From acyclic to cyclic α-amino vinylphosphonates by using ring-closing metathesis

Article abstract of DOI:10.1039/c6ob02548j

Acyclic α-amino vinylphosphonates were alkylated through the Mitsunobu reaction then diolefinic compounds hence formed were subjected to RCM. Studies on the scope and limitations of RCM with these sterically hindered α-amino vinylphosphonates are detailed

Full text of DOI:10.1039/c6ob02548j

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From acyclic to cyclic α-amino vinylphosphonates
by using ring-closing metathesis†
Cite this: DOI: 10.1039/c6ob02548j
a
a
b
a
Pauline Adler, Antoine Fadel, Joëlle Prunet* and Nicolas Rabasso*
Received 21st November 2016,
Accepted 24th November 2016
Acyclic α-amino vinylphosphonates were alkylated through the Mitsunobu reaction then diolefinic
compounds hence formed were subjected to RCM. Studies on the scope and limitations of RCM with
these sterically hindered α-amino vinylphosphonates are detailed.
DOI: 10.1039/c6ob02548j
www.rsc.org/obc
Introduction
Since its discovery in 1968 by Gross and Costisella, the interest
for the synthesis and reactivity of α-amino vinylphosphonates
1
–3
(
AVPs) has not stopped growing. Indeed, α-AVPs are interest-
ing building blocks mainly used as precursors of chiral amino-
4
–18
phosphonates through asymmetric reduction
or Michael
1
9
type addition. Chiral aminophosphonates are of consider-
able interest since they are used as analogues of amino acids.
Aminophosphonates exhibit a wild range of biological activi-
2
0,21
ties such as antibacterial properties or enzyme inhibitions.
Our interest in the chemistry of AVPs started few years ago
with the highly regio and stereoselective synthesis of β-AVPs 2
22
through the hydrophosphonylation of ynamides 1. Although
highly efficient to prepare β-AVPs, this method could not be used
for the synthesis of the α regioisomer 4. To that end, the
reduction of the α-amino allenylphosphonates 3 (AAPs) was
Scheme 1 Strategies for the synthesis of AVPs.
23
developed. However, to date, these two methods have not been
adequate for the synthesis of cyclic AVPs 6 for which the reported
shown that β-substituted vinylphosphonates are unreactive
towards CM and could be considered as type IV olefins.
2,24
methods of preparation are limited.
In order to prepare such
29
compounds as well as to broaden the spectrum of AVPs that
could be prepared, we studied the synthesis of cyclic AVPs 6
from acyclic AVPs 5 through ring-closing metathesis (Scheme 1).
Since the discovery of air-stable ruthenium-based catalysts,
application in natural product synthesis and methodology of
ring-closing metathesis (RCM) has not stopped. According to
Grubbs’ classification of olefins pertaining to their relative
abilities to undergo homodimerization via cross metathesis
However, the use of α-substituted vinylphosphonates as part-
ners for RCM has been successfully demonstrated. To date,
30
no report has been made on RCM with α-AVPs. The latter are
more challenging than regular vinylphosphonates due to the
presence of a nitrogen atom at the α position inducing new
steric and electronic effects on vinylphosphonate. The goal of
our work is to explore the reactivity of such compounds
towards RCM. Indeed, our first investigations on this field
were dedicated to the CM between α-AVPs 4 and type I olefins
2
5
(
CM), terminal vinylphosphonates are type III olefins and do
2
6–28
not dimerize.
Moreover, Spilling and co-workers have
(
allylsilanes and allyl acetate). However, as predicted by
Grubbs’ rules, we observed no reactivity of our substrates with
Grubbs 2 and Hoveyda–Grubbs 2 catalysts.
a
Méthodologie, Synthèse et Molécules Thérapeutiques, ICMMO, UMR CNRS 8182,
Bât. 410, Université Paris-Sud, 15 rue Georges Clemenceau, 91405 Orsay Cedex,
France. E-mail: nicolas.rabasso@u-psud.fr
b
Results and discussion
WestCHEM, School of Chemistry, University of Glasgow, Joseph Black Building,
University Avenue, Glasgow G12 8QQ, UK. E-mail: joelle.prunet@glasgow.ac.uk
The first part of our project is dedicated to the synthesis of
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c6ob02548j
α-AVPs 5. In order to prepare such compounds 5, we started
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Scheme 2 First attempt for the synthesis of diolefinic α-AVPs.
Scheme 3 Deprotection of PMB protected α-AVPs.
from but-3-ene amine hydrochloride 7 that was transformed
in three steps to α-AAPs 10 using our previously reported
3
1
protocol.
However, the reduction of α-AAPs 10 to the
expected α-AVP 11 led to an inseparable mixture of α-AVPs 11
and 12 in a 1 : 1 ratio (Scheme 2). Despite all of our efforts, we
were not able to selectively reduce the allenylphosphonates 10
without the concomitant reduction of the terminal olefin
leading to α-AVP 12. Moreover, it is noteworthy that in this
sequence the copper catalyzed coupling reaction between the
bromoalkyne and the sulfonamide 8 gave the ynamido-alcohol
9
in low yield.
Our revised strategy for the preparation of α-AVP 11 is based
on the preparation of α-AVPs protected on the nitrogen atom
by a PMB group. The removal of the latter under oxidative con-
ditions followed by N-alkylation should lead to the expected
α-AVPs 5. Our previous work in the field of PMB protected
α-AAPs 13 had shown us the easiness of preparation of such
compounds with a large diversity of substituents on the allene
3
2
moiety. Following our previously reported protocol, α-AAPs
3 were reduced in EtOH in the presence of hydrogen and
poisoned palladium on charcoal to provide the corresponding
1
2
3
α-AVPs 14. These compounds were then deprotected with
FeCl ·6H O in refluxing 1,2-DCE to give the expected free
α-AVPs 15 in good yields (Scheme 3).
3
2
3
3
Although inseparable as a PMB protected α-AVP 14, the free
Z- and E-α-AVPs 15 could be separated after purification on
silica gel. The synthesis was continued with the Z isomer,
unless otherwise mentioned, which was obtained as the
major isomer after reduction. It has to be noted that this
deprotection proceeds without isomerization of the carbon–
carbon double bond.
The N-alkylation steps proceeded through the Mitsunobu
reaction between the α-AVPs 15 and an unsaturated alcohol in
the presence of DIAD and PBu
THF at room temperature (Scheme 4).
3
in a mixture of toluene and
3
4,35
This strategy was
highly efficient and led us to prepare a series of diolefinic
α-AVPs 16 in good to excellent yields. Both ene-ols and yne-ols
were used for this reaction, although for the latter, in the case
of α-AVP 16k, we observed an incomplete conversion limited to Scheme 4 N-Alkylation of α-AVPs through the Mitsunobu reaction.
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8
0%. This alkylation strategy could also be applied to the
formation of α-AVPs substituted at the α position from the nitro-
gen atom leading to the formation of compound 16p, although
in a low 39% yield and an incomplete conversion (74%).
Next, with these α-AVPs 16 in hand, we studied their ability
to react with ruthenium catalysts to give the expected cyclic
α-AVP 17. First, we studied RCM with E-α-AVP 16a. With the
Grubbs 2 catalyst, in refluxing CH Cl , only traces of the
2
2
3
1
desired cyclic α-AVP 17a were observed by P NMR along with
6% isolated yield of the dimer 18a. By increasing the boiling
7
point of the reaction solvent we noticed the formation of the
α-AVP 17a in 17% yield along with 30% of the dimer 18a in
1
,2-DCE. In toluene, only dimer 18a was formed in a low 22%
yield. On the other hand, the Z isomer 16b gave, in 1,2-DCE,
the cyclic α-AVP 17a in a high 79% yield along with traces of
the dimer 18b. The Z-α-AVP 16c (R = Et) gave the cyclic α-AVP
1
7a in 23% yield along with 31% of the dimer 18c. However,
with a large R group, the α-AVP 16d (R = i-Pr) was converted to Scheme 6 Scope and limitations of the RCM.
the dimer 18d as the sole product of the reaction (yield not
determined due to the high polarity of the bisphosphonate
1
8d) with no traces of the expected α-AVP 17a (Scheme 5).
