Access to 2,6-disubstituted piperidines: Control of the diastereoselectivity, scope, and limitations. applications to the stereoselective synthesis of (-)-solenopsine A and alkaloid (+)-241D

Article abstract of DOI:10.1021/jo302712f

Scope and limitations in the diastereoselective preparation of 2,6-cis or 2,6-trans disubstituted piperidines are described, through intramolecular reaction of chiral β′-carbamate-α,β-unsaturated ketone. This methodology has been applied to the total synthesis of a few well chosen examples, such as (-)-solenopsine A and alkaloid (+)-241D.

Full text of DOI:10.1021/jo302712f

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Article
An acess to 2,6-disubstituted piperidines : control of the
diastereoselectivity, scope and limitations. Applications to the
stereoselective synthesis of (-)-Solenopsine A and alkaloid (+)-241D
Isabelle Abrunhosa-Thomas, Aurélie Plas, Alexandre Vogrig,
Nishanth Kandepedu, Pierre Chalard, and Yves Troin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo302712f • Publication Date (Web): 11 Feb 2013
Downloaded from http://pubs.acs.org on February 17, 2013
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An access to 2,6-disubstituted piperidines : control of the
diastereoselectivity, scope and limitations. Applications to the
stereoselective synthesis of (-)-Solenopsine A and alkaloid (+)-241D
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,
,
,
,
Isabelle AbrunhosaꢀThomas† ‡, Aurélie Plas† ‡, Alexandre Vogrig† ‡, Nishanth Kandepedu† ‡
,
,
,
Pierre Chalard† ‡, Yves Troin*† ‡
†Clermont Université, ENSCCF, Institut de Chimie de ClermontꢀFerrand (ICCF), BP
10448,Fꢀ63000 CLERMONTꢀFERRAND, France.
‡CNRS, UMR 6296, Institut de Chimie de ClermontꢀFerrand (ICCF), BP 80026, Fꢀ63171
AUBIERE, France.
Corresponding author : yves.troin@ensccf.fr
ABSTRACT :
OH
HO
RO
OR
RO
OR
O
n =1, 2
or
R3O
NH
O
MeOH
R1
R3O
N
R2
R1
N
R2
R2
R1
(CH3O)3CH, p-TsOH
O
R3O
2,6-Cis
R =CH3,-(CH2)2-,-(CH2)3-
O
2,6-Trans
Scope and limitations in diastereoselective preparation of 2,6ꢀcis or 2,6ꢀtrans disubstituted
piperidines are described, through intramolecular reaction of chiral β’ꢀcarbamateꢀα,βꢀ
unsaturated ketone. This methodology has been applied to the total synthesis of a few well
chosen examples, such as (ꢀ)ꢀSolenopsine A and alkaloid (+)ꢀ241D.
Introduction
Substituted piperidines and their analogues are key structural units in numerous naturally
occurring alkaloids and in a number of successful pharmaceutical compounds1 This is the
reason why a number of methodologies for the elaboration of these structures have been
described2ꢀ5 especially when stereogenic centers are involved. In particular, those possessing a
chiral center at Cꢀ2 and/or Cꢀ6, stereoselectivity which is essential for the defined activity,
have attracted much attention because they are one of the most common framework
encountered in many interesting compounds which exhibit a broad range of biological
activities. For example, (ꢀ)ꢀsolenopsin A and (ꢀ)ꢀisosolenopsin A (active components of fire
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ants venom) are reported to possess a broad range of activities,6 alkaloid (+)ꢀ241D (isolated
from methanolic skin extracts of Panamanian poison frogs Dendrobates speciosus) is active
on nicotinic acetylcholine receptors7 and (ꢀ)ꢀlasubine II (extracted from plants of the
Lythraceae family) has showed cytotoxic, haemolytic, necrotic, insecticidal, antibacterial,
antifungal, and antiꢀHIV properties8 (Scheme 1). So, developing approaches to allow the
stereoselective synthesis of 2,6ꢀdialkylpiperidines is of great value.
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Scheme 1
OH
N
OH
H
R2
R1
n-C11H23
N
n-C9H19
N
H
Me
H
MeO
R1= Me, R2= H : (-)-Solenopsine A
R1= H, R2= Me : (-)-Isosolenopsine A
alkaloid(+)-241D
(-)-Lasubine II
OMe
For this purpose, many synthetic methods have been developed including Mannichꢀtype
reaction,9 or RingꢀClosing Metathesis.10 In order to control the diastereoselectivity excess on
the positions α and α’ of the piperidine core, some of those routes have focused on the
construction of the ring by CꢀN ring closure bond formation,11ꢀ13 including reductive
amination,14 intramolecular substitution,15 cyclization of sulfinimides on propargylic ether,16
intramolecular allylic substitution with 1,3ꢀchirality transfer,17 iminium ion cyclization,18
cycloaddition [4+2] of aldimines,19 intramolecular azaꢀ[2,3]ꢀWittig rearrangement,20 catalyzed
hydroamination21 or Michael addition.13,22 Therefore, all these methods show that there is
always a considerable interest in developing stereoselective access to 2,6ꢀdialkylpiperidines.
However, even though cisꢀ2,6ꢀdisubstituted piperidines are readily accessible, only a few
methods have been devoted to the synthesis of transꢀ2,6ꢀdisubstituted isomers.23ꢀ30
During the course of our recent studies on the asymmetric synthesis of 2,6ꢀdisubstituted
piperidines by CꢀN bond formation, we have demonstrated that the Michael “type”
cyclisation,31 using β'ꢀcarbamateꢀα,βꢀunsatured ketone 1 as key precursor, induced
systematically and predominantly the formation of piperidine ring with the 2,6ꢀtrans
configuration (Scheme 2). The relative stereochemistry was confirmed by further
transformation of trans derivative in known chiral compound 330 with an 95% ee.
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Scheme 2
5
6
O
O
O
O
Cbz
HO-(CH2)2-OH
NH
O
p-TsOH:H2O
7
8
9
+
Ph
CH3
Ph
N
H
CH3
Ph
N
CH3
Ph
N
CH3
CH(OCH3)3
20 mn
E or Z
Cbz
2a
Cbz
2b
1
3
10
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[α]25 - 31.3
[α]25 - 32.9
=
lit.20
trans/cis = 86/14
=
D
D
In order to establish this new approach as a general method for the preparation of chiral 2,6ꢀ
disubstituted piperidines and to understand the requirements for the best selectivity, we have
synthesized various β’ꢀcarbamateꢀα,βꢀunsatured ketones and tested their cyclization reaction
using different conditions.
Results and discussion
I- General synthesis of a wide range of β’-carbamate-α,β-insatured ketones
We have previously shown that the necessary β’ꢀcarbamateꢀα,βꢀunsatured ketone 1 could be
easily obtained from the corresponding α,βꢀunsatured methylester in 6 steps with an overall
yield of about 30 %31(Scheme 3).
Scheme 3
Ph
Cbz
O
NBn O
NH
O
b,c,d,e
f
a
CH3
Ph
OCH3
Ph
OCH3
de > 95%
1
Ph
N
OCH3
E/Z: 3/1
a) Davies amine, BuLi, THF, ꢀ78°C; (b) H2, Pd(OH)2/C, MeOH; (c) Na2CO3, CbzCl, CH2Cl2/H2O; (d) NaOH 1N, MeOH; (e)
CDI, (MeO)MeNH.HCl; (f) Mg, 1ꢀbromoꢀ2ꢀpropene, THF, 0°C.
As Grignard’s reagents don’t allow the use of a wide range of functionalities, we have devised
a general and simple method to access a variety of compounds of type 1 easily by using a
more convenient way through a WittigꢀHornerꢀEmmons32 reaction as the key step (Scheme
4). By this method, the needed compounds were prepared in four steps from the
corresponding α,βꢀunsatured methylester according to described procedure.33
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Scheme 4
O
O
O
5
6
7
8
O
R2O
NH O
R2O
NH
O
O
P
R2O
NH
O
OEt
OEt
a,b,c
d
e
R1
OCH3
R1
OCH3
R1
R1
R3
5a-g
4a-d
6a-g
7a-z
R3 = ph
7a R1 = Me R2 = Et
95 %
89 %
86 %
91 %
79 %
91 %
89 %
95 %
87 %
85 %
53 %
95 %
95 %
96 %
78 %
91 %
91 %
84 %
94 %
78 %
95 %
5a
5b
5c
5d
5e
5f
R1 = Me R2 = Et
57 % 6a
R
1 = Me R2 = Et
68 %
4a
4b
4c
4d
R
1 = Me
R1 = Pr
R1 = Oct
1 = Ph
9
R3 = ph(o-NO2)
R3 = ph(m-NO2)
R3 = ph(p-NO2)
7b
7c
7d
7e
7f
7g
7h
7i
R2 = Et
R2 = Et
R2 = Et
R2 = Bn 62 %
R2 = Et
6b
6c
6d
6e
6f
R2 = Bn 57 %
R2 = Et
77 %
73 %
72 %
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R1 = Pr
R1 = Oct
R1 = Ph R2 = Et
65 %
66 %
58 %
R1 = Pr
R2 = Et
R1 = Oct
1 = Ph R2 = Et
R2 = Et
R
R
3 = ph(p-OMe)
R2 = Et
R
R3 = ph(o-Br)
R3 = ph(p-Br)
R2 = Et
R2 = Et
R2 = Et
R2 = t-Bu 76 %
R2 = Bn 66 %
R2 = t-Bu 62 %
R2 = Bn 66 %
5g
6g
R3 = ph(2-Cl)(5-NO2)
R3 = 3-pyridinyl
R3 = ethyl acrylate
R3 = COOEt
R3 = (CH2)2CH3
R3 = (CH2)7CH3
R3 = ph
R3 = (CH2)8CH3
R3 = (CH2)10CH3
R3 = ph
R3 = ph(p-NO2)
R3 = ph
R3 = CH3
R
R
R3 = CH3
R3 = (CH2)2CH3
R3 = (CH2)7CH3
R2 = Et
7j
R2 = Et
R2 = Et
7k*
R2 = Et
7l
R2 = Et
R2 = Bn
R2 = Bn
R2 = Bn
R2 = Et
R2 = Et
7m
7n
7o
7p
7q
7r
7s
7t
7u
7v
7w
7x
R
1 = Pr
R
1 = Oct R2 = Et
R2 = Et
3 = (CH2)2CH3
3 = ph
R2 = Et
R2 = Et
R2 = Et
R2 = Et
R2 = Et
R2 = t-Bu
R2 = Bn
84 %
R1 = Ph
80 %
95 %
89 %
81 %
96 %
7y
7z
1
R
3 = CH3
R3 = CH3
a) Davies amine, BuLi, THF, ꢀ78°C; (b) H2, Pd(OH)2/C, MeOH; (c) Na2CO3, R2CO2Cl, CH2Cl2/H2O; (d) BuLi,
(EtO)2P(O)Me, THF, ꢀ78°C; (e) Ba(OH)2, THF/H2O (40/1), R3CHO.
* In the case of enone 7k, we obtained a mixture of Z and E stereoisomers in a 60/40 ratio respectively.
Addition of enantiopure lithium NꢀbenzylꢀNꢀαꢀmethylbenzylamide on α,βꢀunsaturated ester 4
following by hydrogenation to the corresponding primary amine and further protection as a
carbamate gave the βꢀamino methylester 5a-g. After purification, the ester function was
transformed into the ketophosphonate 6a-g by treatment with 2.5 equivalents of diethyl
lithiomethylphosphonate34 in THF at ꢀ78°C, in moderate yields. Over the years, many
examples of baseꢀpromoted WittigꢀHornerꢀEmmons reaction have been reported in scientific
literature,35ꢀ37 various combinations of bases and solvents (K2CO3/CH3CN, DBU/THF,
NaH/THF, Et3N/LiCl/CH3CN or Ba(OH)2/(THF/H2O)...) have been used. In our case, we
have found that the use of 1.3 equiv of Ba(OH)2 in biphasic medium THF/H2O (40/1) was the
more general and convenient route to obtain compounds 7a-z with good to excellent yield.
II- Scope and limitations of the Michael "type"cyclization
As mentioned previously,31 we have shown that compound 1 could be easily transformed
diastereoselectively by intramolecular Michael “type” reaction in 2,6ꢀdisubstitutedꢀN-
protectedꢀ4ꢀketal piperidine (2a/2b) as a mixture of cis/trans isomers in which the trans
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conformation represents the major compound (Scheme 2). We have also shown, that the
character Z or E of the geometry of the double bond in compound 1 didn’t have any influence
on the diastereoselectivity of the cyclization reaction, as similar results have been obtained
starting either from stereoisomer (E) or (Z) of 1 treated in the same optimized conditions (0.2
equiv. of pꢀtoluenesulphonic acid monohydrate, 5 equiv. of ethylene glycol, 5 equiv. of
trimethyl orthoformate which has been used here as solvent and as a water scavenger).
So, we decided to use this protocol for the cyclization of a range of dissymmetric
(aliphatic/aromatic for R1 and R3) eneꢀcarbamates of type 7, hoping to evaluate at first the
influence of steric hindrance on the selectivity. For a better evaluation of the cis/trans ratio
(1H NMR) the mixture of ketals 8 and 9 were directly converted into the more stable
thioketals 10 and 11 by known procedure, using 1,2ꢀethane dithiol in the presence of boron
trifluoride diethyl etherate, as it has been shown that this transformation induced no variation
of the diastereoisomeric ratio (Scheme 5 and Table 1).
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Scheme 5
HO(CH2)2OH
O
or
HO(CH2)3OH
or
S
S
S
S
RO
OR
RO
OR
Ethanedithiol (5 eq.)
BF3:Et2O (5 eq.)
R2O
R1
NH
O
MeOH
R1
R2
N
R3
R1
R2
N
R3
R1
R2
N
R3
R1
R2
N
R3
R3
CH2Cl2, r.t
(CH3O)3CH
O
O
O
O
O
O
O
O
p-TsOH: H2O
(0.2 equiv.)
