Substrate-Regiocontrolled Synthesis of Enantioenriched Allylic Amines by Palladium-Catalysed Asymmetric Allylic Amination: Formal Synthesis of Fagomine

Article abstract of DOI:10.1002/adsc.201600583

Branched allyl amines or linear amines can be obtained from E-4-hydroxybuten-2-yl methyl carbonate using the palladium/1,2-diaminocyclohexane (DACH)-catalysed allylic amination by just starting from the unprotected or the protected derivative, respectively. Unhindered primary amines can be used as nucleophiles, thus enlarging the scope of the Pd/DACH catalytic system. Hydrogen bonding involving the free hydroxy group in the unprotected allylic carbonate is proposed to be responsible for the control of the regioselectivity to afford branched isomers, obtained in high ee. A short and enantioselective formal synthesis of the glycosidase inhibitor fagomine is described using this method. (Figure presented.).

Full text of DOI:10.1002/adsc.201600583

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DOI: 10.1002/adsc.201600583
Substrate-Regiocontrolled Synthesis of Enantioenriched Allylic
Amines by Palladium-Catalysed Asymmetric Allylic Amination:
Formal Synthesis of Fagomine
Sꢀbastien Soriano,a Margarita Escudero-Casao,a M. Isabel Matheu,a
Yolanda Dꢁaz,a,* and Sergio Castillꢂna,*
a
Departament de Quꢁmica Analꢁtica i Quꢁmica Orgꢃnica, Universitat Rovira i Virgili,
C/Marcel·lꢁ Domingo 1, 43007 Tarragona, Spain
Fax : (+34)-977-558-446; e-mail: yolanda.diaz@urv.cat or sergio.castillon@urv.cat
Received: June 13, 2016; Revised: October 11, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600583.
Abstract: Branched allyl amines or linear amines can bonate is proposed to be responsible for the control
be obtained from E-4-hydroxybuten-2-yl methyl car- of the regioselectivity to afford branched isomers,
bonate using the palladium/1,2-diaminocyclohexane obtained in high ee. A short and enantioselective
(DACH)-catalysed allylic amination by just starting formal synthesis of the glycosidase inhibitor fago-
from the unprotected or the protected derivative, re- mine is described using this method.
spectively. Unhindered primary amines can be used
as nucleophiles, thus enlarging the scope of the Pd/
DACH catalytic system. Hydrogen bonding involving Keywords: amination; enantioselectivity; fagomine;
the free hydroxy group in the unprotected allylic car- palladium; regioselectivity
Introduction
the presence of an achiral phosphine (Scheme 1, path
a). This tendency is even greater when amines are
The palladium-catalysed asymmetric allylic substitu- used as nucleophiles, and could be due to the elec-
tion reaction is one of the most studied reactions in tronic effect of the epoxide oxygen, which directs the
asymmetric synthesis.[1] However, Pd-catalysed allylic
substitution of non-symmetrical monosubstituted al-
lylic electrophiles typically affords achiral linear prod-
ucts (Scheme 1c),[1b] and control of regioselectivity to
afford chiral branched products remains a challenge.[2]
Many factors influence the regioselectivity of allylic
substitution, such as the steric and electronic effects
of both the substrates[3] and the nucleophiles,[4] the
counterion of the nucleophile,[5] the ligand,[4,6] base,[7]
solvent, etc. The chiral 1,2-diaminocyclohexane-N,N’-
bis(2-diphenylphosphinobenzoyl) and 1,2-diaminocy-
lohexane-N,N’-bis(2-diphenylphosphinonaphthoyl) li-
gands (DACH-phenyl and DACH-naphthyl ligands)
developed by Trost efficiently control both enantiose-
lectivity and regioselectivity in non-symmetrical mon-
osubstituted allylic derivatives to afford the branched
regioisomer.[8] Nevertheless, the regioselectivity is
often determined by several of the aforementioned
factors. For instance, vinyl epoxide 1 shows a marked
propensity to give 1,4-addition products (3) in Pd-cat-
alysed allylic alkylation with carbon nucleophiles in unsymmetrical monosubstituted substrates 1 and 2.
Scheme 1. Metal-catalysed allylic substitution reaction with
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attack at the remote side of the allyl terminus.[9] How- philes, but no reports have been made concerning its
ever, the combination of vinyl epoxide 1, DACH li- application with harder amine nucleophiles.[2,10,11] The
gands, and soft nucleophiles such as imides or imido reaction of butadiene monoepoxide (1) with 4-me-
carboxylates affords the branched derivative 4 with thoxybenzylamine (5), 2 mol% [Pd(h3-C3H5)Cl]2 and
excellent regio- and enantioselectivity (R=OH, Nu= 12 mol% PPh3 (Table 1, entry 1), afforded a mixture
phthalimido) (Scheme 1, path b).[10,11] On the other of linear (3a) and branched (4a) amines in a 76:24
hand since the seminal contribution by Takeuchi, who ratio. As expected, the use of chiral (S,S)-DACH
first reported branch-selective allylation of carbon naphthyl ligand under similar conditions increased
and nitrogen nucleophiles using an iridium catalyst,[12] the percentage of the branched product 4a with poor
Lee,[13] Helchem[14] and Hartwig[15] later described the regioselectivity (Table 1, entry 2). The use of a soft
regio- and enantioselective synthesis of compound 4 nucleophile like phthalimide was described to provide
(R=OH or OPG, Nu=nitrogen nucleophiles) from almost exclusively the branched isomer.[2]
linear monosubstituted allylic electrophiles 2 (R=OH
These results confirm the crucial role of the nucleo-
or OPG) using an iridium/phosphoramidite catalyst phile in the control of the regioselectivity of palladi-
(Scheme 1, path d).,Recent studies of the Pd-DACH um-catalysed allylic amination of vinyl epoxide 1.
catalytic system provided structural and mechanistic
We then turned our attention to linear carbonate
information which has been elusive for decades, un- 2a. The reaction with benzylamine 5 in the presence
derlying the importance of hydrogen bonding interac- of [Pd(h3-C3H5)Cl]2/PPh3 furnished a 40:60 mixture of
tions in the regio- and stereochemical outcome of the linear bis-allylated 3a’ and branched 4a amines
process, involving the amide bond contained in the (Table 1, entry 3).[26] Interestingly, the use of the Pd/
chiral ligand, with either the leaving group in the ioni- (S,S)-DACH naphthyl ligand as a catalytic system af-
sation step or with the approaching nucleophile in the forded the branched isomer 4a as the only regioiso-
trapping of the p-allylpalladium complex.[16]
mer (Table 1, entry 4) in a practically enantiopure
Allylamine 4 is a useful chiral building block in or- form [98% ee, (R)].[27] The free hydroxy group at 2a
ganic synthesis.[11,12b,13–15,17–22] In order to explore the was next protected and derivatives 2b and 2e of dif-
synthesis of 4 from 2 using palladium catalysts, and ferent steric hindrances were tested in the Pd-cata-
taking into account the role of DACH ligands in the lysed asymmetric allylic amination. On the one hand,
control of regioselectivity, we wondered whether the reaction of methyl ether 2b with amine 5 in the
structural elements in the substrate able to provide presence of Pd/(S,S)-DACH naphthyl ligand as a cata-
hydrogen bonding could bias the regiochemistry of lytic system afforded a 65:35 mixture of linear 3b/
the palladium-catalysed allylic amination of com- branched 4b (Table 1, entry 6). On the other hand the
pound 2 to afford branched derivatives 4. Here we reaction of the trityl derivative 2e with 5 under the
show that enantiopure branched (4) (Scheme 1e) or standard reaction conditions afforded the linear bis-
linear achiral (3) (Scheme 1c) allylamines can be ob- allylated amine 3e’ in an exclusive manner (Table 1,
tained by a Pd-DACH-catalysed asymmetric allylic entry 9).
amination of compound 2 by starting from the unpro-
Electronic effects were also explored.[28] The reac-
tected (R=OH) or the protected (R=OPG) com- tion of compound 2c, with a methyl group instead of
pound, respectively. Contrary to what happens when a hydroxy moiety, with 5 under similar conditions fur-
starting from vinyl epoxide 1, the use of linear car- nished a 70:30 linear/branched mixture of aminated
bonate 2a tolerates the presence of relatively hard products (Table 1, entry 7) in a process with virtually
primary amines as nucleophiles. Using the method de- the same regioselectivity as that observed in 2b.
veloped here, a short enantioselective formal synthe-
In order to assess the role of hydrogen bonding in-
sis of fagomine,[23,24] an imino sugar of natural origin teractions in the regiochemical outcome of the Pd-cat-
that shows activity against mammalian gut a-glucosi- alysed allylic amination, the reaction of 2a and 5 was
dase and b-galactosidases,[25] is described.
performed in methanol as a solvent, to afford an
80:20 mixture of 3a/4a (Table 1, entry 5), thus provid-
ing the reversed regioselectivity compared to that ob-
tained previously in CH2Cl2, in line with the regiose-
lectivity obtained from 2b and 2c.
