Synthesis of 1,2-amino alcohols by sigmatropic rearrangements of 3-(N-Tosylamino)allylic alcohol derivatives

Article abstract of DOI:10.1002/chem.201003265

Sigmatropic rearrangements of 3-(N-tosylamino)allylic alcohol derivatives, a particular subclass of functionalized enamides, have been investigated. Whereas the presence of the nitrogen atom alters the stereochemical outcome of Ireland-Claisen rearrangeme

Full text of DOI:10.1002/chem.201003265

DOI: 10.1002/chem.201003265
Synthesis of 1,2-Amino Alcohols by Sigmatropic Rearrangements of
AHCTUNGTREGUN3NN -(N-Tosylamino)allylic Alcohol Derivatives
Marion Barbazanges,[a] Christophe Meyer,*[a] Janine Cossy,*[a] and Peter Turner[b]
Abstract: Sigmatropic rearrangements
of 3-(N-tosylamino)allylic alcohol de-
rivatives, a particular subclass of func-
tionalized enamides, have been investi-
gated. Whereas the presence of the ni-
trogen atom alters the stereochemical
outcome of Ireland–Claisen rearrange-
ments of glycolates derived from such
substrates, [2,3]-Wittig rearrangements
of a-allyloxy acetamides or propargylic
ethers derivatives provide access to a
wide variety of functionalized ACTHNUTRGNEUG1N ,2-
amino alcohols usually with high levels
of stereocontrol, as well as to heterocy-
clic compounds. The stereoselectivity
issues of these rearrangements (1,2-dia-
stereoselectivity, auxiliary-induced dia-
stereoselection, chirality transfer, and
double stereodifferentiation) were
thoroughly investigated.
Keywords: amino alcohols · diaste-
reoselectivity · enamides · Wittig re-
arrangement
rangements
· sigmatropic rear-
Introduction
pounds E, the carbonyl group and the olefin could undergo
subsequent transformations and provide access to a variety
of highly functionalized 1,2-amino alcohols, which are found
in many natural and/or biologically active compounds
(Scheme 1).[15]
This route to 1,2-amino alcohols would be complementary
to other strategies involving the formation of a s bond be-
tween the two heterosubstituted asymmetric carbon atoms,
with control of their configuration, such as the addition of
a-amino carbon nucleophiles to aldehydes[16] or conversely,
a-alkoxy carbon nucleophiles to imines,[17] as well as cross-
reductive couplings between C=N and C=O bonds.[18] To in-
vestigate the feasibility of sigmatropic rearrangements in-
volving derivatives B or D, acyclic 3-(N-tosylamino)allylic
alcohols (EWG=Ts) were selected as substrates. Though
sulfonamides are less readily cleaved than some other nitro-
gen protecting groups,[19] they offer the advantage of being
The chemistry of N-alkenyl amides, carbamates, ureas, or
sulfonamides, referred to as “enamides”, has been recog-
nized as an emerging area in organic synthesis.[1] Due to the
presence of an electron-withdrawing group on the nitrogen
atom, these compounds display an enhanced stability rela-
tive to enamines and several methods have been developed
to achieve their efficient stereoselective synthesis.[2–7] En-
ACHTUNGTRENNUNGamides can be involved in reactions that exploit the nucleo-
philic character of their carbon–carbon double bond or in
transformations that are classically carried out with nonhe-
terosubstituted alkenes, with the inclusion of a valuable
amino substituent into the resulting products. Acyclic 3-ami-
noallylic alcohols A, which are stable vinylogous hemiami-
nals,[8] appeared as an interesting subclass of functionalized
enACHTUNGTRENNUNGamides that could be engaged in reactions carried out
with regular allylic alcohol or derivatives.[9–11] We reasoned
that the [3,3]-Ireland–Claisen rearrangement[12] of silyl
ketene acetals C generated from glycolates B[13] or the [2,3]-
Wittig rearrangement of ethers D,[14] triggered by deprotona-
tion with a base, should constitute interesting entries to g,d-
unsaturated a-hydroxy-b-amino acid derivatives E. In com-
[a] Dr. M. Barbazanges, Dr. C. Meyer, Dr. J. Cossy
Laboratoire de Chimie Organique
ESPCI ParisTech, CNRS (UMR 7084)
10 rue Vauquelin 75231 Paris Cedex 05 (France)
Fax : (+33)140-79-46-60
E-mail: christophe.meyer@espci.fr
janine.cossy@espci.fr
[b] Dr. P. Turner
GlaxoSmithKline Stevenage, Medicines Research Centre
Gunnels Wood Road, Stevenage
Hertfordshire, SG12NY (UK)
Scheme 1. Synthesis of 1,2-amino alcohols from 3-(N-tosylamino)allylic
alcohol derivatives by sigmatropic rearrangements. EWG=electron-with-
drawing group; TMSCl=trimethylsilyl chloride.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003265.
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FULL PAPER
stable to a wide variety of reaction conditions and to avoid
the presence of rotamers in equilibrium, a key issue to con-
sider as the stereochemical outcome (1,2-diastereoselectiv-
ity) of the sigmatropic rearrangements will have to be evalu-
ated. While N-alkenyl-oxazolidin-2-ones have typically been
employed as enamides,[1–7] embedding the nitrogen atom
into an oxazolidinone ring excludes the possibility of having
a variety of substituents on the latter atom, which could be
potentially useful for further functionalization.
3-(N-tosylamino)propargyl alcohol derivatives.[21,22] The
copper-catalyzed cross-coupling of sulfonamide 1a with bro-
moalkyne 4[23] under the conditions reported by Hsung
et al.[24] provided the disubstituted ynamide 5 in excellent
yield (99%). Deprotection of the alcohol (TBAF, THF) led
to ynamide 6, which underwent stereoselective hydroalumi-
nation with Red-Al to provide the (E)-3-(N-tosylamino)al-
lylic alcohol 3a (68%, two steps from 5). Alternatively, yna-
mide 5 was treated with an excess of the titanium reagent
Herein, we report a full account of our studies on stereo-
selective sigmatropic rearrangements involving 3-(N-tosyl-
ACTHNGUTERNNUG
[h2-(propene)]Ti(OiPr)2,[6h,i] followed by hydrolysis to pro-
vide enamide 7 and subsequent cleavage of the silyl ether
(TBAF) afforded the isomeric Z allylic alcohol 3’a (59%,
two steps from 5) (Scheme 3).
ACHTUNGTRENNUNGamino)allylic alcohol derivatives as a route to 1,2-amino al-
cohols[9] and their applications to the synthesis of unsaturat-
ed heterocycles.