7
8 Trans
9 Cis
10 Trans
11 Cis
r. t.
Table 1 : first scope of intramolecular Michael reaction
cyclization
(Trans/Cis)
8/9 (%a)
(Trans/Cis)
10/11 %a
[ yield %b]
Entry
Ketone 7
react. time
(min)
alcohol
O
O
86/14
86/14 [68]c
(10a/11a)
NH
O
1
2
20 min
30 min
HO(CH2)2OH
HO(CH2)2OH
(8a/9a)
1
O
83/17
83/17 [71]
(10b/11b)
O
NH
O
(8b/9b)
7z
O
O
NH
O
44/56
44/56 [75]
(10c/11c)
3
4
20 min
20 min
HO(CH2)2OH
HO(CH2)2OH
(8c/9c)
7w
7n
O
O
51/49
51/49 [65]*
(10d/10d)
NH
O
(8d/9d)
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O
3
4
5
6
7
8
9
O
O
39/61
39/61 [73]
(10e/11e)
NH
NH
NH
O
O
O
5
6
7
20 min
40 min
40 min
HO(CH2)2OH
HO(CH2)2OH
HO(CH2)2OH
(8e/9e)
7a
7q
7x
O
≥ 95/5
≥ 95/5 [60]
(10f/11f)
(8f/9f)
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O
O
62/38
62/38 [67]
(10g/11g)
(8g/9g)
O
O
NH
O
62/38
(8h/9h)
95/5
62/38 [65]
(10h/11h)
95/5 [67]
(10h/11h)
7
8
9
7y
2 h
2 h
HO(CH2)2OH
HO(CH2)3OH
(8h/9h)
7y
O
O
NH
7
O
95/5
95/5 [67]
(10i/11i)
10
11
1 h
2h
HO(CH2)2OH
HO(CH2)2OH
(8i/9i)
7s
O
O
≥ 96/4
≥ 96/4 [65]
(10j/11j)
NH
O
(8j/9j)
7v
O
O
NH
O
12
13
2 h
6 h
HO(CH2)2OH
MeOH
see text
85/15
N
7i
7i
85/15 [48]
(10k/11k)
(8k/9k)
a Diastereoisomeric ratio are determined by integration of characteristic protons of the piperidine ring in the crude H1 NMR
b
spectra (Trans and Cis isomers where determined according to their respective coupling constants); Isolated yield of pure
diastereoisomeric mixture after chromatography on silica gel. c10a/11a and 10d/11d are enantiomers; for 10a/11a (10d/11d)
the benzyl carbamate was cleaved during the thioketalation process, leading to the free amine on the piperidine ring, see
experimental part).
According to Table 1, for the defined conditions, the selectivity observed for the cyclization
reaction is predominantly in favour of the trans isomer, which is the less stable conformation
for a 2,6ꢀdisustituted piperidine. This d.e. is markedly dependent of a lot of factors, namely
the nature of the nitrogen protective group and also the nature of steric hindrance (R1, R2 and
R3) on compounds 7. On the one hand, when R1 and R3 are fixed (R1= Ph, R3 = Me, entry 1, 2
and 3), a strong steric hindrance around the nitrogen atom is necessary to induce a good
diastereoselectivity. On the other hand, when R1=Ph and R3 was a much longer alkyl chain
(propyl or nonyl, entry 7, 8, 9), the ethyl carbamate function is sufficient to ensure
predominantly the formation of the trans isomer, however with a small diastereoselectivity
excess (de = 24%). Furthermore, changing ethylene glycol to 1,3ꢀpropane diol now increases
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the de up to 90% showing by this way the importance of the resulting keto protecting group.
Permutation of R1 and R3 (entry 3 versus entry 5) doesn’t show a significant influence on the
diastereoselectivity unless the alkyl chain is much longer than a methyl group (entries 5, 6,
10), or if R1 is a phenyl group (entry 11), in which the observed d.e is again around 90%.
Another observation is the dependency of the cyclization on the nature of the alcohol used.
So, when R1= Me and R3= pyridine (7i) the formation of the piperidine ring is not observed if
ethylene glycol is used to form the ketal (entry 12). The only product which can be identified
(by H NMR spectroscopy), is the ketal 12, in which the double bond is exclusively in a (E)
conformation (J=15,5 Hz). Assuming that the relative hindrance between the dioxolane group
and the pyridine was too high, we decided to realize the reaction with a less crowded acetal.
To our delight, when compound 7i was engaged (entry 13) in presence of trimethyl
orthoformate and pꢀtoluenesulphonic acid, leading to the in situ, formation of methanol, we
could now isolate the corresponding piperidines (10k/11k) with a d.e. of 70% in favour of the
trans conformation (Scheme 6).
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Scheme 6
O
O
O
O
HB
O
O
O
HO
OH
EtO
NH
O
7i
EtO
N
CH3
EtO
N
H
(CH3O)3CH
HA
N
N
p-TsOH
N
JHAHB = 15.5 Hz
12(E)
(CH3O)3CH
p-TsOH
(CH3O)3CH
p-TsOH
S
S
O
O
O
O
O
O
EtO
N
CH3
N
H
CH3
EtO
N
N
EtO
O
N
N
or 12(E) ?
12(Z)
8k / 9k
trans/cis = 85/15
10k / 11k
trans/cis = 85/15
This last result confirmed the fact that the first step, for the elaboration of the piperidine ring,
is the formation of the ketal on compounds 7, and thus, can constitute the critical step for the
diastereoselectivity of the reaction. Moreover, the formation of the ketal induces the E or Z
configuration of the double bond which is dependent of the nature of the ketal. This
hypothesis based on the role of the geometry of the double bond of a Michael acceptor in the
control of the diastereoselectivity, during the formation of 2,6ꢀdisubstituted piperidines, has
already been put forward by Banwell and coꢀworkers38, although in the case of an exoꢀ
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cyclization process. They had demonstrated, that the geometry of the double bond conducted
to two different transition states, resulting in the formation of 2,6ꢀcis or 2,6ꢀtrans piperidine.
Thus, reducing this fact to our model, we suppose that the formation of the 2,6 trans
piperidine or either 2,6 cis piperidine can be correlated with the geometry of the double bond
of the crucial intermediate acetal.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In order to confirm this hypothesis we engaged the compound 7j (Z/E conformers = 40/60) in
reaction with trimethyl orthoformate, with and without ethylene glycol and in presence of acid
(Scheme 7). Compound 7j was specially chosen for the strong steric hindrance which could
be generated in the transition state. At this stage, no formation of piperidine ring was
expected, but rather the formation of the intermediate ketal form and the possibility to
measure the corresponding coupling constant of both intermediates, to validate our
hypothesis.
Scheme 7
O
O
O
O
HB
O
O
O
HO
OH
EtO
NH
O
OEt
EtO
OEt
N
OEt
N
H
(CH3O)3CH
HA
O
O
O
p-TsOH
EtO
mixture Z/E : 40/60
JHAHB = 15.5 Hz
7ka(E)
7k
Transcetalation
(CH3O)3CH
p-TsOH
O
O
O
OEt
O
O
O
OEt
N
HB
EtO
N
H
O
HA
EtO
O
JHAHB = 8.4 Hz
7kb(Z)
Then, it was possible to identify two α,βꢀinsatured ketals 7ka(E) and 7kb(Z), a dioxolane and
1
a dimethylketal respectively. The coupling constant values for the double bond in H NMR
spectroscopy, then, demonstrated the existence of two different stereoisomers depending on
the ketal formed. The E configuration (JHAHB= 15.5 Hz) was observed for the cyclic ketal
7ka(E) whereas the Z (JHAHB= 8.4 Hz) was observed for the dimethyl ketal 7kb(Z). As for
compound 7ka(E), if trimethyl orthoformate is added to the mixture, a transacetalation
reaction is observed, leading to the formation of 7kb(Z). Thus, this result first of all
confirmed the formation of the ketal as the first step of the transformation; and second, it
strongly suggested that the diastereoselectivity of the piperidine formed can be dependent on
the configuration of the double bond of the intermediate ketal in the transition state. However
at this stage we can’t connect the configuration of the double bond with the configuration of
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the piperidine formed. We can only assume the existence of two different transition states
corresponding to the formation of two different acetals.
6
7
8
9
Therefore, to confirm the real role of this geometry on the resulting diastereoisomeric excess
for the piperidine generated, we selected the compound 7q, which gave a d.e. ≥ 90% in favour
of the trans isomer (Table 1, entry 6) and compared the importance of the nature of the
alcohol on the result when methanol, ethylene glycol or propanꢀ1,3ꢀdiol is used in the
cyclization process (Table 2), both enantiomers of 7q were tested. The quantity of acid was
fixed at 0.2 equiv. and all the crude mixtures 8f, 9f were respectively directly converted into
the corresponding 4ꢀthioketal piperidine 10f and 11f (Table 2). The diastereomeric excess was
as before, calculated according to the 1H NMR values.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2 : influence of the ketal formation on the stereoselectivity
S
S
HO(CH2)2OH
or
(5 equiv.)
(5 equiv.)
RO
O
OR
S
S
RO
OR
BF3:Et2O
(5 equiv.)
HO(CH2)3OH
or
MeOH
(1 equiv.)
N
Ph
N
Ph
N
Ph
N
Ph
7q
HS(CH2)2SH
(5 equiv.)
O
O
(CH3O)3CH (5 -10 equiv.)
O
O
O
O
O
p-TsOH (0.2 equiv.)
8f
9f
10f
11f
2,6-Cis
2,6-Trans
R =CH3,-(CH2)2-,-(CH2)3-
Cyclisation
10f/11f (ratio %a)
Entry
Alcohol used
react. time
[yieldb %]
8f/9f (min)
1
2
3
4
HOꢀ(CH2)2ꢀOH (7qR)
HOꢀ(CH2)2ꢀOH (7qS)
HOꢀ(CH2)3ꢀOH
MeOH
20
20
15
15
> 95/5 [67]
> 95/5 [68]
87/13 [68]
64/36 [68]
a Diastereoisomeric ratio are determined by integration of characteristic protons of the piperidine ring in the crude H1 NMR
b
spectra (Trans and Cis isomers where determined according to their respective coupling constants); Isolated yield of pure
diastereoisomeric mixture after chromatography on silica gel.
Cyclization was observed in all cases with a good overall yield, but a significant difference on
the d.e. was observed. The higher diastereoselectivity was obtained (Table 2, entry 1 and 2)
when ethylene glycol is used to form the ketal, corresponding to the more overcrowded
intermediate. On the contrary, the lower diastereoselectivity is observed when methanol is
used (Table 2, entry 4), as the dimethyl acetal gave a higher flexibility to the intermediate.
Both enantiomers of 7q gave the same result (Table 2, entry 1 and 2). If steric hindrance
appeared here as the predominant factor for the stereoselectivity of the reaction, however, in
all cases the trans isomer was obtained. So, in order to reinforce the existence of two
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different transition state according to the geometry of the double bond of the ketal, we
envisaged that this critical step could be under a kinetic control. Compound 7q was now
engaged under two different experimental protocols: on the one hand with ethylene glycol, on
the other hand with methanol. And for each case increasing quantities of acid, from catalytic
to stoechiometric, were used (Table 3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3 : kinetic effect on the stereoselectivity in the cyclization process
Cyclization
pꢀTsOH/H2O
Entry
Alcohol (x equiv.)
react. time
10f/11f (%a)
(x equiv.)
8f/9f (min)
1
2
HOꢀ(CH2)2ꢀOH (5)
HOꢀ(CH2)2ꢀOH (5)
HOꢀ(CH2)2ꢀOH (5)
HOꢀ(CH2)2ꢀOH (5)
HOꢀ(CH2)2ꢀOH (5)
MeOH (1)
0.1
0.2
0.5
1
25
20
85/15
85/15
86/14
87/13
40/60
50/50
55/45
64/36
69/31
72/28
3
15
4
10
5
0.2
0.02
0.05
0.1
0.2
1
24 h
45
6
7
MeOH (1)
40
8
MeOH (1)
20
9
MeOH (0 or 1)
MeOH (0)b
15
10
10
a
Diastereoisomeric ratio are determined by integration of characteristic protons of the piperidine ring in the crude H1 NMR
spectra (Trans and Cis isomers where determined according to their respective coupling constants); b When the concentration
of acid is upper 0.2 equiv. the degradation of trimethyl orthoformate is sufficient to generate methanol in situ.
When ethylene glycol is used for the formation of the ketal, the quantity of acid doesn’t affect
the diastereoisomeric excess obtained for 10f/11f (Entry 1 to 4), only the reaction time is
reduced. After 24 h (entry 5), an epimerisation through retroꢀMannich or retroꢀMichael
reaction is observed, the more stable cis isomer 11f becoming now the major compound. On
the contrary, when methanol was used (Entry 6 to 10) to generate the ketal, there is a
significant difference in the diastereoisomeric excess depending on the quantity of catalyst
used, and this evolution is in agreement with a kinetic effect.
To evaluate the importance of this kinetic effect, in the transition state, compared to the steric
effect, we substituted the aromatic ring of 7a and 7q (respectively table 3, entry 5, 39 % of
trans isomer and entry 6, ≥ 95 % of trans isomer, with the use of ethylene glycol and 0.2 % of
acid) with various ERG or EWG groups in ortho, meta or para position of the aromatic ring,
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and we used the methanol generated by the trimethyl orthoformate for the formation of the
ketal. Results on the selectivity such obtained are reported in Table 4.
Table 4: electronic effects
8
9
O
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(CH3O)3CH (5 equiv.)
O
NH
O
R2
N
R3
R2
N
R3
R2
R3
p-TsOH (0.2-1 equiv.)
O
O
O
O
r. t.
7
8 Trans
9 Cis
Reaction time (min)
(Trans/Cis)
Entry
Ketone 7
pꢀTsOH/H2O (x equiv.)