Results and Discussion
The study was carried out using E-4-hydroxybuten-2-
Homoallylic alcohols could also play a directing
yl methyl carbonate derivatives (2) and for the sake role. To prove this, alcohol 2d was also reacted with
of comparison, butadiene monoepoxide (1), two sub- amine 5 under similar conditions, but in this case
strates that, upon ionisation under Pd-catalysed allylic a complex mixture was obtained (Table 1, entry 8).
amination, could formally give the same p-allylpalla-
Furthermore, the reaction 5 with substrate 2f, re-
dium intermediate. The latter has been extensively sulting from formal replacement of the hydroxy group
used in the Pd-catalysed asymmetric allylic amination by a sulfonamido moiety, also led to the formation of
reaction using relatively acidic soft nitrogen nucleo- the linear bis-allylated product 3f’ (Table 1, entry 10).
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Table 1. Palladium-catalysed allylic amination of 1 and 2.[a]
Entry
Substrate
Ligand
Products
Conversion [%]
Linear/branched ratio[b]
1
2
3
1
1
PPh3
3a, 4a
3a, 4a
3a’, 4a
4a
3a, 4a
3b, 4b
3c, 4c
3d, 4d
3e’
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
76:24[c]
56:44
(S,S)-DACH naphthyl
PPh3
2a
2a
2a
2b
2c
2d
2e
2f
40:60[c]
<2:98[d]
80:20
4
(S,S)-DACH naphthyl
(S,S)-DACH naphthyl
(S,S)-DACH naphthyl
(S,S)-DACH naphthyl
(S,S)-DACH naphthyl
(S,S)-DACH naphthyl
(S,S)-DACH naphthyl
5[e]
6
65:35
70:30
complex mixture
>98:2
>98:2
7
8
9
10
3f’
[a]
Conditions: catalyst [Pd(h3-C3H5)Cl]2 (2 mol%), (S,S)-DACH naphthyl ligand (6 mol%) or PPh3 (12 mol%), 1 equiv. of
substrate, 1.1 equiv. of nucleophile (5), room temperature, reaction time=16 h, solvent, CH2Cl2, concentration=0.02M.
The branched/linear ratio was determined by H NMR spectroscopy of the crude products.
Racemic 4a was obtained.
ee=98% (R). Determined by HPLC, see Ref.[27]
[b]
[c]
[d]
[e]
1
The reaction was performed in MeOH.
Control experiments using PPh3 as a ligand should (Scheme 2c). Furthermore, preferential formation of
give us some information on the key issues governing the branched isomer from the linear substrate 2a
the regioselectivity of the racemic process in the sub- could be explained from intermediate D by hydrogen
strates tested. A comparison of entries 1 and 3 in bonding-assisted nucleophilic attack of the nucleo-
Table 1 infers that the product distribution depends phile with the hydroxy group in the substrate (R=H),
on the structure of the starting material.[29]
counteracting the trans-effect of phosphine in the nu-
When chloride ion conditions are present, i.e., start- cleophilic addition step (Scheme 2d). In turn, Pd-cata-
ing from [Pd(h3-C3H5)Cl]2 as a precatalyst in the pres- lysed asymmetric allylic amination of 1 using [Pd(h3-
ence of PPh3, moderately good levels of regioreten- C3H5)Cl]2/(S,S)-DACH naphthyl ligand (entry 2,
tion should be expected through the intermediacy of Table 1) gave equimolar amounts of branched and
non-symmetrically ligated [Pd(PPh3)(h3-allyl)Cl] com- linear isomer, showing an increase in the branched
plexes A and B, respectively (Scheme 2a and b). isomer compared to the amount obtained in the race-
These complexes are envisioned to be formed by the mic reaction.
trans-effect of phosphorus in the initial ionisation
More interestingly, the reaction of allyl carbonate
step, whereas the subsequent nucleophilic attack step 2a with 5 using DACH-naphthyl ligand produced
essentially results from the preferential attack trans to a dramatic increase in the proportion of the branched
phosphine.[29a,b,d] These memory effects should be es- isomer, so that this was the only regioisomer observed
pecially strong when starting from trans-linear elec- by NMR spectroscopy. This is in contrast with the re-
trophiles with very good leaving groups (e.g., carbo- sults provided by the protected substrates, which gave
nates), as in Scheme 2b. However, the results ob- predominantly linear achiral regioisomers. The high
tained here from 1 and 2a show a slightly different levels of regioretention observed in the protected de-
trend. The large amount of linear isomer from epox- rivatives could be explained by the formation of the
ide 1 could arise from repulsive interactions of the in- Pd-allyl intermediate I. The departure of the leaving
coming amine nucleophile with the alkoxide ion group is likely to be assisted by hydrogen-bonding to
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Scheme 3. Rationalisation of regioselectivity and enantiose-
lectivity in the Pd-catalysed asymmetric allylic amination re-
action of allylic carbonates 2a–c, e with p-methoxybenzyla-
mine.
benzylamine in methanol as a solvent (Table 1,
entry 5, l/b ratio of 80:20), similar to those obtained
with the protected substrates, underlines the impor-
tance of hydrogen-bonding interactions, which are dis-
rupted when the solvent is protic.
Scheme 2. Regioselectivity of the Pd-catalysed allylic amina-
tion of 1 and 2a due to repulsive or hydrogen-bonding inter-
actions and the electronic effects affecting non-symmetically
ligated [Pd(h3-allyl)ClPPh3] complexes.
Furthermore, the divergence in regioselectivity of
the NH amide of the ligand, followed by hydrogen substrate 2f compared to 2a may be attributed to
bonding-mediated delivery of the amine in a process a significant difference in their acid properties. The
with no significant p-s-p equilibration (Scheme 3). TsNH group may expected to be deprotonated under
The high linear regioselectivity obtained from the the reaction conditions, thus possibly leading to a re-
sterically demanding trityl-protected substrate 2e pulsive effect with the nucleophile, in line with the re-
would result from the direct nucleophilic attack of the sults obtained when starting from the vinyl epoxide.
amine on the kinetically favoured complex I, with no Steric factors could also play a role.
apparent isomerisation to the more congested com-
We next generalised the reaction of carbonate 2a
plex II, with important non-bonded interactions of using a range of primary amines 6–9 to give the corre-
the trityl group with the naphthyl moiety in close sponding allylic secondary amines 10–13 in excellent
proximity (Scheme 3).
yields (up to 96%) (Table 2, entries 1–4). Moreover,
The reversed regioselectivity obtained from 2a may excellent enantioselectivities were obtained in all
be explained by a fast p-s-p interconversion of the ki- cases (90 to 98% ee).
netically favoured p-allylpalladium complex I to the
The reaction with secondary amines was then ex-
diastereomeric intermediate II. The driving force for plored. The reaction of 2a with pyrrolidine (14) and
this isomerisation could be the additional stabilisation dibenzylamine (15) using Pd/(S,S)-DACH naphthyl as
of the latter complex compared to I due to hydrogen a catalyst under the optimised reaction conditions in
À
bonding interactions between the N H bond in the both cases predominantly afforded the linear isomers
catalyst and the hydroxy group in the unprotected 17 and 18 with linear/branched ratios of 67:33 and
substrate (Scheme 3). Nucleophilic attack by the 85:15, respectively (Scheme 4a).
amine on the more substituted terminus of the allyl
The reaction of 2a with tert-butylamine (16) as an
moiety on II could result from cooperative hydrogen- example of a bulky primary amine under the same
bonding interactions.[30] Accordingly, the regioselectiv- conditions, furnished linear compound 19 as a major
ity obtained from the reaction of 2a and p-methoxy- regioisomer (branched/linear ratio 30:70 (Scheme 4a).
