Enantioselective synthesis of constrained phenylalanine analogues

Article abstract of DOI:10.1016/j.tetlet.2010.08.057

Constrained phenylalanine derivatives containing hydrophobic groups and hydrogen bond acceptor and/or donor functionalities were synthesized through a tandem palladium-mediated Heck reaction followed by a rhodium(II)-catalyzed asymmetric hydrogenation. Ar

Full text of DOI:10.1016/j.tetlet.2010.08.057

Tetrahedron Letters 51 (2010) 5588–5591
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective synthesis of constrained phenylalanine analogues
⇑
Prasad V. Chaturvedula , Stephen E. Mercer, Leatte Guernon, John E. Macor, Gene M. Dubowchik
Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Constrained phenylalanine derivatives containing hydrophobic groups and hydrogen bond acceptor and/
or donor functionalities were synthesized through a tandem palladium-mediated Heck reaction followed
by a rhodium(II)-catalyzed asymmetric hydrogenation. Aryl bromides were found to be better substrates
in providing products with higher purity and in good yield. The cesium carbonate-mediated cyclization
proceeded smoothly in good yield and optical purity. Aryl iodides reacted selectively over bromides
under Jeffery-type conditions (Pd(OAc)2, Bu4NCl, Et3N) providing an opportunity for further metal-med-
iated functionalization.
Received 13 August 2010
Accepted 17 August 2010
Available online 25 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The development of new therapeutic agents based on peptides
and proteins is of fundamental importance in biomedical re-
search.1 A major effort in many research laboratories has been de-
voted to the development of methodologies to design peptide
surrogates or mimetics for peptides of biological interest. Many
of these mimetics are based on conformationally constrained or-
ganic replacements that contribute a favorable entropic compo-
nent to their binding relative to the flexible peptide ligand.2
1,2,3,4-Tetrahydroisoquinoline 3-carboxylic acid (Tic) is a cyclic
constrained analogue of phenylalanine in which a covalent bond
many biologically active peptides (e.g., opioid, Bradykinin,
Neurokinin A, substance P, Kallikrein, etc.).3 Using solution and
crystal-state conformational analysis, Hruby and his co-workers
showed (Fig. 1) that Tic could be part of a b-turn and/or
a-helix,
and that the preferred conformations were g(ꢀ) (for the D-Tic
enantiomer) or g(+) (for the L-Tic enantiomer).4 New Tic deriva-
tives substituted on the aromatic ring with basic guanidine,5
NO2
is inserted between the
ring. Tic has been incorporated as a phenylalanine replacement in
a
-nitrogen and 20-carbon of the aromatic
Br
OH
Br
NH
B
HO2C
NH2
X
χ1
χ1
HO2C
NH
HN
H
A
Hβ
Hα
Hβ
X
Hα
COOH
COOH
Hβ
Hβ
L
L-Tic
g(+)
L-Tic
g(-)
MeO
Cbz
N
N
H
MeO2C
1
Cbz
O
2
χ1
χ1
NH
HN
X
Hβ
Hα
Hβ
HOOC
X
HOOC
Hα
L
Hβ
Hβ
L
Y
Cbz
D-Tic
D-Tic
g(-)
MeO2C
N
H
Y = Halogen
g(+)
Cbz
Figure 1. v1 rotamers of L- and D-Tic.4
MeO2C
N
H
3
⇑
Corresponding author. Tel.: +1 230 677 6699; fax: +1 203 677 7702.
E-mail address: prasad.chaturvedula@bms.com (P.V. Chaturvedula).
Figure 2. Retrosynthesis of Tic derivatives.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.057

P. V. Chaturvedula et al. / Tetrahedron Letters 51 (2010) 5588–5591
5589
acidic phosphonoethyl, hydroxyl,6 etc. have been used to modu-
late receptor or enzyme function. Most of the classical methods
for the synthesis of Tic derivatives (e.g., Pictet–Spengler, Bisch-
ler–Napieralski, and Pomeranz–Fritsch reactions) involve the
Table 1
Heck reaction of aryl halides with dehydroamino acidsa
Substrate
Product
Conditions Yieldb
OBn
OBn
A
B
74
92
participation of aromatic ring
p electrons in the cyclization step
accompanied by partial racemization under the acidic reaction
conditions.7 In order to synthesize constrained tyrosine ana-
logues, diiodo- or dibromo tyrosine (structure A, Fig. 2) was used
to suppress a phenol-formaldehyde polymerization reaction.8 In
the synthesis of Tic derivatives carrying electron-withdrawing
groups on the aromatic ring, electrophilic substitution reactions
have been used often giving regio isomers (structure B, Fig. 2).9
In connection with our CGRP (calcitonin gene-related peptide)
antagonist medicinal chemistry program,10 we were interested in
the synthesis of Tic derivatives in enantiomerically pure form rep-
resented by 1 (Fig. 2) with a diverse array of substituents carrying
lipophilic groups and hydrogen bond acceptors and donors (R =
alkyl, aryl, heteroaryl or basic moieties).
