a-conhydrine, a piperidine alka-
loid isolated from the seeds and leaves of hemlock Conium macul-
atum L.23 The key step of our synthesis was the high yielding
stereoselective preparation of alkynyl 1,2-sulfinamido alkyl ether
5o (see Table 4, entry 12) which possesses the two stereogenic cen-
ters of the target molecule. The piperidine ring was elaborated
through the selective deprotection of the nitrogen atom of 5o with
methanolic HCl at 0 °C and subsequent condensation of the result-
ing free amine onto the ester moiety under basic treatment. Clas-
sical chemical transformations then allowed (À)-
a-conhydrine to
be obtained in 7 steps and 41% overall yield (Scheme 8).24
Alkynyl 1,2-amino alcohols were finally obtained by treating
compounds 5 with methanolic HCl at reflux (Scheme 6, 2nd step).
Usual basic work-up then allowed crude 1,2-amino alcohols ent-1
to be obtained in high purity (>90%). They were further isolated in
good to excellent yields (66–87%) as diastereo- and enantiopure
products after chromatography over silica gel (Table 4).21
OMOM
S
O
( )-2b
N
CO Me
3
2
MeO2C
TMS
88%
HN
H
3
The methodology was generalized to a-chiral imines in order to
S
(S)-3o
access to 2-amino-1,3-diol subunits which constitute an important
pattern found in many natural molecules of biological interest, such
as indolizidine and pyrrolizidine alkaloids. Thus, performing the
O
anti-5o.
1. TBAF
reaction between
a-alkoxy imines 6 and 4 equiv of ( )-2b (Et2O,
OMOM
OH
HN
0.4 equiv of TMEDA, –80 °C, 2 h) afforded the expected O,N,O-stereo-
triads 7 in a highly stereoselective manner (Scheme 7).22
1. HCl, 0 ºC
2. H2, Pd/C
2. Et3N
78%
3. LiAlH4
TMS
HN
O
4. HCl, 65 ºC
74%
H
BrZn
TMS
(—)-α-conhydrine
•
MOMO
OR
OMOM
2b
( )-
Scheme 8. Synthesis of (À)-
a
-conhydrine.
S
O
(4 equiv)
N
TMS
HN
O
It is also possible to functionalize the alkynyl moiety for
homologation of the carbon chain through reaction with a chlo-
roformate. This was exemplified by the synthesis of (À)-1-
hydroxyquinolizidinone, an intermediate25 of (À)-epiquinamide,
a potential lead for the development of new therapeutics for
neuronal receptors,26,27 and (À)-homopumiliotoxin 223G, which
exhibits myotonic and cardiotonic activity26 (Scheme 9). The
key step of this synthesis was the formation of 1,2-sulfinamido
alkyl ether 5p (see Table 4, entry 13) with a high stereoselectiv-
ity (96:04 dr). The bicyclic core of the target molecule was then
constructed by the intramolecular displacement of the chlorine
atom by the sodium amide, generated upon treatment of 5p with
NaH/15-crown-5 ether, and then condensation of the free sec-
ondary amine of 8 to the propiolic ester moiety. Following this
synthetic scheme, (À)-1-hydroxyquinolizidinone was obtained
in 6 steps and 34% overall yield.28
Et2O, TMEDA
—80 ºC, 2 h
H
S
OR
anti,syn-7a, 77%
anti,syn-7b, 76%
(S,S)-6a: R = TBS
(S,S)-6b: R = Bn
>99% ee
H
BrZn
TMS
•
MOMO
OTBS
Ph
OMOM
( )-2b
(4 equiv)
S
O
N
TMS
HN
O
Ph
Et2O, TMEDA
—80 ºC, 2 h
H
S
OTBS
(R,S)-6c
>99% ee
anti,anti-7c, 91%
Scheme 7. Access to O,N,O-stereotriads.

C. Botuha et al. / Tetrahedron: Asymmetry 21 (2010) 1147–1153
1151
and the formal synthesis of L-1-deoxynojirimycins (L-DNJ), inhibi-
tors of human lysosomal
-mannosidases,30 by combining our
methodology with the ring-closing metathesis reaction. The two
key steps of both syntheses were the highly stereoselective forma-
tion of 1,2-sulfinamido alkyl ethers 5e and 5n (see Table 4, entries
7 and 11) and the ring-closing metathesis reaction of N-allylamines
1. NaH, 15-C-5
2. (i) n-BuLi
(ii) ClCO2Me
OMOM
HN
a
S
O ( )-2b
N
Cl
4
Cl
TMS
3. HCl, 0 ºC
60%
90%
H
4
S
(S)-3p
O
9
using Grubbs 2nd generation catalyst at 40 °C in CH2Cl2
anti-5p, 96:04 dr
(Scheme 10). This allowed to access compound 11 in 7 steps and
56% yield,31 and compound 12 in 6 steps and 38% yield32 using
mainstream chemistry.