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Table 2. Palladium-catalysed allylic amination of 2a with pri-
mary amines 6–9 as nucleophiles.[a]
DACH naphthyl ligand. Similarly, when the reaction
of amine 20 was carried out with an excess of 2a,
compound 22 was obtained (Scheme 4b).
The outcome of this reaction can be explained by
initial Pd-catalysed asymmetric allylic amination of 2a
to give the branched derivative 21, a secondary amine
which acts as a nucleophile in a subsequent allylic
amination of 2a in excess to afford the linear aminat-
ed product 22.
On the other hand, the effect of branching at the
a position to the hydroxy group as in (E)-4-hydroxy-
pent-2-en-1-yl methyl carbonate[31] was also explored.
At the standard concentration used along this study
(0.02M), very low conversion was observed and the
reaction of this allylic carbonate with 5 led to the for-
mation of the corresponding bis-allylated linear prod-
uct in very low yield (<18%) only at a higher concen-
tration (0.2M), probably due to steric factors (for fur-
ther details see the Supporting Information).
The usefulness of this synthetic protocol is illustrat-
ed by the enantioselective two-step synthesis of piper-
idine 25, an ideal precursor of fagomine, an imino
sugar that shows activity against mammalian gut a-
glucosidase and b-galactosidase.[23,32]
En- R-NH2 Product Conversion
try
b/l
ee
(Yield [%])[b] Ratio[c] [%][d]
1
2
3
4
6
7
8
9
10
11
12
13
>98 (93)
>98 (96)
>98 (91)
>98 (90)
>98:2
>98:2
>98:2
>98:2
90 (R)
95
98
96
[a]
Conditions: catalyst [Pd(h3-C3H5)Cl]2 (2 mol%), (S,S)-
DACH naphthyl ligand (6 mol%), 1 equiv. of carbonate,
1.1 equiv. of nucleophile, room temperature, reaction
time=16 h, carbonate concentration=0.02M.
[b]
[c]
Isolated yield of branched regioisomer.
1
Determined by H NMR spectroscopy of the crude reac-
tion.
Our synthetic strategy is based on RCM of amino-
butenol 24 (Scheme 5).[33,34] This approach could give
access to enantiomerically pure, stereochemically de-
fined, five-, six- and seven-membered heterocycles.
[d]
Determined by HPLC, see Ref.[27]
These results clearly show the sensitivity of the regio- Asymmetric syntheses employing these intermediates
selectivity of this reaction to the steric hindrance of could lead to discovery of further biologically relevant
the nucleophile, so that hindered primary or secon- piperidine/azepane alkaloids and imino sugars.[35]
dary amines outweigh the restrictions imposed by the
The key intermediate 24 was thus first obtained
using the (R,R)-DACH naphthyl ligand under stan-
dard conditions in 91% yield and 94% ee. After as-
sessing the high degree of regio- and stereoselectivity
of this reaction, the crude compound 24 obtained by
reaction of 2a with 23 was directly subjected to ring
closing metathesis under Wrightꢅs conditions,[36] using
5 mol% of Grubbsꢅs second generation catalyst in the
presence of one equivalent of p-toluenesulfonic acid
Scheme 4. (a) Pd-catalysed allylic amination of 2a using
bulky amines and (b) branched-linear consecutive allylations
by reaction of 20 with 2a in excess.
Scheme 5. Formal synthesis of fagomine.
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were run on an LC/MS (TOF) instrument. Optical rotations
were measured at room temperature with 10 cm cells. IR
spectra were recorded on an FT-IR-ATR spectrophotome-
ter. Reactions were monitored by TLC, on 0.25 mm silica
gel 60 F254 glass or aluminium plates. Developed TLC
(p-TsOH·H2O) to produce the azacycloalkene 25 in
excellent yield (Scheme 5).
Protection of the hydroxy and the amine function-
alities led to compound 26, a chiral intermediate in
the synthesis of fagomine.[23] The protected compound
26 that we synthesised showed the same spectroscopic
data and optical rotation as reported in the literature
for this compound {[a]2D5: À142.4 (c 0.94, CHCl3),
[a]2D7: À150.0 (c 1.04, CHCl3) described}, so that the
synthesis of 26 constitutes a formal synthesis of fago-
mine.
plates were visualised under
a short-wave UV lamp
(254 nm), by heating plates dipped in ethanol/H2SO4 (15:1),
or in a basic solution of potassium permanganate. Flash
column chromatography was carried out using a forced flow
of the indicated solvent on silica gel 60 (230–400 mesh) and
was performed using flash silica gel (32–63 mm) and using
a solvent polarity correlated with TLC mobility. Absolute
configurations for new non-racemic chiral compounds were
assigned on the basis of a general rule concerning the steric
course of the Pd-catalysed allylic substitution.[37] This rule
was found to be correct for all cases that were verified by
comparison with the data described for compounds inde-
pendently synthesised elsewhere. The configurations of the
compounds obtained from carbonate 2a were identical to
those obtained from 1. Allylic carbonates 2a, 2c and 2e were
synthesised according to reported procedures.[14,15b] Carbon-
ate 2f was synthesised from (E)-4-bromobut-2-en-1-yl
methyl carbonate following an analogous procedure de-
scribed for the Z-isomer[38] (see the Supporting Informa-
tion).
Conclusions
Palladium/DACH naphthyl-catalysed allylic amina-
tion of carbonate 2a affords chiral branched amines 4,
intermediates for preparing biologically important
compounds, in high yields, regio- and enantioselectivi-
ties. The use of linear allylic electrophile 2a as an al-
ternative to vinyl epoxide 1 as a substrate increases
the synthetic possibilities towards chiral allylic amines
as it tolerates the use of hard alkylamines as nucleo-
philes. The excellent control of the regio- and enan-
tioselectivity in this case might be due to hydrogen
bonding interactions between the hydroxy group in
the substrate and the diphenylphosphinobenzoic acid-
derived ligand in the Pd complex, as it can be de-
duced from the dramatic change in the regioselectivi-
ty when the hydroxy group is protected or replaced
by an alkyl chain. The regioselectivity observed in
this study is dependent on the steric hindrance of the
amine nucleophile, so that unhindered primary
amines render high branch-regioselectivity whereas
bulky primary or secondary amines lead to the prefer-
ential formation of the linear allylated product. The
General Procedure for the Palladium-Catalysed
Asymmetric Allylic Amination of Allylic Carbonates
[Pd(h3-C3H5)Cl]2 (1 mg, 2 mol%), the (S,S)-DACH naphthyl
ligand (5.5 mg, 6 mol%) and CH2Cl2 (10 mL) were intro-
duced in a Schlenk tube under an argon atmosphere. The re-
sulting solution was stirred for 20 min. The carbonate
(0.116 mmol) and nucleophile (0.127 mmol) were then suc-
cessively introduced. The mixture was stirred at room tem-
perature for 18 h. The reaction mixture was then diluted
with H2O. The phases were separated and the aqueous
phase was extracted with CH2Cl2. The combined organic
phases were dried over MgSO4, filtered, and concentrated
results described here expand the application of the under vacuum. The resulting crude was purified by flash
chromatography to afford the pure product. The enantio-
meric excess was determined by HPLC analysis using
a DAICEL CHIRALCEL OD-H column. A racemic mix-
ture was initially prepared and separated in order to confirm
the signals of both enantiomers.
palladium-DACH naphthyl system for the preparation
of the type 4 allylic amines, and a short formal enan-
tioselective synthesis of glycosidase inhibitor fago-
mine is reported based on this protocol.