Results and Discussion
Synthesis of 3-(N-tosylamino)allylic alcohols: One of the
most straightforward routes to primary 3-(N-tosylamino)al-
lylic alcohols starts with the conjugate addition of sulfona-
mides 1 to methyl propiolate in the presence of N-methyl-
morpholine (MeCN, 08C).[20] Mixtures of the corresponding
(E)- and (Z)-b-amino acrylates were obtained with moder-
ate to good stereoselectivity (E/Z 70:30–92:8). After separa-
tion by flash chromatography, the major E isomers 2 were
isolated (55–91%) and reduced to the corresponding (E)-3-
(N-tosylamino)allylic alcohols 3 in high yields (93–99%).
The (Z)-b-amino acrylates 2’a and 2’b were also reduced to
the isomeric Z allylic alcohols 3’a (92%) and 3’b (85%), re-
spectively, without alteration of the double bond configura-
tion (Scheme 2).
Scheme 3. Stereoselective synthesis of allylic alcohols 3a and 3’a. Red-
Al=sodium bis(2-methoxyethoxy)aluminumhydride; TBAF=tetrabutyl-
AHCTUNGTREGaNNUN mmonium fluoride; TBDPS=tert-butyldiphenylsilyl.
However, the copper-catalyzed coupling was inefficient
for sulfonamide 1 f derived from p-anisidine. To synthesize
allylic alcohol 3 f, the b,b-dichloroenamide 8 was first pre-
pared[25] and then treated with nBuLi (2 equiv) followed by
acylation of the intermediate alkynyllithium with
ClCO2Me.[25,26] The disubstituted ynamide 9 (87%) was re-
duced with DIBAL-H and subsequent hydroalumination of
the resulting propargylic alcohol with Red-Al afforded the
E enamide 3 f (52%, two steps from 9) (Scheme 4).[27]
Ynamides were also selected as precursors for the synthe-
sis of secondary 3-(N-tosylamino)allylic alcohols. Sulfona-
mides 1a and 1b underwent efficient copper-catalyzed cou-
pling (72–99%) with bromoalkynes 10–12 derived from
chiral propargyl alcohols.[28] After deprotection of the alco-
hol (TBAF) and hydroalumination of the alkyne (Red-Al),
Scheme 2. Synthesis of primary 3-(N-tosylamino)allylic alcohols. DIBAL-
H=diisobutylaluminium hydride; PMB=4-methoxybenzyl; PMP=
4-methoxyphenyl.
Though this route was convenient for providing multigram
quantities of primary (E)-3-(N-
tosylamino)allylic alcohols, the
low stereoselectivity of the con-
jugate addition of sulfonamides
to methyl propiolate led us to
develop other routes relying on
the stereoselective reduction of Scheme 4. Stereoselective synthesis of allylic alcohol 3 f.
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C. Meyer, J. Cossy et al.
Table 1. Synthesis of secondary optically enriched (E)-3-(N-tosylami-
no)allylic alcohols.
Sulfonamide
Bromoalkyne
Ynamide
Enamide
A
ACHTUNGTRENNUNG
1a
10
13 (99)
17 (92)
Scheme 5. ACHTUNTRGNEU[GN 3,3]-Ireland–Claisen rearrangement of glycolate 22. DMAP=
4-dimethylaminopyridine; EDCI=N’-(3-dimethylaminopropyl)-N-ethyl-
carbodiimide hydrochloride; KHMDS=potassium hexamethyl disilazide.
1a
11
12
14 (96)
18 (98)
meric mixture of 1,2-diols (Æ)-25 and (Æ)-25’ (25/25’ 70:30).
On the other hand, the known secondary amine 26, pre-
pared by addition of vinylmagnesium chloride to the
N-benzyl imine derived from d-glyceraldehyde acetonide,[32]
was converted to a 1,2-diol 25, which was identical to the
previous major diastereomer (Scheme 6).
1a
1b
15 R=Bn (98)
16 R=PMB (72) 20 R=PMB (88)
19 R=Bn (92)
the corresponding optically enriched secondary E allylic al-
cohols 17–20 were isolated (88–92%; Table 1).[29]
After having developed efficient routes towards a variety
of 3-(N-tosylamino)allylic alcohols, the sigmatropic rear-
rangements of their derivatives could be investigated.
ACHTUNGTRENNUNG[3,3]-Sigmatropic Ireland–Claisen rearrangement of glyco-
lates derived from 3-(N-tosylamino)allylic alcohols: Our
first aim was to evaluate the feasibility of the [3,3]-sigma-
tropic Ireland–Claisen rearrangement applied to glycolates
derived from 3-(N-tosylamino)allylic alcohols and to address
the influence of the nitrogen atom on the reactivity and the
diastereoselectivity. Alcohol 3a was selected as the test sub-
strate and condensed with p-(methoxybenzyloxy)acetic acid
(21) to provide glycolate 22. This latter compound could be
purified by flash chromatography on silica gel albeit with a
penalty in yield (50%) due to its sensitivity to traces of acid.
The crude glycolate 22 was best directly engaged in the gly-
colate-Ireland–Claisen rearrangement and enolization was
carried out by treatment with excess KHMDS (4 equiv) in
the presence of TMSCl (4 equiv, THF, À788C).[13c] The re-
sulting Z silyl ketene acetal 23 underwent [3,3]-sigmatropic
rearrangement upon warming to RT. After hydrolysis, under
acidic conditions, the crude material was esterified with tri-
methylsilyldiazomethane (MeOH/C6H6, RT).[30] The clean
formation of a mixture of the expected diastereomeric
a-alkoxy-b-amino esters 24 and 24’ was obtained in good
yield (80%) but with a surprisingly low diastereoselectivity
(24/24’ 70:30) in favor of the anti diastereomer 24
Scheme 6. Chemical correlation for the configurational assignment of 25
and 25’. DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
As enolization of 22 was carried out in the presence of an
excess of KHMDS and TMSCl, post-enolization of the rear-
ranged a-alkoxy-b-amino esters trimethylsilyloxyester could
not be ruled out to account for the low diastereoselectiv-
ity.[33] However, these latter conditions have been routinely
used in glycolate-Ireland–Claisen rearrangements with no
adverse effect on the diastereoselectivity.[13,34] By starting
from a purified glycolate 22 and reducing the amount of
base and TMSCl (2 equiv each) the diastereomeric ratio was
not altered. Switching to LiHMDS as the base also led to a
comparable selectivity (24/24’ 60:40). A careful monitoring
indicated that the [3,3]-sigmatropic rearrangement occurred
as low as À308C but keeping the reaction mixture at that
temperature for 48 h did not improve the diastereomeric
ratio.