As a conclusion of these preliminary investigations on the (Scheme 6). These last results lead us to conclude that RCM of
RCM of α-AVPs, we noticed that the Z isomer 16b is more our α-AVPs is highly dependent on the steric hindrance of both
reactive than the E isomer 16a. Moreover, the steric hindrance the vinylphosphonate and the alkene moieties.
on the α-AVPs 16c and 16d lowers the yields of the formation
To continue our investigations on the RCM reaction with
of the expected α-AVP 17a. This is explained by the difficulty in α-AVPs, we next turned our attention to the formation of
the formation of the ruthena–cyclobutane intermediates with 6-membered ring α-AVPs 19 and 21. Surprisingly, the α-AVP 16f
large R groups such as isopropyl.
was converted to the 5-membered ring α-AVP 17a in a good
We extended this reaction to the other diolefinic partners 58% yield with no traces of the expected α-AVP 19. Moreover a
6 previously prepared. Changing the nature of the sulfonyl mixture of dimeric products 20 is observed. The formation of
1
group used to protect the nitrogen atom slightly increased the the 5-membered ring α-AVP 17a is explained by the in situ iso-
yield for the formation of the corresponding α-AVP 17b to merization of the terminal alkene in 16f leading to a 1,2-di-
8
6%. The conversion of the diolefin 16l to the cyclic α-AVP 17c, substituted alkene intermediate that is then cyclized to form
substituted at the α position of the carbon–carbon double the α-AVP 17a. To avoid this isomerization step, we used benzo-
bond, was observed in a comparable 67% yield. The diolefin quinone as an additive to force the formation of the 6-mem-
3
6
1
6p was also converted to the cyclic α-AVP 17d, substituted at bered ring cyclic α-AVP 19. However, in that case the olefin
the α position from the nitrogen atom, in 48% yield. Starting 16f reacted to form the dimer 20 in 71% yield with traces of
from the 1,2-disubstituted alkene 16n we observed a slow con- the 5-membered ring 17a. To block this isomerization, the
version to the desired α-AVP 17a, which is formed in 39% yield α-AVP 16o, bearing a gem-dimethyl group at the allylic position
(conv. 73%). However, the 1,1-disubstituted alkene 16m could was used, but in that case the steric hindrance at the allylic
not be converted into the desired tetrasubstituted α-AVP 17e position prevented the formation of the resulting carbene.
Scheme 5 Preliminary investigations on the RCM of α-AVPs.
Scheme 7 Toward the formation of 6-membered ring cyclic α-AVPs.
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1
Under these conditions the 6-membered ring α-AVP 21 was not (EtOAc); H NMR (500 MHz, CDCl
formed (Scheme 7).
3
) δ 7.71–7.60 (m, 2H), 7.22
(d, J = 7.7 Hz, 2H), 5.69–5.56 (m, 1H), 5.18 (d, J = 10.5 Hz, 2H),
.03–4.84 (m, 2H), 4.16–4.02 (m, 4H), 3.38–3.27 (m, 2H), 2.35
5
(
1
3
s, 3H), 2.29–2.20 (m, 2H), 1.31–1.18 (m, 6H); C NMR
(
1
126 MHz, CDCl ) δ 215.1 (d, J = 26.4 Hz), 143.8, 134.5, 129.5,
Conclusions
3
28.1, 117.1, 100.2 (d, J = 234.5 Hz), 83.2 (d, J = 12.0 Hz), 63.3
3
1
In conclusion, we have reported the preparation of olefinic
α-AVPs through Mitsunobu alkylation. The compounds hence
formed were subjected to ring-closing metathesis to provide
cyclic α-AVPs in good yields. This represents the first examples
of RCM with sterically hindered unsaturated phosphonates.
Indeed, in this work we have successfully used trisubstituted
vinylphosphonates as partners for RCM. In addition, this work
broadens the range of reactivities of α-amino vinylphos-
phonates leading to new perspectives for this type of compounds.
(
d, J = 6.2 Hz), 49.9, 32.5, 21.6, 16.3 (d, J = 6.6 Hz); P NMR
+
(
202 MHz, CDCl ) δ 11.0; HRMS (ESI) m/z [MNa ] calcd for
3
18 5
C H26NNaO PS: 422.1162, found: 422.1143.
General procedure C: deprotection reaction for the preparation
of the α-AVPs 15
To a solution of α-AVPs (0.66 mmol) in 1,2-dichloroethane
(
30 mL) is added FeCl ·6H O (1.66 mmol) at room tempera-
3 2
ture. The mixture is stirred under reflux for 2 hours. The reac-
tion is quenched by adding brine. The aqueous layer was
extracted with dichloromethane. The organic layer was washed
two times with a solution of HCl in water (2 M), and two times
with water and with brine. The organic layer was dried on
anhydrous sodium sulfate. After filtration, the solvent was
removed in vacuo. The crude product was purified by flash
chromatography on silica gel to give the deprotected α-AVP.
Experimental
General methods
All reactions were carried out under argon with magnetic
stirring. All solvents and chemicals were purified based on
standard procedures. Reagent grade solvents were used
without purification for all extractions and work-up pro-
Diethyl
(1-((4-methylphenyl)sulfonamido)prop-1-en-1-yl)
phosphonate (15a). Prepared according to the general pro-
cedure C. Flash chromatography: EtOAc/PE 10/90 to 100/0;
cedures. R values refer to values obtained by TLC on 0.25 mm
f
silica gel plates (60F254). Flash chromatography was carried
out on silica gel 60 (15–40 μm) with various mixtures of ethyl
acetate (EtOAc) and petroleum ether (PE), yields refer to chro-
matographically and spectroscopically pure compounds. NMR
spectra were recorded at 250, 300, 360, 400, and 500 MHz.
HRMS spectra were recorded with a MicroTOFq spectrometer.
brown oil, 1.391 g, quantitative yield; Z stereoisomer: R = 0.66
f
1
(
EtOAc); H NMR (250 MHz, CDCl
3
) δ 7.67 (d, J = 8.3 Hz, 2H),
7
4
7
.21 (d, J = 8.2 Hz, 2H), 6.78 (d, J = 7.8 Hz, 1H), 6.52 (dq, J =
0.4, 7.6 Hz, 1H), 3.84–3.45 (m, 4H), 2.31 (s, 3H), 1.79 (dd, J =
13
.6, 3.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 6H); C NMR (62.9 MHz,
3
CDCl ) δ 143.7, 136.4, 131.6 (d, J = 15.5 Hz), 129.3, 127.7, 124.1
(
d, J = 197.4 Hz), 62.1 (d, J = 5.0 Hz), 21.3, 15.9 (d, J = 6.4 Hz),
General procedure A for the preparation of the ynamides from
the sulfonamides
3
1
1
4.3 (d, J = 4.6 Hz); P NMR (101.25 MHz, CDCl
3
) δ 12.8;
= 0.43 (EtOAc); H NMR (250 MHz, CDCl
δ 7.75 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 6.62 (dd, J =
1
E stereoisomer: R
f
3
)
Sulfonamide (2.05 mmol), CuSO
phenanthroline (0.411 mmol), and K
4
·5H
2
O (0.205 mmol), 1,10-
PO (4.11 mmol) were
3
4
1
2
6
1
5
4.1, 7.1 Hz, 1H), 6.53 (d, J = 4.8 Hz, 1H), 4.00–3.68 (m, 4H),
heated to 70 °C in 2 mL of dry toluene under an inert atmo-
sphere. Bromoalkyne (2.71 mmol) in 2 mL of dry toluene was
then slowly added. After 4 h at 70 °C, the mixture was cooled
to room temperature, filtered through a pad of Celite, and con-
centrated in vacuo. Purification by flash chromatography on
silica gel yielded the ynamide.
.38 (s, 3H), 1.87 (dd, J = 7.0, 3.0 Hz, 3H), 1.15 (t, J = 7.1 Hz,
1
3
H); C NMR (62.9 MHz, CDCl ) δ 143.6 (d, J = 23.8 Hz),
3
43.5, 138.1, 129.4, 127.5, 125.1 (d, J = 211.9 Hz), 62.4 (d, J =
3
1
.7 Hz), 21.5, 16.2 (d, J = 6.1 Hz), 15.2 (d, J = 14.4 Hz); P NMR
+
(
C
101.25 MHz, CDCl ) δ 13.1; HRMS (ESI) m/z [MNa ] calcd for
3
14
H
5
22NNaO PS: 370.0849, found: 370.0840.