(E)-5-Hydroxypent-2-enyl methyl carbonate (2d): But-3-
en-1-ol (30 mg, 0.40 mmol) and allyl methyl carbonate
(47 mg, 0.40 mmol) were added via syringe to a stirred solu-
tion of 2nd generation Grubbs catalyst (17 mg, 0.02 mmol,
5 mol%) in CH2Cl2 (2 mL). The flask was fitted with a con-
denser and the mixture was refluxed under argon for 12 h.
The reaction mixture was then reduced in volume to 0.5 mL
and purified directly on a silica gel column, eluting with hex-
anes:ethyl acetate (6:4) to give 2d as a brown oil; yield:
Experimental Section
General Information
All chemicals used, including DACH-naphthyl ligand and
[Pd(h3-C3H5)Cl]2, were reagent grade and used as supplied
unless otherwise specified. HPLC grade dichloromethane
(CH2Cl2), tetrahydrofuran (THF) and dimethylformamide
1
30 mg (46%). H NMR (400 MHz, CDCl3): d=5.79 (dtt, J=
1
(DMF) were dried using a solvent purification system. H
15.3 Hz, 6.7 Hz, 1.0 Hz, 1H), 5.68 (dtt, J=15.3 Hz, 6.1 Hz,
1 Hz, 1H), 4.57 (dd, J=6.1 Hz, 1.0 Hz, 1H), 3.76 (s, 3H),
3.66 (pseudo q, J=6.1 Hz, 2H), 2.32 (pseudo q, J=6.1 Hz,
2H), 1.73 (t, J=5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d=155.7, 133.0, 126.2, 68.4, 61.6, 54.8, 35.7; HR-MS (ESI-
TOF): m/z=161.0786 [M+H]+, calcd. for C7H13O4:
161.0808.
and 13C NMR spectra were recorded at 400 MHz and
101 MHz, respectively, in CDCl3 as solvent, with chemical
shifts (d) referenced to either CDCl3 (7.26 ppm 1H,
77.16 ppm 13C) or Me4Si (0.00 ppm) as an internal reference,
unless otherwise stated. Spectra were fully assigned using
gCOSY, gHSQC, gHMBC and NOESY. ESI MS (TOF)
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(E)-4-Methoxy-N-(4-methoxybenzyl)but-2-en-1-amine
(3b) and (R)-1-methoxy-N-(4-methoxybenzyl)but-3-en-2-
amine (4b): NaH (0.2 g, 8.2 mmol) was added to a solution
of (E)-4-hydroxybut-2-enyl methyl carbonate (2a) (0.6 mg,
4.1 mmol) in THF (25 mL) at room temperature. After
15 min, CH3I (1.02 mL, 16 mmol) was added dropwise to the
reaction mixture which was then stirred for 4 h. Saturated
NH4Cl/H2O was then added to the reaction mixture and the
organic layer was separated. The aqueous layer was extract-
ed three times with dichloromethane. The combined organic
layers were washed with brine and dried over magnesium
sulfate. After removal of the solvents with a rotary evapora-
tor, the residue was purified by column chromatography
(hexanes:ethyl acetate=8:3) to give 2b as a colourless oil
that appeared to be slightly contaminated with 1,4-dime-
thoxy-but-2-ene, which could not be separated and the mix-
ture was directly used in the next reaction.
Bis-allylated linear product (3e’): Following the general
procedure carbonate 2e was treated with (4-methoxyphe-
nyl)methanamine 5 in the presence of [Pd(h3-C3H5)Cl]2/
(S,S)-DACH naphthyl ligand. The reaction crude was puri-
fied by flash column chromatography (silica gel, hexanes:E-
tOAc, 95:5) to give 3e’ as a colourless oil; yield: 63 mg
1
(71%). H NMR (400 MHz, CDCl3): d=7.50–7.41 (m, 12H),
7.32–7.19 (m, 22H), 5.93–5.61 (m, 4H), 3.79 (s, 3H), 3.64–
3.62 (m, 6H); 13C NMR (100 MHz, CDCl3): d=158.7, 144.4,
131.3, 130.4, 130.3, 129.0, 128.8, 127.9, 127.1, 113.7, 87.0,
64.7, 57.0, 55.4, 55.3; HR-MS (ESI-TOF): m/z=762.3951
[M+H]+, calcd. for C54H52NO3: 762.3942.
Bis-allylated linear product (3f’): Following the general
procedure, carbonate 2f was treated with 4-methoxybenzyla-
mine 5 in the presence of [Pd(h3-C3H5)Cl]2/(S,S)-DACH
naphthyl ligand. The reaction crude was purified by flash
column chromatography (hexane:EtOAc 1:9) to give 3f’ as
a yellow oil; yield: 0.020 g (30%). 1H NMR (400 MHz,
CDCl3): d=7.73 (d, J=8.3 Hz, 4H), 7.29 (d, J=8.0 Hz, 4H),
7.13 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 5.68–5.42
(m, 4H), 4.46 (app t, J=6.0 Hz, 2H), 3.80 (s, 3H), 3.51 (t,
J=5.8 Hz, 4H), 3.36 (s, 2H), 2.90 (d, J=5.7 Hz, 4H), 2.40
(s, 6H); 13C NMR (100 MHz, CDCl3): d=158.7, 143.5, 136.9,
131.6, 129.9, 129.8, 127.5, 127.2, 113.6, 57.5, 55.3, 55.1, 45.0,
21.6; HR-MS (ESI-TOF): m/z=584.2246 [M+H]+, calcd.
for C30H38N3O5S2: 584.2253.
Following the general procedure carbonate 2b was treated
with (4-methoxyphenyl)methanamine 5 in the presence of
the Pd catalyst. The reaction crude was purified by flash
column chromatography (silica gel, hexanes:EtOAc, 1:1) to
give an inseparable mixture of regioisomers 4b and 3b;
yield: 15 mg (60%; ratio 35:65). Spectroscopic data extract-
ed from the spectrum of the mixture are as follows. 4b:
1H NMR (400 MHz, CDCl3): d=7.25–7.17 (m, 2H), 6.89–
6.78 (m, 2H), 5.80–5.63 (m, 1H), 5.27 (dd, J=17.0, 1.7 Hz,
1H), 5.21 (dd, J=10.1, 1.7 Hz, 1H), 3.79 (s, 3H), 3.78 (d,
J=12.8 Hz, 1H), 3.58 (d, J=12.8 Hz, 1H), 3.38–3.32 (m,
(À)-(R)-2-(4-Methoxybenzylamino)but-3-en-1-ol
Following the general procedure carbonate 2a was treated
(4-methoxyphenyl)methanamine in the presence of
(4a):
5
1
3H), 3.32 (s, 3H). 3b: H NMR (400 MHz, CDCl3): d=7.25–
[Pd(h3-C3H5)Cl]2/(S,S)-DACH naphthyl ligand. The reaction
crude was purified by flash column chromatography (silica
gel, hexanes:EtOAc, 1:1) to give 4a as a colourless oil:
yield: 23 mg (96%). HPLC [Daicel Chiralcel OD-H, n-hexa-
ne:i-PrOH, 85:15, flow=0.5 mLminÀ1, detection, UV
210 nm]: retention times (min) 12.68 (99.0%), 16.57
(0.96%); 98% ee; [a]2D5: À6.9 (c 0.41, CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.24 (d, J=8.4 Hz, 2H), 6.86 (d, J=
8.4 Hz, 2H), 5.68 (ddd, J=17.0 Hz, 10.8 Hz, 7.4 Hz, 1H),
5.25 (d, J=10.8 Hz, 1H), 5.23 (d, J=17.0 Hz, 1H), 3.81 (d,
J=13.0 Hz, 1H), 3.80 (s, 3H), 3.61 (d, J=13.0 Hz, 1H), 3.60
(dd, J=10.5 Hz, 6.0 Hz, 1H), 3.38 (dd, J=10.5 Hz, 7.9 Hz,
1H), 3.28–3.13 (m, 1H); 13C NMR (100 MHz, CDCl3): d=
158.8, 137.5, 132.3, 129.5 (2C), 117.9, 114.0 (2C), 64.7, 62.0,
7.17 (m, 2H), 6.89–6.78 (m, 2H), 5.80–5.63 (m, 2H), 3.94–
3.87 (m, 2H), 3.51 (s, 3H), 3.52 (s, 2H), 3.31 (s, 3H), 3.07
(d, J=5.3 Hz, 2H); HR-MS (ESI-TOF, of the mixture):
m/z=222.1480 [M+H]+, calcd. for C13H20NO2: 222.1489.