While these investigations were in progress, Carbery et al.
disclosed their results on the Ireland–Claisen rearrangement
of esters derived from (E)-3-aminoallylic alcohols in which
the nitrogen atom is embedded into an oxazolidinone.[10] In
one of the reported examples, a glycolate was shown to un-
ACHTUNGTRENNUNG
mers 24 and 24’, the methyl ester was reduced and the PMB
ether was cleaved, resulting in the formation of a diastereo-
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Synthesis of 1,2-Amino Alcohols by Sigmatropic Rearrangements
FULL PAPER
dergo Ireland–Claisen rearrangement with abnormal low
diastereoselectivity (anti/syn 67:33). This result confirmed
the stereochemical outcome observed in the rearrangement
of glycolate 22 though the electron-withdrawing group on
the nitrogen atom is different (Scheme 7).
explore the alternative route towards 1,2-amino alcohols E
relying on the use of a [2,3]-Wittig rearrangement.
AHCTUNGTREG[NNUN 2,3]-Sigmatropic Wittig rearrangement of a-allyloxy amides
derived from 3-(N-tosylamino)allylic alcohols: Stereoselec-
tive synthesis of syn-1,2-amino alcohols: The possibility to
achieve the stereoselective [2,3]-Wittig rearrangement of a-
allyloxy acetic acid derivatives D, prepared by alkylation of
3-(N-tosylamino)allylic alcohols, was investigated as a route
to functionalized 1,2-amino alcohols E (Scheme 9).
Scheme 7. Ireland–Claisen rearrangement of a glycolate derived from a
3-aminoallylic alcohol by Carbery et al.[10]
It has been reported that Ireland–Claisen rearrangement
of esters derived from 3-alkoxyallylic alcohols display a sub-
stantial rate acceleration attributed to a vinylogous anome-
ric effect.[35] However, the stereochemical outcome of the re-
arrangement of propionates,[35] glycolates,[36] and glyci-
nates[37] derived from acyclic 3-alkoxyallylic alcohols was
similar to those observed with a regular allylic alcohol lack-
ing a heteroatom at C3 and in agreement with the usual
chairlike transition-state model (E to syn and Z to anti 1,2-
diastereoselectivity).[12] Only cyclic derivatives (3-hydroxy
pyranoid and furanoid glycals) were found to rearrange
preferentially through boat transition states.[35] By contrast,
the results reported by Carbery et al.[10] and ours demon-
strate that glycolates derived from acyclic 3-aminoallylic al-
cohols exhibit a different behavior. It is plausible that the
usual chairlike transition state TS1 may suffer from a
gauche interaction between the alkoxy group and the
N-benzyl-N-sulfonyl amino substituent. This interaction may
be similar to A1,3 strain if one considers a vinylogous anome-
Scheme 9. ACTHUNRTGNEUNG[2,3]-Wittig rearrangement of 3-(N-tosylamino)allylic alcohols
derivatives D as a route to 1,2-amino alcohols E.
As a-allyloxy esters (Z=OR’’) display a lower reactivity
than a-allyloxy amides (Z=NR’’2) in [2,3]-Wittig rearrange-
ments,[13,39] a-allyloxy acetamides derived from primary
3-(N-tosylamino)allylic alcohols were selected as substrates
and the 1,2-diastereoselectivity of such reactions was first
addressed.
1,2-Diastereoselectivity of the Wittig rearrangement of a-allyl-
AHCTUNGTREGoNNUN xy acetamides derived from primary 3-(N-tosylamino)allylic
alcohols: Initial studies were conducted with the pyrrolidine
amide 27a, easily synthesized from alcohol 3a (95%) by a
phase-transfer-catalyzed alkylation with N-(bromoacetyl)-
pyrrolidine (nBu4NHSO4 (20 mol%), 35% aq. NaOH/tolu-
ene, RT). Treatment of 27a with LDA (THF, À788C, 1.5 h)
triggered the [2,3]-Wittig rearrangement and afforded an
80:20 diastereomeric mixture of the syn- and anti-1,2-amino
alcohols 28a and 29a (62%), respectively, which could be
separated by flash chromatography.[31] Upon switching from
LDA to the less basic LiHMDS, a higher temperature had
to be used to observe the formation of 28a and 29a (À40 to
08C, 2 h) and the yield (73%) and diastereoselectivity (28a/
29a 87:13) were improved. Changing the counter cation to
magnesium had no effect on the diastereoselectivity. The in-
fluence of polar additives was next investigated. The use of
LiHMDS (2 equiv) and hexamethylphosphoramide (HMPA)
(4 equiv) allowed the reaction to proceed at À788C and the
syn-1,2-amino alcohol 28a was now formed as a single de-
tectable diastereomer (syn/anti>96:4),[31] which was isolated
in 77% yield. Although the use of N,N’-dimethylpropyl-
ric effect[35] resulting in a shorter N C6 bond (iminium char-
À
acter).[38] Thus, the rearrangement may proceed in part
through a boatlike transition state, TS2, which would ac-
count for the formation of the anti diastereomer 24 as the
major one (Scheme 8).
The low and abnormal diastereoselectivity observed in
the Ireland–Claisen rearrangement of glycolate 22 led us to
AHCTUNGTREGeNNNU neurea (DMPU) also improved the diastereomeric ratio, it
was necessary to use up to 30 equivalents of this latter addi-
tive to reach a level of diastereoselectivity comparable to
the one reached in the presence of HMPA (4 equiv)
(Table 2).
The relative configuration of the 1,2-amino alcohols 28a
and 29a was assigned by chemical correlation (detailed in
Scheme 8. Chairlike versus boatlike transition states in the Ireland–
Claisen rearrangement of glycolate 22.
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C. Meyer, J. Cossy et al.
Table 2.
G
Table 3. ACTHNGUTRENNU[G 2,3]-Wittig rearrangement of amides 27b–f.
Base [equiv], additive [equiv]
Conditions
28a/29a
Yield [%]
Substrate
R
28/29
Product 28
ACHTUNGTRENNUNG(yield [%])
LDA (2), none
LiHMDS (1.5), none
À788C
80:20
87:13
87:13
>96:4
90:10
93:7
62
73
92
77
65
64
66
À40 to 08C
À78 to À108C
À788C
27b
27c
27d
27e
27 f
PMB
CH2CH=CH2
AHCTNUGTERN(GNNU CH2)2CH=CH2
CH2CH
PMP
>96:4
>96:4
>96:4
95:5
28b (49)
28c (71)
28d (75)
28e (64)
28 f (52)
LiHMDS (2), MgBr2 (4)
LiHMDS (2), HMPA (4)
LiHMDS (2), DMPU (4)
LiHMDS (2), DMPU (10)
LiHMDS (2), DMPU (30)
À788C
ACHTUNGERTN(NUNG OMe)2
À788C
90:10
À788C
>96:4
Scheme 13). Formation of the major syn diastereomer was
in agreement with the cyclic five-membered transition-state
model of envelope conformation proposed for the [2,3]-
Wittig rearrangement.[40] The p-acceptor substituent is
known to preferentially occupy an endo position (with
respect to the envelope concavity) due to favorable stabiliz-
ing electrostatic interactions with the negatively charged
olefinic moiety in the transition state (Scheme 10).
of products. For this substrate possessing a Z olefin, enoliza-
tion or/and subsequent [2,3]-Wittig rearrangement presuma-
bly proceed at a much slower rate resulting in side reactions.