Diethyl (1-((4-methylphenyl)sulfonamido)but-1-en-1-yl)phos-
phonate (15b). Prepared according to the general procedure C.
Flash chromatography: EtOAc/PE 10/90 to 90/10; colorless oil,
General procedure B for the preparation of the α-AAPs from
the ynamides
3
1
To a solution of ynamide (2.05 mmol) in 16 mL of anhydrous 206 mg, 73% yield; R
tetrahydrofuran cooled at 0 °C were added triethylamine isomer: H NMR (400 MHz, CDCl ) δ 7.68 (d, J = 8.3 Hz, 2H),
f
= 0.50 (EtOAc/PE = 90/10); Z stereo-
1
3
(2.26 mmol) and chlorophosphite (2.26 mmol). After 18 h of 7.23 (d, J = 8.2 Hz, 2H), 6.55 (d, J = 5.8 Hz, 1H), 6.54–6.39 (m,
stirring at room temperature, the mixture was filtered through 1H), 3.86–3.71 (m, 2H), 3.63–3.51 (m, 2H), 2.34 (s, 3H),
a pad of Celite®, the solvent was removed in vacuo, and the 2.27–2.12 (m, 2H), 1.08 (t, J = 7.1 Hz, 6H), 0.92 (t, J = 7.5 Hz,
1
3
crude product was purified by flash chromatography on silica 3H); C NMR (75 MHz, CDCl
gel to yield the amino allenylphosphonates. 136.0, 129.2, 127.8, 122.7 (d, J = 197.7 Hz), 62.1 (d, J = 5.0 Hz),
Diethyl (1-((N-(but-3-en-1-yl)-4-methylphenyl)sulfonamido) 22.0 (d, J = 4.3 Hz), 21.2, 15.8 (d, J = 6.6 Hz), 13.5; P NMR
3
) δ 143.7, 138.0 (d, J = 15.9 Hz),
3
1
1
propa-1,2-dien-1-yl)phosphonate (10). Prepared according to (162 MHz, CDCl
the general procedures A and B. Flash chromatography: EtOAc/ CDCl ) δ 7.76 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 6.47
PE 40/60; yellow oil, 122 mg, 14% yield (2 steps); R = 0.50 (dt, J = 14.5, 7.3 Hz, 1H), 5.96 (d, J = 5.2 Hz, 1H), 4.03–3.74
3
) δ 13.3; E stereoisomer: H NMR (300 MHz,
3
f
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(
1
m, 4H), 2.41 (s, 3H), 1.31–1.13 (m, 2H), 1.21 (t, J = 7.1 Hz, 6H), general procedure D. Flash chromatography: EtOAc/PE 50/50
.02 (t, J = 7.5 Hz, 3H); C NMR (62.9 MHz, CDCl ) δ 149.8 (d, to 75/25; yellow oil, 199 mg, quantitative yield; Rf = 0.60
3
1
3
J = 21.7 Hz), 143.7, 138.0, 129.5, 127.6, 123.1 (d, J = 210.0 Hz), (EtOAc/PE = 80/20); IR (neat) 2978, 2932, 2878, 1713, 1597,
1
1
6
2.5 (d, J = 5.7 Hz), 22.8, 21.6, 16.2 (d, J = 6.0 Hz), 13.0; 1443 cm−
;
H NMR (400 MHz, CDCl
3
) δ 7.80–7.85 (m, 2H),
3
1
+
P NMR (121.5 MHz, CDCl ) δ 13.4; HRMS (ESI) m/z [MH ] 7.24–7.29 (m, 2H), 7.01 (dq, J = 12.6, 7.0 Hz, 1H), 5.64 (ddt, J =
3
calcd for C15
H
25NO
5
PS: 362.1186, found: 362.1171.
17.1, 10.3, 6.7 Hz, 1H), 4.94–5.03 (m, 2H), 3.94–4.10 (m, 4H),
Diethyl (Z)-(3-methyl-1-((4-methylphenyl)sulfonamido)but-1- 3.35–3.45 (m, 1H), 3.23–3.35 (m, 1H), 2.39 (s, 3H), 2.26–2.35
en-1-yl)phosphonate (15c). Prepared according to the general (m, 1H), 2.14–2.26 (m, 1H), 1.97 (dd, J = 7.0, 3.1 Hz, 3H), 1.26
1
3
procedure C. Flash chromatography: EtOAc/PE 50/50 to 60/40; (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H); C NMR (101 MHz,
yellow oil, 152 mg, 96% yield; R = 0.71 (EtOAc); Z stereo- CDCl ) δ 150.2 (d, J = 28.5 Hz), 143.4, 137.1, 134.5, 129.4, 128.2
isomer: H NMR (400 MHz, CDCl ) δ 7.78–7.72 (m, 2H), (d, J = 214.5 Hz), 128.1, 117.0, 62.3 (d, J = 5.1 Hz), 62.1 (d, J =
f
3
1
3
3
1
7
1
.31–7.27 (m, 2H), 6.56 (d, J = 8.5 Hz, 1H), 6.38 (dd, J = 40.4, 5.9 Hz), 48.7, 32.7, 21.5, 16.2 (br. s), 16.0, 15.9; P NMR
+
3
1.3 Hz, 1H), 3.89–3.74 (m, 2H), 3.68–3.56 (m, 2H), 2.87–2.74 (162 MHz, CDCl ) δ 13.7; HRMS (ESI) m/z [MNa ] calcd for
(
m, 1H), 2.41 (s, 3H), 1.15 (td, J = 7.1, 0.5 Hz, 6H), 0.97 (d, J = C H NNaO PS: 424.1318, found: 424.1302.
18 28 5
1
3
6
1
5
.6 Hz, 6H); C NMR (62.9 MHz, CDCl
3
) δ 144.0, 142.9 (d, J =
(Z)-Diethyl (1-((N-(but-3-en-1-yl)-4-methylphenyl)sulfonamido)
5.9 Hz), 136.2, 129.5, 128.3, 121.4 (d, J = 197.9 Hz), 62.4 (d, J = prop-1-en-1-yl)phosphonate (16b). Prepared according to the
.0 Hz), 28.6 (d, J = 4.0 Hz), 22.6, 21.6, 16.1 (d, J = 6.7 Hz); general procedure D. Flash chromatography: EtOAc/PE 40/60
3
1
+
P NMR (162 MHz, CDCl
3
) δ 13.7; HRMS (ESI) m/z [MH ] to 50/50; yellow oil, 44 mg, 73% yield; R
f
= 0.59 (EtOAc);
1
calcd for C16 PS: 376.1342, found: 376.1329.
H
27NO
5
H NMR (360 MHz, CDCl ) δ 7.72 (d, J = 8.1 Hz, 2H), 7.24 (d,
3
Diethyl (1-(methylsulfonamido)prop-1-en-1-yl)phosphonate J = 8.1 Hz, 2H), 6.45 (dq, J = 38.3, 7.5 Hz, 1H), 5.64 (ddt, J =
15d). Prepared according to the general procedure C. Flash 16.9, 10.2, 6.7 Hz, 1H), 5.01–4.91 (m, 2H), 4.10–3.93 (m, 4H),
(
chromatography: EtOAc/CyH 20/80 to 80/20; yellow oil, 3.46–3.36 (m, 2H), 2.36 (s, 3H), 2.22 (dt, J = 7.1, 6.9 Hz, 2H),
1
3
1
2
52 mg, 62% yield; Z stereoisomer: R = 0.23 (EtOAc/PE = 80/ 2.03 (dd, J = 7.5, 3.0 Hz, 3H), 1.24 (t, J = 7.0 Hz, 6H); C NMR
f
1
3 3
0); H NMR (300 MHz, CDCl ) δ 6.69 (d, J = 5.9 Hz, 1H), 6.52 (91 MHz, CDCl ) δ 150.6 (d, J = 27.9 Hz), 143.3, 137.3, 134.7,
(
(
(
dq, J = 40.3, 7.6 Hz, 1H), 4.17–3.95 (m, 4H), 2.93 (s, 3H), 1.92 129.3, 128.6 (d, J = 210.9 Hz), 127.9, 116.9, 62.0 (d, J = 5.6 Hz),
13
31
dd, J = 7.6, 3.0 Hz, 3H), 1.26 (t, J = 7.1 Hz, 6H); C NMR 49.3, 32.6, 21.5, 16.3 (d, J = 6.3 Hz), 15.2;
P NMR
) δ 12.0; HRMS (ESI) m/z [MNa ] calcd for
PS: 424.1318, found: 424.1302.
