Stereoselective synthesis of syn-β-amino propargylic ethers: Application to the asymmetric syntheses of (+)-β-conhydrine and (-)-balanol

Article abstract of DOI:10.1002/adsc.201100333

The stereoselective synthesis of syn-β-amino propargylic ethers by the addition of racemic lithio 3-(methoxymethoxy)allenylcuprates, and more particularly (cyano) and (mesityl)cuprates, to enantiopure chiral N-tert-butylsulfinylimines is reported. The sco

Full text of DOI:10.1002/adsc.201100333

FULL PAPERS
DOI: 10.1002/adsc.201100333
Stereoselective Synthesis of syn-b-Amino Propargylic Ethers:
Application to the Asymmetric Syntheses of (+)-b-Conhydrine
and (ꢀ)-Balanol
Julien Louvel,a Fabrice Chemla,a,* Emmanuel Demont,b Franck Ferreira,a,*
Alejandro Pꢀrez-Luna,a,* and Arnaud Voiturieza
a
UPMC-Univ Paris 6, UMR CNRS 7201, Institut Parisien de Chimie Molꢀculaire, Institut de Chimie Molꢀculaire
ACHTUNGTRENNUNG(FR 2769), case 183, 4 Place Jussieu, 75005 Paris, France
Fax : (+33)-1-4427-7567; phone: (+33)-1-442755-71; e-mail: fabrice.chemla@upmc.fr,
franck.ferreira@upmc.fralejandro.perez_luna@upmc.fr
Immuno-Inflammation CEDD Medicinal Chemistry, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage, SG1
2NY, Hertfordshire, U.K.
b
Received: April 28, 2011; Published online: August 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100333.
Abstract: The stereoselective synthesis of syn-b- of compounds having a syn-1,2-amino alcohol unit is
amino propargylic ethers by the addition of racemic shown through the development of the asymmetric
lithio 3-(methoxymethoxy)allenylcuprates, and more syntheses of (+)-b-conhydrine and of an advanced
particularly (cyano) and (mesityl)cuprates, to enan- intermediate of (ꢀ)-balanol.
tiopure chiral N-tert-butylsulfinylimines is reported.
The scope and limitations of the reaction is studied. Keywords: amino alcohols; asymmetric synthesis;
The usefulness of the methodology for the synthesis chiral resolution; copper; nitrogen heterocycles
[3a]
Introduction
lenic ketones with LiAlH4 or chiral oxazaborolidi-
nes,[3h] and the diastereoselective addition of racemic
b-Amino propargylic ethers of type 1 (Scheme 1) 3-(methoxymethoxy)allenylzinc bromide to iminium
have proven to be valuable building blocks for the ions.[6] Thus, a general stereoselective entry to syn-b-
synthesis of number of bioactive natural products.[1]
amino propargylic ethers 1 is still lacking. In this
Owing to their great synthetic potential, numerous paper we report our recent efforts towards this goal.
efforts for the stereoselective preparation of b-amino
propargylic ethers 1 have been undertaken.[2] The syn-
thesis of anti-b-amino propargylic ethers 1 has been Results and Discussion
the subject of frequent publications.[1b,c,i,k,3] By con-
trast, access to their syn counterparts has been report- Reactions of Zinc Reagents with Racemic Imines
ed only in a few special cases. These include the
regio- and stereoselective attack of oxygen nucleo- As part of our ongoing research on the preparation
philes at the propargylic position of cis-ethynylaziridi- and the use of 3-heterosubstituted allyl- and allenyl-
nes,[3f–j,4] the addition of several alkynylmetals to a- metals,[7] we have recently demonstrated that the re-
amino aldehydes,[1b,c,5] the reduction of a-amino acety- action of 4 equivalents of racemic 3-(meth-
oxymethoxy)allenylzinc bromide (ꢁ)-3-ZnBr with
(SS)-N-tert-butylsulfinylimines 4,[8] in Et2O and in the
presence of TMEDA (0.1 equivalent relative to the
zinc species), leads to the formation of anti-
(SS,1R,2S)-b-amino propargylic ethers 5 within 1 h at
ꢀ808C (Scheme 2). In all cases, adducts 5 were ob-
tained in high yields (up to 94%) with a high level of
stereoselectivity as only one anti isomer of the four
Scheme 1. b-Amino propargylic ethers 1.
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Table 1. Reaction of (ꢁ)-4a with allenylzincs (ꢁ)-3-[Zn] in
THF at ꢀ808C.
Scheme 2. Synthesis of anti-(SS,1R,2S)-b-amino propargylic
ethers 5.
possible stereomers could be detected. The excellent
stereoselectivity of the reaction was assumed to arise
from transition state model M1 wherein the imine
adopts its less energetic conformation. In M1, because
of the possible chelation of a lithium cation [coming
from n-BuLi employed for the formation of (ꢁ)-3- Entry [Zn][a]
Sol-
vent
Additive
dr[b]
Yield
[%][c]
ZnBr] by both the oxygen atoms of the methoxy-
methyl ether moiety and the sulfinyl auxiliary, the
(aS) enantiomer of (ꢁ)-3-ZnBr approaches from the
si face of imine (SS)-4, opposite to the bulky tert-butyl
group. This corresponds to an anti relationship be-
tween the substituent of the imine and the methoxy-
methyl ether moiety (Scheme 2).
1
2
3
4
5
6
7
8
ZnBr
ZnBr
ZnBr
ZnBr
ZnBr
Zn-t-Bu
ZnO-t-Bu
Et2O
THF
THF
THF
THF
THF
THF
THF
THF
THF
–
–
<02:98
62:38
77:23
62:38
62:38
83:17
76:24
83:17
82:18
50:50
82[d]
76
76
70
75
35
38
52
37
75
HMPA
ACHTUNGERTN(NUNG EtO)3P
ZnBr2
HMPA
HMPA
HMPA
HMPA
HMPA
Building on M1 as working model, we reasoned
that syn-(SS,1R,2R)-b-amino propargylic ethers might
be obtained if chelation of the lithium cation by the
oxygen atoms of both the N-tert-butylsulfinylimine
and the methoxymethyl ether moiety was prevented.
We carried out our initial experiments with racemic
N-tert-butylsulfinylimine (ꢁ)-4a. At first the reaction
was performed with 2 equivalents of 3-(methoxyme-
thoxy)allenylzinc bromide, (ꢁ)-3-ZnBr, generated by
deprotonation of propargylic ether 2 with t-BuLi
(1.1 equiv., ꢀ958C, 1 h) and susbsequent transmetala-
tion with ZnBr2 (1 equiv., ꢀ808C, 30 min), in THF in-
stead of Et2O. Under these conditions, two unsepara-
ble diastereomeric adducts 5a were obtained in 76%
yield within 1 h at ꢀ808C with a fair syn:anti ratio of
62:38 (Table 1, entry 2). The minor adduct could be
ZnN
Zn
(TMP)[e]
Zn(t-Bu)2Li[f]
ACHTUNGTRNE(NUNG SiMe3)2
9
10
ACHTUNGTRENNUNG
[a]
[b]
[c]
See the Supporting Information for the detailled prepa-
ration of allenylzincs (ꢁ)-3-[Zn].
syn-(ꢁ)-5a:anti-(ꢁ)-5a ratio determined by 1H NMR
analysis of the crude reaction mixture.
Combined isolated yield of unseparable syn- and anti-
(ꢁ)-5a.
[d]
[e]
[f]
See Refs.[3f,i]
TMP=2,2,6,6-tetramethylpiperidine.