(E)-N-(4-Methoxybenzyl)pent-2-en-1-amine (3c): Carbon-
ate 2c was treated with (4-methoxyphenyl) methanamine 5
following the general procedure. The reaction crude was pu-
rified by flash column chromatography (silica gel, hexane-
s:EtOAc, 9:1) to give 3c as a colourless oil; yield: 16 mg
1
(68%). H NMR (400 MHz, CDCl3): d=7.25–7.19 (m, 2H),
6.87–6.80 (m, 2H), 5.66–5.55 (m, 1H), 5.52–5.42 (m, 1H),
3.80 (s, 3H), 3.48 (s, 2H), 2.99 (dd, J=1.0 Hz, J=6.5 Hz,
2H), 2.09–1.99 (m, 2H), 0.99 (t, J=7.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=158.7, 136.2, 131.2, 130.5 (2C), 125.7,
113.6 (2C), 56.6, 55.4, 55.3, 25.6, 13.8; FT-IR-ATR: n=2961,
2932, 1511, 1247, 969 cmÀ1; HR-MS (ESI-TOF): m/z=
206.1531 [M+H]+, calcd. for C13H20NO: 206.1539.
55.4, 50.4; FT-IR-ATR: n=3297, 2924, 1512, 1247 cmÀ1
;
HR-MS (ESI-TOF): m/z=208.1311 [M+H]+, calcd. for
C12H18NO2: 208.1332.
N-(4-Methoxybenzyl)pent-1-en-3-amine (4c): Carbonate
2c was treated with (4-methoxy-phenyl)methanamine 5 fol-
lowing the general procedure. The reaction crude was puri-
fied by flash column chromatography (silica gel, hexanes:E-
tOAc, 9:1) to give 4c as a colourless oil; yield: 3 mg (12%).
1H NMR (400 MHz, CDCl3): d=7.25–7.19 (m, 2H), 6.89-
6.83 (m, 2H), 5.61 (ddd, J=17.1, 10.3, 8.2 Hz, 1H), 5.19–
5.07 (m, 2H), 3.79 (s, 3H), 3.76 (d, J=12.9 Hz, 1H), 3.59 (d,
J=12.9 Hz, 1H), 2.93 (td, J=8.2, 5.4 Hz, 1H), 1.61–1.36 (m,
2H), 0.87 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=158.6, 141.2, 132.9, 129.5, 116.4, 113.9, 62.8, 55.4, 50.8,
28.5, 10.4; HR-MS (ESI-TOF): m/z=206.1542 [M+H]+,
calcd. for C13H20NO: 206.1539.
Bis-allylated linear product 3a’: Following the general pro-
cedure carbonate 2a was treated with (4-methoxyphenyl)-
methanamine 5 in the presence of [Pd(h3-C3H5)Cl]2 and
PPh3 as the ligand. The product ratio was determined by
1H NMR spectroscopy (bis-allylated linear 3a’/branched
4a=40:60). The reaction crude was purified by flash column
chromatography (silica gel, EtOAc:methanol, 95:5) to give
3a’ as
a
colourless oil: yield: 9 mg (29%). 1H NMR
(400 MHz, CDCl3): d=7.19–7.12 (m, 2H), 6.84–6.71 (m,
2H), 5.79–5.59 (m, 4H), 4.10–4.02 (m, 2H), 3.73 (s, 3H),
3.47 (s, 2H), 3.07–2.96 (m, 4H); 13C NMR (100 MHz,
CDCl3): d=158.8, 132.3, 130.3, 129.6, 129.5, 113.7, 63.5, 57.6,
55.4, 55.4; FT-IR-ATR: n=3297, 2924, 1512, 1247 cmÀ1
;
(À)-(R)-2-(Benzylamino)but-3-en-1-ol (10): Carbonate 2a
was treated with benzylamine following the general proce-
dure. The reaction crude was isolated by flash column chro-
HR-MS (ESI-TOF): m/z=278.1736 [M+H]+, calcd. for
C16H24NO3: 278.1751.
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matography
(silica
gel,
hexanes:
1.41 (m, 2H), 1.37–1.23 (m,4H), 0.95–0.85 (m, 3H);
13C NMR (100 MHz, CDCl3): d=137.1, 118.0, 64.3, 63.0,
47.0, 29.7, 29.6, 22.6, 14.2; FT-IR-ATR: n=3298, 2927, 2857,
1457, 1048 cmÀ1; HR-MS (ESI-TOF): m/z=337.2859 [2M+
Na]+, calcd. for C18H38N2NaO2: 337.2831.
EtOAc, 1:1) to give 10 as a colourless oil; yield:18 mg
(93%). HPLC [Daicel Chiralcel OD-H, n-hexane:i-PrOH,
85:15, flow=0.5 mLminÀ1, detection, UV 210 nm]: retention
times (min), 11.67 (95.18%), 14.89 (4.82%); 90% ee; [a]2D5:
1
À6.8 (c 0.6, CHCl3); H NMR (400 MHz, CDCl3): d=7.36–
(E)-4-(Pyrrolidin-1-yl)but-2-en-1-ol (17):[39] Carbonate 2a
was treated with pyrrolidine (14) following the general pro-
cedure. The reaction crude was purified by flash column
chromatography (silica gel, EtOAc) to give compound 17 as
a colourless oil; yield: 11 mg (69%). 1H NMR (400 MHz,
CDCl3): d=5.91–5.72 (m, 2H), 4.15–4.09 (m, 2H), 3.15–3.09
(m, 2H), 2.57–2.50 (m, 4H), 1.83–1.76 (m, 4H); 13C NMR
(100 MHz, CDCl3): d=133.5, 127.8, 59.8, 53.8, 52.4, 23.5.
(E)-4-(Dibenzylamino)but-2-en-1-ol (18):[40] Carbonate 2a
was treated with dibenzylamine (15) following the general
procedure. The reaction crude was purified by flash column
chromatography (silica gel, hexanes:EtOAc, 1:1) to give
compound 18 as a colourless oil; yield: 21 mg (71%).
1H NMR (400 MHz, CDCl3): d=7.43–7.16 (m, 10H), 5.83–
5.71 (m, 2H), 4.10 (d, J=4.3 Hz, 2H), 3.58 (s, 4H), 3.07 (d,
J=4.8 Hz, 2H).
7.30 (m, 3H), 7.29–7.24 (m, 2H), 5.75–5.64 (m, 1H), 5.29–
5.20 (m, 2H), 3.89 (d, J=13.0 Hz, 1H), 3.69 (d, J=13.0 Hz,
1H), 3.63 (dd, J=10.6, 4.5 Hz, 1H), 3.40 (dd, J=10.6,
7.9 Hz, 1H), 3.24 (td, J=7.8, 4.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=140.0, 137.2, 128.6, 128.4, 127.3,
118.1, 64.7, 62.2, 51.0; FT-IR-ATR: n=3303, 2926,
2851 cmÀ1; HR-MS (ESI-TOF): m/z=178.1199 [M+H]+,
calcd. for C11H16NO: 178.1226.