8/9 (%)a [yield %]b
O
O
NH
O
(90min)
(20min)
83/17 [71]
NO2
(0.2 equiv.)
(1 equiv.)
(8l/9l)
1
7r
O
O
NH
O
(120min)
(30 min)
89/11 [80]
NO2
7d
(0.2 equiv.)
(1 equiv.)
(8m/9m)
2
3
4
O
O
NH
O
(60min)
40/60 [71]
NO2
(1 equiv.)
(8n/9n)
7c
O
O
O
O
NH
O
NO2
(60min)
60/40 [67]
(1 equiv.)
(8o/9o)
7b
NH
O
(45 min)
33/67 [73]
(1 equiv.)
(8p/9p)
5
6
Br 7g
O
O
O
NH
O
(60min)
29/71 [75]
(1 equiv.)
(8q/9q)
Br
7f
O
NH
O
Cl
(180min)
(1 equiv.)
56/43 [76]
NO2
(8r/9r)
7
7h
O
O
NH
O
decomposition
OMe
OEt
8
9
7e
7j
O
(240min)
90/10 [93]
O
NH
O
O
(0.2 equiv.)
(8s/9s)
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a Diastereoisomeric ratio are determined by integration of characteristic protons of the piperidine ring in the crude H1 NMR
b
spectra (Trans and Cis isomers where determined according to their respective coupling constants); Isolated yield of pure
5
diastereoisomeric mixture after chromatography on silica gel..
6
7
8
9
Strong EWG located in para position on the aromatic ring for 7r and 7d (Table 4, entries 1
and 2) or placed on a conjugated system 7j (Table 4, entry 9), led predominantly and
respectively to 83, 89 or 90 % in favour to the trans isomer, but, no significant influence on
the selectivity can be related with the quantity of acid used. When the EWG is in meta
position, (compound 7c, Table 4, entry 3), a deactivating position, the opposite
diastereoselectivity (40/60) is observed and a longer reaction time is required. Concerning the
ortho position (compound 7b, Table 4, entry 4), the EWG effect is counterbalanced by steric
hindrance in the transition state and therefore a small diastereoisomeric excess (60/40) is
obtained. As expected, the presence of an ERG group in ortho or para position (Table 4,
entries 5 and 6) led predominantly to the cis derivative (30/70). However, if this effect is too
strong, decomposition of the starting material is observed (Table 4, entry 8). Thus, when
compounds 7 have an aromatic or a conjugated system as a substituent on the double bond, a
lot of parameters (steric hindrance, angle pressure, kinetic effect and electronic effect) has to
be considered to access a high selectivity and this selectivity is in favour of the trans isomer
of the piperidine.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
So, in order to validate the existence of two transition states, according to the alcohol used in
the cyclization step, we carried out the reaction with four representative ketones 7k,l,t,u in
which only a steric hindrance was induced by the size of an alkyl chain. As usual, we
measured the outcomes observed for the diastereoselectivity when a cyclic ketal or a dimethyl
ketal formation was involved. Here too, we converted all the crude mixture 8 and 9 or 8’ and
9’directly into the corresponding 4ꢀthioketal piperidines 10 and 11 (Table 5).
Table 5 : Michael cyclization of enones 7 bearing aliphatic substituents
O
O
O
O
O
O
O
O
O
O
HO(CH2)2OH (5 equiv.)
(CH3O)3CH (5 equiv.)
R1
N
R3
R1
N
8
R3
p-TsOH (0.2-1 equiv.)
r. t.
O
S
S
S
S
O
O
O
O
9
O
NH
O
R1
N
R3
R1
N
R3
R1
R3
7
O
O
O
O
10
11
(CH3O)3CH (5 equiv.)
R1
N
R3
R1
N
8'
R3
p-TsOH (0.2-1 equiv.)
r. t.
O
O
9'
Entry
Ketone 7
Cyclisation
Alcohol
(Trans/Cis)
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(React. time)
p-TsOH
10/11 (%a) [ yield %]
6
7
8
9
[x equiv.]
O
O
NH
O
O
1
2
3
40 min [0.2]
1 h [0.2]
HO(CH2)2OH
HO(CH2)2OH
MeOHc
80/20 [73] (10v/11v)
80/20 [62] (10t/11t)
20/80 [66] (10t/11t)
7l
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
NH
O
7
1 h [0.2]
7m
4
5
6
7
2 h [0.2]
0.5 h [1]
0.5 h [0.2]
0.5 h [1]
HO(CH2)2OH
HO(CH2)2OH
MeOHc
82/18 [68] (10s/11s)
65/35 [70] (10s/11s)
20/80 [71] (10s/11s)
20/80 [69] (10s/11s)
O
O
NH
O
7
7t
MeOHc
O
O
NH
7
O
8
2 h [0.2]
HO(CH2)2OH
83/17 [70] (10u/11u)
7u
a
Diastereoisomeric ratio are determined by integration of characteristic protons of the piperidine ring in the crude H1 NMR
b
spectra (Trans and Cis isomers where determined according to their respective coupling constants); Isolated yield of pure
compounds after chromatography on silica gel; c MeOH was generated in situ by decomposition of trimethyl orthoformate
According to the results obtained (Table 5) and the stereoselectivity observed, it becomes
evident now to affirm the formation of two different transition states in the formation of the
piperidine ring. Both transition states are strongly dependent on the alcohol used to generate
the ketal on the α,βꢀinsatured ketone. As we have mentioned in Table 3, there are two behave
according the nature of the ketal group. When dioxolane is used, trans isomer is the major
product formed, ~ 80 %, with a catalytic amount of acid (Table 5, entries 1, 4, 5, 7), however
when stoechiometric quantity of acid is used, a fast epimerisation process occurs (retro
Mannich or Michael reaction) and consequently a higher formation of the thermodynamic
specie, namely the 2,6ꢀcis piperidine is observed, even if the trans isomere was the fisrt
formed. In contrary, as observed in table 3, there is no kinetic effect on the cyclisation when
methanol is used. In this case, cis isomer was the major product, ~ 80 % of the reaction,
whatever the quantity of acid engaged (Table 5, entries 3, 6, 8), the thermodynamic product
was formed predominantly. And then, as for Banwell’s studies, our results are in agreement
with the formation of two possible conformations depending of the conformation of the
double bond before nucleophilic attack of the carbamate, leading to the formation of the
piperidine. At this stage, after examination of all potential parameters which can interfere with
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diastereoselectivity, it becomes easy to prepare either the trans or the cis isomer by a wise
choice of experimental conditions. In order to demonstrate this, we applied these protocols to
the synthesis of (ꢀ)ꢀsolenopsinꢀA39,40 and (+)ꢀalkaloid 241D41ꢀ43 (Scheme 8 and 9). (ꢀ)ꢀ
Solenopsin A can be rapidly prepared from compound 7p by using for the cyclization step,
ethylene glycol which led, as a major product, the trans isomer 8w (82 %, Scheme 8). Then,
after subsequent transformations we already described in previous paper44 (thioketalation
10w, Boc protection, desulfuration 12), (ꢀ)ꢀsolenopsin A was obtained in 10 steps, after
regeneration of the free amine, from the α,βꢀethylenic ester 4, with an overall yield of 9 %
with [α]D = ꢀ1.21 (c 0.94 MeOH, litt.34[α]D = ꢀ1.30 (c 1.30 MeOH).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8
O
O
S
S
Cbz
CH3
NH
e
b
O
a
c,d
CH3
C11H23
N
CH3
C11H23
N
C11H23
CH3
C11H23
CH3
N
C11H23
H
N
87 %
70 %
81 %
76 %
Boc
H
Cbz
8w Trans
8w/9w : 82/18
(-)-Solénopsine A
12
10w
7p
a) OH(CH2)2OH, (CH3O)3CH, pꢀTsOH ; (b) SH(CH2)2SH, BF3:Et2O, CH2Cl2; (c) (Boc)2O, DMAP, CH2Cl2; (d) Wꢀ2 Raney
Nickel, EtOH, reflux ; (e) TFA, CH2Cl2.
To reach (+)ꢀalkaloid 241D, methanol is now used for the cyclization, starting from
compound 7o. The intermediates 8’x/9’x were obtained in a ratio of 15/85 in a favour of the
cis isomer. After separation on deactivated silica, 9’x was ketoꢀdeprotected using a 40%
aqueous trifluoroacetic acid solution at room temperature to give the corresponding
piperidones 13 in very good yield. Nꢀdeprotection of the piperidone 13, followed by reduction
with NaBH4 gave selectively (+)ꢀalkaloid 241D in 9 steps from the α,βꢀethylenic ester 4 with
an overall yield of 16 % with a de ≥ 95 % and an ee of 92 % (Scheme 9).
Scheme 9
O
OH
Cbz
H3CO OCH3
H3CO OCH3
NH
O
4
2
c,d
a
b
CH3
C9H19
6
H3C
C9H19
N
H3C
C9H19
N
quant.
72 %
CH3
C9H19 84 %
CH3
N
C9H19
+
N
CO2Bn
H
CO2Bn
CO2Bn
13
7o
(+)-alkaloid 241D
8'x
9'x
8'x/9'x : 15/85
a) (CH3O)3CH, pTsOH ; (b) TFA/H2O, CH2Cl2 (c) Pd/C (5 %), MeOH, H2, 1 atm. ; (d) NaBH4, MeOH.
Conclusion
In conclusion, we have described herein a methodology to prepare stereoselectively either
2,6ꢀcis or 2,6ꢀtrans disubstituted piperidines. The efficient of this methodology has been
demonstrated through the asymmetric synthesis of (ꢀ)ꢀsolenopsine A and (+)ꢀalkaloid 241D
together with their respective isomer in Cꢀ6, demonstrating by this way that this strategy will
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be applied efficiently to the total synthesis of other piperidinic alkaloids exhibiting important
biological interest.
6
7
Experimental Section
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Generalities
Organic solutions were dried over Na2SO4 and filtered. When anhydrous solvents were used,
they were prepared as follows: tetrahydrofuran (THF) was distilled under N2 from sodium
benzophenone ketyl, and used immediately; anhydrous acetonitrile was freshly distilled from
1
CaH2. All H NMR and 13C spectra were measured in CDCl3 or C6D6 and recorded on a
Brüker 400 MHz (101 MHz for 13C) spectrometer using TMS as the internal standard.
Chemical shifts are expressed in ppm and J values are given in Hertz. The following
abbreviations are used: singlet (s), broad singlet (brs), doublet (d), doubled doublet (dd),
triplet (t), multiplet (m). High resolution mass spectroscopy (HRMS, TOF) were carried out in
electrospray mode. Monitoring of the reactions was performed using silica gel TLC plates.
Spots were visualized by UV light at 254 nm. Flash chromatography columns were performed
using silica gel 60 (70–230 mesh).
General procedure for the synthesis of β-aminoesters 5
(R)ꢀmethyl 3ꢀ(ethoxycarbonylamino)butanoate 5a
To a cold solution (0°C) of (+)ꢀ(R)ꢀNꢀbenzylꢀNꢀαꢀmethyl benzylamine (23.0 mL, 110 mmol,
1.1 equiv.) in dry THF (280 mL) was added slowly under argon, nꢀbutyl lithium (75.0 mL, 1.6
M in hexane, 120 mmol, 1.2 equiv). The resultant pink solution of lithium amide was stirred
for 30 min at 0°C then cooled to ꢀ78°C before drop wise addition of a solution of methyl
crotonate (10.0 mL, 100 mmol, 1 equiv.) in dry THF (100 mL). The mixture was stirred at –
78°C for 3h30. Then, a saturated aqueous solution of NH4Cl (100 mL) was added slowly and
the resulting solution was allowed to warm to room temperature. Then, the solution was
extracted twice with ethyl acetate. Combined organic extracts were dried over Na2SO4,
filtered and evaporated. The crude product was added to a suspension of 10 % Pd/C (5.00 g)
in methanol (200 mL). The mixture was placed on a Parr apparatus and stirred under a
hydrogen atmosphere (60 Psi) for 4 days. The catalyst was then removed by filtration on
Celite®. The residue was concentrated in vacuum and dissolved in dichloromethane (200 mL)
and water (200 mL). Then, sodium carbonate (42.4 g, 400 mmol, 4.0 equiv.) and ethyl
chloroformate (28.5 mL, 200 mmol, 2 equiv.) were added drop wise. The resulting solution
was stirred at room temperature for 3 h. The aqueous material was extracted with
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dichloromethane and the combined organic extracts were dried over Na2SO4, filtered and
concentrated in vacuo. Purification by chromatography on silica gel (cyclohexane/EtOAc :
9/1 to 5/5) afforded 5a as a yellow oil (10.8 g, 57 % over 3 steps): [α]D = ꢀ 35.60 (c = 0.99,
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CHCl3), litt.27 [α]D = ꢀ 37.07 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3) δ 5.03 (brs, 1H,
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NH), 4.03 (m, 3H), 3.62 (s, 3H), 2.46 (d, J = 6.9 Hz, 2H), 1.16 (t, J = 6.9Hz, 3H), 1.15 (d, J =
6.6Hz, 3H). Spectral data are identical with those reported.27
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(R)ꢀmethylꢀ3ꢀ(ethoxycarbonylamino)butanoate 5a. (starting from 0.100 mol of 4a, yellow oil,
10.8 g, yield = 57 %)
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Spectral data are identical with those reported45 : [α]D = ꢀ 37.07 (c 1, CHCl3). H NMR (400
MHz, CDCl3) δ 5.03 (brs, 1H), 4.03 (m, 3H), 3.62 (s, 3H), 2.46 (d, J = 6.9 Hz, 2H), 1.16 (t, J
= 6.9 Hz, 3H), 1.15 (d, J = 6.6 Hz, 3H)
(R)ꢀmethylꢀ3ꢀ(benzyloxycarbonylamino)butanoate 5b. (starting from 0.100 mol of 4a, yellow
oil, 15.6 g, yield = 62 %)
Spectral data are identical with those reported46 : [α]D = + 16.9 (c 1.4, CHCl3). 1H NMR (400
MHz, CDCl3) δ 5.03 (brs, 1H), 4.03 (m, 3H), 3.62 (s, 3H), 2.46 (d, J = 6.9 Hz, 2H), 1.16 (t, J
= 6.9 Hz, 3H), 1.15 (d, J = 6.6, 3H).