Zincate generated by adding 2 equivalents of t-BuLi to
(ꢁ)-3-ZnBr.
easily assigned as the anti isomer, with the istry between the two stereogenic carbon atoms of the
(S*S,1R*,2S*) relative configuration, as it was identi- major isomer, it could be deduced unambiguously to
cal to the one obtained as the only product in Et2O[3f,i] be syn following acidic removal of the chiral N-tert-
(Table 1, entry 1). Regarding the relative stereochem- butylsulfinyl auxiliary with dry HCl in MeOH at 08C.
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Stereoselective Synthesis of syn-b-Amino Propargylic Ethers
Scheme 3. Competitive transition state models M2a-ZnBr
and M3a-ZnBr.
Indeed, under these conditions, a mixture of the two
adducts 5a led to a mixture of two different N-depro-
tected b-amino propargylic ethers in the same ratio,
thus meaning that the relative stereochemistries of
the two newly created stereogenic carbon atoms of
the adducts were opposite.
Scheme 4. Reaction of (ꢁ)-4b with allenylzinc bromide (ꢁ)-
3-ZnBr.
The selectivity observed in favour of the syn isomer
under these conditions could be explained by the two
competitive transition state models M2a-ZnBr and
We next examined the influence of the electronic
M3a-ZnBr in which the imine adopts its less energetic nature and the bulkiness of the zinc atom of the or-
conformation and no chelation occurs (Scheme 3). ganometallic reagent on the reaction outcome using
Similarly to the reaction of racemic 3-chloroallenyl- various 3-(methoxymethoxy)allenylzincs (ꢁ)-3-[Zn].
zinc bromide with N-tert-butylsulfinylimines at ꢀ158C These zinc species were readily formed by the ligand-
in a mixture of Et2O and HMPA (hexamethylphos- exchange reaction of (ꢁ)-3-ZnBr with 1 or 2 equiva-
phoric triamide), transition state model M3a-ZnBr lents of the appropriate organolithium species to
[leading to syn-(ꢁ)-5a] could be assumed to be fav- obtain zinc or zincate reagents, respectively. In all the
oured relative to M2a-ZnBr [leading to anti-(ꢁ)-5a] cases (Table 1, entries 6–9), the desired syn isomer
as a result of a less demanding steric interaction be- (ꢁ)-5a was formed within 1 h at ꢀ808C with selectivi-
tween the methoxymethyl ether moiety and the N- ty up to 83:17, albeit in modest isolated yields (37–
tert-butylsulfinyl auxiliary. On the basis of M3a-ZnBr, 52%). Noteworthy, when the reaction was run with a
the (S*S,1R*,2R*) relative configuration might be rea- zincate species, no syn:anti selectivity was observed
sonably assigned to the major syn isomer, although (Table 1, entry 10), which contrasts with reported
this could not be confirmed at this stage.
work on the additon of di-tert-butylzincate reagent
Thus, in agreement with our working model, using derived from propargylic dibenzylamine to alde-
THF (which is a stronger Lewis base than Et2O) al- hydes.[10]
lowed the stereoselectivity of the reaction to be
Encouraged by these preliminary results, we then
switched in favour of the syn-(SS*,1R*,2R*) adduct. envisoned extending the reaction to a-branched N-
Other additives that could prevent lithium cation che- tert-butylsulfinylimines. When reacting (ꢁ)-4b with
lation in order to disfavour M1 and drive the reaction 2 equivalents of (ꢁ)-3-ZnBr, two unseparable isomer-
through M3a were next considered. To our delight, ic adducts (ꢁ)-5b were obtained in 75% yield within
when adding HMPA (8 equivalents relative to the or- 1 h at ꢀ808C in THF and in the presence of 8 equiva-
ganometallic species), which is well-known to be able lents HMPA relative to the zinc species (Scheme 4).
to coordinate various metal ions[9a] and more particu- Surprisingly, this reaction led to a syn:anti ratio of
larly lithium,[9b–e] the syn selectivity was significantly 16:84. The major product could be unambiguously as-
increased to 77:23 (Table 1, entry 3). However, the signed to be the same anti isomer obtained earlier as
use of other additives such as (EtO)3P (able to play the single product in Et2O,[3f,i] thus with the
the same role as HMPA) and ZnBr2 (a Lewis acid (S*S,1R*,2S*) relative configuration. As before, the
possibly coordinated to the oxygen atom of the sulfi- stereochemistry of the minor isomer was found to be
nyl auxiliary) did not prove beneficial (Table 1, en- syn through removal of the N-tert-butylsulfinyl auxili-
tries 4 and 5).
ary.
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The high anti selectivity observed in this case could Reactions of Copper Reagents with Racemic Imines
be attributed to the bulkiness of the isopropyl group
of the imine that makes the steric interaction of the Facing the severe limitations of the use of 3-(methox-
methoxymethyl ether moiety more important with the ymethoxy)allenylzincs in the preparation of syn-b-
isopropyl group than with the N-tert-butylsulfinyl aux- amino propargylic ethers, we then planned to examine
iliary. Thus, transition state model M3b-ZnBr (giving their copper analogues.[11] All these copper reagents
the minor syn isomer) should be disfavoured relative were generated by deprotonation of propargylic ether
to M2b-ZnBr (giving the major anti isomer). The 2 with t-BuLi (1.1 equiv., ꢀ958C, 1 h) followed by
(S*S,1R*,2R*) relative configuration was reasonably transmetalation with the appropriate copper salt
assigned to the minor syn isomer on the basis of M3b- (1.5 equiv., ꢀ808C, 30 min).
ZnBr, although this could not be ascertained at this
The reaction of 2 equivalents of lithio cuprates (ꢁ)-
stage. This disappointing and unexpected result limits 3-Cu(X)Li with imine (ꢁ)-4a (Table 2, entries 1–8) in
significantly the synthetic utility of the zinc reagents THF and in the presence of HMPA (8 equivalents rel-
to access syn-b-amino propargylic ethers.
ative to the organometallic reagent), resulted in the
formation of two unseparable isomeric adducts syn-
and anti-(ꢁ)-5a within 1 to 2 h at ꢀ808C. In these
Table 2. Reaction of (ꢁ)-4a and b with allenylcoppers (ꢁ)-3-[Cu] in THF-HMPA at ꢀ808C.
Entry
R
Imine
[Cu][a]
Product
dr[b]
Yield [%][c]
1
2
3
4
5
6
7
8
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
i-Pr
(ꢁ)-4a
(ꢁ)-4a
(ꢁ)-4a
(ꢁ)-4a
(ꢁ)-4a
(ꢁ)-4a
(ꢁ)-4a
(ꢁ)-4a
(ꢁ)-4a
(ꢁ)-4a
(ꢁ)-4a
(ꢁ)-4a
(ꢁ)-4b
(ꢁ)-4b
(ꢁ)-4b
Cu(Me)Li[d]
Cu(CN)Li
(ꢁ)-5a
(ꢁ)-5a
(ꢁ)-5a
(ꢁ)-5a
(ꢁ)-5a
(ꢁ)-5a
(ꢁ)-5a
(ꢁ)-5a
(ꢁ)-5a
(ꢁ)-5a
(ꢁ)-5a
(ꢁ)-5a
(ꢁ)-5b
(ꢁ)-5b
(ꢁ)-5b
82:18
90:10
92:08
88:12
88:12
92:08
90:10
73:27
79:21
86:14
91:09
62:38
85:15
–
40
90
65
15
50
35
<10
58
70
Cu
G
Cu(C C C5H11)Li
Cu(2-thienyl)Li
Cu
G
Cu(TC)Li[e]
CuACTHNGUTER(NNUG SCN)Li
9
Cu·LiI[f]
10
11
12
13
14
15
Cu·LiBr·Me2S[g]
68
46
50
[h]
Cu·LiI·PPh3
Cu(CN)(2-thienyl)Li2
Cu(CN)Li
[i]
95
i-Pr
i-Pr
Cu
N
n.r.[j]
50
Cu(SPh)Li
G
83:17
[a]
See the Supporting Information for the detailled preparation of allenylcoppers (ꢁ)-3-[Cu].