OMOM
OH
1. H2, Pd/C
Our methodology was also successfully applied in combination
with the cross-metathesis reaction in the synthesis of four sphing-
oid-type bases. These compounds are found in a number of bioac-
tive products and more particularly in ceramides and
sphingolipids.33 Amongst them, sphinganine is of particular inter-
est as the biogenetical precursor of sphingosine, the most preva-
lent sphingoid base.34 The hydrolysis product of clavaminol-H,
like almost all of its congeners, has been recently discovered and
has been shown to possess high cytotoxic properties against a wide
range of tumor cell lines.35 The same promising cytotoxic activity
has also been reported for unnatural and natural spisulosines
ES271 and ES285.36 We have succeeded into developing a straight-
forward synthesis of these compounds in which the long carbon
chain is elaborated by cross-metathesis employing Hoveyda–Grub-
bs 2nd generation catalyst and the appropriate terminal long-chain
alkenes at 40 °C in CH2Cl2. Following our synthetic scheme, all of
these sphingoid-type bases have been prepared in 6 steps from
imines 3h and 3n (see Table 4, entries 9 and 11) in >56% overall
yields (Scheme 11).37
MeO2C
HN
N
2. HCl, 65 ºC
64%
8
O
(—)-1-hydroxyquinolizidinone
ref25
OH
N
NHAc
N
(—)-epiquinamide
(—)-homopumuliotoxin 223G
Scheme 9. Synthesis of (À)-1-hydoxyquinolizidinone.
More recently we reported the synthesis of a known advanced
key intermediate of various human non-peptide NK-1 receptors,29
OMOM
1. ( )-2b
2. TBAF or K2CO3, MeOH
R
S
O
N
N
OMOM
3. H2, Lindlar Pd
4. NaH, allylBr
R = Ph, 66%
1. ( )-2b
2. TBAF or K2CO3,MeOH
S
R
H
S
R
O
N
O
(R)-3e: R = Ph
(R)-3n: R = OTBS
9
3. H2, Lindlar Pd
HN
13
R = OTBS, 51%
R
H
S
R = Me, 94%, 91:09 dr
R = OTBS, 78%.
(R)-3h: R = Me
(R)-3n: R = OTBS
O
OMOM
R
Grubbs II
CH2Cl2, 40 ºC
Hoveyda—Grubbs II
CH3(CH2)n
CH2Cl2, 40 ºC
N
S
R = Ph, 95%
R = OTBS, 91%
OMOM
R
O
10
CH3(CH2)n
R
HN
n
Yield (%)
E:Z
R
S
OH
Ph
14
ref 29
>98:02
>98:02
90:10
Me
Me
TBSOCH2
11 67
12 72
6
1. H2, Raney Ni
O
Y
10
R = Ph
Ph
2. HCl, 65 ºC
3. Et3N, Boc2O
89%
NBoc
78
11
NH
(+)-LP-733,060
Y = NH, R = 2-MeO (+)-CP-99,994
86:14
TBSOCH2 12 78
OH
Y = O,R = 3,5-CF3
1. HCl, 65 ºC
2. H2, Raney Ni
14
R = Me
CH3(CH2)n
(+)-CP-122,721
Y = NH, R = 2-MeO
3-OCF3
NH2
ES271 (n = 11): 93%
ES285 (n = 12): 92%
OH
OH
HO
OH
NH
1. H2, Raney Ni
2. HCl, 65 ºC
14
HO
• HCl
OH
CH3(CH2)n
OH
OH
R = OTBS
L-allo-DNJ
NH2
ref30
1. HCl, 65 ºC
10
clavaminol-H hydrolysis product•HCl (n = 6): 92%
sphinganine•HCl (n = 12): 92%
NBoc
OH
OH
2. Et3N, Boc2O
R = OTBS
HO
HO
82%
12
Scheme 11. Syntheses of sphingoid-type bases.
NH
Very recently, we have undertaken the stereoselective forma-
tion of 2-amino-1,3-diols for the synthesis of bioactive polyhydr-
oxylated alkaloids, such as indolizidine and pyrrolizidine
L-manno-DNJ
Scheme 10. Syntheses of human non-peptide NK-1 receptors and L-DNJ.

1152
C. Botuha et al. / Tetrahedron: Asymmetry 21 (2010) 1147–1153
1. TsCl
2. LiCl
S
O
N
2b
( )-
OTBDPS
3. TBAF
4. Swern ox.
5. (S)-sulfinamide
84%
H
OH OPMB
Cl
OPMB
(S,S)-6d
61%
MOMO
MOMO
OPMB
OPMB
1. NaH, 15-C-5
2. H2, Lindlar Pd
Cl
N
3. HCl, 0 °C
2. Et3N, allylBr
TMS
HN
S
15
O
67%
anti,syn-7d
OH
MOMO
OH
1. OsO4
2. HCl, 65 °C
OPMB
HO
HO
Grubbs II
N
3. H2, Pd/C
4. Dowex
toluene, 100°C
80%
N
16
(+)-6-epi-castanospermine
30%
Scheme 12. Synthesis of (+)-6-epi-castanospermine.