(R)ꢀmethylꢀ3ꢀ(benzyloxycarbonylamino)butanoate
5c
and
(S)ꢀmethylꢀ3ꢀ
(benzyloxycarbonylamino)butanoate 5c’. (starting from 0.100 mol of 4b, yellow oil, 16.7 g,
yield = 77 %)
R enantiomer: [α]D = + 41.5 (c 1.03, CHCl3), S enantiomer: [α]D = ꢀ 40.9 (c 1.035, CHCl3);
1H NMR (400 MHz, CDCl3) δ 4.98 (brs, 1H), 4.02 (m, 2H), 3.90 (m, 1H), 3.61 (s, 3H), 2.49
(dd, J = 15.8, 4.8 Hz, 1H), 2.43 (dd, J = 15.8, 5.3 Hz, 1H), 1.48 – 1.22 (m, 2H), 1.16 (t, J = 7.0
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Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H); C NMR (101 MHz, CDCl3) δ 172,0, 156.0, 60.7, 51.6,
47.7, 38.9, 36.6, 19.3, 14.6, 13.8. HRMSꢀESI (M + Na), m/z: calcd. for C10H19NO4Na
240.1212, found 240.1216.
(R)ꢀmethylꢀ3ꢀ(ethoxycarbonylamino)undecanoate 5d. (starting from 0.100 mol of 4c, yellow
oil, 20.9 g, yield = 73 %)
[α]D = + 29.2 (c 1.05, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.07 (brs, 1H), 4.22 – 4.03 (m,
2H), 3.98 (m, 1H), 3.69 (s, 3H), 2.57 (dd, J = 15.1, 4.6 Hz, 1H), 2.51 (dd, J = 15.1, 5.1, Hz
1H), 1.55 – 1.45 (m, 2H), 1.41 – 1.10 (m, 15H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 172.1, 156.1, 60.7, 51.5, 48.0, 38.9, 34.4, 31.8, 29.4, 29.3, 29.2, 26.1, 22.6, 14.6,
14.1; HRMSꢀESI (M + Na), m/z: calcd. for C15H29NO4Na 310.1994, found 310.1996.
(S)ꢀmethylꢀ3ꢀ(ethoxycarbonylamino)ꢀ3ꢀphenylpropanoate 5e. (starting from 0.100 mol of 4d,
yellow oil, 18.0 g, yield = 72 %)
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[α]D = ꢀ 9.7 (c 0.99, CHCl3). H NMR (400 MHz, CDCl3) δ 7.36 – 7.25 (m, 5H), 5.75 (brs,
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1H), 5.17 (m, 1H), 4.11 (q, J = 7.0 Hz, 2H), 3.62 (s, 3H), 2.91 (dd, J = 15.5, 6,0 Hz, 1H), 2.84
(dd, J = 15.5, 5.9 Hz, 1H), 1.23 (t, J = 7.0, 3H); 13C NMR (101 MHz, CDCl3) δ 171.3, 155.8,
140.9, 128.6, 127.6, 126.2, 61.0, 51.8, 51.7, 40.5, 14.6; HRMSꢀESI (M + Na), m/z: calcd. for
C13H17NO4Na 274.1055, found 274.1069.
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(S)ꢀmethylꢀ3ꢀ(tertꢀbutoxycarbonylamino)ꢀ3ꢀphenylpropanoate 5f (starting from 0.100 mol of
4d, yellow oil, 21.2 g, yield = 76 %)
Spectral data are identical with those reported.47 (S)ꢀmethylꢀ3ꢀ(benzyloxycarbonylamino)ꢀ3ꢀ
phenylpropanoate 5g . (starting from 0.100 mol of 4d, yellow oil, 20.7 g, yield = 66 %)
Spectral data are identical with those reported52 : [α]D = ꢀ 16.1 (c 0.97, CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.22 (m, 10 H), 5.73 (brs, 1H), 5.09 (m, 1H), 5.01 (d, J = 12.3 Hz, 1H), 4.97
(d, J = 12.3 Hz, 1H), 3.50 (s, 3H), 2.81 (dd, J = 15.3, 5.0 Hz, 1H), 2.74 (dd, J = 15.3, 5.7 Hz,
1H).
General procedure for the synthesis of ketophosphonates 6
(R)ꢀethyl 5ꢀ(diethoxyphosphoryl)ꢀ4ꢀoxopentanꢀ2ꢀylcarbamate 6a
To a solution of diethyl methylphosphonate (5.8 mL, 39.7 mmol, 2.5 equiv.) in anhydrous
THF (15 mL) placed at ꢀ78°C, was added drop wise nꢀbutyl lithium (24.8 mL, 1.6 M in
hexane, 39.7 mmol, 2,5 equiv.). After 20 min at ꢀ78°, a solution of 5a (3 g, 15.9 mmol, 1
equiv.) in anhydrous THF (15 mL) was added dropwise. After addition, the temperature of the
reaction was kept at ꢀ78°C for 30 min and then allowed to reach 0°C in 1 hour, and quenched
with a solution of ammonium chloride and extracted twice with ethyl acetate. After drying
over Na2SO4 and concentrated under vacuum, the crude oil was first distillated at low pressure
to remove excess of diethyl methylphosphonate and the residue purified by flash
chromatography (eluent: cyclohexane/EtOAc 2/1 to EtOAc) afforded compound 6a as a
yellow oil (3.3 g, 68% yield): [α]D = + 33.60 (c = 1.17, CHCl3). 1H NMR (400 MHz, CDCl3)
δ 5.03 (brs, 1H,), 4.16 – 3.94 (m, 7H), 3.08 (dd, J = 23.0, 14.0 Hz, 1H), 2.99 (dd, J = 22.6,
14.0 Hz, 1H), 2.84 (dd, J = 17.1, 6.0 Hz, 1H), 2.71 (dd, J = 17.1, 5.7 Hz, 1H), 1.33 – 1.21 (m,
13
6H), 1.15ꢀ1.20 (m, 6H); C NMR (101 MHz, CDCl3) δ 200.6, 155.8, 62.6 (d, J = 6.6 Hz),
62.5 (d, J = 6.5 Hz), 60.5, 49.6, 43.5, 42.9 (d, J = 127.4 Hz), 20.7, 16.2, 16.1, 14.6; HRMSꢀ
ESI (M + Na), m/z calcd. for C12H24NO6PNa 332.1239, found 332.1239.
(R)ꢀbenzylꢀ5ꢀ(diethoxyphosphoryl)ꢀ4ꢀoxopentanꢀ2ꢀylcarbamate 6b. (starting from 16 mmol
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of 5b, yellow oil, 3.4 g, yield = 57 %); [α]D = ꢀ 26.4 (c 0.85, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.36 – 7.22 (m, 5H), 5.26 (brs, 1H), 5.00 (s, 2H), 4.03 (m, 5H), 3.05 (dd, J = 23.2,
13.6 Hz, 1H), 2.96 (dd, J = 22.7, 13.6 Hz, 1H), 2.85 (dd, J = 17.3, 5.8 Hz, 1H), 2.70 (dd, J =
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17.3, 5.6 Hz, 1H), 1.26 (t, J = 6.2 Hz, 6H), 1.16 (d, J = 6.7 Hz, 3H); C NMR (101 MHz,
CDCl3) δ 200.7, 155.6, 136.6, 128.5, 128.0, 66.5, 62.7 (d, J = 6.6 Hz), 62.6 (d, J = 6.8 Hz),
49.5, 43.6, 43.3 (d, J = 129.5 Hz), 20.4, 16.3, 16.2; HRMSꢀESI (M + Na), m/z: calcd. for
C17H26NO6PNa 394.1395, found 394.1395.
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(R and S)ꢀethylꢀ1ꢀ(diethoxyphosphoryl)ꢀ2ꢀoxoheptanꢀ4ꢀylcarbamate 6c and 6c’. (starting
from 16 mmol of 5c, yellow oil, 3.4 g, yield = 65 %); R enantiomer: [α]D = + 43.09 (c 1.03,
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CHCl3), S enantiomer: [α]D = ꢀ 42.55 (c 1.075, CHCl3). H NMR (400 MHz, CDCl3) δ 5.00
(d, J = 9.0 Hz, 1H), 4.15 – 3.97 (m, 6H), 3.90 (m, 1H), 3.09 (dd, J = 22.9, 13.5 Hz, 1H), 2.96
(dd, J = 22.5, 13.5 Hz, 1H), 2.80 (dd, J = 17.2, 5.9 Hz, 1H), 2.74 (dd, J = 17.2, 5.3 Hz, 1H),
1.48 – 1.39 (m, 2H), 1.37 – 1.29 (m, 2H), 1.27 (dt, J = 7.2, 2.0 Hz, 6H), 1.15 (t, J = 7.1 Hz,
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3H), 0.84 (t, J = 7.2 Hz); C NMR (101 MHz, CDCl3) δ 200.9, 156.2, 62.7 (d, J = 6.5 Hz),
62.6 (d, J = 6.6 Hz), 60.6, 48.2, 47.5, 42.9 (d, J = 126.6 Hz), 36.7, 19.3, 16.3, 16.2, 14.6, 13.8;
HRMSꢀESI (M + Na), m/z: calcd. for C14H28NO6PNa 360.1552, found 360.1562.
(R)ꢀethylꢀ1ꢀ(diethoxyphosphoryl)ꢀ2ꢀoxododecanꢀ4ꢀylcarbamate 6d. (starting from 16 mmol of
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5d, yellow oil, 4.2 g, yield = 66 %); [α]D = + 30.06 (c 1.00, CHCl3). H NMR (400 MHz,
CDCl3) δ 5.02 (brs, 1H), 4.17 – 3.99 (m, 6H), 3.95 (m, 1H), 3.07 (dd, J = 23.1, 13.5 Hz, 1H),
2.98 (dd, J = 22.7, 13.5 Hz, 1H), 2.83 (dd, J = 17.4, 5.8 Hz, 1H), 2.75 (dd, J = 17.4, 5.2 Hz,
1H), 1.51 – 1.41 (m, 2H), 1.39 – 1.23 (m, 12H), 1.21 (t, J = 7.2 Hz, 6H), 1.16 (t, J = 7.1 Hz,
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3H), 0.86 (t, J = 7.2 Hz, 3H); C NMR (101 MHz, CDCl3) δ 200.8, 156.1, 62.9 (d, J = 6.6
Hz), 62.8 (d, J = 6.7 Hz), 60.7, 48.2, 48.1, 42.7 (d, J = 127.1 Hz), 34.4, 31.8, 29.4, 29.3, 29.2,
26.1, 22.6, 16.4, 16.3, 14.6, 14.0; HRMSꢀESI (M + Na), m/z: calcd. for C19H38NO6PNa
430.2334 found 430.2349.
(S)ꢀethyl 4ꢀ(diethoxyphosphoryl)ꢀ3ꢀoxoꢀ1ꢀphenylbutylcarbamate 6e. (starting from 16 mmol
1
of 5e, yellow oil, 3.4 g, yield = 58 %); [α]D = + 1.65 (c 1.09, CHCl3). H NMR (400 MHz,
CDCl3) δ 7.29 – 7.21 (m, 4H), 7.16 (m, 1H), 5.72 (s, 1H), 5.09 (dd, J = 12.7, 6.7 Hz, 1H),
4.11 – 3.94 (m, 6H), 3.26 (dd, J = 16.9, 7.3 Hz, 1H), 3.04 (dd, J = 23.3, 13.1 Hz, 1H), 2.97
(dd, J = 16.9, 12.7 Hz, 1H), 2.93 (dd, J = 22.9, 13.1 Hz, 1H), 1.22 (td, J = 7.1, 1.9 Hz, 6H),
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1.13 (t, J = 6.7 Hz, 3H); C NMR (101 MHz, CDCl3) δ 199.9, 155.9, 141.4, 128.6, 127.4,
126.3, 62.8 (d, J = 6.2 Hz), 62.6 (d, J = 6.5 Hz), 60.8, 51.1, 49.4, 43.3 (d, J = 125.5 Hz), 16.2
(d, J = 6.1 Hz), 14.6; HRMSꢀESI (M + Na), m/z: calcd. for C17H26NO6PNa 394.1395, found
394.1414.
(S)ꢀtertꢀbutyl 4ꢀ(diethoxyphosphoryl)ꢀ3ꢀoxoꢀ1ꢀphenylbutylcarbamate 6f. (starting from 16
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mmol of 5f, yellow oil, 3.9 g, yield = 62 %); [α]D = + 3.12 (c 1.01, CHCl3); H NMR (400
MHz, CDCl3) δ 7.26 – 7.12 (m, 4H), 7.16 (m, 1H), 5.44 (brs, 1H), 5.03 (brs, 1H), 4.04 – 3.95
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(m, 4H), 3.20 (dd, J = 16.8, 7.4 Hz, 1H), 3.01 (dd, J = 23.1, 12.9 Hz, 1H), 2.99 (m, 1H), 2.92
(dd, J = 22.7, 12.9 Hz, 1H), 1.32 (s, 9H), 1.21 (td, J = 7.1, 1.9 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ 200.2, 155.1, 133.6, 130.9, 128.5, 126.3, 66.7, 62.8 (d, J = 6.3 Hz), 62.6 (d, J = 6.2
Hz), 50.9, 49.6, 41.0 (d, J = 127.6 Hz), 16.3 (d, J = 5.8 Hz), 16.2 (d, J = 5.6 Hz); HRMSꢀESI
(M + Na), m/z: calcd. for C19H30NO6PNa 422.1708, found 422.1722.