In the absence of a polar additive (LiHMDS (2 equiv), THF,
À40 to 08C), the formation of a 90:10 mixture of the anti-
and syn-1,2-amino alcohols 29a and 28a, respectively, was
effectively obtained.[31] Although this result confirmed the
reversal of 1,2-diastereoselectivity upon changing the config-
uration of the enamide, the reaction was not clean and the
rearranged 1,2-amino alcohols were isolated in modest yield
(51%). One isolated byproduct was found to be the allylic
alcohol 3’a (20%). Although its origin is unclear, it is plau-
sible that the lithium enolate derived from 27’a may under-
go the [2,3]-Wittig rearrangement at a slow rate and evolve
by a competitive a-elimination resulting in the formation of
alcohol 3’a. The experimental conditions had to be slightly
modified to observe the formation of the rearranged 1,2-
amino alcohol 29b in modest yield (44%) from the Z en-
AHCTUNGTRENNUNG
Scheme 10. Stereochemical outcome of the [2,3]-Wittig rearrangement of
amide 27a.
Although the precise role of HMPA is not clear, this addi-
tive is expected to coordinate the lithium cation and hence
increase the carbanionic character of the carboxamide eno-
late and of the olefinic moiety in the transition state. Unlike
in the Ireland–Claisen rearrangement, the presence of the
N-tosylamino substituent had no adverse effect on the 1,2-
diastereoselectivity of the Wittig rearrangement.[41]
The other a-allyloxy amides 27b–f derived from primary
(E)-3-(N-tosylamino)allylic alcohols were found to undergo
a diastereoselective [2,3]-Wittig rearrangement (diastereo-
meric ratio (d.r.)=90:10 to >96:4) under the previously op-
timized conditions. The syn-1,2-amino alcohols 28b–f were
obtained predominantly (Table 3).[42]
To access the epimeric anti-a-hydroxy-b-amino acid deriv-
atives, the [2,3]-Wittig rearrangement of a-alkoxy acet-
amides derived from primary (Z)-3-(N-tosylamino)allylic al-
cohols was studied.
Scheme 11. ACTHNUTRGNE[UNG 2,3]-Wittig rearrangement of the Z enamides 27’a and 27’b.
Unfortunately, suitable conditions could not be found to
achieve the [2,3]-Wittig rearrangement of the other (Z)-a-al-
lyloxy acetamides 27’c and 27’d in which the nitrogen atom
is substituted by an allyl or a homoallyl group, respectively.
Although anti-1,2-amino alcohols are, in principle, accessible
by [2,3]-Wittig rearrangement of derivatives of (Z)-3-(N-
tosylamino)allylic alcohols, the rather low yields obtained,
the narrow substrate scope, and the fact that the reaction
Treatment of the (Z)-a-alkoxy amide 27’a under the pre-
viously optimized reaction conditions (LiHMDS (2 equiv),
HMPA (4 equiv), THF, À788C) afforded a complex mixture
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Synthesis of 1,2-Amino Alcohols by Sigmatropic Rearrangements
FULL PAPER
conditions had to be tuned-up
for each substrate discouraged
us to pursue other investiga-
tions with this class of sub-
strates. An access to anti-1,2-
amino alcohols was later devel-
oped by the [2,3]-Wittig rear-
rangement of propargylic ethers
derived from (E)-3-(N-tosyl-
amino)allylic alcohols (vide
infra).
Scheme 13. Synthesis of oxygen heterocycles from 28a and 29a.
Application to the synthesis of
heterocycles: The products aris-
ing from the Wittig rearrangement of the E enamides 27
were found to be useful for the preparation of several syn-
1,2-amino alcohol derivatives as well as heterocyclic com-
pounds incorporating such subunits. The pyrrolidine amide
in 28a was reduced to the corresponding primary alcohol by
using an excess of lithium aminoborohydride (THF, RT) to
afford the corresponding 1,2-diol 25’ (58%).[43] Cleavage of
the N-tosyl group required protection of the free alcohol
and the tert-butyldiphenylsilyl ether 30 was prepared (86%).
Upon treatment with sodium naphthalenide (THF, À788C),
compound 30 was cleanly converted to the free secondary
amine 31 (75%).[44] Alternatively, protection of the 1,2-diol
25’ as an acetonide 32 (97%) and subsequent reductive
cleavage of the tosyl group provided secondary amine 33 in
good yield (77%; Scheme 12).
(Grubbs II[46], CH2Cl2, reflux) afforded dihydropyrans 34
(78%) and 35 (81%), respectively. After catalytic hydroge-
nation of the olefin, the epimeric tetrahydropyrans 36
(96%) and 37 (97%) were isolated and their relative config-
1
uration was assigned by H NMR spectroscopy (Scheme 13).
The a-hydroxy-b-amino amides 28c and 28d, in which the
nitrogen atom is substituted by an unsaturated side chain,
were appropriately substituted for the synthesis of nitrogen
heterocycles by RCM. Thus, upon treatment of 28c and 28d
with Grubbs second-generation catalyst (10 mol%) in re-
fluxing CH2Cl2, the corresponding pyrroline 38 (90%) and
tetrahydropyridine 39 (64%) were obtained, respectively
(Scheme 14).
Scheme 14. Synthesis of nitrogen heterocycles from 28c and 28d by
RCM.
It is worth pointing out that the [2,3]-Wittig rearrange-
ment was not restricted to amides derived from pyrrolidine.
Interestingly, the synthesis of substituted azepinones was en-
visioned from N-allyl-a-allyloxy acetamides by combining
the [2,3]-Wittig rearrangement with RCM. Alkylation of 3a
with bromoacetamide 40 derived from N-allylbenzylamine
led to amide 41, which underwent a [2,3]-Wittig rearrange-
ment (LiHMDS (2 equiv), HMPA (4 equiv), THF, À788C)
to generate a 90:10 mixture of diastereomeric 1,2-amino al-
cohols.[31] The major diastereomer 42 was isolated in 61%
yield and RCM of the 1,7-diene could be subsequently
achieved by using Grubbs second-generation catalyst in re-
fluxing 1,2-dichloroethane to afford tetrahydroazepinone 43
(77%; Scheme 15).
Scheme 12. Synthesis of 1,2-amino alcohol derivatives from 28a.