[b]
[c]
[d]
[e]
[f]
syn-(ꢁ)-5a, b:anti-(ꢁ)-5a, b ratio determined by 1H NMR analysis of the crude reaction mixture.
Combined isolated yield of unseparable syn- and anti-(ꢁ)-5a, b.
Prepared by transmetalation with CuBr·Me2S and then addition of 1 equivalent of MeLi to the resulting copper species.
TC=2-thiophenylcarboxylate.
Transmetalation carried out with CuI.
[g]
[h]
[i]
Transmetalation carried out with commercially available CuBr·Me2S.
Transmetalation carried out with preformed CuI·PPh3.
Transmetalation carried out with Cu(CN)(2-thienyl)Li.
No reaction.
[j]
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Stereoselective Synthesis of syn-b-Amino Propargylic Ethers
Table 3. Reaction of (SS)-4a and b with (ꢁ)-3-Cu(CN)Li in
cases, while the isolated yields varied significantly
with the copper species used, the desired syn-b-amino
propargylic ether was always formed as the major
isomer. A high syn:anti ratio ꢃ82:18 was obtained,
except when lithio (thiocyano)cuprate (ꢁ)-3-Cu-
THF-HMPA.
ACHTUNGTRENNUNG(SCN)Li was used (Table 2, entry 8).
Similar selectivities were observed with copper re-
agents (ꢁ)-3-Cu (Table 2, entries 9–11). Conversely,
the high order cuprate (ꢁ)-3-Cu(CN)(2-thienyl)Li2
led to a significantly lower selectivity of 62:38
(Table 2, entry 12). Noteworthy, although the syn se-
lectivity was good in most cases, both high isolated
yield and syn:anti ratio ꢃ90:10 were only obtained
when the reaction was performed with (ꢁ)-3-
En-
try
R
Imine
(Equiv.[a])
T
Prod-
dr[b]
Yield
[%][c]
AHCTUNGTRENNUNG
[8C] uct
1
2
3
4
5
6
7
8
9
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
i-Pr
i-Pr
i-Pr
i-Pr
(ꢁ)-4a (2)
(SS)-4a (1)
(SS)-4a (2)
(SS)-4a (4)
(SS)-4a (6)
(SS)-4a (6)
(ꢁ)-4b (2)
(SS)-4b (4)
(SS)-4b (6)
ꢀ80 (ꢁ)-5a 90:10 90
ꢀ80 (SS)-5a 54:46 78
ꢀ80 (SS)-5a 81:19 74
ꢀ80 (SS)-5a 85:15 90
ꢀ80 (SS)-5a 87:13 90
ꢀ20 (SS)-5a 75:25 63
ꢀ80 (ꢁ)-5b 85:15 95
ꢀ80 (SS)-5b 71:29 90
ꢀ80 (SS)-5b 76:24 91
Cu(CN)Li (Table 2, entry 2) or (ꢁ)-3-Cu
ACHTUNGTRNE(NUNG Mes)Li
(Table 2, entry 3).
To our great delight, when (ꢁ)-3-Cu(CN)Li was re-
acted with a-branched imine (ꢁ)-4b (Table 2,
entry 13) a mixture of the two isomeric adducts (ꢁ)-
5b was obtained in 95% yield. These two diastereo-
mers were found to be similar to the ones previously
obtained using allenylzinc (ꢁ)-3-ZnBr, but this time
with a ratio of 85:15 in favour of the syn isomer. A
10
(SS)-4b (6[d]) ꢀ80 (SS)-5b 80:20 81
[a]
Equivalents of (ꢁ)-3-Cu(CN)Li used.
similar selectivity was reached with (ꢁ)-3-Cu
ACHTUNGTRNE(NUNG SPh)Li
[b]
[c]
[d]
1
syn-5a, b:anti-5a, b ratio determined by H NMR analysis
of the crude reaction mixture.
(Table 2, entry 15), albeit in a modest 50% yield. In-
explicably, no reaction occurred under the same reac-
Combined isolated yield of unseparable syn- and anti-5a,
b.
Reaction conducted in the presence of 10 equivalents of
tion conditions when (ꢁ)-3-Cu
ACHTUNGTREN(NGNU Mes)Li was used
(Table 2, entry 14).
HMPA relative to the organometallic species.
Reactions of (ꢁ)-3-Cu(CN)Li with Enantiopure
Imines
(ꢁ)-4a (Table 3, entry 2 vs. 5).[12] Thus, under these
conditions almost the highest kinetic resolution was
Having in hand a method for the preparation of race- attained.
mic syn-b-amino propargylic ethers (ꢁ)-5a and b, we
The absolute (SS,1R,2R) configuration of the major
further considered their synthesis in enantioenriched syn isomer 5a was ascertained, from a diastereomeri-
form through the addition of (ꢁ)-3-Cu(CN)Li to cally pure sample, through the formation of trans-oxa-
enantiopure N-tert-butylsulfinylimines (SS)-4a and b zolidine (4R,5R)-6 which had previously been ob-
(Table 3).
Optimization of the reaction conditions was con- tert-butylsulfinylaziridine (SS,2S,3R)-7 (Scheme 5).
ducted with enantiopure imine (SS)-4a. When reacted To account for the observed stereochemical out-
tained and fully characterized[3d] from cis-ethynyl-N-
in THF in the presence of HMPA (8 equivalents rela- come of the addition reaction, we postulated that the
tive to the organometallic species) at ꢀ808C with reaction proceeds through transition state model
1 equivalent of (ꢁ)-3-Cu(CN)Li, enantiopure imine M3a-Cu(CN)Li wherein the (aR) enantiomer of the
(SS)-4a gave a mixture of syn- and anti-b-amino prop- allenylcopper approaches from the si face of the
argylic ethers 5a in 78% yield and in a 54:46 syn:anti imine (matched situation) (Scheme 6). Worthy of
ratio (Table 3, entry 2). The syn:anti selectivity signifi- note, the formation of the minor anti isomer
cantly deviated from that obtained when racemic (SS,1R,2S)-5a could possibly arise from the approach
imine (ꢁ)-4a was reacted with 2 equivalents of the of the (aS) enantiomer of the allenylcopper from the
racemic organocopper species (Table 3, entry 1 vs. 2). same face of the imine, via M2a-Cu(CN)Li.
The use of an excess of (ꢁ)-3-Cu(CN)Li allowed nev-
Interestingly, according to Hoffmannꢂs studies on
ertheless the stereoselectivity to be improved the configurational stability of chiral organometallic
(Table 3, entries 3–5). With 6 equivalents of (ꢁ)-3- reagents,[12a,b] (ꢁ)-3-Cu(CN)Li could be considered as
Cu(CN)Li, the desired b-amino propargylic ether 5a configurationally stable with respect to the time scale
was formed in 90% yield within 2 h at ꢀ808C with a defined by the rate of its reaction with imine (SS)-4a.
syn:anti ratio of 87:13, very close to the theoretical This result contrasted with previous works which had
upper 90:10 ratio obtained with the racemic imine shown that allenylcoppers derived from propargylic
Adv. Synth. Catal. 2011, 353, 2137 – 2151
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Julien Louvel et al.