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(S)ꢀbenzylꢀ4ꢀ(diethoxyphosphoryl)ꢀ3ꢀoxoꢀ1ꢀphenylbutylcarbamate 6g. (starting from 16
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mmol of 5g, yellow oil, 4.5 g, yield = 66 %) ; [α]D = + 8.66 (c 1.55, CHCl3). H NMR (400
MHz, CDCl3) δ 7.31 – 7.20 (m, 8H), 7.16 (m, 2H), 5.88 (brs, 1H), 5.11 (dd, J = 13.1, 7.4 Hz,
1H), 5.04 (d, J = 12.3 Hz, 1H), 4.96 (d, J = 12.3 Hz, 1H), 4.02 – 3.89 (m, 4H), 3.27 (dd, J =
16.6, 7.4 Hz, 1H), 3.02 (dd, J = 23.3, 13.1 Hz, 1H), 2.97 (m, 1H), 2.90 (dd, J = 22.6, 13.1 Hz,
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1H), 1.21 (t, J = 7.0 Hz, 3H), 1.15 (t, J = 6.8 Hz, 3H); C NMR (101 MHz, CDCl3) δ 200.0,
155.6, 141.3, 136.5, 128.6, 128.4, 128.0, 127.5, 126.3, 66.7, 62.9 (d, J = 5.3 Hz), 62.6 (d, J =
6.4 Hz), 51.3, 49.3, 43.5 (d, J = 123.8 Hz), 16.3 (d, J = 4.1 Hz), 16.2 (d, J = 3.7 Hz); HRMSꢀ
ESI (M + Na), m/z: calcd. for C22H28NO6PNa 456.1552, found 456.1559.
General procedure for the synthesis of enones 7
(R,E)ꢀethyl 4ꢀoxoꢀ6ꢀphenylꢀhexꢀ5ꢀenꢀ2ꢀylcarbamate 7a
To a solution of 6a (0.5 g, 1.6 mmol, 1equiv.) in THF (7 mL), was poured in one time
Ba(OH)2 (0.346 g, 2.0 mmol, 1.25 equiv.) at room temperature. After 30 min, a solution of
benzaldehyde (0.172 ml, 1.7 mmol, 1.05 equiv.) in THF/H2O: 40/1 (7 mL) was slowly added
at room temperature. After 1 hour, the reaction mixture was quenched with an aqueous
solution of ammonium chloride and extracted three times with ethyl acetate. Then the organic
layer was dried over Na2SO4, concentrated under vacuum and purified by flash
chromatography (eluent: cyclohexane to cyclohexane/EtOAc 8/2) and gave compound 7a as a
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white solid (0.40 g, 95%): mp 74 °C; [α]D = + 9.50 (c = 1.21, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.50 (d, J = 16.7 Hz, 1H), 7.47 (dd, J = 7.8, 3.0 Hz, 1H), 7.33 – 7.30 (m, 3H), 6.65
(d, J = 16.7 Hz, 1H), 5.14 (s, 1H), 4.14 – 4.06 (m, 1H), 4.02 (q, J = 6.9 Hz, 2H), 2.95 (dd, J =
15.9, 4.2 Hz, 1H), 2.71 (dd, J = 15.9, 6.5 Hz, 1H), 1.19 (d, J = 6.8 Hz, 3H), 1.14 (t, J = 6.9 Hz,
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3H); C NMR (101 MHz, CDCl3) δ 198.8, 155.9, 143.4, 134.3, 130.6, 128.9, 128.4, 126.3,
60.6, 46.3, 44.1, 20.5, 14.6; HRMSꢀESI (M + Na): calcd. for C15H19NO3Na 284.1263, found
284.1275.
(R,E)ꢀethylꢀ6ꢀ(2ꢀnitrophenyl)ꢀ4ꢀoxohexꢀ5ꢀenꢀ2ꢀylcarbamate 7b.
[α]D = + 21.94 (c 1.015, CHCl3) ; Yellow solid ; starting from 1.6 mmol of 6a, 0.43g, yield =
89 % ; mp 90°C; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 16.1 Hz,
1H), 7.71 – 7.59 (m, 2H), 7.56 (t, J = 7.4 Hz, 1H), 6.58 (d, J = 16.1 Hz, 1H), 5.08 (brs, 1H),
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= 6.7 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H) ; C NMR (101 MHz, CDCl3) δ 198.3, 155.8, 148.3,
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138.7, 133.7, 131.1, 130.8, 130.5, 129.1, 125.1, 60.7, 46.0, 43.9, 20.6, 14.6 ; HRMSꢀESI (M +
Na), m/z: calcd. for C15H18N2O5Na 329.1113, found 329.1117.
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[α]D = + 5.92 (c 0.995, CHCl3) ; Yellow solid ; starting from 1.6 mmol of 6a, 0.41g, yield =
86 % ; mp 97°C; 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.87 (d,
J = 7.7 Hz, 1H), 7.65 (d, J = 16.2 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 16.2 Hz, 1H),
5.08 (brs, 1H), 4.27 – 4.04 (m, 3H), 3.07 (dd, J = 16.1, 3.3 Hz, 1H), 2.84 (dd, J = 16.1, 6.6 Hz,
1H), 1.31 (d, J = 6.7 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H) ; 13C NMR (101 MHz, CDCl3) δ 198.3,
155.6, 148.5, 140.2, 136.0, 133.9, 130.0, 128.6, 124.8, 122.6, 60.8, 47.0, 44.0, 20.5, 14.6 ;
HRMSꢀESI (M + Na), m/z: calcd. for C15H18N2O5Na 329.1113, found 329.1125.
(R,E)ꢀethylꢀ6ꢀ(4ꢀnitrophenyl)ꢀ4ꢀoxohexꢀ5ꢀenꢀ2ꢀylcarbamate 7d.
[α]D = + 16.42 (c 0.52, CHCl3) ; Yellow solid ; starting from 1.6 mmol of 6a, 0.44g, yield =
91 % ; mp 98°C. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.5 Hz,
2H), 7.53 (d, J = 16.2 Hz, 1H), 6.75 (d, J = 16.2 Hz, 1H), 4.97 (s, 1H), 4.10 (m, 1H), 4.03 (q, J
= 7.0 Hz, 2H), 2.99 (dd, J = 15.6, 3.5 Hz, 1H), 2.74 (dd, J = 15.6, 6.5 Hz, 1H), 1.21 (d, J = 6.8
Hz, 1H), 1.15 (t, J = 7.0 Hz, 1H) ; 13C NMR (101 MHz, CDCl3) δ 198.0, 155.9, 140.5, 140.1,
128.5, 128.9, 124.8, 124.2, 60.8, 47.1, 44.0, 20.5, 14.6 ; HRMSꢀESI (M + Na), m/z: calcd. for
C15H18N2O5Na 329.1113, found 329.1119.
(R,E)ꢀethylꢀ6ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀoxohexꢀ5ꢀenꢀ2ꢀylcarbamate 7e.
[α]D = + 6.1 (c 1.055, CHCl3) ; Yellow solid ; starting from 1.6 mmol of 6a, 0.37g, yield = 79
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% ; mp 108°C; H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 16.1 Hz, 1H), 7.50 (d, J = 7.9 Hz,
2H), 6.91 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 16.1 Hz, 1H), 5.21 (brs, 1H), 4.22 – 4.07 (m, 3H),
3.83 (s, 3H), 2.99 (dd, J = 15.8, 4.4 Hz, 1H), 2.76 (dd, J = 15.8, 5.8 Hz, 1H), 1.25 (d, J = 6.8
Hz, 1H), 1.21 (t, J = 7.0 Hz, 1H) ; 13C NMR (101 MHz, CDCl3) δ 198.8, 161.9, 155.9, 143.2,
130.3, 127.1, 124.3, 114.6, 60.8, 55.5, 46.2, 44.4, 20.6, 14.7 ; HRMSꢀESI (M + Na), m/z:
calcd. for C16H21NO4Na 314.1368, found 314.1371.
(R,E)ꢀethyl 6ꢀ(2ꢀbromophenyl)ꢀ4ꢀoxohexꢀ5ꢀenꢀ2ꢀylcarbamate 7f.
[α]D = + 18.2 (c 1.175, CHCl3) ; Yellow solid ; starting from 1.6 mmol of 6a, 0.53g, yield =
91 % ; mp 65°C. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 16.2 Hz, 1H), 7.56 (d, J = 7.8 Hz,
1H), 7.56 (d, J = 7.8 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.17 (td, J = 7.8, 1.5 Hz, 1H), 6.57 (d, J
= 16.2 Hz, 1H), 5.08 (brs, 1H), 4.15 – 3.88 (m, 3H), 2.96 (dd, J = 16.4, 4.8 Hz, 1H), 2.79 (dd,
J = 16.3, 6.2 Hz, 1H), 1.22 (d, J = 6.8 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H) ; 13C NMR (101 MHz,
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CDCl3) δ 198.8, 158.1, 145.0, 141.6, 133.5, 131.5, 129.0, 127.8, 60.7, 46.5, 44.0, 20.6, 14.6 ;
HRMSꢀESI (M + Na), m/z: calcd. for C15H18BrNO3Na 362.0368, found 362.0371.
(R,E)ꢀethylꢀ6ꢀ(4ꢀbromophenyl)ꢀ4ꢀoxoꢀhexꢀ5ꢀenꢀ2ꢀylcarbamate 7g.
[α]D = + 4.0 (c 1.03, CHCl3) ; Yellow solid ; starting from 1.6 mmol of 6a, 0.48g, yield = 89
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% ; mp 90°C. H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 16.2 Hz,
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1H), 7.41 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 16.2 Hz, 1H), 5.10 (s, 1H, NH), 4.14 (m, 1H), 4.09
(q, J = 7.1 Hz, 1H), 3.01 (dd, J = 15.5, 3.4 Hz, 1H), 2.77 (dd, J = 15.5, 6.6 Hz, 1H), 1.27 (d, J
= 6.8 Hz, 1H), 1.23 (t, J = 7.1, 1H) ; 13C NMR (101 MHz, CDCl3) δ 198.4, 156.0, 141.9,
133.2, 132.2, 129.7, 126.7, 124.9, 60.7, 50.0, 46.5, 44.1, 20.5, 14.6 ; HRMSꢀESI (M + Na),
m/z: calcd. for C15H18BrNO3Na 362.0368, found 362.0380.
(R,E)ꢀethylꢀ6ꢀ(2ꢀchloroꢀ5ꢀnitrophenyl)ꢀ4ꢀoxoꢀhexꢀ5ꢀenꢀ2ꢀylcarbamate 7h.
[α]D = + 15.06 (c 1.06, CHCl3) ; Yellow solid ; starting from 1.6 mmol of 6a, 0.52g, yield =
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95 % ; mp 149°C ; H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 16.0
Hz, 1H), 7.62 (s, 1H), 7.51 (d, J = 8.6, 1H), 6.57 (d, J = 16.0 Hz, 1H), 5.09 (brs, 1H), 4.23 –
4.03 (m, 3H), 3.05 (dd, J = 16.5, 5.2 Hz, 1H), 2.84 (dd, J = 16.5, 6.5 Hz, 1H), 1.28 (d, J = 6.9
Hz, 3H), 1.21 (t, J = 7.5 Hz, 3H) ; 13C NMR (101 MHz, CDCl3) δ 198.0, 158.9, 146.5, 140.4,
137.7, 132.9, 131.9, 130.5, 129.3, 126.7, 60.9, 46.5, 44.1, 20.7, 14.7 ; HRMSꢀESI (M + Na),
m/z: calcd. for C15H17ClN2O5Na 363.0724, found 363.0717.
(R,E)ꢀethylꢀ4ꢀoxoꢀ6ꢀ(pyridinꢀ3ꢀyl)hexꢀ5ꢀenꢀ2ꢀylcarbamate 7i.
[α]D = + 10.25 (c 0.865, CHCl3) ; White solid ; starting from 1.6 mmol of 6a, 0.36g, yield =
87 % ; mp 90°C; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 1.6 Hz, 1H), 8.56 (d, J = 4.7 Hz,
1H), 7.82 (dt, J = 7.9,1.6, 1H), 7.51 (d, J = 16.3 Hz, 1H), 7.30 (dd, J = 7.9, 4.9 Hz, 1H), 6.72
(d, J = 16.3 Hz, 1H), 5.03 (brs, 1H), 4.20 – 3.70 (m, 3H), 2.98 (dd, J = 16.1, 4.0 Hz, 1H), 2.74
(dd, J = 16.1, 6.7 Hz, 1H), 1.21 (d, J = 6.9 Hz, 3H), 1.16 (t, J = 7.5 Hz, 3H) ; 13C NMR (101
MHz, CDCl3) δ 198.1, 155.9, 151.1, 149.9, 139.4, 134.5, 130.2, 128.0, 123.8, 60.7, 46.7, 44.1,
20.5, 14.6 ; HRMSꢀESI (M + Na), m/z: calcd. for C14H18N2O3Na 285.1215, found
285.1210.
(R,2E,4E)ꢀethylꢀ8ꢀ(ethoxycarbonylamino)ꢀ6ꢀoxoꢀnonaꢀ2,4ꢀdienoate 7j.
[α]D = + 17.6 (c 0.695, CHCl3) ; Viscous yellow oil ; starting from 1.6 mmol of 6a, 0.38g,
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yield = 85 % . H NMR (400 MHz, CDCl3) δ 7.24 (dd, J = 14.9, 11.4 Hz, 1H), 7.14 (dd, J =
15.1, 11.4 Hz, 1H), 6.35 (d, J = 15.0 Hz, 1H), 6.19 (d, J = 15.0 Hz, 1H), 4.97 (s, 1H), 4.17 (q,
J = 7.1 Hz, 2H), 4.05 – 4.00 (m, 3H), 2.89 (d, J = 12.5 Hz, 1H), 2.67 (dd, J = 16.3, 6.5 Hz,
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1H), 1.25 (t, J = 7.1 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H) ; C NMR
(101 MHz, CDCl3) δ 198.4, 165.7, 155.8, 141.1, 139.1, 135.3, 129.5, 60.9, 60.7, 46.7, 43.9,
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20.4, 14.6, 14.2 ; HRMSꢀESI (M + Na), m/z: calcd. for C14H21NO5Na 306.1317, found
306.1331.