The synthesis of oxygen and nitrogen heterocycles was in-
vestigated from the products arising from the [2,3]-Wittig re-
arrangement of a-allyloxy amides derived from 3-(N-tosyl-
ACHTUNGTRENNUNGamino)allylic alcohols. Thus, the hydroxyl group in the
amides 28a and 29a was converted to an allyl ether without
epimerization[45] and subsequent ring-closing metathe-
sis (RCM) by using Grubbs second-generation catalyst
We had, therefore, identified suitable classes of 3-(N-tosy-
lamino)allylic alcohol derivatives as substrates for the [2,3]-
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4485

C. Meyer, J. Cossy et al.
separated by flash chromatography and isolated in 65–80%
yield. Cleavage of the chiral auxiliary was then achieved by
methanolysis in the presence of concentrated hydrochloric
acid to afford the corresponding methyl esters 48a–c (65–
89%) without epimerization (Table 4).
Table 4. Diastereoselective [2,3]-Wittig rearrangement of amides 44a–c.
Substrate 44
R
d.r.[a]
Product 45
(yield [%])
Product 48
ACHTUNGTRENNUNG(yield [%])
U
Scheme 15. Synthesis of tetrahydroazepinone 43 by sequential [2,3]-
Wittig rearrangement and RCM.
44a
44b
44c
Bn
PMB
allyl
90:10
87:13
94:6
45a (77)
45b (65)
45c (80)
48a (89)
48b (65)
48c (78)
Wittig rearrangement and demonstrated their utility to syn-
thesize 1,2-amino alcohols and heterocycles. The next task
was to control the absolute configuration of the two hetero-
substituted stereogenic centers created during the course of
the rearrangement. Several options were possible, such as
the use of a chiral auxiliary or chirality transfer from opti-
cally enriched secondary (N-tosylamino)allylic alcohols.[47]
[a] d.r.=45/ACTHNUGRTNEUNG(46+47).
The syn relationship between the hydroxyl and amino
groups in the major diastereomer 45a was confirmed by
1
analysis of the H NMR spectrum of acetonide 49 prepared
by ozonolysis of the alkene followed by reduction to the 1,3-
diol and subsequent ketalization (Scheme 17, [Eq. (1)]). The
3R absolute configuration of 45a was established by a chem-
ical correlation. Methyl ester 48a was carried out through a
four-step sequence involving reduction of the ester, hydroge-
nation of the alkene, oxidative cleavage of the 1,2-diol, and
reduction of the resulting a-amino aldehyde to provide com-
pound (R)-50 (68%, four steps from 48a) (Scheme 17,
[Eq. (2)]). On the other hand, the known optically active
diol 25 was similarly converted to the primary alcohol (S)-50
(72%, three steps from 25) the optical rotation of which was
Control of the absolute configuration of the two heterosubsti-
tuted stereogenic centers by using a chiral auxiliary: Kress
et al. have shown that a-allyloxy amides derived from opti-
cally active 1-aminoindan-2-ol led to synthetically useful
levels of auxiliary-induced diastereoselection in Wittig rear-
rangements.[48] Initial studies were thus conducted with
amide 44a, which was easily obtained by alkylation of 3a
with the N-bromoacetyl amide prepared from (1R,2S)-
1-aminoindan-2-ol.[48,49] Treatment of amide 44a with
LiHMDS (2 equiv) in the presence of HMPA (4 equiv, THF,
À788C) provided a mixture of three diastereomeric a-hy-
droxy-b-amino amides 45a, 46a, and 47a in a 79:17:4 ratio
(69% combined yield).[31] HMPA was found to exert a
strong influence on the syn diastereoselectivity of the [2,3]-
Wittig rearrangement and increasing the quantity of this
polar additive up to 30 equivalents raised the diastereomeric
ratio of 45a/46a/47a to 90:5:5 (83%; Scheme 16).
These conditions were also applied to the other amides
44b and 44c. In all cases, the major diastereomers 45 were
Scheme 16.
ACHTUNGTRENNUNG[2,3]-Wittig rearrangement of amide 44a derived from
(1R,2S)-1-aminoindan-2-ol.
Scheme 17. Configurational assignment of 45a and 46a.
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Synthesis of 1,2-Amino Alcohols by Sigmatropic Rearrangements
FULL PAPER
opposite to the product obtained from 48a (Scheme 17,
[Eq. (3)]). Additionally, the anti relative orientation of the
amino and hydroxyl groups in the minor diastereomeric
amide 46a was ascertained after methanolysis showing that
the resulting methyl ester 51a was an epimer of 48a
(Scheme 17, [Eq. (4)]). The configuration of the third minor
diastereomer 47a was not unambiguously ascertained.[50]
It appeared that the stereochemical outcome of the [2,3]-
Wittig rearrangement of the a-allyloxy amides derived from
optically active 1-aminoindan-2-ol was similar whatever the
nature of the substituent at C3 in the allylic ether moiety
(N-tosylamino, ethyl, or phenyl).[48] Interestingly, formation
of the syn and anti diastereomers 45a and 46a, respectively,
correspond to different stereogenic faces of the enamide
moiety involved in the [2,3]-Wittig rearrangement. Though
there has not been any explanation for the sense of dia-
derivatives should afford functionalized 1,2-amino alcohols
and create, at the same time, a disubstituted alkene. The
presence of a stereocenter in the starting substrates may
alter the 1,2-diastereoselectivity and this had to be checked
prior to investigating chirality transfer in the absolute sense
(Scheme 19).
Scheme 19. Chirality transfer in the [2,3]-Wittig rearrangement of secon-
dary 3-(N-tosylamino)allylic alcohol derivatives.
A
The [2,3]-Wittig rearrangement of amide 52, prepared by
a phase-transfer-catalyzed alkylation of the secondary alco-
hol (Æ)-17 with N-(bromoacetyl)pyrrolidine, proceeded
with negligible diastereoselectivity (d.r.=55:45) and provid-
ed an inseparable mixture of the isomeric 1,2-amino alco-
hols 53 and 54 possessing E and Z olefins, respectively. Ozo-
nolysis of the mixture of 53 and 54, followed by reduction,
led to a single syn-1,2-diol 55 (69%), which was also ob-
tained from the syn-a-hydroxy-b-amino amide 28a by the
same sequence of reactions (56%; Scheme 20).
seems to induce a different facial bias depending on its posi-
tion in the five-membered-envelope transition state of the
Wittig rearrangement. Thus, in the normally favored endo
position,[40] the (1R,2S) auxiliary favors attack of the Si face
of the enamide (formation of 45), whereas the Re face is
preferentially attacked when the aminoindanol carboxamide
occupies an exo orientation (formation of the anti diastereo-
mer 46). The third diastereomer 47, the configuration of
which was attributed by analogy with previous results,[48]
would probably result from the attack of the Re face of the
enamide when the carboxamide occupies an endo position
(Scheme 18).