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Scheme 5. Determination of the configuration of syn-
(SS,1R,2R)-5a.
Scheme 6. Possible transition state models for the origin of
the stereoselectivity.
Scheme 7. Configurational stability of (ꢁ)-3-Cu(CN)Li in
THF-HMPA at ꢀ808C.
oxazolidinones are configurationally unstable during
With the aim of decreasing the amount of (ꢁ)-3-
their reaction with aldehydes at ꢀ808C in THF.[11b]
Cu(CN)Li used, we next planned to carry out the ad-
To gain more insight on the configurational stability dition reaction at ꢀ208C in the hope of making the
of (ꢁ)-3-Cu(CN)Li we plotted the syn:anti ratio copper species at least partially configurationally un-
against the amount of organometallic used stable at this temperature.[12] However, when 6 equiv-
(Scheme 7). Thus, our results fitted well the theoreti- alents of (ꢁ)-3-Cu(CN)Li were reacted with imine
cal curve calculated by Hoffmann for the variation of (SS)-4a at ꢀ208C in THF in the presence of HMPA
the diastereomeric ratio as a function of the conver- (8 equivalents relative to the organometallic species),
sion of a configurationally stable chiral organometal- a syn:anti ratio of 75:25 was observed (Table 3,
lic reacting with an enantiopure electrophile with an entry 6). The syn:anti selectivty was thus significantly
intrinsic selectivity s=90:10. In our case, s corre- lower at ꢀ208C than the one observed at ꢀ808C
sponds to the upper theoretical selectivity observed (Table 3, entry 5 vs. 6) which prevented the use of less
with racemic imine (ꢁ)-4a (i.e., s=k(aR):k(aS)), the dia- equivalents of (ꢁ)-3-Cu(CN)Li in this reaction.
stereomeric ratio is the observed syn:anti ratio, and
With a-branched imine (SS)-4b, not only 6 equiva-
the conversion of the chiral organometallic reagent is lents of (ꢁ)-3-Cu(CN)Li but also 10 equivalents of
the reciprocal of the number of equivalents of (ꢁ)-3- HMPA (relative to the organometallic reagent) were
Cu(CN)Li used.
required to obtain adduct 5b in 81% yield with a ste-
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Stereoselective Synthesis of syn-b-Amino Propargylic Ethers
The absolute (SS,1R,2R) configuration of the major
syn isomer 5b was confirmed by the formation of
trans-oxazolidine (4R,5R)-8 which was physically and
spectroscopically in good agreement with its de-
scribed antipode (Scheme 8).[14] Thus, transition state
models analogous to M3a-Cu(CN)Li and M2a-
Cu(CN)Li (Scheme 6) could reasonably be invoked to
explain the stereoselectivity observed with imine (SS)-
4b.
Reactions of (ꢁ)-3-Cu
ACHTUNGERTN(NUNG Mes)Li with Enantiopure
Imines
The reaction conditions to obtain syn-b-amino propar-
gylic ethers (ꢁ)-5a and b in enantioenriched form
were optimized through the addition of (ꢁ)-3-Cu-
Scheme 8. Determination of the configuration of syn-
(SS,1R,2R)-5b.
AHCTUNGTREG(NNUN Mes)Li to enantiopure N-tert-butylsulfinylimines
(SS)-4a and b (Table 4). When reacting 6 equivalents
reoselectivity of 80:20 close to the upper theoretical of (ꢁ)-3-Cu
ACHTUNGTRENNUNG
limit of 85:15 obtained with racemic imine (ꢁ)-4b THF in the presence of HMPA (8 equivalents relative
(Table 3, entry 7 vs. 8–10). The influence of the to the organometallic species) a mixture of two b-
amount of HMPA upon the stereochemical outcome amino propargylic ethers 5a was obtained in 65%
of the reaction is not clear. However a similar effect yield and in a syn:anti ratio of 92:08 (Table 4,
had been evidenced in the addition of racemic 3- entry 2). As the syn:anti selectivity was identical to
chloroallenylzinc bromide onto N-tert-butylsulfinyl- the upper theoretical one obtained with the racemic
imines.[13]
imine (ꢁ)-4a (Table 4, entry 1 vs. 2) it could be rea-
Table 4. Reaction of (SS)-4a, b with (ꢁ)-3-Cu
ACHTUNGTREN(NUNG Mes)Li in THF-HMPA.
Entry
R
Imine
Equiv.[a]
T [8C]
Product
5a:9a, b
dr[b]
Yield [%][c]
1
2
3
4
5
6
7
8
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
i-Pr
(ꢁ)-4a
(SS)-4a
(SS)-4a
(SS)-4a
(SS)-4a
(SS)-4a
(SS)-4b
(SS)-4b
6
6
6
4
ꢀ80
ꢀ80
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ80
ꢀ20
(SS)-5a
(SS)-5a
(SS)-9a
(SS)-9a
(SS)-9a
(SS)-9a
(SS)-9b
(SS)-9b
100:0
100:0
0:100
08:92
13:83
33:67
–
92:08
92:08
92:08
90:10
88:12
81:19
–
65
65
84
89
3
85
2
78
6[d]
6[d]
n.r.[e]
76
i-Pr
0:100
70:30
[a]
Equivalents of (ꢁ)-3-Cu
ACHTUNGTRENNUNG
[b]
[c]
[d]
[e]
1
syn-ACHTUNGTRENNUNG(5a+9a, b):anti-ACTHUNGTRENNUNG
Combined isolated yield of unseparable 5a and 9a, b.
Reaction conducted in the presence of 10 equivalents of HMPA relative to the organometallic species.
No reaction.
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Julien Louvel et al.
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sonably concluded that the highest kinetic resolution In a typical procedure, the reaction was carried out at
was attained under these conditions.[12a,b]
ꢀ808C with 6 equivalents of (ꢁ)-3-Cu(CN)Li or (ꢁ)-
Surprisingly, the same reaction conducted at ꢀ208C 3-Cu(Mes)Li in THF and in the presence of HMPA
AHCTUNGTRENNUNG
gave a mixture of two unseparable desilylated b- (10 equivalents relative to the organocuprate) until
amino propargylic ethers 9a in excellent 84% isolated completion as indicated by TLC (1 to 2 h). Using
yield and in a syn:anti ratio of 92:08 (Table 4, both cuprates with the two functionalized primary
entry 3). The stereochemistry of both major and imines (SS)-4c, d, furnished the desired syn-b-amino
minor isomers could be unambiguously deduced fol- propargylic ethers in good yields with good levels of
lowing quantitative desilylation of the acetylenic posi- syn:anti selectivity ꢃ80:20 (Table 5, entries 1–4).
tion through treatment with TBAF in THF at room Noteworthy, in these cases, (ꢁ)-3-Cu
ACHTUNGTREN(NGNU Mes)Li gave sig-
temperature. Indeed, under these conditions a mix- nificantly higher selectivities (Table 5, entries 1 vs. 2
ture of syn- and anti-b-amino propargylic ethers 5a af- and 3 vs. 4). Inexplicably, under the same conditions,
forded a mixture of the two isomeric products 9a in primary a-silyloxyimine (SS)-4e led to the desired
the same ratio.
Thus, the syn:anti stereoselectivty observed at in variable yields (Table 4, entries 5 and 6).