AcO
AcO
X
CbzHN
H
Me
nOe
5a
4a
O
O
3J(Hvinyl, Ccarbonyl) = 6.7 Hz
NHBoc
NHBoc
A (X = I)
B (X = Br) 96
C (X = I)
62
56
AcO
AcO
AcO
X
BocHN
4b
CO2Me
5b
NHBoc
Our retrosynthetic bond disconnection is shown in Figure 2. A
leaving group at the benzylic position could easily be displaced
with a-nitrogen. The synthesis of key intermediate 2 with a leaving
NHBoc
A (X = I)
B (X = Br) 97
C(X = I)
71
54
AcO
group (L) would follow via a tandem palladium-mediated Heck
coupling11,12 of an aryl halide with a dehydroamino acid, followed
by asymmetric hydrogenation mediated by rhodium(II)-based chi-
ral catalysts.13 We and others have previously disclosed an effi-
cient approach to the synthesis of 2 using a Heck coupling
followed by asymmetric hydrogenation.14 The halogen functional-
ity Y needed for a Heck coupling could easily be introduced regio-
selectively under the directing influence of functional group X.
Successful implementation of this approach under mild conditions
is described below.
X
CbzHN
4c
CO2Me
5c
Me
Me
AcO
AcO
AcO
AcO
AcO
B
66
Br
CbzHN
4d
CO2Me
5d
F
Aryl halides 4a–c (Table 1) were synthesized regioselectively
with either iodine monochloride or N-bromosuccinimide in 62–
85% yield.15 Aryl halides 4d–g (Table 1) were synthesized from
the corresponding carboxylic acids by (i) activation with 1,10-car-
bonyldiimidazole followed by reduction (NaBH4), and then (ii)
acetylation under standard conditions (Ac2O, DMAP). The aryl ha-
lides were coupled to dehydroamino acid 3 (Fig. 2) under differ-
ent sets of Heck reaction conditions, depending on the halide.
Aryl iodides were coupled in the presence of tetrabutylammo-
nium chloride and a base such as Et3N (Condition A) or NaHCO3
(Condition C), mediated by 5–10 mol % of palladium(II) acetate in
refluxing THF (Table 1). The aryl bromides 4a–f (X = Br) were
coupled to dehydroamino acid in the presence of N-meth-
yldicyclohexylamine (Condition B), mediated by bis (tri-tert-
butylphosphine) palladium(0) (0.05 mol %) under Fu’s reaction
conditions (dioxane, 100 °C).12 Aryl bromides were found to be
superior substrates as they provided cleaner products ( 5a, 5b,
5c and 5f) in good yields and higher purities (>95% purities),
from quaternary ammonium salt (N-methyldicyclohexylammoni-
um bromide) contamination. Simple dilution of the reaction mix-
ture with diethyl ether followed by filtration was the purification
method used to accomplish this. This easy purification was found
to have significant impact in the subsequent hydrogenation step
since the quaternary ammonium salts were detrimental, even in
trace quantities, to the asymmetric rhodium(II) catalysts. As
observed earlier,14 the coupled products 5a–g (Table 1) were
obtained as single isomers with (Z)-stereochemistry in 38–96%
yield, except 5f, which was obtained as a mixture of (Z) and (E)
isomers [(Z)/(E) = 10/1)]. The geometry of the double bond
for Heck coupled products was determined by proton coupled
13C NMR experiments using a gated decoupled pulse sequence.