(Z)-Diethyl (1-((N-(but-3-en-1-yl)-4-methylphenyl)sulfonamido)
but-1-en-1-yl)phosphonate (16c). Prepared according to the
+
75 MHz, CDCl
3
) δ 136.1 (d, J = 18.7 Hz), 124.2 (d, J = (202 MHz, CDCl
28NNaO
3
2
01.4 Hz), 62.5 (d, J = 5.6 Hz), 39.6, 16.1 (d, J = 6.2 Hz), 14.4 (d,
C
18
H
5
3
1
J = 3.8 Hz); P NMR (121.5 MHz, CDCl ) δ 12.6; HRMS (ESI)
m/z [MH ] calcd for C H19NO PS: 272.0716, found: 272.0712.
8 5
3
+
Dimethyl (Z)-(3-methyl-1-((4-methylphenyl)sulfonamido)but- general procedure D. Flash chromatography: EtOAc/PE 20/80
1
-en-1-yl)phosphonate (15e). Prepared according to the general to 50/50; colorless oil, 56 mg, 74% yield; R = 0.56 (EtOAc/PE =
f
procedure C. Flash chromatography: EtOAc/PE 40/60 to 100/0; 80/20); IR (neat) 2978, 2931, 2878, 1728, 1643, 1597,
1
1
yellow solid, 393 mg, 43% yield; R
f
= 0.56 (EtOAc/PE = 80/20); 1451 cm−
;
H NMR (400 MHz, CDCl
7.28–7.22 (m, 2H), 6.29 (dt, J = 38.3, 8.2 Hz, 1H), 5.67 (ddt, J =
) δ 7.73 (d, J = 8.2 Hz, 2H), 7.27–7.32 17.0, 10.3, 6.7 Hz, 1H), 5.03–4.94 (m, 2H), 4.13–3.95 (m, 4H),
m, 2H), 6.49 (d, J = 8.2 Hz, 1H), 6.38 (dd, J = 41.5, 9.7 Hz, 1H), 3.50–3.40 (m, 2H), 2.49 (dqd, J = 7.6, 7.5, 2.6 Hz, 2H), 2.39 (s,
.40 (d, J = 11.5 Hz, 6H), 2.70–2.87 (m, 1H), 2.40 (s, 3H), 0.95 3H), 2.29–2.21 (m, 2H), 1.26 (t, J = 7.1 Hz, 6H), 1.01 (t, J =
3
) δ 7.77–7.71 (m, 2H),
−
1
IR (neat): 3133, 2955, 2924, 2862, 1728, 1628, 1597, 1450 cm
;
1
H NMR (400 MHz, CDCl
3
(
3
1
3
13
(d, J = 6.7 Hz, 6H); C NMR (126 MHz, CDCl
3
) δ 144.9 (d, J = 7.5 Hz, 3H); C NMR (126 MHz, CDCl
3
) δ 156.9 (d, J =
1
5
6.8 Hz), 144.1, 136.0, 129.5, 128.2, 120.0 (d, J = 199.3 Hz), 28.4 Hz), 143.4, 137.2, 134.8, 129.4, 128.1, 127.3 (d,
3
1
2.5 (d, J = 5.1 Hz), 28.6 (d, J = 3.6 Hz), 22.7, 21.6; P NMR J = 212.4 Hz), 117.0, 62.2 (t, J = 16.7 Hz), 49.4, 32.6, 22.7 (d, J =
+
31
3
(162 MHz, CDCl ) δ 16.6; HRMS (ESI) m/z [MNa ] calcd for 2.6 Hz), 21.6, 16.4 (d, J = 6.6 Hz), 13.1 (d, J = 1.6 Hz); P NMR
+
C
14
H
22NNaO
5
PS: 370.0849, found: 370.0832.
(162 MHz, CDCl
3
) δ 12.2; HRMS (ESI) m/z [MNa ] calcd for
C H NNaO PS: 438.1475, found: 438.1454.
1
9
30
5
General procedure D: Mitsunobu reaction for the preparation
of the α-AVPs 16
(Z)-Diethyl (1-((N-(but-3-en-1-yl)-4-methylphenyl)sulfonamido)-
3-methylbut-1-en-1-yl)phosphonate (16d). Prepared according to
To a solution of deprotected α-AVP (0.19 mmol), tributyl- the general procedure D. Flash chromatography: EtOAc/PE 20/
phosphine (0.28 mmol, 1.5 eq.) and alcohol (0.28 mmol, 1 eq.) 80 to 80/20; yellow oil, 73 mg, 80% yield; R = 0.61 (EtOAc/PE =
) δ 7.52 (d, J = 8.3 Hz, 2H),
azodicarboxylate (DIAD, 0.28 mmol, 1.5 eq.) in toluene 7.06 (d, J = 8.3 Hz, 2H), 5.81 (dd, J = 38.2, 11.4 Hz, 1H), 5.47
0.63 mL) at room temperature. After stirring for one hour, the (ddt, J = 17.1, 10.3, 6.8 Hz, 1H), 4.83–4.73 (m, 2H), 3.93–3.80
f
1
in THF (1.9 mL), was added dropwise a solution of diisopropyl 80/20); H NMR (400 MHz, CDCl
3
(
reaction mixture was concentrated under reduced pressure. (m, 4H), 3.33–3.17 (m, 2H), 3.06–2.93 (m, 1H), 2.19 (s, 3H),
The crude residue was purified by flash column chromato- 2.08–2.01 (m, 2H), 1.06 (t, J = 7.1 Hz, 6H), 0.78 (d, J = 6.5 Hz,
1
3
graphy (AcOEt/EP).
E)-Diethyl (1-((N-(but-3-en-1-yl)-4-methylphenyl)sulfonamido) 137.0, 134.7, 129.2, 127.9, 125.6 (d, J = 213.3 Hz), 116.9, 62.0
prop-1-en-1-yl)phosphonate (16a). Prepared according to the (d, J = 5.9 Hz), 49.3, 32.4, 28.4, 21.7, 21.5, 16.3 (d, J = 6.6 Hz);
3
6H); C NMR (75 MHz, CDCl ) δ 161.3 (d, J = 28.7 Hz), 143.2,
(
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3
1
+
P NMR (162 MHz, CDCl
3
) δ 12.4; HRMS (ESI) m/z [MH ] 2H), 7.21 (d, J = 8.0 Hz, 2H), 5.92 (dd, J = 38.2, 11.3 Hz, 1H),
5.67 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 4.96–4.83 (m, 2H),
calcd for C H NO PS: 430.1812, found: 430.1791.
2
0
33
5
Diethyl (1-(N-(but-3-en-1-yl)methylsulfonamido)prop-1-en-1- 4.08–3.95 (m, 4H), 3.36–3.27 (m, 2H), 3.21–3.08 (m, 1H), 2.34
yl)phosphonate (16e). Prepared according to the general pro- (s, 3H), 1.96 (td, J = 7.1, 6.6 Hz, 2H), 1.53 (tt, J = 7.5, 7.4 Hz,
1
3
cedure D. Flash chromatography: EtOAc/PE 40/60 to 50/50; 2H), 1.22 (t, J = 7.1 Hz, 6H), 0.92 (d, J = 6.5 Hz, 6H); C NMR
colorless oil, 51 mg, 85% yield; R = 0.55 (EtOAc); Z stereo- (126 MHz, CDCl ) δ 160.7 (d, J = 28.6 Hz), 143.3, 137.6, 137.0,
) δ 6.66 (dq, J = 37.4, 7.6 Hz, 129.4, 128.1, 126.2 (d, J = 214.5 Hz), 115.2, 62.1 (d, J = 5.5 Hz),
f
3
1
isomer: H NMR (500 MHz, CDCl
3
3
1
1
4
2
H), 5.72 (ddt, J = 16.9, 10.4, 6.7 Hz, 1H), 5.09–5.00 (m, 2H), 49.8, 30.6, 28.6, 27.1, 21.9, 21.6, 16.4 (d, J = 6.6 Hz); P NMR
+
.17–4.06 (m, 4H), 3.47 (br. s, 2H), 3.03 (s, 3H), 2.31–2.24 (m, (162 MHz, CDCl
3
) δ 12.5; HRMS (ESI) m/z [MNa ] calcd for
PS: 466.1788, found: 466.1788.