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(R)ꢀethylꢀ6ꢀ(ethoxycarbonylamino)ꢀ4ꢀoxoheptꢀ2ꢀenoate 7k.
Mixture of Z and E isomers (Z/E : 60/40): Colorless oil ; starting from 1.6 mmol of 6a, 0.22g,
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yield = 53 %. H NMR (400 MHz, CDCl3) δ 6.96 (d, J = 16.0 Hz, 1H), 6.62 (d, J = 16.0 Hz,
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1H), 6.43 (d, J = 12.0 Hz, 1H), 5.97 (d, J = 12.0 Hz, 1H), 5.18 (s, 1H), 5.12 (s, 1H), 4.25 –
4.11 (m, 6H), 2.91 (d, J = 15.0 Hz, 1H), 2.81 (dd, J = 16.9, 5.7 Hz, 1H), 2.78 – 2.67 (m, 1H),
1.27 – 1.13 (m, 12H) ; 13C NMR (101 MHz, CDCl3) (mixture of Z and E) δ 201.1, 197.3,
164.4, 164.2, 155.7, 155.0, 140.6, 138.3, 130.4, 124.0, 60.5, 60.3, 59.8, 59.7, 47.3, 46.0, 42.7,
42.4, 19.6, 19.4, 13.6, 13.1, 13.0 ; HRMSꢀESI (M + Na), m/z: calcd. for C12H19NO5Na
280.1161, found 280.1163.
(R,E)ꢀethylꢀ4ꢀoxoꢀnonꢀ5ꢀenꢀ2ꢀylcarbamate 7l.
[α]D = + 12.13 (c 1.025, CHCl3) ; Colorless oil ; starting from 1.6 mmol of 6a, 0.34g, yield =
95 % .1H NMR (400 MHz, CDCl3) δ 6.84 (dt, J = 15.9, 7.2 Hz, 1H), 6.07 (dd, J = 15.9, 1.5
Hz, 1H), 5.13 (brs, 1H), 4.11 – 4.02 (m, 3H), 2.87 (dd, J = 16.1, 4.4 Hz, 1H), 2.65 (dd, J =
16.1, 6.4 Hz, 1H), 2.19 (td, J = 7.2, 1.5 Hz, 2H), 1.49 (qd, J = 7.2 Hz, 2H), 1.22 (t, J = 7.2 Hz,
3H), 1.21 (d, J = 6.8 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H) ; 13C NMR (101 MHz, CDCl3) δ 199.1,
156.0, 148.5, 130.9, 60.7, 45.5, 44.2, 34.6, 21.4, 20.6, 14.7, 13.8 ; HRMSꢀESI (M + Na), m/z:
calcd. for C12H21NO3Na 250.1419, found 250.1421.
(R,E)ꢀethyl 4ꢀoxoꢀtetradecꢀ5ꢀenꢀ2ꢀylcarbamate 7m.
[α]D = + 10.71 (c 1.025, CHCl3) ; Yellow oil ; starting from 1.6 mmol of 6a, 0.42g, yield = 88
% .1H NMR (400 MHz, CDCl3) δ 6.79 (dt, J = 15.8, 6.9 Hz, 1H), 6.01 (d, J = 15.8 Hz, 1H),
5.16 (s, 1H), 4.07 – 4.03 (m, 1H, 3H), 2.86 (dd, J = 16.0, 4.0 Hz, 1H), 2.63 (dd, J = 16.0, 6.4
Hz, 1H), 2.14 (q, J = 6.9 Hz, 2H), 1.45 – 1.32 (m, 2H), 1.30 – 1.18 (m, 15H), 1.15 (d, J = 7.1
Hz, 3H), 0.81 (t, J = 6.9 Hz, 3H) ; 13C NMR (101 MHz, CDCl3) δ 199.1, 155.9, 148.7, 130.7,
60.7, 45.5, 44.1, 32.6, 31.9, 29.5, 29.4, 29.3, 29.2, 28.1, 22.7, 20.5, 14.7, 14.2 ; HRMSꢀESI
(M + Na), m/z: calcd. for C17H31NO3Na 320.2202, found 320.2209.
(R,E)ꢀbenzylꢀ4ꢀoxoꢀ6ꢀphenylꢀhexꢀ5ꢀenꢀ2ꢀylcarbamate 7n.
[α]D = + 2.56 (c 1.95, CHCl3) ; White solid ; starting from 1.3 mmol of 6b, 0.40g, yield = 96
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% ; mp 96°C ; H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 16.1 Hz, 1H), 7.48 – 7.46 (m, 2H),
7.33 – 7.19 (m, 8H), 6.64 (d, J = 16.1 Hz, 1H), 5.23 (s, 1H), 5.10 – 4.96 (m, 2H), 4.18 – 4.06
(m, 1H), 2.97 (d, J = 15.7 Hz, 1H), 2.73 (dd, J = 15.7, 5.6 Hz, 1H), 1.21 (d, J = 6.2 Hz, 3H) ;
13C NMR (101 MHz, CDCl3) δ 199.5, 155.6, 143.1, 134.0, 130.7, 129.0, 128.5, 128.4, 128.1,
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126.3, 66.6, 46.1, 44.3, 20.5 ; HRMSꢀESI (M + Na), m/z: calcd. for C20H21NO3Na 346.1419,
found 346.1424.
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(R,E)ꢀbenzylꢀ4ꢀoxoꢀpentadecꢀ5ꢀenꢀ2ꢀylcarbamate 7o.
[α]D = ꢀ9.86 (c 0.975, CHCl3) ; Yellow oil ; starting from 1.3 mmol of 6b, 0.38g, yield = 78
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% . H NMR (400 MHz, CDCl3) δ 7.42 – 7.30 (m, 5H), 6.87 (dt, J = 16.0, 6.7 Hz, 1H), 6.09
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(d, J = 16.0 Hz, 1H), 5.29 (brs, 1H), 5.10 (brs, 2H), 4.13 (m, 1H), 2.91 (dd, J = 16.1, 3.1 Hz,
1H), 2.69 (dd, J = 16.1, 6.1 Hz, 1H), 2.22 (dt, J = 6.7, 7.1 Hz, 2H), 1.52 – 1.41 (m, 2H), 1.36
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– 1.27 (m, 12H), 1.25 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.1 Hz, 3H) ; C NMR (101 MHz,
CDCl3) δ 200.4, 155.6, 148.7, 139.5, 130.5, 128.5, 128.1, 128.0, 66.5, 45.2, 44.2, 32.5, 31.8,
29.5, 29.4, 29.3, 29.2, 28.04, 22.6, 20.4, 14.1 ; HRMSꢀESI (M + H)+, m/z: calcd. for
C23H36NO3 374.2695, founꢀ 374.2706.
(R,E)ꢀbenzylꢀ4ꢀoxoꢀheptadecꢀ5ꢀenꢀ2ꢀylcarbamate 7p.
[α]D = ꢀ9.80 (c 1.015, CHCl3) ; Yellow oil ; starting from 1.3 mmol of 6b, 0.45g, yield = 91
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% . H NMR (400 MHz, CDCl3) δ 7.42 – 7.30 (m, 5H), 6.87 (dt, J = 15.9, 7.2 Hz, 1H), 6.06
(d, J = 15.9 Hz, 1H), 5.31 (brs, 1H), 5.08 (brs, 2H), 4.10 (m, 1H), 2.89 (d, J = 15.6 Hz, 1H),
2.66 (dd, J = 15.6, 5.3 Hz, 1H), 2.19 (q, J = 7.2 Hz, 2H), 1.47 – 1.40 (m, 6H), 1.33 – 1.21 (m,
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15H), 0.88 (t, J = 6.9 Hz, 3H); C NMR (101 MHz, CDCl3) δ 199.1, 155.7, 148.9, 136.7,
130.6, 128.6, 128.1, 66.6, 45.3, 44.3, 32.6, 32.0, 29.7, 29.6, 29.5, 29.4, 29.3, 28.1, 27.0, 22.8,
20.5, 14.2; HRMSꢀESI (M + H) +, m/z: calcd. for C25H40NO3 402.3008, found 402.3015.
(E)ꢀethylꢀ6ꢀoxoꢀ8ꢀphenylꢀoctꢀ7ꢀenꢀ4ꢀylcarbamate 7q and 7q’.
R enantiomer: [α]D = + 21.87 (c 0.97, CHCl3) ; S enantiomer: [α]D = ꢀ 21.32 (c 0.76 CHCl3) ;
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White solid ; starting from 1.5 mmol of 6c, 0.39g, yield = 91 % ; mp 96°C; H NMR (400
MHz, CDCl3) δ 7.48 (d, J = 16.8 Hz, 1H), 7.45 – 7.3 (m, 2H), 7.33 – 7.30 (m, 3H), 6.64 (d, J
= 16.8 Hz, 1H), 5.06 (brs, 1H), 4.09 – 3.91 (m, 3H), 2.90 (dd, J = 17.2, 6.0 Hz, 1H), 2.78 (dd,
J = 17.2, 5.5 Hz, 1H), 1.62 – 1.29 (m, 4H), 1.17 (t, J = 6.9 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 199.0, 156.2, 143.2, 134.3, 130.6, 128.9, 128.4, 126.3, 60.6,
48.1, 44.8, 36.5, 19.5, 14.6, 13.8; HRMSꢀESI (M + Na), m/z: calcd. for C17H23NO3Na
312.1576, found 312.1585.
(R,E)ꢀethylꢀ8ꢀ(4ꢀnitrophenyl)ꢀ6ꢀoxoꢀoctꢀ7ꢀenꢀ4ꢀylcarbamate 7r.
[α]D = + 13.8 (c 0.985, CHCl3) ; Yellow solid; starting from 1.5 mmol of 6c, 0.42g, yield = 84
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%; mp 102°C; H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.1 Hz,
2H), 7.60 (d, J = 16.2 Hz, 1H), 6.83 (d, J = 16.2 Hz, 1H), 5.01 (s, 1H), 4.14 – 4.01 (m, 3H),
3.01 (d, J = 16.2 Hz, 1H), 2.85 (dd, J = 16.2, 5.7 Hz, 1H), 1.64 – 1.49 (m, 2H), 1.47 – 1.30 (m,
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2H), 1.22 (t, J = 6.8 Hz, 3H), 0.92 (t, J = 7.2 Hz, 1H); C NMR (101 MHz, CDCl3) δ 198.5,
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156.2, 140.6, 140.0, 129.5, 128.9, 124.2, 124.2, 60.8, 48.1, 45.8, 36.6, 19.5, 14.6, 13.8;
HRMSꢀESI (M + Na), m/z: calcd. for C17H22N2O5Na 357.1426, found 357.1420.
(R,E)ꢀethyl 3ꢀoxoꢀ1ꢀphenylꢀtridecꢀ1ꢀenꢀ5ꢀylcarbamate 7s.
[α]D = + 17.26 (c 1.015, CHCl3) ; White solid ; starting from 1.2 mmol of 6d, 0.40g, yield =
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2H), 7.44 – 7.36 (m, 3H), 6.74 (d, J = 16.1 Hz, 1H), 5.23 (d, J = 7.4 Hz, 1H), 4.21 – 3.94 (m,
3H), 3.01 (d, J = 15.2 Hz, 1H), 2.84 (dd, J = 15.2, 3.8 Hz, 1H), 1.69 – 1.49 (m, 2H), 1.48 –
1.11 (m, 15H), 0.85 (t, J = 6.8 Hz, 3H) ; 13C NMR (101 MHz, CDCl3) δ 199.0, 156.2, 143.2,
134.3, 130.6, 129.6, 128.9, 128.4, 126.3, 60.6, 48.4, 44.9, 34.4, 31.8, 29.5, 29.2, 26.3, 22.6,
14.6, 14.1 ; HRMSꢀESI (M + Na), m/z: calcd. for C22H33NO3Na 382.2358, found 382.2364.
(R,E)ꢀethylꢀ4ꢀoxoꢀtetradecꢀ2ꢀenꢀ6ꢀylcarbamate 7t.
[α]D = + 17.44 (c 1.12, CHCl3) ; White solid ; starting from 1.2 mmol of 6d, 0.27g, yield = 78
% ; mp 59°C ; 1H NMR (400 MHz, CDCl3) δ 6.87 (dt, J = 15.8, 6.8, 1H), 6.10 (d, J = 15.8, 1.6
Hz, 1H), 5.1 (brs, 1H), 4.07 (q, J = 7.2 Hz, 2H), 3.91 (m, 1H), 2.84 (dd, J = 15.8, 4.2 Hz, 1H),
2.67 (dd, J = 15.8, 5.5 Hz, 1H), 1.90 (d, 3H, J = 6.8 Hz), 1.55 – 1.46 (m, 2H), 1.33 – 1.20 (m,
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15H), 0.86 (t, J = 6.9 Hz, 3H) ; C NMR (101 MHz, CDCl3) δ 199.2, 156.3, 143.6, 132.4,
60.7, 48.5, 44.0, 34.5, 31.9, 29.6, 29.5, 29.4, 26.4, 22.8, 18.5, 14.7, 14.2 ; HRMSꢀESI (M +
Na), m/z: calcd. for C17H31NO3Na 320.2202, found 320.2207.
(R,E)ꢀethylꢀ6ꢀoxoꢀhexadecꢀ4ꢀenꢀ8ꢀylcarbamate 7u.