Scheme 20. ACTHNUGTRNEUNG[2,3]-Wittig rearrangement of amide 52.
Amides 53 and 54, which both possess a syn-1,2-amino al-
cohol moiety, arose from the participation of opposite ste-
reogenic faces of the enamide in the [2,3]-Wittig rearrange-
ment. The syn diastereoselectivity entails that the carboxa-
mide group invariably occupies an endo position in the tran-
sition state. The endo (pseudoequatorial) position of the
methyl group in TS3, though slightly preferred, may result
in steric interactions with the pyrrolidine amide. In the alter-
native transition state, TS4, the exo methyl group leads to
an unfavorable 1,3-interaction with the vinylic hydrogen lo-
cated close in space.[40] This would result in a nearly stereo-
random [2,3]-Wittig rearrangement leading to a 55:45 mix-
ture of 53 and 54 (Scheme 21).
Scheme 18. Stereochemical outcome of the [2,3]-Wittig rearrangement of
amides 44.
To control the absolute configuration of the two hetero-
substituted stereocenters, a more attractive option relies on
a chirality transfer from secondary optically active 3-(N-
tosylamino)allylic alcohol derivatives.[11]
Chirality transfer with a-allyloxy acetamides derived from
secondary 3-(N-tosylamino)allylic alcohols: The [2,3]-Wittig
rearrangement of secondary 3-(N-tosylamino)allylic alcohol
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4487

C. Meyer, J. Cossy et al.
the chiral auxiliary. Whilst TS4 is disfavored due to the pres-
ence of a 1,3-interaction between the methyl group and the
vinylic hydrogen close in space, TS6 has the carboxamide
oriented in the exo position, which is normally disfavored
for electronic reasons. This could explain why the isomeric
a-hydroxy-b-amino amides 57 and 58 are formed with low
diastereoselectivity (57/58 60:40; Scheme 23).
Scheme 21. Stereochemical outcome of the [2,3]-Wittig rearrangement of
amide 52.
The lack of inherent 1,2-diastereoselectivity in the [2,3]-
Wittig rearrangement of a-allyloxy acetamides derived from
secondary allylic alcohols led us to investigate double
stereodifferentiating reactions with an optically active amide
derived from 1-aminoindan-2-ol. Amide 56, derived from
the optically active secondary allylic alcohol 17 and
ACHTUNGTRENNUNG(1R,2S)-1-aminoindan-2-ol, was subjected to a [2,3]-Wittig
rearrangement (LiHMDS (2 equiv), HMPA (10 equiv),
THF, À788C). Unfortunately, the reaction proceeded with
negligible diastereocontrol as a mixture of two major diaste-
reomeric amides 57 and 58 was obtained in a 60:40 ratio
(80%).[31] These two diastereomers were partially separated
by flash chromatography (19 and 23% isolated yields) and
then individually converted to the diastereomeric methyl
esters 59 (61%) and 60 (76%), respectively (Scheme 22).[51]
Scheme 23. Stereochemical outcome of the doubly stereodifferentiated
[2,3]-Wittig rearrangement of amide 56.
The [2,3]-Wittig rearrangement of the diastereomeric
amide 61 derived from the enantiomeric (1S,2R)-1-aminoin-
dan-2-ol was next studied hoping that it would lead to a
better diastereoselectivity (matched mannifold). Indeed,
under the previous conditions (LiHMDS (2 equiv), HMPA
(10 equiv), THF, À788C), an 88:12 mixture of two diastereo-
meric 1,2-amino alcohols was generated, from which the
major diastereomer 62 was isolated in 78% yield.[51] Subse-
quent acidic methanolysis afforded the enantio- and diaste-
reomerically pure a-hydroxy-b-amino ester 63 (78%). The
formation of 62 can be understood by considering the [2,3]-
Wittig envelope transition-state model TS8. The carbox-
Scheme 22. Double stereodifferentiating [2,3]-Wittig rearrangement of
amide 56. [a] Determined by analysis of the 1H NMR spectrum of the
crude material. [b] Isolated yields after separation by flash chromatogra-
phy on silica gel.
We have previously mentioned that with (1R,2S)-1-amino-
indan-2-ol as a chiral auxiliary, attack of the Si face of the
enamide preferentially occurs when the carboxamide occu-
pies a (more favorable) endo position and conversely the Re
face of the enamide when lying in the opposite exo orienta-
tion. Among the four possible transition states TS4–TS7,
only TS4 and TS6 accommodate the facial bias exerted by
AHCTUNGTREGaNNNU mide derived from (1S,2R)-1-aminoindan-2-ol, when occu-
pying the preferred endo position, favors attack of the Re
face of the enamide and the methyl group is now lying in
the pseudoequatorial (endo) position (Scheme 24).
Double stereodifferentiating [2,3]-Wittig rearrangements,
with an appropriate selection of the configuration of the
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Synthesis of 1,2-Amino Alcohols by Sigmatropic Rearrangements
FULL PAPER
We have demonstrated that the [2,3]-Wittig rearrange-
ment of a-allyloxy acetamides derived from 3-(N-sulfonyl-
AHCTUNGTREGaNNUN mino)allylic alcohols affords a useful and stereoselective
entry to g,d-unsaturated a-hydroxy-b-amino acid derivatives.
However, the method is limited to the synthesis of syn-1,2-
amino alcohols as only derivatives of E enamides were
found to be satisfactory substrates. With the aim of develop-
ing a stereoselective access to anti-1,2-amino alcohols, the
reactivity of propargylic ethers derived from 3-(N-sulfonyl-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ethers derived from 3-(N-tosylamino)allylic alcohols: Ste-
reoselective synthesis of anti-1,2-amino alcohols: Upon
switching from a p-acceptor carboxamide to a p-donating al-
kynyl substituent, it is known that the stereochemical out-
come of the [2,3]-Wittig rearrangement is inverted due to a
more favorable exo position occupied by the latter in the
five-membered ring envelope transition state.[14] When ap-
plied to enamides F bearing a propargylic ether, enynes G
bearing an anti-1,2-amino alcohol subunit should be ob-
tained (Scheme 26).
Scheme 24. Double stereodifferenting [2,3]-Wittig rearrangement of
amide 61.
chiral auxiliary matching with the substrate stereocenter,
were also carried out with amides 64 and 65, synthesized
from optically active 3-(N-tosylamino)allylic alcohols 19 and
20 by using the N-bromoacetyl amide derived from (1R,2S)-
1-aminoindan-2-ol. These reactions proceeded with a syn-
thetically useful level of diastereoselectivity (d.r.=91:9 and
93:7, respectively) and after purification by flash chromatog-
raphy, the major diastereomeric a-hydroxy-b-amino amides
66 and 67 were isolated in good yields (75–77%). Acidic
methanolysis of 66 occurred with concomitant cleavage of
the PMB ether and delivered methyl ester 68 (80%). With
the aim of achieving cleavage of the tosyl group, compound
68 was protected as a (bis)TBS ether 69 (90%) and subse-
quent treatment with sodium naphthalenide (THF, À788C)
afforded the desired b-amino ester 70 (45%) accompanied
by the b-lactam 71 (27%) (Scheme 25).