Diethyl (1-(N-(pent-4-en-1-yl)methylsulfonamido)prop-1-en-
H), 2.04 (dd, J = 7.6, 3.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 6H);
21 5
C H34NNaO
1
3
C NMR (126 MHz, CDCl ) δ 152.9 (d, J = 28.4 Hz), 134.6,
3
1
3
27.2 (d, J = 204.0 Hz), 117.2, 62.2 (d, J = 5.6 Hz), 48.6, 39.2, 1-yl)phosphonate (16i). Prepared according to the general pro-
3
1
2.9, 16.3 (d, J = 6.6 Hz), 15.2; P NMR (162 MHz, CDCl
3
)
cedure D. Flash chromatography: EtOAc/PE 30/70 to 70/30;
1
δ 13.2; characteristic signals for E isomer: H NMR (500 MHz, yellow oil, 122 mg, 77% yield; R = 0.50 (EtOAc/PE = 80/20);
CDCl
J = 6.9, 3.2 Hz, 3H); C NMR (126 MHz, CDCl
2
f
1
3
) δ 6.91 (dq, J = 13.8, 6.9 Hz, 1H), 3.05 (s, 3H), 1.93 (dd, Z stereoisomer: H NMR (400 MHz, CDCl
3
) δ 6.60 (dq, J = 37.4,
) δ 150.6 (d, J = 7.6 Hz, 1H), 5.71 (ddt, J = 16.8, 10.2, 6.6 Hz, 1H), 5.03–4.80 (m,
8.0 Hz), 134.4, 117.3, 48.7, 39.1, 33.0; P NMR (162 MHz, 2H), 4.18–3.94 (m, 4H), 3.35 (t, J = 7.3 Hz, 2H), 2.99 (s, 3H),
1
3
3
3
1
+
CDCl
24NNaO
Z)-Diethyl (1-((4-methyl-N-(pent-4-en-1-yl)phenyl)sulfonamido) CDCl ) δ 152.5 (d, J = 28.6 Hz), 137.6, 127.5 (d, J = 203.1 Hz),
3
)
δ
13.9; HRMS (ESI) m/z [MNa ] calcd for 2.04–1.97 (m, 2H), 2.00 (dd, J = 7.6, 3.2 Hz, 3H), 1.57 (tt, J =
1
3
C
12
H
5
PS: 348.1005, found: 348.0992.
7.5, 7.3 Hz, 2H), 1.28 (t, J = 7.1 Hz, 6H); C NMR (91 MHz,
(
3
prop-1-en-1-yl)phosphonate (16f). Prepared according to the 115.4, 62.2 (d, J = 5.2 Hz), 49.0, 39.2, 30.6, 27.7, 16.4 (d, J =
3
1
general procedure D. Flash chromatography: EtOAc/PE 10/90 6.4 Hz), 15.3; P NMR (162 MHz, CDCl
3
) δ 13.2; characteristic
1
to 90/10; yellow oil, 90 mg, quantitative yield; R = 0.46 (EtOAc/ signals for E isomer: H NMR (400 MHz, CDCl ) δ 6.86 (dq, J =
PE = 80/20); H NMR (300 MHz, CDCl ) δ 7.71 (d, J = 8.3 Hz, 13.7, 6.9 Hz, 1H), 3.00 (s, 3H), 1.89 (dd, J = 6.9, 3.1 Hz, 3H);
3
f
3
1
3
1
+
2
5
4
7
2
H), 7.22 (d, J = 8.2 Hz, 2H), 6.40 (dq, J = 38.4, 7.5 Hz, 1H),
3
P NMR (162 MHz, CDCl ) δ 13.9; HRMS (ESI) m/z [MNa ]
.67 (ddt, J = 16.8, 10.2, 6.6 Hz, 1H), 4.97–4.81 (m, 2H), calcd for C H NNaO PS: 362.1162, found: 362.1159.
1
3
26
5
.07–3.92 (m, 4H), 3.36–3.27 (m, 2H), 2.35 (s, 3H), 2.01 (dd, J =
(Z)-Dimethyl
(1-((N-(hex-5-en-1-yl)-4-methylphenyl)sulfon-
.5, 3.2 Hz, 3H), 1.98–1.87 (m, 2H), 1.54 (tt, J = 7.7, 7.3 Hz, amido)-3-methylbut-1-en-1-yl)phosphonate (16j). Prepared
H), 1.22 (t, J = 7.1 Hz, 6H); C NMR (91 MHz, CDCl ) δ 149.9 according to the general procedure D. Flash chromatography:
1
3
3
(
2
2
d, J = 27.9 Hz), 143.2, 137.5, 137.1, 129.3, 129.0 (d, J = EtOAc/PE 20/80 to 50/50; colorless oil, 47 mg, 64% yield; R
f
=
;
−
1
12.1 Hz), 127.9, 115.1, 62.0 (d, J = 5.8 Hz), 49.6, 30.5, 27.1, 0.57 (EtOAc/PE = 80/20); IR (neat) 2932, 2870, 1712, 1458 cm
3
1
1
1.5, 16.2 (d, J = 6.4 Hz), 15.2; P NMR (121.5 MHz, CDCl3)
H NMR (400 MHz, CDCl ) δ 7.72 (d, J = 8.3 Hz, 2H), 7.27 (d,
3
+
δ 11.9; HRMS (ESI) m/z [MNa ] calcd for C19
38.1475, found: 438.1459.
H
30NNaO
5
PS: J = 8.2 Hz, 2H), 5.99 (dd, J = 39.0, 11.3 Hz, 1H), 5.72 (ddt, J =
16.9, 10.2, 6.7 Hz, 1H), 4.99–4.84 (m, 2H), 3.70 (d, J = 11.2 Hz,
4
(Z)-Diethyl (1-((4-methyl-N-(pent-4-en-1-yl)phenyl)sulfonamido) 6H), 3.40–3.31 (m, 2H), 3.23–3.11 (m, 1H), 2.41 (s, 3H),
but-1-en-1-yl)phosphonate (16g). Prepared according to the 2.04–1.94 (m, 2H), 1.55–1.43 (m, 2H), 1.39–1.29 (m, 2H), 0.98
1
3
general procedure D. Flash chromatography: EtOAc/PE 20/80 (d, J = 6.5 Hz, 6H); C NMR (126 MHz, CDCl
3
) δ 161.5 (d, J =
to 40/60; colorless oil, 69 mg, 91% yield; R = 0.66 (EtOAc/PE = 29.2 Hz), 143.4, 138.4, 137.0, 129.4, 128.1, 125.3 (d, J = 215.0
f
8
0/20); IR (neat) 2978, 2932, 1728, 1643, 1597, 1450 cm−1
;
Hz), 114.8, 52.8 (d, J = 5.5 Hz), 50.2, 33.3, 28.7, 27.3, 25.7, 22.0
1
31
H NMR (400 MHz, CDCl
3 3
) δ 7.69 (d, J = 8.3 Hz, 2H), 7.21 (d, (br. s), 21.6; P NMR (162 MHz, CDCl ) δ 15.2; HRMS (ESI)
+
J = 8.3 Hz, 2H), 6.21 (dt, J = 38.4, 8.2 Hz, 1H), 5.67 (ddt, J = m/z [MNa ] calcd for C H NNaO PS: 452.1631, found:
2
0
32
5
1
3
3
1
6.9, 10.2, 6.6 Hz, 1H), 4.95–4.83 (m, 2H), 4.06–3.93 (m, 4H), 452.1615.