(À)-(R)-2-(3,4-Dimethoxyphenethylamino)but-3-en-1-ol
(11): Carbonate 2a was treated with 2-(3,4-dimethoxyphen-
ACHTUNGTRENNUNGyl)ethanamine (7) following the general procedure. The re-
action crude was purified by flash column chromatography
(silica gel, hexanes:EtOAc, 1:1) to give 11 as a colourless
oil; yield: 28 mg (96%). HPLC [Daicel Chiralcel OD-H,
heptane (0.1% DEA):EtOH, 95:5, flow=1 mLminÀ1, detec-
tion, UV 210 nm]: retention times (min), 25.97 (97.3%),
(E)-4-(tert-Butylamino)but-2-en-1-ol (19): Carbonate 2a
was treated with tert-butylamine 16 following the general
procedure. The reaction crude was purified by flash column
chromatography (silica gel, CH2Cl2:MeOH) to give com-
29.11 (2.7%); 95% ee; [a]2D0: À15.5 (c 0.18, CHCl3); H NMR
1
(400 MHz, CDCl3): d=6.83–6.70 (m, 3H), 5.62 (ddd, J=
17.0 Hz, J=10.7 Hz, 7.6 Hz, 1H), 5.17 (d, J=10.7 Hz, 1H),
5.15 (d, J=17.0 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.58 (dd,
J=10.4 Hz, 4.5 Hz, 1H), 3.33 (dd, J=10.4 Hz, 7.9 Hz, 1H),
3.22–3.15 (m, 1H), 3.00–2.67 (m, 4H); 13C NMR (100 MHz,
CDCl3): d=149.0, 147.6, 137.5, 132.5, 120.7, 117.6, 112.0,
111.4, 64.6, 62.8, 56.0, 56.0, 48.5, 36.2; FT-IR-ATR: n=3297,
2927, 1514, 1260, 1026 cmÀ1; HR-MS (ESI-TOF): m/z=
252.1592 [M+H]+, calcd. for C14H22NO3: 252.1594.
1
pound 19 as a colourless oil; yield: 10 mg (60%). H NMR
(400 MHz, CDCl3): d=5.83–5.79 (m, 2H), 4.13–4.08 (m,
2H), 3.21 (d, J=4.6 Hz, 2H), 2.30 (bs, 1H), 1.13 (s, 9H);
13C NMR (100 MHz, CDCl3): d=131.4, 130.1„ 63.0, 51.1,
44.3, 28.8; HR-MS (ESI-TOF): m/z=166.1225 [M+Na]+,
calcd. for C8H17NNaO: 166.1202.
(E)-4-[(1-Hydroxybut-3-en-2-yl)(pent-4-en-1-yl)amino]-
but-2-en-1-ol (22): Carbonate 2a (0.068 g, 0.464 mmol) was
treated with pentan-1-amine 20 (0.0197 g, 0.232 mmol) fol-
lowing the general procedure. The reaction crude was puri-
fied by flash column chromatography (silica gel, EtOAc:-
MeOH, 9:1) to give 22 as a colourless oil; yield: 45 mg
(86%).1H NMR (400 MHz, CDCl3): d=5.86–5.62 (m, 4H),
5.27 (ddd, J=10.5 Hz, 1.7 Hz, 0.6 Hz, 1H), 5.15 (ddd, J=
17.2 Hz, 1.7 Hz, 0.9 Hz, 1H), 4.16–4.12 (m, 2H), 4.14 (d, J=
5.4 Hz, 2H), 3.49–3.44 (m, 2H) 3.38–3.26 (m, 2H), 2.95 (dd,
J=14.4 Hz, 7.5 Hz, 1H), 2.63–3.53 (m, 1H), 2.33 (ddd, J=
13.0 Hz, 8.3 Hz, 4.6 Hz, 1H), 2.14–1.96 (m, 2H), 1.64–1.47
(m, 2H); 13C NMR (100 MHz, CDCl3): d=138.4, 132.6,
132.2, 130.1, 120.1, 114.9, 63.6, 63.3, 60.8, 51.7, 48.7, 31.5,
27.6; FT-IR-ATR: n=3366, 2924, 1418, 997, 912 cmÀ1; HR-
MS (ESI-TOF): m/z=226.1830 [M+H]+, calcd. for
C13H24NO2: 226.1802.
(À)-(R)-2-(Cyclohexylamino)but-3-en-1-ol (12): Following
the general procedure carbonate 2a was treated with cyclo-
hexanamine (8).The reaction crude was purified by flash
column chromatography (silica gel, EtOAc:MeOH, 9:1) to
give 12 as a white foam; yield: 18 mg (91%). HPLC [Daicel
Chiralcel
OD-H,
n-hexane:i-PrOH,
85:15,
flow=
0.5 mLminÀ1, detection, UV 306 nm]: retention times (min),
6.54 (99.14%), 5.59 (0.86%); 98% ee; [a]2D5: À25.0 (c 0.72,
1
CHCl3); H NMR (400 MHz, CDCl3): d=5.71–5.60 (m, 1H),
5.20–5.14 (m, 2H), 3.59–3.53 (m, 1H), 3.36–3.25 (m, 2H),
2.52 (tt, J=10.3 Hz, 3.8 Hz, 1H), 2.32 (bs, 1H), 1.94–1.86
(m, 1H), 1.82–1.67 (m, 3H), 1.63–1.54 (m, 1H), 1.33–1.09
(m, 4H), 1.07–0.94 (m, 1H):; 13C NMR (100 MHz, CDCl3):
d=138.1, 117.0, 64.7, 59.1, 53.6, 37.7, 33.3, 26.2, 25.2, 24.8;
FT-IR-ATR: n=3248, 2923, 2855, 1088 cmÀ1; HR-MS (ESI-
TOF): m/z=170.1567 [M+H]+, calcd. for C10H20NO:
170.1539.
(+)-(S)-2-(But-3-enylamino)but-3-en-1-ol (24): Carbonate
2a was treated with but-3-en-1-amine (23) in the presence of
the (R,R)-DACH naphthyl ligand following the general pro-
cedure. The reaction crude was purified by flash column
chromatography (silica gel, EtOAc:MeOH, 9:1) to give 24
as a colourless oil; yield: 14 mg (91%). HPLC [Daicel Chir-
alcel OD-H, n-hexane:i-PrOH, 85:15, flow=0.5 mLminÀ1,
detection, UV 280 nm]: retention times (min), 11.7 (3%),
(À)-(R)-2-(Pentylamino)but-3-en-1-ol (13): Carbonate 2a
was treated with pentan-1-amine (9) following the general
procedure. The reaction crude was purified by flash column
chromatography (silica gel, EtOAc:MeOH, 9:1) to give
compound 13 as a colourless oil; yield: 16 mg (90%). HPLC
[Daicel Chiralcel OD-H, n-hexane:i-PrOH, 85:15, flow=
0.5 mLminÀ1, detection, UV 313 nm]: retention times (min),
6.23 (98.18%), 7.81 (1.82%); 96% ee; [a]2D5: À9.9 (c 1.15,
1
13.4 (97%); 94% ee; [a]2D5: +12.1 (c 4.1, CHCl3); H NMR
1
CHCl3); H NMR (400 MHz, CDCl3): d=5.73–5.61 (m, 1H),
(400 MHz, CDCl3): d=5.78 (tdd, J=17.0 Hz, 10.1 Hz,
6.8 Hz, 1H), 5.64 (ddd, J=17.2 Hz, 10.6 Hz, 7.6 Hz, 1H),
5.23–5.17 (m, 2H), 5.14–5.01 (m, 2H), 3.59 (dd, J=10.5 Hz,
4.5 Hz, 1H), 3.35 (dd, J=10.5 Hz, 8.0 Hz, 1H), 3.22–3.13
(m, 1H), 2.76 (td, J=11.2 Hz, 7.0 Hz, 1H), 2.56 (td, J=
5.26–5.17 (m, 2H), 3.62 (dd, J=10.6 Hz, 4.7 Hz, 1H), 3.39
(dd, J=10.6 Hz, 7.8 Hz, 1H), 3.20 (tdt, J=7.8 Hz, 4.7 Hz,
0.9 Hz, 1H), 2.85 (bs, 1H), 2.71 (ddd, J=11.4 Hz, 8.1 Hz,
6.6 Hz, 1H), 2.50 (ddd, J=11.4 Hz, 8.1, 6.4 Hz, 1H), 1.58–
Adv. Synth. Catal. 0000, 000, 0 – 0
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11.2 Hz, 6.7 Hz, 1H), 2.30–2.19 (m, 2H); 13C NMR
(100 MHz, CDCl3): d=137.7, 136.5, 117.5, 116.7, 64.6, 62.8,
46.1, 34.6; FT-IR-ATR: n=3277, 3075, 2919, 2849, 1455,
1101 cmÀ1; HR-MS (ESI-TOF): m/z=141.1241 [M+H]+,
calcd. for C8H16NO: 142.1226.