ꢀ208C was the same as the one observed at ꢀ808C When reacting secondary imine (RS)-4f with (ꢁ)-3-
(Table 4, entry 2 vs. 3). Encouraged by this result, we Cu(CN)Li, the corresponding syn-b-amino propargyl-
envisaged decreasing the amount of (ꢁ)-3-Cu(Mes)Li ic ether was obtained in 66% yield with a selectivity
used at ꢀ208C while keeping a syn:anti selectivity of 83:17 (Table 5, entry 7), whereas no reaction oc-
close to 92:08. Interestingly, suitable syn:anti selectivi- cured with (ꢁ)-3-Cu(Mes)Li (Table 5, entry 8).
ties ꢃ88:12 were observed when employing either 4 Disappointingly, with unsaturated N-tert-butylsulfi-
adduct with slightly lower selectivities close to 70:30
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
or 3 equivalents of (ꢁ)-3-Cu(Mes)Li at ꢀ208C. Nev- nylimines 4g–i almost no selectivity was observed in
G
ertheless, in both cases compounds 9a were obtained the reaction with (ꢁ)-3-Cu(CN)Li (Table 5, entries 9,
as major products in 85% and 89% yields in unsepar- 11 and 13). However, better selectivities were at-
able mixture with syn- and anti-b-amino propargylic tained using (ꢁ)-3-Cu
ethers 5a (Table 4, entries 4 and 5). On the other slight with aromatic and acetylenic imines (RS)-4g and
(Mes)Li led (SS)-4i (Table 5, entries 9 vs. 10 and 13 vs. 14). Inter-
ACHTUNGTNER(NUNG Mes)Li. Improvements were
hand, the use of 2 equivalents of (ꢁ)-3-Cu
ACHTUNGTRENNUNG
to a lower syn:anti selectivity of 81:19, albeit in still estingly, in the case of ethylenic imine (RS)-4h the
good 78% yield (Table 4, entry 6). These results thus syn:anti selectivity could be improved from 50:50 to
precluded the use of a lesser amount of (ꢁ)-3-Cu- 77:23 furnishing the expected b-amino propargylic
ACHTUNGTRENNUNG(Mes)Li in the reaction with imine (SS)-4a under ether in 68% yield (Table 5, entry 11 vs. 12).
these conditions.
Noteworthy, as observed with (ꢁ)-3-Cu(CN)Li, the
variation of the syn:anti ratio against the number of Asymmetric Synthesis of (+)-b-Conhydrine
equivalents of (ꢁ)-3-Cu
ACHTUNGTNER(NUNG Mes)Li fitted well the theo-
retical curve calculated by Hoffmann, meaning that The synthetic usefulness of our new reaction was next
(ꢁ)-3-Cu(Mes)Li is configurationally stable at ꢀ208C demonstrated by developing a new short asymmetric
U
in THF in the presence of HMPA with respect to the synthesis of (+)-b-conhydrine (Figure 1), one of the
time scale defined by the rate of its reaction with alkaloids in hemlock Conium maculatum isolated
imine (SS)-4a.
from the seeds and leaves of this poisonous plant.[15]
To the best of our knowledge, four syntheses of the
As expected, no reaction occured when 6 equiva-
lents of (ꢁ)-3-Cu
ACHTUNGTNER(NUNG Mes)Li were reacted with a- two enantiomers of this alkaloid have been reported
branched imine (SS)-4b at ꢀ808C in THF in the pres- to date from carbohydrate sources (d-mannitol,[16a,b]
ence of 10 equivalents of HMPA relative to the or- d-serine,[16c] or l-aspartic acid[16d). Eight other synthe-
ganometallic (Table 4, entry 7), while carrying out the ses from non-carbohydrate sources have also been de-
reaction at ꢀ208C afforded a mixture of two unsepar- scribed including various diastereoselective reactions
able desilylated adducts 9b in 76% yield but in a induced by chiral auxiliaries,[16e–h] a diastereo- and
modest syn:anti ratio of 70:30 established as before enantioselective nitroaldolisation reaction,[16i] an
(Table 4, entry 8).
asymmetric hetero-Diels–Alder reaction,[16j] or substi-
tutions of N-Boc-2-lithiopiperidine by dynamic reso-
lution as key steps.[16k,l]
Generalization of the Reactions of (ꢁ)-3-Cu(CN)Li
As for us, we planned to prepare (+)-b-conhydrine
starting from the known imine (SS)-4c[1p] obtained in
two steps and 92% overall yield from commercially
and (ꢁ)-3-Cu
ACHTUNGTRENNUNG(Mes)Li with Enantiopure Imines
The optimized reaction conditions with both (ꢁ)-3- available 5-chloropentanal (Scheme 9). As indicated
Cu(CN)Li and (ꢁ)-3-Cu(Mes)Li were next applied to in Table 5 (entry 2), the reaction of (SS)-4c with (ꢁ)-
other enantiopure N-tert-butylsulfinylimines (SS)-4c–e. 3-Cu(Mes)Li afforded syn-b-amino propargylic ether
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
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Adv. Synth. Catal. 2011, 353, 2137 – 2151

Stereoselective Synthesis of syn-b-Amino Propargylic Ethers
Table 5. Scope and limitations of the reaction of (SS)-4c–i with (ꢁ)-3-Cu(CN)Li and (ꢁ)-3-Cu
ꢀ808C.
ACHTUNGTREN(NUNG Mes)Li in THF-HMPA at
Entry
R
Imine
X
Product
dr[a]
Yield [%][b]
1
2
3
4
5
6
7
8
Cl
Cl
AllylN
AllylN
TBSOCH2
TBSOCH2
c-Hex
c-Hex
Ph
Ph
N
(SS)-4c
(SS)-4c
(SS)-4d
(SS)-4d
(SS)-4e
(SS)-4e
(RS)-4f
(RS)-4f
(RS)-4g
(RS)-4g
(RS)-4h
(RS)-4h
(SS)-4i
(SS)-4i
CN
Mes
CN
Mes
CN
Mes
CN
Mes
CN
Mes
CN
Mes
CN
Mes
(SS)-5c
(SS)-5c
(SS)-5d
(SS)-5d
(SS)-5e
(SS)-5e
(RS)-5f
(RS)-5f
(RS)-5g
(RS)-5g
(RS)-5h
(RS)-5h
(SS)-5i
(SS)-5i
83:13
91:09
80:20
90:10
70:30
66:34
83:17
–
40:60
60:40
50:50
77:23
60:40
65:35
81
72
80
G
E
81 (68)[c]
79
44
66
0
83
90
72
68
86
9
10
11
12
13
14
(E)-PhCH=CH
(E)-PhCH=CH
ꢂ
CH
CH
(CH2)5C C
(CH2)5C C
ꢂ
3A
85
[a]
1
syn-5c–i:anti-5c–i ratio determined by H NMR analysis of the crude reaction mixture.
Combined isolated yield of unseparable syn- and anti-5c–i.
In parentheses, the yield of the purified major syn isomer.