Scheme 26. ACTHNUTRGENUG[N 2,3]-Wittig rearrangement of propargylic ethers F.
Propagylic ethers F appeared to be challenging substrates
as the acidity of the propargylic hydrogen is considerably
lower than for carboxamides and metalation of other acidic
hydrogen atoms, such as those at the ortho position of the
sulfonyl group,[52] could compete.
1,2-Diastereoselectivity of the rearrangement of propargyl
ethers derived from primary 3-(N-tosylamino)allylic alco-
hols: The preparation of trimethylsilyl-substituted propar-
gylic ether was first studied. Alkylation of allylic alcohols
3a–e with propargyl bromide under phase-transfer catalysis
provided the corresponding propargylic ether 72a–e in good
yields (92–99%). Attempts to achieve the [2,3]-Wittig rear-
rangement of 72a by formation of the dilithiated derivative
(nBuLi (2.5 equiv), THF, À788C) led to a complex mixture
of products.[53] Therefore, substitution of the terminal alkyne
by a trimethylsilyl group was considered. This operation was
successfully achieved under standard conditions (Table 5,
method A) in the case of ethers 72a and 72e, which afford-
ed alkynylsilanes 73a (68%) and 73e (91%; Table 5, en-
tries 1 and 7). Surprisingly, silylation of 72b and 72c ap-
peared troublesome by this protocol and the expected prod-
ucts (73b and 73c) could not be isolated (Table 5, entries 2
and 4). Silylation of 72d effectively provided 73d albeit in
31% yield (Table 5, entry 6) and all attempts to improve
this reaction by varying the quantity of reagents and the re-
Scheme 25. Double stereodifferentiating rearrangement of amides 64 and
65. TBSOTf=tert-butyldimethylsilyl trifluoromethanesulfonate
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4489

C. Meyer, J. Cossy et al.
Table 5. Synthesis of (trimethylsilyl)propargylic ethers 72a–e.
Table 7. ACHTNGUTERNNU[G 2,3]-Wittig rearrangement of (trimethylsilyl)propargylic ethers
73a–e.
Substrate 73
R
d.r. (76/77)
Yield [%]
73a
73b
73c
73d
73e
Bn
PMB
CH2CH=CH2
AHCTUNGTRENNUNG
93:7
94:6
91:9
92:8
96:4
92
89
81
74
81
Entry Substrate
R
Product 72 Method Product 73
(yield [%]) (yield [%])
G
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
3a
3b
Bn
PMB
72a (99)
72b (95)
A
A
B
73a (68)
73b (0)[a]
73b (54)
73c (0)[a]
73c (38)
73d (31)
73e (91)
AHCTUNGTRENNUNG
3c
CH2CH=CH2
72c (94)
A
B
ditions and provided the anti-1,2-amino alcohols 78b–d with
even higher diastereoselectivities, since the minor epimer
was barely detected by analysis of the H NMR spectrum of
3d
3e
G
A
A
AHCTUNGTRENNUNG
1
[a] A complex mixture of products was formed.
the crude material (d.r.>96:4; Table 8).
action conditions failed. An alternative procedure relying on
the use of 1,8-diazabicycloundec-7-ene (DBU) and AgCl in
the presence of TMSCl (Table 5, method B) allowed us to
isolate the desired alkynylsilanes 73b and 73c in modest
yields (38 and 54%, respectively) (Table 5, entries 3
and 5).[54]
Table 8. ACTHUNRTGNEUNG[2,3]-Wittig rearrangement of (triisopropylsilyl)propargylic
ethers 75b–d.
The formation of triisopropylsilyl-substituted propargylic
ethers was more conveniently accomplished in one step by a
phase-transfer-catalyzed alkylation of alcohol 3b–d with the
readily available propargylic bromide 74 due to the more
robust character of the acetylenic triisopropylsilyl (TIPS)
group under alkaline conditions. The corresponding propar-
gylic ethers 75c–e were isolated in 86–91% yields (Table 6).
Substrate 75
R
d.r. (78/79)
Product 78
(yield [%])
ACHTUNGTRENNUNG
75b
75c
75d
PMB
CH2CH=CH2
AHCTNUGTERN(GNNU CH2)2CH=CH2
>96:4
>96:4
>96:4
78b (93)
78c (89)
78d (76)
The relative configuration of 76a was unambiguously con-
firmed by a chemical correlation. Chemoselective ozonolysis
of the alkene in enyne 76a followed by reduction (PPh3,
CH2Cl2, À788C to RT then NaBH4, MeOH, RT) afforded
the 2-amino-1,3-diol 80 (45%), which was converted to ace-
tonide 81 (66%), allowing assignment of the relative config-
Table 6. Synthesis of (triisopropylsilyl)propargylic ethers 75b–d.
Substrate
R
Product
Yield [%]
1
uration by H NMR spectroscopy. On the other hand, it was
3b
3c
3d
PMB
CH2CH=CH2
ACHTUNGTRENNUNG(CH2)2CH=CH2
75b
75c
75d
91
89
86
checked that the stereochemical outcome of the [2,3]-Wittig
rearrangement of trimethylsilyl- and triisopropylsilyl-substi-
tuted propargylic ethers was similar by achieving desilyla-
tion of compounds 76c and 78c, which afforded the same
terminal alkyne 82 (Scheme 27).
The use of nBuLi as the base was initially considered to
achieve the [2,3]-Wittig rearrangement of 73a but the reac-
tion delivered the desired 1,2-amino alcohol 76a in 24%
yield only (anti/syn 93:7) together with several unidentified
byproducts. Switching to a milder base, such as lithium diiso-
propylamide (LDA, THF, À788C), was essential to achieve
the desired [2,3]-Wittig rearrangement of the trimethylsilyl-
substituted propargylic ethers 73a–e, which led to diastereo-
meric mixtures of anti- and syn-1,2-amino alcohols, 76a–e
and 77a–e, respectively, in good yields (74–92%) and with
high anti diastereoselectivity (d.r.=91:9–96:4) (Table 7).