The observed H-C three-bond coupling constant (3J Hvinyl,
F
F
F
AcO
C
38
57
Br
CbzHN
4e
CO2Me
5e
NO2
A
B
NO2
89c
AcO
Br
4f
CbzHN
CO2Me
5f
Br
Br
AcO
A
45
I
CbzHN
4g
CO2Me
5g
a
Reaction conditions: 70 °C for 4.5 h, 1.1 equiv Bu4NCl, 0.05 mol % Pd(OAc)2,
1.3 equiv dehydroamino acid, 3.0 equiv Et3N, in THF (Condition A); 100 °C for 12 h,
1.1 equiv N,N-dicyclohexylmethyamine, 1.2 equiv dehydroamino acid, 0.05 equiv
bis(tri-t-butylphosphine)palladium(0) in dioxane (Condition B); 70 °C for 6 h,
1.1 equiv Bu4NCl, 0.05 mol % Pd(OAc)2, 1.3 equiv dehydroamino acid, 2.7 equiv
NaHCO3, in THF (Condition C).
b
Yields refer to weight of product obtained after flash chromatography. All the
examples in the table were >95% pure as determined by 1H NMR.
c
Yield refers to combined yield of (E) and (Z)-isomers.
Cmethyl
carbonyl = 6.9 Hz) is consistent with the cis-3JCOOR,
on the acetate group. As shown in Table 1, alkoxy, alkyl, amine,
nitro and bromo functionalities on the aryl halide were
compatible with the Jeffery-type reaction conditions. Asymmetric
acetate
H
coupling.16 The (Z)-configuration was further supported by the
observed NOE between the vinyl proton and the methyl protons

5590
P. V. Chaturvedula et al. / Tetrahedron Letters 51 (2010) 5588–5591
hydrogenations of (Z)-alkyl-substituted enamides were carried
out either with (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)ben-
zene(cyclooctadiene)rhodium (II) tetrafluoroborate13 (or its
(R,R)-enantiomer) in dichloromethane or in 1:1 dichlorometh-
Table 2 (continued)
Substrate
Yield
(ee)
Product yield (ee)c,f
Br
Br
13a: X = OAc
13b: X = OH
13c: X = Cl
a
b
X
99
(98.8)
88
Table 2
(nd)d
Functionalization and formation of Tic derivativesa,b
CbzHN
N
Product yield (ee)c,f
Cbz
Substrate
Yield
(ee)
CO2Me
CO2Me
20
a
OBn
BnO
Reaction conditions: (a) 1.3 equiv of Mg(OMe)2 in CHCl3–methanol (2:1) at rt
4–6 h; (b) 1.2 equiv CH3SO2Cl, 1.2 equiv Hunig’s base in CH2Cl2; (c) 1.05 equiv
CsCO3 in DMF; (d) combined yield for two steps (chloride formation and cycliza-
tion); (e) combined yield for three steps (hydrolysis, chloride formation and cycli-
zation); (f) ee refers to enantiomeric excess determined by chiral column.17,19 nd:
not determined; (g) combined yield for hydrolysis and cyclization under DEAD/
PPh3.
7a: X = OAc
7b: X = OH
7c: X = Cl
a
b
X
95
(99.4)
93
(97)
CbzHN
N
Cbz
CO2Me
14
b
CO2Me
Yields refer to weight of product obtained after flash chromatography. All the
examples in the Table were >95% pure as determined by 1H NMR.
99
(97.7)
86
(97.5)
NHBoc
BocHN
ane–methanol to give the reduced chiral product in >95% yield.
Chiral HPLC analysis of amino acid esters 7a, 8a, 9a, 11a, and
12a (Table 2) and their enantiomers suggested that reduction
proceeded in >99% ee.17 The absolute configuration of hydrogena-
tion products 7a–13a were tentatively assigned based on re-
ported chiral preference of cationic rhodium catalysts. Cleavage
of the acetate group proceeded with catalytic K2CO3 in MeOH
or NaOMe in CHCl3–MeOH in good yield, but the obtained alco-
hol had a compromised chiral purity (80–95% ee). However, mag-
8a: X = OAc
8b: X = OH
8c: X = Cl
a
X
96
(99.8)
98
(98)
b
CbzHN
N
Cbz
CO2Me
15
CO2Me
91
(99.0)
92
nesium methoxide18 in
a 2:1 mixture of chloroform and
(98.8)
methanol provided the alcohols 7b, 8b, and 9b with >98% ee
and in quantitative yield. Treatment of alcohol with excess meth-
anesulfonyl chloride and N,N0-diisopropylethyl amine in dichloro-
methane provided chlorides 7c–13c.