[b]
[c]
(SS,1R,2R)-5c with a syn:anti-selectivity of 91:09. The steps and 33% overall yield from 5-chloropentanal
mixture of the two unseparable isomers (obtained in was physically and spectroscopically in good agree-
72% isolated yield) was then treated with NaH ment with the literature data.[16e]
(4 equiv.) in THF in the presence of 15-crown-5
(3 equiv.) at room temperature to achieve piperidine
ring formation by intramolecular displacement of the Formal Asymmetric Synthesis of (ꢀ)-Balanol
chlorine atom.[1o,p] Under these conditions, the desily-
lation of the acetylenic position also occurred, fur- (ꢀ)-Balanol (Figure 2) is an unusual metabolite iso-
nishing cyclized product (SS,1’R,2R)-10 as a single lated from the fungus Verticillium balanoides in
isomer in 83% yield after chromatography over silica 1993[17a] and again in 1994 from Fusarium meris-
gel, the minor isomer being separated at this stage.
moides and initially termed azepinostatin.[17b] The
The removal of the N-tert-butylsulfinyl auxiliary main core of balanol was identified to be a hexahy-
and the concomitant deprotection of the methoxy- droazepine ring with amide and ester substituents at
methyl ether by treatment with HCl (10 equiv.) in re- C-3 and C-4, respectively. Due to the promising inhib-
fluxing MeOH, followed by the complete hydrogena- itory activity of (ꢀ)-balanol and number of its ana-
tion (1 atm) of the carbon-carbon triple bond over logues against protein kinases C and A (which are
Pd/C led to crude (+)-b-conhydrine. Further chroma- two important targets in oncology) at low nanomolar
tography over acidic SCX resin, gave pure (+)-b-con- concentrations,[18] efforts towards the asymmetric syn-
hydrine in 66% yield. The product so obtained in six thesis of this molecule have been undertaken since its
discovery. More particularly, studies have been fo-
cused on the synthesis of the benzophenone frag-
ment[19] and hexahydroazepine core of (ꢀ)-balanol.[20]
Amongst the reported total syntheses of (ꢀ)-bal-
anol, some have been based on the use of chiral start-
ing materials (d-serine[21a–f] or l-ascorbic acid[21g]) or
on the resolution of racemic mixtures.[22] In others,
Figure 1. Structure of (+)-b-conhydrine.
the two stereogenic carbon atoms of the hexahydro-
Adv. Synth. Catal. 2011, 353, 2137 – 2151
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Julien Louvel et al.
FULL PAPERS
Scheme 9. Asymmetric synthesis of (+)-b-conhydrine.
ACHTUNGTRENNUNGazepine core had been simultaneously created desilylation of the acetylenic position through reac-
through the diastero- and enantioselective epoxida- tion with TBAF (1.1 equiv.) under classic conditions,
tion reactions of allylic alcohols or a,b-unsaturated es- hydrozirconation of the carbon-carbon triple bond
ters,[23a–c] the aminohydroxylation reaction of an a,b- with Schwartzꢂs reagent (1.4 equiv.) at room tempera-
unsaturated aryl ester,[23d] the asymmetric aziridina- ture in THF,[26] and ring-closing metathesis with 2nd
tion of an allylic alcohol,[23e] or the intramolecular ste- generation Grubbs’ catalyst (2ꢃ5 mol%) in refluxing
reoselective addition of a sulfonium ylide to an N- CH2Cl2. The crude product was purified by flash chro-
tert-butylsulfinyl
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
imine.[23f] The enantioselective desy- matography over silica gel to give the ex
metrization reactions of meso-epoxides,[23e,24a] as well 2,3,4,7-tetrahydro-1H-azepine
as the dynamic kinetic resolutions of a bis allylic alco- (SS,3R,4R)-13 in 81% overall yield. Finally, the target
hol,[24b] of an a-amino-b-keto ester,[24c] or of a vinylic molecule was obtained through acidic removal of the
aziridine[24d] have also been successfully employed. In N-tert-butylsulfinyl auxiliary and concomitant depro-
this field, we envisioned to develop a formal synthesis tection of the methoxymethyl ether with dry HCl
of (ꢀ)-balanol using our methodology.
(10 equiv.) at 658C in MeOH, followed by the succes-
Our approach started from N-Cbz-a-amino acetal sive additions of Et3N (5 equiv.) and (4-benzyloxy)-
12, the preparation of which had already been report- phenyl chloroformate (1 equiv.). After flash chroma-
ed[25] in three steps and 86% yield from commercially tography over silica gel of the crude mixture, the de-
available a-aminoacetaldehyde dimethyl acetal 11 sired molecule (SS,3R,4R)-14 was isolated in 85%
(Scheme 10). The condensation of (SS)-N-tert-butyl- yield in an analytically pure form. Compound 14 was
sulfinylamide under classical conditions[8] then al- thus synthetized in seven steps and 35% overall yield
lowed us to obtain the desired enantiopure imine from the known acetal 12, and exhibited spectroscopic
(SS)-4d in 73% yield. As reported in Table 5 (entry 4), and physical data in good agreement with the ones re-
the reaction of (SS)-4d with (ꢁ)-3-Cu
(Mes)Li gave a ported in the literature.[21a] It could then be concluded
ACHTUNGTRENNUNG
mixture of two b-amino propargylic ethers with a that we have disclosed a new formal synthesis of (ꢀ)-
syn:anti selectivity of 90:10. The major syn isomer balanol as (3R,4R)-1-(benzyloxy)carbonyl-2,3,4,7-tet-
(SS,1R,2R)-5d could be isolated in 68% yield as a dia- rahydro-4-hydroxy-1H-azepin-3-ylcarbamate (14) had
stereo- and enantiopure compound by column chro- already been reported to give (ꢀ)-balanol in three
matography over silica gel. It was then subjected to steps and 74% yield.[21a,c,d]
Conclusions
In summary, we have disclosed a new stereoselective
entry to syn-(SS,1R,2R)-b-amino propargylic ethers
through the addition of racemic lithio 3-(methoxyme-
thoxy)allenylcoppers to (SS)-N-tert-butylsulfinyli-
mines. The scope and limitation of the methodology
have been investigated. Amongst these copper re-
Figure 2. Structure of (ꢀ)-balanol.
agents, (cyano)cuprates and (mesityl)cuprates have
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Adv. Synth. Catal. 2011, 353, 2137 – 2151

Stereoselective Synthesis of syn-b-Amino Propargylic Ethers
Scheme 10. Formal asymmetric synthesis of (ꢀ)-balanol.
Bruker ARX 200 spectrometer fitted with a dual probe
(13C/1H). Chemical shifts are reported in d units relative to
an internal standard of residual chloroform (d =7.27 ppm
been demonstrated to be the most efficient leading to
up to 92:08 syn:anti selectivity. The synthetic utility of
this new methodology has been exemplified by the
development of a new asymmetric synthesis of (+)-b-
conhydrine obtained in six steps and 33% overall
yield from commercially available 5-chloropentanal,
which constitues the most efficient synthesis of this al-
kaloid to date. A known advanced intermediate of
(ꢀ)-balanol has also been prepared in seven steps and
35% overall yield. This new formal synthesis of (ꢀ)-
balanol represents a competitive alternative to those
previously reported.
1
for H NMR spectra and d=77.16 ppm for 13C NMR spec-
tra). IR spectra were recorded with a diamond ATR spec-
trometer. High-resolution mass spectra (HR-MS) were ob-
tained with a Finnigan MAT 95 instrument.
Addition of Allenylcuprates (ꢁ)-3-[Cu] to
Enantiopure N-tert-Butylsulfinylimines: Typical
Procedure [Compound (SS,1R,2R)-5c, Table 5,
entry 2]
Under N2, to a solution of [3-(methoxymethoxy)prop-1-
ynyl]trimethylsilane[27] (570 mL, 3.00 mmol) in THF (20 mL)
at ꢀ958C was added dropwise t-BuLi (1.7M solution in pen-
tane, 1.90 mL, 3.25 mmol) at ꢀ908C. After 1 h of stirring at
ꢀ908C, mesitylcopper (1.0M solution in THF, 4.50 mL,
4.50 mmol) was added and the mixture was stirred for
30 min at ꢀ808C. At ꢀ808C, to the resulting solution of
Experimental Section
General Information
Experiments involving organometallic compounds were car-
ried out in dried glassware under a positive pressure of dry
N2. Liquid nitrogen was used as a cryoscopic fluid. A three-
necked, round-bottomed flask equipped with an internal
thermometer, a septum cap and a nitrogen inlet was used.