0.3H), 2.90 (td, J=12, 12, 4 Hz, 0.7H), 2.31–1.73 (m, 2H),
1.46 (s, 3H), 1.38 (s, 6H), 1.01 (s, 9H); 13C NMR (100 MHz,
CDCl3, Boc rotamers): d=162.4, 135.5, 135.5, 133.4, 129.6,
127.6, 127.5, 126.8, 79.9, 66.7, 55.6, 41.0, 36.4, 31.3, 26.8, 26.0,
19.2.
(À)-(1S)-(1,2,5,6-Tetrahydropyridin-2-yl)methanol
(25):
[Pd(h3-C3H5)Cl]2 (0.8 mg, 2 mol%), the (R,R)-DACH naph-
thyl ligand (5.5 mg, 6 mol%) and CH2Cl2 (10 mL), were in-
troduced in a Schlenk tube under an argon atmosphere. The
resulting solution was stirred for 20 min, and then, the car-
bonate 2a (16.8 mg, 0.115 mmol) and but-3-en-1-amine (23)
(9.0 mg, 0.127 mmol) were successively introduced. The mix-
ture was stirred at room temperature for 18 h. Then, p-tol-
uenesulfonic acid monohydrate (22 mg, 0.115 mmol) was
added to the solution and the mixture was stirred for 30 min
at room temperature until the mixture became a homogene-
ous solution. Grubbsꢅ second-generation catalyst (5 mg,
0.0058 mmol, 5 mol%) was then added, and the mixture was
stirred under reflux for 18 h. Water (20 mL) was added, the
phases were separated, and the aqueous layer was extracted
with CH2Cl2 (3ꢆ10 mL). The aqueous phase was concentrat-
ed under vacuum. The residue was dissolved in MeOH and
AmberliteTM-OH was added. The heterogeneous mixture
was stirred for 2 h and then, filtered, and concentrated to
afford pure product 25 as a colourless oil; yield: 12 mg
(92%); [a]2D5: À50.6 (c 3.2, MeOH). 1H NMR (400 MHz,
CD3OD): d=5.92–5.82 (m, 1H), 5.63 (ddd, J=10.3, 4.2 Hz,
2.2 Hz, 1H), 3.50 (dd, J=6.2, 3.1 Hz, 2H), 3.41–3.33 (m,
1H), 3.05 (ddd, J=12.1 Hz, 5.5 Hz, 3.9 Hz, 1H), 2.81 (ddd,
J=12.1 Hz, 8.8, 4.9 Hz, 1H), 2.24–2.11 (m, 1H), 2.10–1.96
(m, 1H); 13C NMR (100 MHz, D2O): d=128.0, 124.4, 63.1,
54.4, 39.9, 23.4; FT-IR-ATR: n=3301, 3027, 2922, 2852,
1636, 1454 cmÀ1; HR-MS (ESI-TOF): m/z=114.0908 [M+
H]+, calcd. for C6H12NO: 114.0913.
Acknowledgements
The authors would like to thank the Ministerio de Economꢀa
y Competitividad, Spain (grant DGI CTQ2014-58664-R). SS
and MEC thank the URV for a predoctoral fellowship and
the CONACYT for a postdoctoral grant, respectively. Sup-
port by SRC (URV) is also acknowledged.
References
[1] For selected publications see: a) M. Mori, Chem.
Pharm. Bull. 2005, 53, 457–470; b) B. M. Trost, J. Org.
Chem. 2004, 69, 5813–5837; c) O. Belda, C. Moberg,
Acc. Chem. Res. 2004, 37, 159–167; d) B. M. Trost,
M. L. Crawley, Chem. Rev. 2003, 103, 2921–2943.
[2] S. Norsikian, C.-W. Chang, Curr. Org. Synth. 2009, 6,
264–289.
[3] a) B-S. Kim, M. M. Hussain, P-O. Norrby, P. J. Walsh,
Chem. Sci. 2014, 5, 1241–1250; b) G. R. Cook, H. Yu, S.
Sankaranarayanan, P. S. Shanker, J. Am. Chem. Soc.
2003, 125, 5115–5120; c) P. S. Shanker, K. Pararajasing-
ham, Angew. Chem. 1999, 111, 226–228; Angew. Chem.
Int. Ed. 1999, 38, 110–113.
[4] M. H. Katcher, A. Sha, A.; A. G. Doyle, J. Am. Chem.
(S)-tert-Butyl 2-[(tert-butyldimethylsilyloxy)methyl]-5,6-
dihydropyridine-1(2H)-carboxylate (26):[23] Compound 25
(0.010 g, 0.088 mmol) was dissolved in dry CH2Cl2 (1 mL)
and treated under argon with tert-butyldiphenyl chloride
(0.03 mL, 0.1 mmol) and imidazole (0.01 g, 0.2 mmol). The
mixture was stirred for 16 h at room temperature, and then
diluted with H2O. The phases were separated and the aque-
ous layer extracted with CH2Cl2. The combined organic
phases were dried over MgSO4, filtered and concentrated
under vacuum. (Boc)2O (0.03 mL, 0.13 mmol) was added at
room temperature to a stirred solution of the crude mixture
(0.088 mmol), Et3N (0.019 mL, 0.13 mmol) and DMAP
(1.1 mg, 10 mol%) in CH2Cl2 (2 mL). After being stirred
overnight, the solvents were removed under reduced pres-
sure. The residue was then partitioned with H2O and
EtOAc. The aqueous layer was extracted with EtOAc (3
times) and the combined organic layers were washed with
saturated aqueous NaHCO3, brine, dried (MgSO4) and con-
centrated under vacuum. The reaction crude was purified by
flash column chromatography (4% EtOAc in hexanes) to
give 26 as a colourless oil; yield: 25 mg (87%); [a]2D5: À142.4
(c 0.94, CDCl3), {[a]2D7: À150.0 (c 1.04, CDCl3) described].
1H NMR (400 MHz, CDCl3, Boc rotamers): d=7.69–7.61
(m, 4H), 7.48–7.34 (m, 6H), 6.03–5.95 (m, 0.7H), 5.95–5.88
(m, 0.3H), 5.84–5.75 (m, 0.7H), 5.73–5.65 (m, 0.3H), 4.64–
4.53 (m, 0.3H), 4.45–4.35 (m, 0.7H), 4.18 (dd, J=12.0 Hz,
4.0 Hz, 0.7H), 4.00 (dd, J=12.0, 4.0 Hz, 0.3H), 3.76 (dd, J=
12.0, 4.0 Hz, 0.3H), 3.68–3.57 (m, 1.7H), 3.04–2.95 (m,
Soc. 2011, 133, 15902–15905.
[5] J-P. Chen, Q. Peng, B-L. Lei, X-L. Hou, Y. D. Wu, J.
Am. Chem. Soc. 2011, 133, 14180–14183.
[6] B. M. Trost, S. Malhotra, W. H. Chan, J. Am. Chem.
Soc. 2011, 133, 7328–7331.
[7] I. Dubovik, I. D. G. Watson, A. K. Yudin, J. Org.
Chem. 2013, 78, 1559–1575.
[8] B. M. Trost, Acc. Chem. Res. 1996, 29, 355–364.
[9] a) B. M. Trost, G.-H. Kuo, T. Benneche, J. Am. Chem.
Soc. 1988, 110, 621–622; b) B. M. Trost, S.-F. Chen, J.
Am. Chem. Soc. 1986, 108, 6053–6054; c) B. M. Trost, J.
Cossy, J. Am. Chem. Soc. 1982, 104, 6881–6882.
[10] B. M. Trost, D. R. Frandick, Aldrichimica Acta 2007,
40, 59–72.
[11] B. M. Trost, R. C. Bunt, R. C. Lemoine, T. L. Calkins, J.
Am. Chem. Soc. 2000, 122, 5968–5976.