[α]D = + 12.1 (c 1.05, CHCl3) ; Colorless oil ; starting from 1.2 mmol of 6d, 0.37g, yield = 95
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% . H NMR (400 MHz, CDCl3) δ 6.83 (dt, J = 15.9, 7.2 Hz, 1H), 6.07 (dd, J = 15.9, 1.4 Hz,
1H), 5.11 (brs, 1H), 4.07 (qd, J = 6.9, 2H), 3.91 (m, 1H), 2.85 (dd, J = 16.3, 4.5 Hz, 1H),
2.69 (dd, J = 16.3, 5.7 Hz, 1H), 2.18 (dd, J = 7.2, 1.4 Hz, 1H), 1.53 – 1.44 (m, 2H), 1.49 (qd, J
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= 7.2 Hz, 2H), 1. 29 – 1.19 (m, 15H), 0.92 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H); C
NMR (101 MHz, CDCl3) δ 199.4, 156.3, 148.3, 130.9, 60.7, 46.5, 44.1, 34.6, 34.5, 31.9, 29.6,
29.5, 29.4, 26.4, 22.8, 21.4, 14.7, 14.2, 13.8; HRMSꢀESI (M + Na), m/z: calcd. for
C19H35NO3Na 348.2515, found 348.2525.
(S,E)ꢀethylꢀ3ꢀoxoꢀ1,5ꢀdiphenylꢀpentꢀ4ꢀenylcarbamate 7v.
[α]D = + 6.6 (c 0.94, CHCl3) ; Yellow oil ; starting from 1.3 mmol of 6e, 0.35g, yield = 84 %.
1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 16.2 Hz, 1H), 7.41 – 7.11 (m, 10H), 6.59 (d, J =
16.2 Hz, 1H), 5.74 (brs, 1H), 5.16 (m, 1H), 4.01 (q, J = 6.3 Hz, 1H), 3.26 (dd, J = 15.9 Hz,
1H), 3.06 (dd, J = 15.9, 5.0 Hz, 1H), 1.13 (t, J = 6.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
197.9, 155.9, 143.6, 134.2, 130.7, 128.9, 128.6, 128.4, 127.5, 126.3, 126.0, 61.0, 51.7, 46.1,
14.6; HRMSꢀESI (M + Na), m/z: calcd. for C20H21NO3Na 346.1419, found 346.1414.
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(S,E)ꢀethylꢀ3ꢀoxoꢀ1ꢀphenylꢀhexꢀ4ꢀenylcarbamate 7w.
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[α]D = ꢀ 13.3 (c 0.715, CHCl3) ; Yellow oil ; starting from 1.3 mmol of 6e, 0.27g, yield = 80
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% . H NMR (400 MHz, CDCl3) δ 7.32 – 7.12 (m, 5H), 6.75 (dq, J = 15.9, 6.8 Hz, 1H), 5.96
(dd, J = 15.9,1.5 Hz, 1H), 5.68 (brs, 1H), 5.09 (m, 1H), 4.01 (q, J = 6.9 Hz, 2H), 3.12 (dd, J =
16.6, 5.8 Hz, 1H), 2.93 (dd, J = 16.6, 6.8 Hz, 1H), 1.79 (dd, J = 6.8, 1.5 Hz, 3H), 1.10 (t, J =
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6.9 Hz, 3H); C NMR (101 MHz, CDCl3) δ 200.2, 158.2, 146.2, 143.7, 134.2, 130.8, 129.6,
128.5, 63.2, 53.9, 45.5, 20.6, 16.8; HRMSꢀESI (M + Na), m/z: calcd. for C15H19NO3Na
284.1263, found 284.1275.
(S,E)ꢀethylꢀ3ꢀoxoꢀ1ꢀphenylꢀoctꢀ4ꢀenylcarbamate 7x.
[α]D = ꢀ 9.11 (c 1.14, CHCl3) ; Colorless oil ; starting from 1.3 mmol of 6e, 0.36g, yield = 95
%. 1H NMR (400 MHz, CDCl3) δ 7.35ꢀ7.21 (m, 5H), 6.80 (dt, J = 15.9, 6.9 Hz, 1H), 6.05 (td,
J = 15.9, 1.5, 1H), 5.75 (s, 1H), 5.15 (dd, J = 5.8,3.1 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.23
(dd, J = 16.1, 3.1 Hz, 1H), 3.04 (dd, J = 16.1, 5.8 Hz, 1H), 2.16 (qd, J = 6.9, 1.5 Hz, 2H), 1.47
(sex, J = 6.8 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 198.3, 156.1, 148.8, 141.6, 130.6, 128.6, 127.4, 126.4, 61.0, 51.8, 45.3, 34.6, 21.3,
14.6, 13.7; HRMSꢀESI (M + Na), m/z: calcd. for C17H23NO3Na 312.1576, found 312.1576.
(S,E)ꢀethylꢀ3ꢀoxoꢀ1ꢀphenylꢀtridecꢀ4ꢀenylcarbamate 7y.
[α]D = ꢀ 1.22 (c 0.995, CHCl3) ; White solid ; starting from 1.3 mmol of 6e, 0.41g, yield = 89
% ; mp 60°C; 1H NMR (400 MHz, CDCl3) δ 7.23 – 7.17 (m, 4H), 7.13 (m, 1H), 6.70 (dt, J =
15.9, 6.9 Hz, 1H), 5.93 (d, J = 15.9 Hz, 1H), 5.88 (brs, 1H), 5.07 (m, 1H), 3.98 (q, J = 7.1 Hz,
2H), 3.09 (d, J = 16.1 Hz, 1H), 2.89 (dd, J = 16.1, 5.7 Hz, 1H), 2.06 (q, J = 6.9 Hz, 2H), 1.39 –
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1.29 (m, 2H), 1.27 – 1.13 (m, 10H), 1.10 (t, J = 7.1 Hz, 3H), 0.79 (t, J = 6.9 Hz, 3H); C
NMR (101 MHz, CDCl3) δ 198.2, 156.0, 148.9, 141.7, 130.3, 128.5, 127.3, 126.3, 60.8, 51.6,
45.3, 32.5, 31.8, 29.4, 29.3, 29.2, 29.1, 27.9, 22.6, 14.5, 14.1; HRMSꢀESI (M + Na), m/z:
calcd. for C22H33NO3Na 382.2358, found 382.2362.
(S,E)ꢀtertꢀbutylꢀ3ꢀoxoꢀ1ꢀphenylꢀhexꢀ4ꢀenylcarbamate 7z.
[α]D = ꢀ 10.68 (c 1.015, CHCl3) ; White solid ; starting from 1.2 mmol of 6f, 0.28g, yield = 81
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%; mp 94°C; H NMR (400 MHz, CDCl3) δ 7.32 – 7.18 (m, 5H), 6.84 (dq, J = 15.9, 6.8 Hz,
1H), 6.06 (dd, J = 15.9, 1.6 Hz, 1H), 5.55 (brs, 1H), 5.09 (m, 1H), 3.12 (d, J = 16.6 Hz, 1H),
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2.98 (dd, J = 16.6, 5.6 Hz, 1H), 1.85 (dd, J = 6.8, 1.6 Hz, 3H), 1.40 (s, 9H); C NMR (101
MHz, CDCl3) δ 198.2, 155.3, 144.0, 132.1, 128.7, 127.4, 126.4, 51.5, 45.6, 28.5, 18.5;
HRMSꢀESI (M + Na), m/z: calcd. for C17H23NO3Na 312.1576, found 312.1591.
(S,E)ꢀbenzylꢀ3ꢀoxoꢀ1ꢀphenylꢀhexꢀ4ꢀenylcarbamate 1.
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[α]D = ꢀ 5.34 (c 1.05, CHCl3) ; White solid ; starting from 1.1 mmol of 6g, 0.34g, yield = 96
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%; mp 60°C; H NMR (400 MHz, CDCl3) δ 7.42 – 7.17 (m, 5H), 6.80 (dq, J = 15.8, 6.8 Hz,
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1H), 6.05 (d, J = 15.8 Hz, 1H), 5.88 (brs, 1H), 5.18 (dd, J = 6.2, 5.6 Hz, 1H), 5.10 (d, J = 12.3
Hz, 1H), 5.05 (d, J = 12.3 Hz, 1H), 3.19 (dd, J = 16.2, 5.6 Hz, 1H), 3.00 (dd, J = 16.2, 6.2 Hz,
1H), 1.85 (d, J = 6.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 197.8, 155.7, 144.0, 136.4,
136.2, 131.9, 128.7, 128.6, 128.5, 128.0, 126.4, 126.3, 66.8, 51.8, 45.1, 18.3; HRMSꢀESI (M
+ Na), m/z: calcd. for C21H21NO3Na 346.1419, found 346.1426.
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General procedure for the synthesis of piperidines 8l-s/9l-s
(2S,6R)ꢀethyl 4,4ꢀdimethoxyꢀ6ꢀmethylꢀ2ꢀ[(4ꢀnitrophenyl)]piperidineꢀ1ꢀcarboxylate 8m (trans
isomer)
and
(2R,6R)ꢀethyl
4,4ꢀdimethoxyꢀ6ꢀmethylꢀ2ꢀ[(4ꢀnitrophenyl)]piperidineꢀ1ꢀ
carboxylate 9m (cis isomer).
In a one neck flash, to compound 7d (0.1 g, 0.32 mmol 1 equiv.) were added successively,
trimethyl orthoformate (1.75 ml, 1.60 mmol, 5 equiv.) and pꢀtoluenesulphonic acid (5.5 mg,
0.32 mmol, 1 equiv.). The reaction is followed by TLC and after 0.5h ethyl acetate was added
to the crude mixture, then a saturated solution of NaHCO3 and extracted twice with ethyl
acetate. The organic layer was dried and concentrated under vacuum before purified by flash
chromatography (eluent: cyclohexane to cyclohexane/EtOAc 8/2) to yield a mixture of both
isomer 8m and 9m (86 mg, 81 % yield) in a ratio of 8m/9m: 89/11 in favor of the trans
isomer. 8m : 1H NMR (400 MHz, C6D6) δ 7.87 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H),
4.98 (t, J = 5.3 Hz, 1H), 4.26 (m, 1H), 4.09 – 3.92 (m, 2H), 2.87 (s, 3H), 2.58 (s, 3H), 2.03 (d,
J = 5.3 Hz, 2H), 1.67 (dd, J = 3.5, 14.4 Hz, 1H),1.61 (dd, J = 5.5, 14.4 Hz, 1H), 1.37 (d, J =
6.7 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, C6D6) δ 155.7 , 150.8, 146.8,
123.3, 126.6, 98.2, 61.2, 53.7, 47.6, 47.2, 47.0, 37.6, 36.7, 20.6, 14.4;. HRMS (M+H)+ ion by
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direct probe): calcd. for C17H25N2O6 353.1713, found 353.1699. 9m: H NMR (400 MHz,
C6D6) δ 7.84 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 5.19 (dd, J = 6.6, 6.9 Hz, 1H), 4.43
(m, 1H), 4.09 – 3.92 (m, 2H), 2.98 (s, 3H), 2.79 (s, 3H), 2.01 (dd, J = 6.9, 14.1 Hz, 1H), 1.94
(dd, J = 6.6, 14.1 Hz, 1H), 1.79 (dd, J = 6.7, 14.2 Hz, 1H), 1.43 (dd, J = 5.9, 14.2 Hz, 1H),
1.16 (d, J = 6.7 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, C6D6) δ 155.7, 151.9,
146.8, 123.8, 126.9, 98.6, 61.5, 54.0, 48.2, 47.2, 47.0, 36.9, 34.0, 23.0, 14.4.
(6R,2S)ꢀethylꢀ4,4ꢀdimethoxyꢀ6ꢀmethylꢀ2ꢀ(pyridinꢀ3ꢀyl)piperidineꢀ1ꢀcarboxylate
8k
and
(6R,2R)ꢀethylꢀ4,4ꢀdimethoxyꢀ6ꢀmethylꢀ2ꢀ(pyridinꢀ3ꢀyl)piperidineꢀ1ꢀcarboxylate 9k. (yellow
oil, starting from 0.8 mmol of 7i, 0.20g, yield = 81 % in a ratio of 8k/9k: 85/15 in favor of the
trans isomer. 8k):
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8k : 1H NMR (400 MHz, CDCl3) δ 8.40 (m, 1H), 8.38 (d, J = 4.5 Hz, 1H), 7.44 (d, J = 7.3 Hz,
1H), 7.16 (dd, J = 7.3, 4.5 Hz, 1H), 5.09 (t, J = 5.3 Hz, 1H), 4.26 (m, 1H), 4.06 – 3.94 (m,
2H), 3.11 (s, 3H), 2.85 (s, 3H), 2.35 (dd, J = 14.4, 5.3 Hz, 1H), 2.29 (dd, J = 14.4, 5.3 Hz,
1H), 1.88 (dd, J = 14.4, 5.3 Hz, 1H), 1.82 (dd, J = 14.4, 5.5 Hz, 1H), 1.32 (d, J = 6.8 Hz, 3H),
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1.04 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, CDCl3) δ 156.1, 147.7, 147.5, 137.9, 133.5,
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122.9, 98.2, 61.3, 51.7, 47.8, 47.6, 46.8, 37.3, 36.6, 20.6, 14.4.
9k :1H NMR (400 MHz, CDCl3) δ 8.53 (m, 1H), 8.37 (d, J = 4.5 Hz, 1H), 7.55 (d, J = 7.3 Hz,
1H), 7.18 (dd, J = 7.3, 4.5 Hz, 1H), 5.16 (dd, J = 7.1, 6.4 Hz, 1H), 4.35 (m, 1H), 4.06 – 3.94
(m, 2H), 3.16 (s, 3H), 3.05 (s, 3H), 2.27 (m, 1H), 2.15 (dd, J = 14.6, 6.4 Hz, 1H), 2.00 (dd, J =
14.4, 6.9 Hz,1H), 1.66 (dd, J = 14.4, 5.5 Hz, 1H), 1.22 (d, J = 6.9 Hz, 3H), 1.04 (t, J = 7.1 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 155.9, 147.4, 147.9, 138.1, 133.8, 123.1, 98.4, 61.5,
52.3, 47.9, 47.6, 47.3, 37.4, 36.7, 22.9, 14.4; HRMSꢀESI (M + Na), m/z: calcd. for
C16H24N2O4Na 331.1634, found 331.1634.