NHBoc
BocHN
9a: X = OAc
9b: X = OH
9c: X = Cl
a
b
X
98
(99)
97(99.4)
Cyclization of benzylic chlorides to the desired Tic derivatives
was examined using different bases (NaH, CsCO3–DMF). Alterna-
tively, cyclization of benzylic alcohol 12b under Mitsunobu condi-
tions (DEAD, PPh3) was also explored. Substrates 7–9 were
carefully examined by measuring the enantiomeric excess at each
step from acetate hydrolysis through cyclization. As shown in Ta-
ble 2, cesium carbonate in DMF provided optimal conditions for
providing Tic derivatives in high optical purities.19 Partial racemi-
zation was observed with substrates 11 and 12 where electron-
withdrawing groups have been attached to the aromatic ring
(88–91% ee). Under milder Mitsunobu conditions (PPh3, DEAD,
CH2Cl2, 0 °C, 12 h) 12b was obtained in improved optical purity
but in lower yield. Substrate 13c also provided desired cyclized
product 20 in good yield where the bromo functionality should
facilitate further derivatization under standard metal-catalyzed
conditions.20
In summary, an efficient enantioselective approach to con-
strained phenylalanine derivatives has been developed using a pal-
ladium-mediated Heck reaction followed by asymmetric reduction
with cationic rhodium catalysts. Functional group manipulation
and cyclization proceeded with a minimal amount of racemization.
Application of this methodology in our CGRP antagonist drug dis-
covery program will be reported in due course.
CbzHN
N
Cbz
CO2Me
16
CO2Me
96(99.4)
89(99.1)
10a: X = OAc
10b: X = OH
10c: X = Cl
X
a
78
76
78
(nd)d
b
CbzHN
N
Cbz
CO2Me
17
CO2Me
F
F
F
F
11a: X = OAc
11b: X = OH
11c: X = Cl
X
a
b
75
(99.9)
65
(91)e
CbzHN
N
Cbz
CO2Me
18
CO2Me
NO2
O2N
12a: X = OAc
12b: X = OH
12c: X = Cl
a
X
96
(98.8)
84
Acknowledgments
(88)d
b
CbzHN
N
Cbz
We would like to thank Dr. Stella Huang and Dr. Yingzi Wang of
Discovery Analytical Services (DAS) for their skillful NMR assis-
tance and to Edward Kozlowski of DAS for determining enantio-
meric excess values.
CO2Me
19
CO2Me
98
36
(95)g

P. V. Chaturvedula et al. / Tetrahedron Letters 51 (2010) 5588–5591
5591
17. Chiral HPLC analysis was performed to determine the enantiomeric excess of
7a–c, 8a–c, 9a–c, 11a–b, 12a–b and their enantiomers. The analysis was
performed on a Chiralcel OD-H analytical column (4.6 ꢁ 250 mm, 5 mm) using
15% isopropanol in CO2 at 150 Bar and at 35 °C as mobile phase at a flow rate of
References and notes
1. Hruby, V. J.; Li, G.; Haskell-Luevano, C.; Shenderovich, M. Biopolymers 1997, 43,
219.
2.0 mL/min. Absorbance was measured at 220 nm and 5 lL of 1 mg/mL of 7a–c
2. (a) Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooks, J. R.; Saperstein, R.
Science 1980, 210, 656; (b) Warshawsky, A. M.; Flynn, G. A.; Koehl, J. R.; Mehdi,
S. Bioorg. Med. Chem. Lett. 1996, 6, 957; (c) Valle, G.; Kazmierski, W. M.; Crisma,
M.; Bonora, G.; de Laszlo, S. E.; Bush, B. L.; Doyle, J. J.; Greenlee, W. J.; Hangauer,
D. G.; Halgren, T. A.; Lynch, R. J.; Schorn, T. W.; Siegl, P. K. S. J. Med. Chem. 1992,
35, 833.
3. (a) Kazmierski, W. M.; Yamamura, H. I.; Hruby, V. J. J. Am. Chem. Soc. 1991, 113,
2275; (b) Kyle, D. J.; Martin, J. A.; Burch, R. M.; Carter, J. P.; Lu, S.; Meeker, S.;
Prosser, J. C.; Sullivan, J. P.; Togo, J.; Noronha-Blob, L.; Sinsko, J. A.; Walters, R.