[12] Carbon nucleophiles: a) R. Takeuchi, M. Kashio,
Angew. Chem. 1997, 109, 268–270; Angew. Chem. Int.
Ed. Engl. 1997, 36, 263–264; b) amines: R. Takeuchi, N.
Ue, K. Tanabe, K. Yamashita, N. Shiga, J. Am. Chem.
Soc. 2001, 123, 9525–9534.
[13] J. H. Lee, S. Shin, J. Kang, S. Lee, J. Org. Chem. 2007,
72, 7443–7446.
[14] C. Gnamm, G. Franck, N. Miller, T. Stork, K. Brçdner,
G. Helmchen, Synthesis 2008, 3331–3350.
[15] a) J. F. Hartwig, L. M. Stanley, Acc. Chem. Res. 2010,
43, 1461–1475; b) L. M. Stanley, J. F. Hartwig, J. Am.
Chem. Soc. 2009, 131, 8971–8983.
Adv. Synth. Catal. 0000, 000, 0 – 0
9
ꢄ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
[16] C. P. Butts, E. Filali, G. C. Lloyd-Jones, P.-O. Norrby,
D. A. Sale, Y. Schramm, J. Am. Chem. Soc. 2009, 131,
9945–9957.
[17] S. M. Nanavati, B. Silverman, J. Am. Chem. Soc. 1991,
113, 9341–9349.
[18] a) C. S. Lee, L. Z. Benet, Anal. Profiles Drug Subst.
1978, 7, 231–249; b) W. H. Beggs, in: Antibiotics, (Ed.:
F. E. Hahn), Springer, New York, 1979; Vol. 5, pp 43–
66.
[19] B. M. Trost, D. B. Horne, M. J. Woltering, Angew.
Chem. 2003, 115, 6169–6172; Angew. Chem. Int. Ed.
2003, 42, 5987–5990.
[29] a) P. Fristrup, M. Ahlquist, D, Tanner, P.-O. Norrby, J.
Phys. Chem. A 2008, 112, 12862–12867; b) P. Fristrup,
T. Jensen, J. Hoppe, P.-O. Norrby, Chem. Eur. J. 2006,
12, 5352–5360; c) M. P. T. Sjçgren, S. Hansson, B. Aker-
mark, A. Vitagliano, Organometallics 1994, 13, 1963–
1971; d) B. Goldfuss, U. Kazmaier, Tetrahedron 2000,
56, 6493–6496.
[30] a) H. S. Frank, W. Y. Wen, Discuss. Faraday Soc. 1957,
24, 133–140; b) G. A. Jeffrey, W. Sainger, in: Hydrogen
Bonding in Biological Structures, Springer Verlag,
Berlin, 1991, p 569; c) M. Lopez de La Paz, C. Gonza-
lez, C. Vicent, Chem. Commun. 2000, 411–412.
[31] This substrate exists as a racemate and, therefore, the
potential formation of the enantiopure branched ami-
nated product would result from a dynamic kinetic
asymmetric transformation (DYKAT).
[32] For recent asymmetric syntheses of fagomine, see:
a) K. Csatayova, D. G. Davis, A. M. Fletcher, J. G.
Ford, D. J. Klauber, P. M. Roberts, J. E. Thomson, Tet-
rahedron 2015, 71, 7170–7180; b) P. K. Kundu, S. K.
Gosh, Tetrahedron: Asymmetry 2011, 22, 1090–1096.
[33] For a review on olefin metathesis, see: a) T. M. Trnka,
R. H. Grubbs, Acc. Chem. Res. 2001, 34, 18–29; b) A.
Fꢇrstner, Angew. Chem. 2000, 112, 3140–3172; Angew.
Chem. Int. Ed. 2000, 39, 3012–3143.
[20] B. M. Trost, D. B. Horne, M. J. Woltering, Chem. Eur. J.
2006, 12, 6607–6620.
[21] G. Helmchen, A. Dahnz, P. Dꢇbon, M. Schelwies, R.
Weihofen, Chem. Commun. 2007, 675–691.
[22] a) J. Llaveria, Y. Dꢁaz, M. I. Matheu, S. Castillꢂn, Org.
Lett. 2009, 11, 205–208; b) J. Llaveria, Y. Dꢁaz, M. I.
Matheu, S. Castillꢂn, Eur. J. Org. Chem. 2011, 1514–
1519.
[23] a) H. Takahata, Y. Banba, H. Ouchi, H. Nemoto, A.
Kato, I. Adachi, J. Org. Chem. 2003, 68, 3603–3607;
b) Y. Banba, C. Abe, H. Nemoto, A. Kato, I. Adachi,
H. Takahata, Tetrahedron: Asymmetry 2001, 12, 817–
819.
[24] For a recent review about the chiral synthesis of imino
sugars, see: H. Takahata, Heterocycles 2012, 85, 1351–
1376.
[25] a) T. Mena-Barragan, M. I. Garcia Moreno, E. Nanba,
K. Higaki, A. L. Concia, P. Clapes, J. M. Garcꢁa Fernꢈn-
dez, C. Ortiz-Mellet, Eur. J. Med. Chem. 2016, 121,
880–891; b) A. M. Scofield, L. E. Fellows, R. J. Nash,
G. W. J. Fleet, Life Sci. 1986, 39, 645–650.
[26] Bis-allylated amines are common by-products in Pd-
catalysed allylic aminations with primary amines: a) S.-
C. Yang, W.-H. Chung, Tetrahedron Lett. 1999, 40, 953–
956; b) A. R. Katritzky, J. Yao, M. Qi, J. Org. Chem.
1998, 63, 5232–5234; c) E. Blart, J. P. GenÞt, M. Safi,
M. Savignac, D. Sinou, Tetrahedron 1994, 50, 505–514;
d) B. M. Trost, E. Keinan, J. Org. Chem. 1979, 44,
3451–3457.
[27] Assignment of the absolute configuration was deter-
mined by comparison of the optical rotation with that
of the (S)-enantiomer described in ref.[14]
[28] a) G. R. Cook, H, Yu, S. Sankaranarayanan, P. S.
Shanker, J. Am. Chem. Soc. 2003, 125, 5115–5120; b) J.
Catalꢈn, J. Org. Chem. 1997, 62, 8231–8234.
[34] For a recent review on the use of RCM in the synthesis
of imino sugars, see: I. Dragutan, V. Dragutan, A. De-
monceau, RSC Adv. 2012, 2, 719–736.
[35] I. Dragutan, V. Dragutan, C. Mitan, H. C. M. Vosloo,
L. Delaude, A. Demonceau, Beilstein J. Org. Chem.
2011, 7, 699–716.
[36] D. L. Wright, J. P. Schulte II, M. A. Page, Org. Lett.
2000, 2, 1847–1850.
[37] B. M. Trost, M. R. Machacek, A. Aponick, Acc. Chem.
Res. 2006, 39, 747–760.
[38] I. R. Mꢈrquez, A. Millꢈn, A. G. CampaÇa, J. M.
Cuerva, Org. Chem. Front. 2014, 1, 373–381.
[39] L. F. Hennequin, E. S. E. Stokes, A. P. Thomas, C.
Johnstone, P. A. Plꢀ, D. J. Ogilvie, M. Dukes, S. R.
Wedge, J. Kendrew, J. O. Curwen, J. Med. Chem. 2002,
45, 1300–1312.
[40] A. J. Cresswell, S. G. Davies, J. A. Lee, M. J. Morris,
P. M. Roberts, E. J. Thomson, J. Org. Chem. 2012, 77,
7262–7281.
Adv. Synth. Catal. 0000, 000, 0 – 0
10
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Substrate-Regiocontrolled Synthesis of Enantioenriched
Allylic Amines by Palladium-Catalysed Asymmetric Allylic
Amination: Formal Synthesis of Fagomine
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Adv. Synth. Catal. 2016, 358, 1 – 11
Sꢀbastien Soriano, Margarita Escudero-Casao,
M. Isabel Matheu, Yolanda Dꢁaz,* Sergio Castillꢂn*
Adv. Synth. Catal. 0000, 000, 0 – 0
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