.36–3.25 (m, 2H), 2.44 (ddq, J = 7.6, 7.5, 2.6 Hz, 2H), 2.34 (s, (Z)-Dimethyl (3-methyl-1-((4-methyl-N-(pent-4-yn-1-yl)phenyl)
H), 1.95 (dt, J = 7.2, 7.1 Hz, 2H), 1.54 (tt, J = 7.7, 7.3 Hz, 2H), sulfonamido)but-1-en-1-yl)phosphonate (16k). Prepared
.21 (t, J = 7.1 Hz, 6H), 0.96 (t, J = 7.5 Hz, 3H); C NMR according to the general procedure D. Flash chromatography:
) δ 156.2 (d, J = 28.4 Hz), 143.3, 137.6, 137.1, EtOAc/PE 20/80 to 70/30; colorless oil, 48 mg, 74% yield (80%
29.4, 128.1, 127.7 (d, J = 213.2 Hz), 115.2, 62.1 (d, J = 5.7 Hz), conversion); R = 0.58 (EtOAc/PE = 80/20); IR (neat) 3287, 3233,
1
3
(126 MHz, CDCl
3
1
4
1
f
9.8, 30.6, 27.1, 22.7 (d, J = 2.1 Hz), 21.6, 16.4 (d, J = 6.5 Hz), 2955, 2870, 2114, 1736, 1597, 1458 cm− ; H NMR (400 MHz,
1
1
3
1
3.1; P NMR (162 MHz, CDCl
3
) δ 12.2; HRMS (ESI) m/z CDCl
5.97 (dd, J = 38.8, 11.3 Hz, 1H), 3.72 (d, J = 11.2 Hz, 6H), 3.45
Z)-Diethyl (3-methyl-1-((4-methyl-N-(pent-4-en-1-yl)phenyl) (t, J = 7.2 Hz, 2H), 3.23–3.09 (m, 1H), 2.41 (s, 3H), 2.18 (td, J =
sulfonamido)but-1-en-1-yl)phosphonate (16h). Prepared accord- 7.0, 2.6 Hz, 2H), 1.91 (t, J = 2.6 Hz, 1H), 1.71 (tt, 7.3, 7.2 Hz,
3
) δ 7.73 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H),
+
[MNa ] calcd for C H NNaO PS: 452.1631, found: 452.1610.
20 32 5
(
13
ing to the general procedure D. Flash chromatography: EtOAc/ 2H), 0.98 (d, J = 6.5 Hz, 6H); C NMR (126 MHz, CDCl3)
PE 30/70 to 50/50; yellow oil, 66 mg, 80% yield; R δ 161.4 (d, J = 28.9 Hz), 143.6, 136.7, 129.5, 128.1, 125.7 (d, J =
.75 (EtOAc); IR (neat) 2978, 2932, 2870, 1721, 1597, 215.6 Hz), 83.3, 69.0, 52.9 (d, J = 5.3 Hz), 49.6, 28.7, 27.0,
f
=
0
1
451 cm− ; H NMR (500 MHz, CDCl ) δ 7.68 (d, J = 8.3 Hz, 22.0, 21.7, 15.7; P NMR (162 MHz, CDCl ) δ 15.1; HRMS (ESI)
1
1
31
3
3
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+
m/z [MNa ] calcd for
4
C
19
H
28NNaO
5
PS: 436.1318, found: 143.3, 137.5, 129.4, 128.9 (d, J = 211.4 Hz), 128.0, 111.3, 62.0
(d, J = 5.8 Hz), 46.8, 40.0, 35.6, 26.8, 22.0, 21.6, 16.4 (d, J =
36.1300.
Z)-Diethyl
sulfonamido)prop-1-en-1-yl)phosphonate
according to the general procedure D. Flash chromatography: 444.1951.
EtOAc/PE 10/90 to 70/30; yellow oil, 74 mg, quantitative yield; Diethyl (Z)-(1-((4-methyl-N-(pent-4-en-2-yl)phenyl)sulfonamido)
) δ 7.68 prop-1-en-1-yl)phosphonate (16p). Prepared according to the
d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 6.62–6.35 (m, 1H), general procedure D. Flash chromatography: EtOAc/PE 20/80
3
1
(
(1-((4-methyl-N-(2-methylbut-3-en-1-yl)phenyl) 6.5 Hz), 15.3; P NMR (101.25 MHz, CDCl
3
) δ 12.1; HRMS
+
(16l).
Prepared (ESI) m/z [MH ] calcd for C21H35NO PS: 444.1968, found:
5
1
f 3
R = 0.50 (EtOAc/PE = 90/10); H NMR (300 MHz, CDCl
(
5
4
2
7
.60 (ddd, J = 17.5, 10.5, 7.4 Hz, 1H), 4.97–4.81 (m, 2H), to 80/20; yellow oil, 47 mg, 39% yield (conv. 74%); R
f
= 0.70
) δ 7.82 (d, J = 7.9 Hz, 2H),
.39–2.28 (m, 1H), 2.00 (dd, J = 7.6, 3.2 Hz, 3H), 1.20 (t, J = 7.25–7.15 (m, 2H), 6.33 (br. s, 1H), 5.53 (br. s, 1H), 4.94–4.77
1
.06–3.85 (m, 4H), 3.32 (d, J = 7.2 Hz, 2H), 2.35 (s, 3H), (EtOAc); H NMR (360 MHz, CDCl
3
1
3
.1 Hz, 6H), 0.92 (d, J = 6.7 Hz, 3H); C NMR (91 MHz, CDCl
3
)
(m, 2H), 4.21–4.01 (m, 4H), 3.81–3.65 (m, 1H), 2.34 (s, 2H),
δ 150.4 (d, J = 27.3 Hz), 143.1, 141.1, 137.2, 129.1, 128.0, 127.4, 2.07–1.87 (m, 5H), 1.31–1.18 (m, 6H), 1.14–0.85 (m, 4H);
1
3
1
14.5, 61.8, 54.9, 36.2, 21.9, 21.4, 16.2 (d, J = 6.0 Hz), 15.1;
C NMR (91 MHz, CDCl ) δ 151.9 (d, J = 28.0 Hz), 143.3, 137.8,
3
3
1
+
P NMR (121.5 MHz, CDCl
calcd for C19 PS: 416.1655, found: 416.1643.
Z)-Diethyl (1-((4-methyl-N-(3-methylbut-3-en-1-yl)phenyl) 15.5; P NMR (101.25 MHz, CDCl ) δ 13.5; HRMS (ESI) m/z
sulfonamido)prop-1-en-1-yl)phosphonate (16m). Prepared [MH ] calcd for C19
according to the general procedure D. Flash chromatography: Diethyl (Z)-(1-((N-(2-(allyloxy)ethyl)-4-methylphenyl)sulfon-
EtOAc/PE 10/90 to 100/0; yellow oil, 55 mg, 93% yield; R = 0.55 amido)prop-1-en-1-yl)phosphonate (16q). Prepared according
3
) δ 12.0; HRMS (ESI) m/z [MH ] 134.9, 129.4, 128.1, 127.1 (d, J = 217.8 Hz), 117.2 (d, J =
H
31NO
5
24.6 Hz), 62.3 (br. s), 55.7, 40.0, 21.5, 18.3, 16.3 (d, J = 6.3 Hz),
3
1
(
3
+
H
5
31NO PS: 416.1655, found: 416.1664.