(2S,6R)ꢀethylꢀ4,4ꢀdimethoxyꢀ6ꢀpropylꢀ2ꢀ[(4ꢀnitrophenyl)]piperidineꢀ1ꢀcarboxylate 8l and 9l.
(yellow oil, starting from 0.6 mmol of 7r, 0.16g, yield = 71 % in a ratio of 8l/9l: 83/17 in
favor of the trans isomer. 8l).
8l : 1H NMR (400 MHz, C6D6) δ 7.83 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.87 (t, J =
5.4 Hz, 1H), 3.99 (m, 1H), 4.09 – 3.92 (q, J = 7.1 Hz, 2H), 2.82 (s, 3H), 2.56 (s, 3H), 1.95 (d,
J = 5.4 Hz, 2H), 1.78 (dd, J = 14.6, 4.0 Hz, 1H), 1.58 (m, 1H), 1.51 (dd, J = 14.6, 5.3 Hz, 1H),
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1.37 – 1.25 (m, 3H), 0.97 (t, J = 7.5 Hz, 3H), 0.81 (t, J = 7.1 Hz, 3H); C NMR (101 MHz,
C6D6) δ 155.9, 150.5, 146.8, 126.7, 123.2, 98.7, 61.2, 53.6, 52.0, 47.4, 47.0, 37.0, 36.4, 34.1,
20.6, 14.5, 14.1; HRMSꢀESI (M + Na), m/z: calcd. for C19H28N2O6Na 403.1845, found
403.1831
(2S,6R)ꢀethylꢀ4,4ꢀdimethoxyꢀ6ꢀmethylꢀ2ꢀ[(4ꢀnitrophenyl)]piperidineꢀ1ꢀcarboxylate 8m and
(2R,6R)ꢀethylꢀ4,4ꢀdimethoxyꢀ6ꢀmethylꢀ2ꢀ[(4ꢀnitrophenyl)]piperidineꢀ1ꢀcarboxylate
9m.
(yellow oil, starting from 1.0 mmol of 7d, 0.28g, yield = 80 % in a ratio of 8m/9m: 89/11 in
favor of the trans isomer. 8m)
8m : 1H NMR (400 MHz, C6D6) δ 7.87 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.98 (t, J
= 5.3 Hz, 1H), 4.26 (m, 1H), 4.09 – 3.92 (m, 2H), 2.87 (s, 3H), 2.58 (s, 3H), 2.03 (d, J = 5.3
Hz, 2H), 1.67 (dd, J = 14.4, 3.5 Hz, 1H),1.61 (dd, J = 14.4, 5.5 Hz, 1H), 1.37 (d, J = 6.7 Hz,
3H), 0.86 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, C6D6) δ 155.7, 150.8, 146.8, 123.3, 126.6,
98.2, 61.2, 53.7, 47.6, 47.2, 47.0, 37.6, 36.7, 20.6, 14.4.
9m : 1H NMR (400 MHz, C6D6) δ 7.84 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 5.19 (dd,
J = 6.9, 6.6 Hz, 1H), 4.43 (m, 1H), 4.09 – 3.92 (m, 2H), 2.98 (s, 3H), 2.79 (s, 3H), 2.01 (dd, J
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= 14.1, 6.9 Hz, 1H), 1.94 (dd, J = 14.1, 6.6 Hz, 1H), 1.79 (dd, J = 14.2, 6.7 Hz, 1H), 1.43 (dd,
J = 14.2, 5.9 Hz, 1H), 1.16 (d, J = 6.7 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
C6D6) δ 155.7, 151.9, 146.8, 123.8, 126.9, 98.6, 61.5, 54.0, 48.2, 47.2, 47.0, 36.9, 34.0, 23.0,
14.4; HRMS (M+H)+ ion by direct probe: calcd. for C17H25N2O6 353.1713, found 353.1699.
(2S,6R)ꢀethylꢀ4,4ꢀdimethoxyꢀ6ꢀmethylꢀ2ꢀ[(3ꢀnitrophenyl)]piperidineꢀ1ꢀcarboxylate 8n and
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(2R,6R)ꢀethylꢀ4,4ꢀdimethoxyꢀ6ꢀmethylꢀ2ꢀ[(3ꢀnitrophenyl)]piperidineꢀ1ꢀcarboxylate
9n.
(yellow oil, starting from 1.0 mmol of 7c, 0.25g, yield = 71 % in a ratio of 8n/9n: 40/60 in
favor of the cis isomer. 9n)
8n : 1H NMR (400 MHz, C6D6) δ 8.21 (m, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 7.8 Hz,
1H), 6.91 (dd, J = 8.0, 7.8 Hz, 1H), 4.98 (dd, J = 5.3, 4.5 Hz, 1H), 4.26 (m, 1H), 4.18 – 4.10
(m, 2H), 2.96 (s, 3H), 2.71 (s, 3H), 2.18 (dd, J = 14.4, 4.5 Hz, 1H), 2.13 (dd, J = 14.4, 5.3 Hz,
1H), 1.67 (dd, J = 14.4, 4.0 Hz, 1H), 1.73 (dd, J = 14.4, 4.8 Hz, 1H), 1.47 (d, J = 6.8 Hz, 3H),
1.02 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, C6D6) δ 155.8, 148.7, 145.6, 131.6, 128.8,
121.3, 121.1, 98.2, 61.2, 53.5, 47.5, 47.2, 47.0, 37.4, 36.8, 20.6, 14.5.
9n : 1H NMR (400 MHz, C6D6) δ 8.40 (m, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 7.8 Hz,
1H), 6.91 (dd, J = 8.0, 7.8 Hz, 1H), 5.40 (dd, J = 6.8, 6.6 Hz, 1H), 4.55 (qd, J = 6.8, 5.8 Hz,
1H), 4.13 – 4.04 (m, 2H), 3.02 (s, 3H), 2.90 (s, 3H), 2.19 (dd, J = 14.6, 6.8 Hz, 1H), 2.06
(ddd, J = 14.6, 6.6, 0.7 Hz, 1H), 1.90 (ddd, J = 14.1, 6.8, 0.7 Hz, 1H), 1.55 (dd, J = 14.4, 5.8
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Hz, 1H), 1.29 (d, J = 6.8 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, C6D6) δ
156.3, 148.7, 146.8, 132.2, 129.0, 121.5, 121.4, 98.6, 61.5, 54.0, 47.6, 47.6, 47.2, 37.4, 36.7,
23.0, 14.5; HRMS (M+H)+ ion by direct probe): calcd. for C17H25N2O6 353.1713, found
353.1710.
(2S,6R)ꢀethylꢀ4,4ꢀdimethoxyꢀ6ꢀmethylꢀ2ꢀ[(2ꢀnitrophenyl)]piperidineꢀ1ꢀcarboxylate 8o and
(2R,6R)ꢀethylꢀ4,4ꢀdimethoxyꢀ6ꢀmethylꢀ2ꢀ[(2ꢀnitrophenyl)]piperidineꢀ1ꢀcarboxylate
9o.
(yellow oil, starting from 1.0 mmol of 7b, 0.23g, yield = 67 % in a ratio of 8o/9o: 60/40 in
favor of the trans isomer. 8o)
8o : 1H NMR (400 MHz, C6D6) δ 7.51 (dd, J = 8.0, 1.2 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.07
(td, J = 8.0, 1.0 Hz, 1H), 6.77 (ddd, J = 8.0, 7.8, 1.2 Hz, 1H), 5.59 (dd, J = 12.4, 5.3 Hz, 1H),
4.72 (qtd, J = 6.8, 4.5 Hz, 1H), 3.91 – 3.71 (m, 2H), 3.2 (s, 3H), 3.01 (s, 3H), 2.18 (ddd, J =
14.4, 5.3, 1.2 Hz, 1H), 2.80 (ddd, J = 14.4, 6.8, 1.2 Hz, 1H), 1.95 (dd, J = 14.4, 12.4 Hz,
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1H),1.71 (dd, J = 14.4, 4.5 Hz, 1H), 1.52 (d, J = 6.8 Hz, 3H), 0.74 (t, J = 7.1 Hz, 3H); C
NMR (101 MHz, C6D6) δ 156.1, 149.6, 141.5, 132.6, 127.6, 126.9, 124.5, 98.4 , 61.2, 52.2,
47.9, 47.7, 47.0, 37.9, 36.9, 24.0, 13.9.
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9o : 1H NMR (400 MHz, C6D6) δ 7.55 (dd, J,= 8.0, 1.2 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.03
(td, J = 8.0, 1.0 Hz, 1H), 6.76 (ddd, J = 8.0, 7.8, 1.2 Hz, 1H), 5.94 (dd, J = 6.6, 5.3 Hz, 1H),
4.55 (m, 1H), 4.02 – 3.84 (m, 2H), 3.00 (s, 3H), 2.79 (s, 3H), 2.40 (dd, J = 14.4, 5.3 Hz, 1H),
2.21 (dd, J = 14.4, 6.6 Hz, 1H), 1.86 (dd, J = 14.4, 5.5 Hz, 1H), 1.80 (dd, J = 14.4, 3.3 Hz,
9
13
1H), 1.47 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, C6D6) δ 156.0,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
149.2, 139.3, 132.0, 127.8, 127.0, 123.8, 98.1, 61.1, 50.6, 48.5, 47.7, 47.4, 38.8, 37.4, 20.2,
14.3; HRMS (M+H)+ ion by direct probe): calcd. for C17H25N2O6 353.1713, found 353.1711.
(2S,6R)ꢀethylꢀ2ꢀ(4ꢀbromophenyl)ꢀ4,4ꢀdimethoxyꢀ6ꢀmethylpiperidineꢀ1ꢀcarboxylate 8p and
(2R,6R)ꢀethylꢀ2ꢀ(4ꢀbromophenyl)ꢀ4,4ꢀdimethoxyꢀ6ꢀmethylpiperidineꢀ1ꢀcarboxylate
9p.
(yellow oil, starting from 0.9 mmol of 7g, 0.25g, yield = 73 % in a ratio of 8p/9p: 33/67 in
favor of the cis isomer. 9p)
8p : 1H NMR (400 MHz, C6D6) δ 7.13 (d, J = 8.3 Hz, 2H), 6.68 (d, J = 8.3 Hz, 2H), 4.91 (dd,
J = 5.3, 4.5 Hz, 1H), 4.15 (m, 1H), 3.91 (qd, J = 7.1 Hz, 2H), 2.75 (s, 3H), 2.49 (s, 3H), 2.10
(dd, J = 14.4, 4.5 Hz, 1H), 2.03 (dd, J = 14.4, 5.3 Hz, 1H), 1.82 (dd, J = 14.4, 5.3 Hz, 1H),
13
1.78 (dd, J = 14.4, 3.8 Hz, 1H), 1.40 (d, J = 6.8 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H); C NMR
(101 MHz, C6D6) δ 155.9, 142.5, 131.3, 128.0, 120.1, 98.5, 61.0, 53.5, 47.7, 47.5, 47.4, 37.5,
36.7, 20.6, 14.6.
9p : 1H NMR (400 MHz, C6D6) δ 7.12 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.13 (t, J
= 6.8 Hz, 1H), 4.32 (sex, J = 6.6 Hz, 1H), 3.88 (qd, J = 7.1 Hz, 2H), 2.79 (s, 3H), 2.69 (s, 3H),
2.09 (dd, J = 14.6, 6.8 Hz, 1H), 2.01 (ddd, J = 14.6, 6.8, 0.7 Hz, 1H), 1.82 (ddd, J = 14.1, 6.6,
0.7 Hz, 1H), 1.49 (dd, J = 14.1, 6.6 Hz, 1H), 1.18 (d, J = 6.6 Hz, 3H), 0.87 (t, J = 7.1 Hz, 3H);
13C NMR (101 MHz, C6D6) δ 156.5, 143.8, 131.5, 128.3, 120.5, 98.8, 61.3, 53.8, 47.2, 47.0,
37.6, 36.9, 23.0, 14.5; HRMSꢀESI (M + Na), m/z: calcd. for C17H24NO4BrNa 408.0786, found
408.0794
(2S,6R)ꢀethylꢀ2ꢀ(4ꢀbromophenyl)ꢀ4,4ꢀdimethoxyꢀ6ꢀmethylpiperidineꢀ1ꢀcarboxylate 8q and
(2R,6R)ꢀethylꢀ2ꢀ(4ꢀbromophenyl)ꢀ4,4ꢀdimethoxyꢀ6ꢀmethylpiperidineꢀ1ꢀcarboxylate
9q.
(yellow oil, starting from 0.9 mmol of 7f, 0.26g, yield = 75 % in a ratio of 8q/9q: 29/71 in
favor of the cis isomer. 9q)
1
8q : H NMR (400 MHz, C6D6) δ 7.51 (dd, J = 7.7, 1.2 Hz, 1H), 7.47 (dd, J = 7.7, 0.7 Hz,
1H), 7.09 (t, J = 7.7 Hz, 1H), 6.79 (t, J = 7.7 Hz, 1H), 5.58 (dd, J = 12.4, 5.1 Hz, 1H), 4.85
(qtd, J = 7.0, 3.7 Hz, 1H), 3.91ꢀ4.08 (m, 2H), 3.15 (s, 3H), 2.97 (s, 3H), 2.57 (dd, J = 14.3, 5.1
Hz, 1H), 2.11 (dd, J = 14.1, 7.5 Hz, 1H), 1.93 (dd, J = 14.3, 12.4 Hz, 1H), 1.72 (dd, J = 14.1,
3.7 Hz, 1H), 1.40 (d, J = 7,0 Hz, 3H), 0.83 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, C6D6) δ
29
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