Anhydrous solvents were distilled to remove stabilizers and
dried with a double column purification system. ZnBr2
(98%) was melted under dry N2 and, immediately after cool-
ing to room temperature, was dissolved in anhydrous Et2O
or THF. CuCN·2LiCl was dried at 1308C under vacuum for
2 h and dissolved in THF upon cooling to room tempeature.
All other reagents and solvents were of commercial quality
and were used without further purification. 1H and
13C NMR spectra were recorded with a Bruker AVANCE
400 spectrometer fitted with a BBFO probe or with a
lithio (mesityl)cuprate, (ꢁ)-3-Cu
ACHTUNGERTN(NUNG Mes)Li, was added HMPA
(5.25 mL, 30.00 mmol). After 5 min, a solution of imine (SS)-
4c (112 mg, 0.50 mmol) in THF (1 mL) was added dropwise.
The resulting reaction mixture was stirred for 1 h at ꢀ808C
and then quenched by addition of a 2:1 mixture of saturated
aqueous NH4Cl and 30% aqueous NH3 (40 mL). Et2O
(20 mL) was added and the stirring was continued under air
until a clear, deep-blue solution was obtained. The layers
were then separated, the aqueous one extracted with Et2O
(2ꢃ20 mL), the organic layers washed with water (20 mL)
and brine (20 mL), dried over MgSO4, and the solvents re-
moved under vacuum. Purification of the crude residue by
silica gel flash chromatography (50:50 pentane/Et2O) afford-
ed the title compound 5c as a mixture of two isomers; yield:
143 mg (72%, syn:anti=91:09). Further purification by silica
Adv. Synth. Catal. 2011, 353, 2137 – 2151
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Julien Louvel et al.
FULL PAPERS
gel flash chromatography afforded a stereochemically pure
sample of the major syn-isomer. [a]2D0: ꢀ54.5 (c 0.89 in
CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d=4.91 (AB
system, J=6.7 Hz, 1H), 4.61 (AB system, J=6.7 Hz, 1H),
4.38 (d, J=4.2 Hz, 1H), 3.54 (t, J=6.6 Hz, 2H), 3.46 (d, J=
8.1 Hz, 1H), 3.38 (s, 3H), 3.37–3.32 (m, 1H), 1.90–1.76 (m,
3H), 1.76–1.62 (m, 2H), 1.58–1.50 (m, 1H), 1.23 (s, 9H),
0.14 (s, 9H); 13C NMR (100 MHz, CDCl3, 258C): d=102.0,
94.6, 92.2, 69.2, 60.1, 56.6, 56.1, 44.8, 32.4, 31.4, 23.3, 22.8,
ꢀ0.1; IR (neat): n=2956, 2172, 1457, 1250, 1151, 1023, 841,
12.5 and 3.8 Hz, 1H), 0.95 (t, J=7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3, 258C): d=75.3, 61.1, 46.5, 29.1, 26.4,
26.2, 24.5, 10.3; IR (neat): n=3298, 3110, 2929, 2852, 1669,
1435, 1131, 1110, 1054, 874, 841 cmꢀ1; HR-MS (ESI): m/z=
144.1385, calcd. for C8H18NO [M+ +H]: 144.1388.
(+)-(3R,4R)-Benzyl 3,4-Dihydro-4-methoxymethoxy-
3-(SS)-[(2-methylpropyl)sulfinyl]amino-2H-azepine-
1(7H)-carboxylate (13)
758 cmꢀ1
;
HR-MS (ESI): m/z=418.1596, calcd. for
To a solution of (SS,1R,2R)-5d (628 mg, 1.44 mmol) in THF
(15 mL) was added TBAF (1M solution in THF, 1.60 mL,
1.60 mmol). After 10 min of stirring at room temperature,
H2O (15 mL) was added dropwise and the resulting mixture
was extracted with EtOAc (3ꢃ15 mL). The combined or-
ganic layers were washed with brine (15 mL) and dried over
MgSO4. The solvents were removed under vacuum and the
crude product (yield: 485 mg) was used in the next step
without purification.
C17H34NNaO3SSi [M+ +Na]: 418.1609. The minor anti-
isomer displayed analytical data identical to those reported
in the literature.[3i]
(ꢀ)-(SS)-(R)-1-(2-Methylpropyl)sulfinyl-2-[(R)-1-
(methoxymethoxy)prop-2-ynyl]piperidine (10)
To a solution of 5c (666 mg, 1.68 mmol, syn:anti=91:09) in
THF (50 mL) at 08C were added 15-crown-5 (1.00 mL,
5.05 mmol) and NaH (60% dispersion in mineral oil,
267 mg, 6.73 mmol). The mixture was then allowed to warm
to room temperature and stirred for 15 h, after which satu-
rated aqueous NH4Cl (13 mL) was added dropwise. The re-
sulting mixture was extracted with EtOAc (3ꢃ13 mL). The
combined organic layers were washed with brine (13 mL),
dried over MgSO4, and the solvents were removed under
vacuum. Silica gel flash chromatography (70:30!20:80 pen-
tane/Et2O) afforded the diastereomerically pure title com-
pound as a colourless oil; yield: 410 mg (83%). [a]2D0: ꢀ76.0
To a solution of the crude product (485 mg, 1.11 mmol) in
THF (12 mL) at room temperature was added Schwartzꢂs
reagent (406 mg, 1.60 mmol) in small fractions over a period
of 30 min. The resulting mixture was then quenched by addi-
tion of aqueous HCl (1M, 12 mL) and extracted with
EtOAc (3ꢃ12 mL). The organic layers were gathered and
washed with brine (15 mL) and saturated aqueous NaHCO3
(12 mL), H2O (12 mL), brine (12 mL), and dried over
MgSO4. The solvents were removed under vacuum and the
crude product (yield: 415 mg) was used in the next step
without purification.
To a solution of the crude product (415 mg, 0.95 mmol) in
CH2Cl2 (100 mL) was added 2nd generation Grubbs’ catalyst
(40 mg, 0.47 mmol). After 1 h of stirring at reflux, an addi-
tional portion of 2nd generation Grubbs’ catalyst (40 mg,
0.47 mmol) was added. The resulting mixture was then
stirred at reflux for 1 h, cooled down to room temperature,
and the solvent was removed under vacuum to give a dark
oil. The crude product was purified by flash silica gel chro-
matography (40:60!100:0 EtOAc/cyclohexane) to afford
1
(c 0.60 in CHCl3); H NMR (400 MHz, CDCl3, 258C): d=
4.86 (AB system, J=6.8 Hz, 1H), 4.69 (dd, J=8.3 and
2.1 Hz, 1H), 4.47 (AB system, J=6.8 Hz, 1H), 3.37–3.23 (m,
2H), 3.28 (s, 3H), 2.94–2.87 (m, 1H), 2.44 (d, J=2.1 Hz,
1H), 1.99–1.88 (m, 1H), 1.83–1.68 (m, 1H), 1.62–1.44 (m,
3H), 1.43–1.35 (m, 1H), 1.08 (s, 9H); 13C NMR (75 MHz,
CDCl3, 258C): d=94.1, 80.6, 76.0, 64.9, 62.4, 59.0, 55.9, 39.7,
26.1, 25.7, 23.4, 19.6; IR (neat): n=3209, 2946, 1446, 1153,
1040 cmꢀ1
;
HR-MS (ESI): m/z=288.1631, calcd. for
the title compound as
a brown oil; yield: 315 mg
C14H26NO3S [M+ +H]: 288.1633.