f
1
(EtOAc/PE = 80/20); H NMR (250 MHz, CDCl
3
) δ 7.75 (d, J = to the general procedure D. Flash chromatography: EtOAc/PE
8
0
3
.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 6.50 (dqd, J = 16.0, 7.4, 20/80 to 80/20; orange oil, 139 mg, 99% yield; R = 0.42 (EtOAc/
f
1
.8 Hz, 1H), 4.71 (br. s, 1H), 4.61 (br. s, 1H), 4.11–3.92 (m, 4H), PE = 60/40); H NMR (250 MHz, CDCl ) δ 7.77 (d, J = 8.2 Hz,
3
.57–3.40 (m, 2H), 2.39 (s, 3H), 2.27–2.14 (m, 2H), 2.11–2.00 2H), 7.26 (d, J = 8.2 Hz, 2H), 6.46 (dq, J = 38.2, 7.5 Hz, 1H),
1
3
(m, 3H), 1.66 (d, J = 0.5 Hz, 3H), 1.30–1.21 (m, 6H); C NMR 5.80 (ddd, J = 22.7, 10.7, 5.5 Hz, 1H), 5.25–5.08 (m, 2H),
(
62.9 MHz, CDCl ) δ 150.7 (d, J = 28.1 Hz), 143.3, 142.3, 137.4, 4.18–3.96 (m, 4H), 3.88 (d, J = 5.6 Hz, 2H), 3.61 (t, J = 5.5 Hz,
3
1
4
29.4, 128.6 (d, J = 210.9 Hz), 128.0, 112.0, 62.1 (d, J = 5.9 Hz), 2H), 3.51 (t, J = 5.7 Hz, 2H), 2.40 (s, 3H), 2.04 (dd, J = 7.5, 3.2
31
13
3
8.5, 36.4, 22.5, 21.6, 16.4 (d, J = 6.4 Hz), 15.3; P NMR Hz, 3H), 1.28 (t, J = 7.1 Hz, 6H); C NMR (62.9 MHz, CDCl )
+
(101.25 MHz, CDCl ) δ 12.0; HRMS (ESI) m/z [MNa ] calcd for δ 150.5 (d, J = 28.0 Hz), 143.3, 137.4, 134.6, 129.3, 129.0 (d, J =
3
C
19
H
30NNaO
5
PS: 438.1475, found: 438.1468.
211.1 Hz), 128.1, 117.0, 71.8, 67.6, 62.1 (d, J = 5.8 Hz), 49.2,
31
Diethyl ((Z)-1-((N-((Z)-hex-3-en-1-yl)-4-methylphenyl)sulfon- 21.6, 16.3 (d, J = 6.4 Hz), 15.2; P NMR (101.25 MHz, CDCl
3
)
+
amido)prop-1-en-1-yl)phosphonate (16n). Prepared according δ 11.9; HRMS (ESI) m/z [MH ] calcd for C H NO PS:
1
9
31
6
to the general procedure D. Flash chromatography: EtOAc/PE 432.1604, found: 432.1611.
0/90 to 65/35; yellow oil, 59 mg, 97% yield; R = 0.65 (EtOAc);
1
f
1
H NMR (250 MHz, CDCl ) δ 7.75 (d, J = 8.4 Hz, 2H), 7.30–7.20
3
General procedure E: metathesis reactions
(m, 2H), 6.49 (dq, J = 38.3, 7.5 Hz, 1H), 5.44–5.32 (m, 1H),
5
.22–5.11 (m, 1H), 4.13–3.95 (m, 4H), 3.41–3.29 (m, 2H), 2.39 To a solution of α-AVP 16 (0.16 mmol) in 1,2-dichloroethane
(s, 3H), 2.22 (dt, J = 7.4, 7.3 Hz, 2H), 2.06 (dd, J = 7.6, 3.2 Hz, (2 mL) is added the Grubbs 2 catalyst (0.0082 mmol, 0.05 eq.)
3
H), 1.94 (dq, J = 7.4, 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 6H), 0.90 at room temperature. After stirring overnight at reflux, the reac-
1
3
(t, J = 7.5 Hz, 3H); C NMR (62.9 MHz, CDCl
3
) δ 150.6 (d, J = tion mixture was concentrated under reduced pressure (if the
8.2 Hz), 143.3, 137.4, 134.3, 129.4, 128.6 (d, J = 211.1 Hz), reaction is not complete, addition of an extra 5 mol% of the
28.1, 124.5, 62.1 (d, J = 5.9 Hz), 49.7, 26.3, 22.0, 21.6, 20.7, Grubbs 2 catalyst and reflux for 18 h). The crude residue was
2
1
1
3
1
6.4 (d, J = 6.4 Hz), 14.3; P NMR (101.25 MHz, CDCl
3
) δ 12.0; purified by flash column chromatography (AcOEt/EP).
Diethyl (1-tosyl-4,5-dihydro-1H-pyrrol-2-yl)phosphonate
(17a). Prepared according to the general procedure E. Flash
Z)-Diethyl (1-((N-(3,3-dimethylpent-4-en-1-yl)-4-methylphenyl) chromatography: EtOAc/PE 40/60 to 80/20; orange oil, 26 mg,
sulfonamido)prop-1-en-1-yl)phosphonate (16o). Prepared 79% yield; R = 0.58 (EtOAc); IR (neat) 2985, 2924, 1736, 1597,
according to the general procedure D. Flash chromatography: 1442 cm− ; H NMR (400 MHz, CDCl
+
HRMS (ESI) m/z [MH ] calcd for C H NO PS: 430.1812,
found: 430.1795.
2
0
33
5
(
f
1
1
3
) δ 7.94 (d, J = 8.3 Hz,
EtOAc/PE 10/90 to 90/10; yellow oil, 64 mg, quantitative yield; 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.18 (dt, J = 6.5, 2.9 Hz, 1H),
1
Rf = 0.66 (EtOAc); H NMR (250 MHz, CDCl ) δ 7.74 (d, J = 4.32–4.19 (m, 4H), 3.81 (t, J = 8.9 Hz, 2H), 2.41 (s, 3H), 2.24
3
1
3
8
1
1
3
1
.3 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.46 (dq, J = 38.5, 7.5 Hz, (tdd, J = 8.9, 3.2, 3.1 Hz, 2H), 1.38 (t, J = 7.0 Hz, 6H); C NMR
H), 5.63 (dd, J = 17.3, 10.9 Hz, 1H), 4.87 (dd, J = 17.3, 1.2 Hz, (91 MHz, CDCl ) δ 144.0, 135.6 (d, J = 219.0 Hz), 134.2, 134.0,
H), 4.84 (dd, J = 10.8, 1.3 Hz, 1H), 4.14–3.96 (m, 4H), 131.4, 129.7, 128.4, 63.4 (d, J = 6.0 Hz), 51.1 (d, J = 8.7 Hz), 29.3
.34–3.20 (m, 2H), 2.38 (s, 3H), 2.06 (dd, J = 7.5, 3.2 Hz, 3H), (d, J = 13.7 Hz), 21.7, 16.5 (d, J = 6.6 Hz); P NMR (162 MHz,
.53–1.43 (m, 2H), 1.26 (t, J = 7.1 Hz, 6H), 0.92 (s, 6H); CDCl
3
3
1
+
3
)
δ
7.0; HRMS (ESI) m/z [MNa ] calcd for
1
3
C NMR (62.9 MHz, CDCl ) δ 150.3 (d, J = 28.4 Hz), 147.1, C H NNaO PS: 382.0849, found: 382.0830.
3
15 22
5
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Diethyl (1-(methylsulfonyl)-4,5-dihydro-1H-pyrrol-2-yl)phos-
Diethyl ((Z)-1-((N-((E)-6-((N-((Z)-1-(diethoxyphosphoryl)but-1-
phonate (17b). Prepared according to the general procedure E. en-1-yl)-4-methylphenyl)sulfonamido)hex-3-en-1-yl)-4-methyl-
Flash chromatography: EtOAc/PE 50/50 to 100/0; brown oil, phenyl)sulfonamido)but-1-en-1-yl)phosphonate (18c). Prepared
2
0
5 mg, 68% yield (86% yield based on Z stereomer only); R
f
=
;
according to the general procedure E. Flash chromatography:
.22 (EtOAc); IR (neat) 2986, 2932, 2862, 1736, 1597 cm−1
EtOAc; brown oil, 17 mg, 31% yield; R = 0.42 (EtOAc); H NMR
1
f
1
H NMR (400 MHz, CDCl
3 3
) δ 6.11 (dt, J = 7.0, 2.9 Hz, 1H), (360 MHz, CDCl ) δ 7.73 (d, J = 8.2 Hz, 4H), 7.27 (d, J = 8.1 Hz,
4
.26–4.10 (m, 4H), 3.93 (t, J = 9.4 Hz, 2H), 3.11 (s, 3H), 2.68 4H), 6.26 (dt, J = 38.3, 8.2 Hz, 2H), 5.40–5.26 (m, 2H),
1
3
(tdd, J = 9.3, 3.4, 3.1 Hz, 2H), 1.35 (td, J = 7.1, 0.4 Hz, 6H);
C
4.12–3.98 (m, 8H), 3.42–3.32 (m, 4H), 2.48 (dtd, J = 15.5, 7.6,
NMR (126 MHz, CDCl
3
) δ 134.7 (d, J = 214.4 Hz), 130.2 (d, J = 2.5 Hz, 4H), 2.40 (s, 6H), 2.19 (br. s, 4H), 1.26 (t, J = 7.0 Hz,
1
3
1
5.5 Hz), 63.5 (d, J = 5.9 Hz), 51.5 (d, J = 8.6 Hz), 37.2, 29.2 (d, 6H), 1.26 (t, J = 7.0 Hz, 6H), 1.01 (t, J = 7.5 Hz, 6H); C NMR
3
1
J = 14.1 Hz), 16.4 (d, J = 6.6 Hz); P NMR (162 MHz, CDCl3) (91 MHz, CDCl ) δ 156.8 (d, J = 28.5 Hz), 143.4, 137.2, 129.4,
3
+
δ 6.4; HRMS (ESI) m/z [MNa ] calcd for C
06.0536, found: 306.0527.