2. For
a recent review, see: Guillarme, S.; Plé, K.; Blanchet, A.; Liard, A.;
alkaloids, in which such an O,N,O-stereotriad is found. In this con-
text, we have developed a synthesis of (+)-6-epi-castanospermine,
extracted from Castanospermum Australe, and which has been thor-
oughly studied for its biological properties such as its potency to
Haudrechy, A. Chem. Rev. 2006, 106, 2355–2403.
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5320; (b) Andrés, J. M.; Pedrosa, R.; Pérez-Encabo, A. Eur. J. Org. Chem. 2006,
3442–5320.
4. (a) Ferreira, F.; Denichoux, A.; Chemla, F.; Bejjani, J. Synlett 2004, 2051–2065;
(b) Chemla, F.; Ferreira, F.; Hebbe, V.; Stercklen, E. Eur. J. Org. Chem. 2002, 1385–
1391; (c) Chemla, F.; Bernard, N.; Ferreira, F.; Normant, J. F. Eur. J. Org. Chem.
2001, 3295–3300; (d) Ferreira, F.; Herse, C.; Riguet, E.; Normant, J. F.
Tetrahedron Lett. 2000, 41, 1733–1736.
5. For recent reviews on the ring-opening reaction of aziridines with nucleophiles,
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60, 2701–2743.
6. For a review on alkynyl aziridines, see: Chemla, F.; Ferreira, F. Curr. Org. Chem.
2002, 6, 539–569.
7. For a similar example of ring-opening reaction at the propargylic position of an
alkynyl aziridine, see: (a) Li, P.; Evans, C. D.; Wu, Y. W.; Cao, B.; Hamel, E.;
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M.A.; Ellman, J.A. Chem. Res. 2010. doi:10, 1021/cr900382t.; (b) Ferreira, F.;
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inhibit
sponded to the stereoselective preparation of alkynyl anti,syn-2-
amino-1,2-diol 7d from -alkoxy imine 6d. The indolizidine core
a
-glycosidases.38 In our synthesis, the key step corre-
a
of the target molecule was constructed through the intramolecular
displacement of the chlorine atom of 7d (as described in the syn-
thesis of (À)-1-hydroxyquinolizidinone, see Scheme 9) and subse-
quent ring-closing metathesis conducted on pyrrolidine 15 using
Grubbs 2nd generation catalyst at 100 °C in toluene. The two last
stereocenters were created by the stereoselective dihydroxylation
of the cyclic alkene function of 16. The overall synthesis then al-
lowed us to isolate (+)-6-epi-castanospermine in 15 steps and
8.5% yield (Scheme 12).39
4. Conclusion
In conclusion, we have disclosed new efficient methodologies
for the stereoselective preparation of synthetically useful alkynyl
1,2-amino alcohols and 2-amino-1,3-diols through the addition
of 3-chloro- and 3-methoxymethoxy-allenylzinc reagents to chiral
tert-butylsulfinylimines. The high synthetic potential of these new
methodologies has been demonstrated by developing several
asymmetric syntheses of naturally occurring and/or bioactive alka-
loids. Further efforts in the synthesis of polyhydroxylated alkaloids
will be reported in due course.
9. Chemla, F.; Ferreira, F. Synlett 2004, 6, 983–986.
10. (a) Hoffmann, R. W.; Julius, M.; Chemla, F.; Ruhland, T.; Frenzen, D. Tetrahedron
1994, 50, 6049–6060; (b) Hirsch, R.; Hoffmann, R. W. Chem. Ber. 1992, 125,
975–982; For a review on the configurational stability of enantioenriched
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Ed. 2002, 41, 716–738.
11. (a) Botuha, C.; Chemla, F.; Ferreira, F.; Pérez-Luna, A.; Roy, B. New J. Chem. 2007,
31, 1552–1567; (b) Chemla, F.; Ferreira, F. J. Org. Chem. 2004, 69, 8244–8250.
12. MAD is the acronym for methylaluminium bis(2,6-di-tert-butyl-4-
methylphenoxide).
13. HMPA is the acronym for hexamethylphosphoric triamide.
14. For examples of the coordination of metallic ions by HMPA, see: (a) Ozutsumi,
K.; Abe, Y.; Takahashi, R.; Ishiguro, S.-I. J. Phys. Chem. 1994, 98, 9894–9899; (b)
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8728–8741; (c) Reich, H. J.; Green, D. P. J. Am. Chem. Soc. 1989, 111, 8729–8731.
and references therein; (d) Nee, G.; Leroux, Y.; Seyden-Penne, J. Tetrahedron
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19. Palais, L.; Chemla, F.; Ferreira, F. Synlett 2006, 1039–1042.
20. Chemla, F.; Ferreira, F. Synlett 2006, 2613–2616.
Acknowledgments
The authors are indebted to all the former collaborators who
participated in the works presented in this paper. The authors also
cordially thank UPMC, CNRS, and the JCEMolChem project for
financial support, GlaxoSmithKline for a Ph.D grant to J. Louvel,
and Dr E. Demont (GSK) for fruitful discussions.
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