The triisopropylsilyl-substituted propargylic ethers 75b–d
underwent [2,3]-Wittig rearrangement under the same con-
Besides their greater ease of preparation and higher dia-
stereoselectivities obtained during the [2,3]-Wittig rear-
rangement, TIPS propargylic ethers offer another advantage
as substrates. Whereas the N-allyl derivative 76c, in which
the alkyne is substituted by a TMS group, could not undergo
diene RCM to the corresponding dihydropyrrole 83 and re-
mained unaffected by treatment with a catalytic amount of
Grubbs second-generation catalyst (CH2Cl2, reflux),[55] the
TIPS substituted analogue 78c provided the RCM product
84 in quantitative yield. The bulky TIPS group presumably
shields the alkyne and prevents its interaction with rutheni-
um carbenes, allowing diene RCM to proceed
(Scheme 28).[56]
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Chem. Eur. J. 2011, 17, 4480 – 4495

Synthesis of 1,2-Amino Alcohols by Sigmatropic Rearrangements
FULL PAPER
whereas the allylic methyl
group occupies a pseudoequato-
rial
(endo)
position
(Scheme 29).
As propargyl ethers were
good candidates to evaluate the
chirality transfer in the absolute
sense, the optically active alco-
hol 18 was converted to the (tri-
methylsilyl)propargylic ether 89
according to a standard two-
step procedure, but the latter
compound was sensitive and
partially decomposed during at-
Scheme 27. Configurational assignment of the 1,2-amino alcohols of type G. CSA=camphorsulfonic acid.
tempted purification by flash chromatography on silica gel.
To avoid the isolation of 89 obtained after silylation of the
terminal alkyne 88, LDA (2 equiv) was directly added to the
reaction mixture at À788C to trigger the Wittig rearrange-
ment in a one-pot manner. Under these conditions, the 1,2-
amino alcohol 90 was obtained in good yield (76%, two
steps from 88) and with high diastereoselectivity (d.r.=
90:10). The enantiomeric excess of 90 was determined by
1H NMR spectroscopy after formation of the diastereomeric
O-methyl-mandelates (d.r.>95:5) and was found to be
greater than 90%. This method also enabled the assignment
of a S absolute configuration to the hydroxyl-substituted ste-
reocenter.[58] Additionally, hydration of the alkynylsilane in
89 afforded methyl ketone 91 (87%) without epimeriza-
tion[59] and subsequent cleavage of the PMB ether with
DDQ provided the highly functionalized 1,2-amino alcohol
92 (84%) bearing a synthetically useful allylic alcohol
moiety (Scheme 30).
Scheme 28. Diene RCM of 78c.
The control of the absolute configuration of the two ste-
reocenters was then investigated by using a chirality transfer
from secondary 3-(N-tosylamino)allylic alcohol derivatives.
Chirality transfer with propargylic ethers derived from secon-
dary 3-(N-tosylamino)allylic alcohols: The effect of a secon-
dary propargylic ether on the 1,2-diastereoselectivity was
first evaluated. Compound 85, prepared by a phase-transfer-
catalyzed propargylation of the racemic secondary alcohol
(Æ)-17, was silylated at the terminal alkyne position to
afford alkynylsilane 86 (78%). Subsequent [2,3]-Wittig rear-
rangement was efficiently triggered by deprotonation with
LDA ((1.5 equiv), THF, À788C) and the desired anti-1,2-
amino alcohol 87 possessing a disubstituted alkene of E con-
figuration was obtained with a reasonably high level of dia-
stereoselectivity (d.r.=91:9, 87% yield).[57] The stereochemi-
cal outcome was in agreement with the transition-state
model TS9 in which the alkynyl p-donating substituent oc-
cupies an exo position in the five-membered envelope,
Scheme 29. 1,2-Diastereoselectivity of the [2,3]-Wittig rearrangement of
Scheme 30. Chirality transfer in the [2,3]-Wittig rearrangement of propar-
ether 84.
gylic ether 89.
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C. Meyer, J. Cossy et al.
2139–2142; Angew. Chem. Int. Ed. 2008, 47, 2109–2112; o) G.
Evano, M. Toumi, A. Coste, Chem. Commun. 2009, 4166–4175.
[4] For a review on copper-catalyzed cross-coupling reactions, see: G.
Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054–3131.
[5] For a review on the synthesis of enamines, enol ethers and related
compounds by cross-coupling reactions, see: J. R. Dehli, J. Legros,
C. Bolm, Chem. Commun. 2005, 973–986.
Conclusion
We have explored [3,3]-glycolate-Ireland–Claisen and [2,3]-
Wittig rearrangements of derivatives of 3-(N-tosylamino)al-
lylic alcohols, a class of stable functionalized enamides.
Whereas the nitrogen substituent has a deleterious influence
on the diastereoselectivity of the [3,3]-sigmatropic rear-
rangements, the [2,3]-Wittig rearrangement of a-allyloxy
acetamides derived from primary (E)-3-(N-tosylamino)allyl-
ic alcohols was found to deliver highly functionalized syn-a-
hydroxy-b-amino acid derivatives. As a complementary ap-
proach, the [2,3]-Wittig rearrangement of propargyl ethers
derived from primary (E)-3-(N-tosylamino)allylic alcohols
provided an efficient access to anti-1,2-amino alcohols. The
[2,3]-Wittig rearrangement of propargylic ethers derived
from chiral secondary 3-(N-tosylamino)allylic alcohols pro-
ceeded with efficient chirality transfer but related a-allyloxy
acetamides require the use of a double stereodifferentiating
reaction with a chiral auxiliary to reach satisfactory levels of
diastereoselectivity. The highly functionalized 1,2-amino al-
cohols obtained by these [2,3]-Wittig rearrangements were
found to be useful precursors of heterocycles.
[6] Enamides can be synthesized from ynamides by a variety of reac-
tions including hydrogenation: a) X. Zhang, Y. Zhang, R. P. Hsung,
K. C. M. Kurtz, J. Oppenheimer, M. E. Petersen, I. K. Sagamanova,
L. Shen, M. R. Tracey, J. Org. Chem. 2006, 71, 4170–4177; hydroha-
logenation–cross-coupling: b) J. A. Mulder, K. C. M. Kurtz, R. P.
Hsung, H. Coverdale, M. O. Frederick, L. Shen, C. A. Zificsak, Org.
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Experimental Section
The entire Experimental Section can be found in the Supporting Infor-
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M.B. thanks GlaxoSmithKline and the CNRS for a BDI grant.
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4492
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 4480 – 4495

Synthesis of 1,2-Amino Alcohols by Sigmatropic Rearrangements
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Chem. Eur. J. 2011, 17, 4480 – 4495

Synthesis of 1,2-Amino Alcohols by Sigmatropic Rearrangements
FULL PAPER
[57] Oxidative cleavage of the alkene in compound 87 (cat. OsO4, NMO,
citric acid, tBuOH/H2O followed by NaIO4, THF, H2O) and subse-
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1,3-diol 80. This compound had also been synthesized from 76a (see
Scheme 27).
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Received: November 12, 2010
Published online: February 17, 2011
Chem. Eur. J. 2011, 17, 4480 – 4495
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4495