Diethyl (4-methyl-1-tosyl-4,5-dihydro-1H-pyrrol-2-yl)phos- HRMS (ESI) m/z [MNa ] calcd for C H N NaO P S :
phonate (17c). Prepared according to the general procedure E. 825.2744, found: 825.2706.
Flash chromatography: EtOAc/PE 20/80 to 80/20; brown oil, Diethyl ((Z)-1-((N-((E)-8-((N-((Z)-1-(diethoxyphosphoryl)prop-
9 5
H18NNaO PS: 128.7, 128.0, 127.4 (d, J = 212.4 Hz), 62.2, 49.8, 31.5, 22.7, 21.6,
3
1
3
3
16.4 (d, J = 6.3 Hz), 13.1; P NMR (101.25 MHz, CDCl ) δ 12.2;
+
3
6
56
2
10 2 2
1
1
6 mg, 67% yield; R = 0.46 (EtOAc); H NMR (360 MHz, 1-en-1-yl)-4-methylphenyl)sulfonamido)oct-4-en-1-yl)-4-methyl-
f
CDCl
3
) δ 7.94 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.05 phenyl)sulfonamido)prop-1-en-1-yl)phosphonate (20). Prepared
(dd, J = 6.6, 2.7 Hz, 1H), 4.35–4.17 (m, 4H), 3.91 (dd, J = 11.4, according to the general procedure F. Flash chromatography:
1
2
0.0 Hz, 1H), 3.32 (dd, J = 11.6, 6.7 Hz, 1H), 2.76–2.61 (m, 1H), EtOAc/PE/MeOH = 20/80/0 to 90/0/10; brown oil, 37 mg, 71%
1
.40 (s, 3H), 1.38 (t, J = 7.0 Hz, 6H), 0.69 (d, J = 7.0 Hz, 3H); yield; R
f
= 0.13 (EtOAc); H NMR (360 MHz, CDCl
3
) δ 7.69 (d,
1
3
C NMR (91 MHz, CDCl
3
) δ 143.9, 138.6 (d, J = 15.7 Hz), 134.1 J = 8.2 Hz, 4H), 7.26–7.15 (m, 4H), 6.51–6.29 (m, 2H), 5.27–5.18
(d, J = 217.8 Hz), 133.8, 129.6, 128.5, 63.4 (d, J = 6.6 Hz), 57.9 (m, 2H), 4.06–3.89 (m, 8H), 3.37–3.20 (m, 4H), 2.34 (s, 6H),
(
6
d, J = 8.2 Hz), 36.5 (d, J = 13.3 Hz), 21.7, 19.2, 16.4 (d, J = 2.00 (dd, J = 7.5, 3.1 Hz, 6H), 1.91–1.76 (m, 4H), 1.53–1.42 (m,
3
1
13
.3 Hz); P NMR (121.5 MHz, CDCl
3
) δ 7.1; HRMS (ESI) m/z 4H), 1.21 (t, J = 7.1 Hz, 12H); C NMR (91 MHz, CDCl
δ 150.1 (d, J = 28.0 Hz), 143.3, 137.2, 129.8, 129.4, 128.9 (d, J =
(5-methyl-1-tosyl-4,5-dihydro-1H-pyrrol-2-yl)phos- 211.5 Hz), 128.0, 62.1 (d, J = 5.6 Hz), 49.8, 29.5, 27.9, 21.6, 16.4
3
)
+
[MH ] calcd for C H NO PS: 374.1186, found: 374.1185.
16 25 5
Diethyl
phonate (17d). Prepared according to the general procedure E. (d, J = 6.4 Hz), 15.3; P NMR (101.25 MHz, CDCl
3
1
3
) δ 12.0;
Flash chromatography: EtOAc/PE 10/90 to 90/10; brown oil, HRMS (ESI) m/z [MH ] calcd for C H N O P S : 803.2924,
+
3
6
57 2 10 2 2
1
2
f
0 mg, 48% yield; R = 0.53 (EtOAc/PE = 90/10); H NMR found: 803.2928.
(
360 MHz, CDCl ) δ 7.92 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz,
3
2
2
1
H), 6.24–6.17 (m, 1H), 4.38–4.18 (m, 5H), 2.44 (s, 3H),
.34–2.22 (m, 1H), 1.97–1.88 (m, 1H), 1.44 (d, J = 7.2 Hz, 3H),
Acknowledgements
13
.42 (d, J = 7.2 Hz, 3H), 1.32 (d, J = 6.6 Hz, 3H); C NMR
(
91 MHz, CDCl ) δ 143.9, 134.6, 134.4 (d, J = 18.1 Hz), 133.9 (d, P. A. is the beneficiary of an Allocation Spécifique pour
3
J = 219.1 Hz), 129.7 (s, J = 3.5 Hz), 128.1, 63.6 (d, J = 6.4 Hz), Normalien doctoral research grant from the French Ministry of
6
2
3.0 (d, J = 5.8 Hz), 59.6 (d, J = 8.0 Hz), 36.9 (d, J = 13.3 Hz), Higher Education and Research. P. A. thanks the Fondation de
3
1
2.8, 21.7, 16.5 (d, J = 6.1 Hz), 16.5 (d, J = 5.6 Hz); P NMR la Maison de la Chimie for financial support for a doctoral
+
3
(101.25 MHz, CDCl ) δ 7.5; HRMS (ESI) m/z [MNa ] calcd for stay in Glasgow. We thank the University Paris-Sud, the CNRS
C
16
H
24NNaO
5
PS: 396.1005, found: 396.1006.
and the University of Glasgow for financial support.
Diethyl
((E)-1-((N-((E)-6-((N-((E)-1-(diethoxyphosphoryl)
prop-1-en-1-yl)-4-methylphenyl)sulfonamido)hex-3-en-1-yl)-4-
methylphenyl)sulfonamido)prop-1-en-1-yl)phosphonate (18a).
Prepared according to the general procedure E. Flash
Notes and references
chromatography: EtOAc; orange oil, 35 mg, 76% yield; R
f
=
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1
7
3
2
1
1
.13 (EtOAc); IR (neat) 2978, 2924, 2862, 1728, 1597,
443 cm−
1
;
1
H NMR (400 MHz, CDCl ) δ 7.91–7.74 (m, 4H),
3
.29 (d, J = 8.1 Hz, 4H), 7.07–6.95 (m, 2H), 5.29 (dd, J = 7.3,
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3
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) δ 150.2 (d, J = 28.5 Hz),
43.5, 137.2, 129.5, 128.7, 128.2 (d, J = 214.7 Hz), 128.1, 62.4
(
(
d, J = 5.1 Hz), 62.2 (d, J = 5.7 Hz), 49.0, 31.7, 21.6, 16.3, 16.0
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1
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+
m/z [MNa ] calcd for C34
97.2397.
H
52
N
2
NaO10
P
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S
2
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