(0.77 mmol, 81% over three steps). [a]2D0: +10.5 (c 0.95 in
CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d=7.48–7.29
(m, 5H), 5.75–5.61 (m, 2H), 5.21 and 5.16 (2 ꢃ s, 2H for two
rotamers), 5.06 (d, J=6.1 Hz, 1H), 4.76–4.56 (m, 2H), 4.50
and 4.42 (2 ꢃ d, J=17.7 Hz, 1H for two rotamers), 4.30 (d,
J=6.5 Hz, 1H), 4.11 (d, J=14.9 Hz, 1H), 3.97–3.52 (m,
3H), 3.38 and 3.36 (2 ꢃ s, 3H for two rotamers), 1.22 and
1.08 (2 ꢃ s, 9H for two rotamers); 13C NMR (75 MHz,
CDCl3, 258C): d=157.1 and 155.8 (two rotamers), 136.5 and
136.4 (two rotamers), 131.8 and 130.6 (two rotamers), 128.8,
128.6, 128.3, 128.0 and 127.9 (two rotamers), 97.1 and 96.6
(two rotamers), 76.5, 67.8, 60.3 and 59.4 (two rotamers),
55.9, 55.8, 51.0 and 50.3 (two rotamers), 48.2, 22.9 and 22.6
(two rotamers); IR (neat): n=3246, 2954, 1687, 1466,
(+)-(R)-1-[(R)-Piperidin-2-yl]propan-1-ol [(+)-b-
Conhydrine]
To a stirred solution of 10 (187 mg, 0.66 mmol) in MeOH
(6.60 mL) was added HCl (4M solution in dioxane, 1.65 mL,
6.60 mmol) and the mixture was heated to reflux for 2 h.
The solvents were evaporated under vacuum and the residue
was taken up in MeOH (10 mL). Pd/C (10% wt, 20 mg) was
added and the flask was purged with H2 (3ꢃ). After 20 h of
stirring under H2 (1 atm), the mixture was filtered on Celite
(MeOH). The solvents were removed under vacuum, and
the residue was purified by ion-exchange chromatography
(SCX column, H+ form, elution with MeOH, washed with a
2M solution of NH4OH in MeOH), affording the title com-
pound as a white solid; yield: 57 mg (66%); mp 608C
[Lit.[16a] mp 67–688C]. [a]D20: +5.7 (c 0.70 in EtOH) [Lit.[16e]
[a]2D0: +8.6 (c 1 in EtOH)]; 1H NMR (400 MHz, CDCl3,
258C): d=3.38 (br s, 2H), 3.18 (td, J=7.9 Hz, 5.4 Hz, 1H),
3.04 (d, J=11.9 Hz, 1H), 2.53 (td, J=11.8 and 2.8 Hz, 1H),
2.29 (ddd, J=10.6, 7.7 and 2.6 Hz, 1H), 1.83–1.71 (m, 1H),
1.68–1.47 (m, 3H), 1.44–1.21 (m, 3H), 1.08 (ddd, J=23.6,
1036 cmꢀ1
C20H31N2O5S [M+ +H]: 411.1954.
;
HR-MS (ESI): m/z=411.1950, calcd. for
2148
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 2137 – 2151

Stereoselective Synthesis of syn-b-Amino Propargylic Ethers
cella, R. Blumenthal, V. Marquez, Bioorg. Med. Chem.
2009, 17, 1498–1505; m) D. Uraguchi, S. Nakamura, T.
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Inuki, Y. Yoshimitsu, S. Oishi, N. Fujii, H. Ohno, J.
Org. Chem. 2010, 75, 3831–3842; o) A. Voituriez, F.
Ferreira, F. Chemla, J. Org. Chem. 2007, 72, 5358–
5361; p) A. Voituriez, F. Ferreira, A. Pꢀrez-Luna, F.
Chemla, Org. Lett. 2007, 9, 4705–4708; q) B. Hꢀlal, F.
Ferreira, C. Botuha, F. Chemla, A. Pꢀrez-Luna, Synlett
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F. Chemla, A. Pꢀrez-Luna, J. Org. Chem. 2009, 74,
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(ꢀ)-4-(Benzyloxy)phenyl [(3R,4R)-1-(Benzyloxy)-
carbonyl-2,3,4,7-tetrahydro-4-hydroxy-1H-azepin-3-
yl]carbamate (14)
To a solution of 13 (100 mg, 0.24 mmol) in MeOH (5 mL)
was added HCl (4M solution in 1,4-dioxane, 0.60 mL,
2.4 mmol). The mixture was heated at reflux for 2 h and
evaporated to dryness. The residue was taken up in CH2Cl2
(5 mL) and Et3N (0.17 mL, 1.20 mmol) was added followed
by 4-(benzyloxy)benzoyl chloride (62 mg, 0.25 mmol). After
1 h of stirring at room temperature, the mixture was
quenched by addition of H2O (3 mL). The layers were sepa-
rated and the aqueous one extracted with CH2Cl2 (3ꢃ
5 mL). The combined organic layers were washed with
aqueous NaHSO4 (1M, 3 mL), dried over Na2SO4, and the
solvents were removed under vacuum. Silica gel flash chro-
matography (75:25 EtOAc/cyclohexane) furnished the title
compound as a white foam; yield: 98 mg (85%); mp 808C
[Lit.[21a] mp 848C]. [a]D20: ꢀ63.6 (c 1.03 in CHCl3) [Lit.[21a]
1
[a]2D0: ꢀ51.74 (c 0.69 in CHCl3)]; H NMR (400 MHz, CDCl3,
258C): d=8.67 (d, J=8.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 2H),
7.51–7.27 (m, 10H), 7.04 (d, J=8.8 Hz, 2H), 5.78–5.75 (m,
1H), 5.48–5.41 (m, 1H), 5.39 (s, 1H), 5.23 (AB system, J=
12.3 Hz, 2H), 5.14 (s, 2H), 4.73–4.64 (m, 1H), 4.64 (dd, J=
18.3 and 2.6 Hz, 1H), 4.32 (dd, J=12.9 and 5.6 Hz, 1H),
3.99 (d, J=15.1 Hz, 1H), 3.77–3.67 (m, 1H), 3.62 (dd, J=
15.1 and 5.6 Hz, 1H); 13C NMR (75 MHz, CDCl3, 258C):
d=168.9, 161.7, 157.8, 136.4, 136.0, 134.7, 129.3, 128.74,
128.71, 128.4, 128.2, 128.0, 127.5, 125.7, 123.9, 114.8, 74.7,
70.1, 68.2, 59.5, 48.9, 48.5; IR (neat): n=3344, 1681, 1635,
1605, 1498, 1239, 1177, 1024 cmꢀ1; HR-MS (ESI): m/z=
473.2063, calcd. for C28H29N2O5 [M+ +H]: 473.2076.
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Acknowledgements
The authors cordially thank UPMC and CNRS for financial
support, GlaxoSmithKline for a Ph.D grant to J. Louvel and
CNRS for a postdoctoral fellowship to A. Voituriez.
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