F.; Whaley, L. W.; Hiner, R. N. J. Med. Chem. 1991, 34, 2649–2653; (c) Otvos, F.;
Gembitsky, D. S.; Murphy, R. F.; Lovas, S. Int. J. Peptide Protein Res. 2007, 13, 329;
(d) Caliendo, G.; Calignano, A.; Grieco, P.; Mancuso, F.; Perisutti, E.; Santini, A.;
Santagada, V. Biopolymers 1995, 36, 409; Pimenta, D. C.; Melo, L. R.; Caliendo,
G.; Santagada, V.; Fiorono, F.; Severino, B.; De Nucci, G.; Juliano, M. Biol. Chem.
2002, 383, 853.
or their enantiomers in ethanol was injected. Compound 7a had a retention
time of 11.91 min (its enantiomer had a retention time of 14.2 min) and an
enantiomeric excess of 7a was determined to be 99.4%. The retention times for
the other compounds are: 8a has a retention time of 4.51 min (Chiracel AD-H
column, 15% methanol in CO2 as mobile phase, 8.63 min for its enantiomer), 8b
has a retention time of 9.99 min (Chiracel OD-H column, 15% isopropanol in
CO2 as mobile phase, 8.43 min for its enantiomer), 8c has a retention time of
13.27 min (Chiracel AD-H column, 15% isopropanol in CO2 as mobile phase,
14.25 min for its enantiomer), 9a has a retention time of 18.36 min (Chiracel
OJ-H column, 8% isopropanol in CO2 as mobile phase, 20.81 min for its
enantiomer), 9b has a retention time of 33.15 min (Chiracel OJ-H column, 8%
isopropanol in CO2 as mobile phase, 29.97 min for its enantiomer), 9c has
,
30.60 min (Chiracel OJ-H column, 7% isopropanol in CO2 as mobile phase,
27.50 min for its enantiomer), 11a has a retention time of 10.6 min (Chiracel AS
column, 90% heptane—10% methanol as mobile phase, 13.0 min for its
enantiomer), 12a has a retention time of 12.65 min (Chiracel OJ-H column,
10% methanol in CO2 as mobile phase, 11.2 min for its enantiomer).
4. Valle, G.; Kazmierski, W. M.; Crisma, M.; Bonora, G. M.; Toniolo, C.; Hruby, V. J.
Int. J. Peptide Protein Res. 1992, 40, 222.
5. Severino, B.; Santagada, V.; Frecentese, F.; Perisutti, E.; Terracciano, S.; Fiorino,
F.; Cirillo, D.; Salvadori, S.; Balboni, G.; Calendo, G. Synthesis 2004, 18, 3011.
6. Page, D.; McClory, A.; Mischki, T.; Schmidt, R.; Butterworth, J.; St-Onge, S.;
Labarre, M.; Payza, K.; Brown, W. Bioorg. Med. Chem. Lett. 2000, 10, 167.
7. (a) Julian, P. L.; Karpel, W. J.; Magnani, A.; Meyer, E. W. J. Am. Chem. Soc 1948,
70, 182; (b) Archer, S. J. Org. Chem. 1951, 16, 430; (c) Hayashi, K.; Ozaki, Y.;
Nunami, K.; Yoneda, N. Chem. Pharm. Bull. 1983, 31, 312; Ruzza, P.; Caldern, A.;
Osler, A.; Elardo, S.; Borin, G. Tetrahedron Lett. 2002, 43, 3769–3771.
8. (a) Verschueren, K.; Toth, G.; Tourwe, D.; Lebl, M.; Van Binst, G.; Hruby, V.
Synthesis 1992, 458; (b) Faul, M. M.; Winneroski, L. L.; York, J. S.; Reinhard, M.
R.; Hoying, R. C.; Gritton, W. H.; Dominiami, S. J. Heterocycles 2001, 55, 689; (c)
Liu, C.; Thomas, J. B.; Brieaddy, L.; Berrang, B.; Ivy Carroll, F. Synthesis 2008, 6,
856.
18. Xu, Y.-C.; Bizuneh, A.; Walker, C. J. Org. Chem. 1996, 61, 9086.
19. Chiral HPLC analysis was performed to determine the enantiomeric excess of
14, 15, 16, 18 and 19 and their enantiomers. The analysis was performed on a
Chiralcel analytical column (4.6 ꢁ 250 mm, 5 mm) using 15% isopropanol in
CO2 at 150 Bar and at 35 °C as mobile phase at a flow rate of 2.0 mL/min.
Absorbance was measured at 220 nm and 5 lL of 1 mg/mL of compound in
ethanol was injected. The retention times are: 15 has a retention time of
5.01 min (Chiracel OD-H column, 20% isopropanol in CO2 as mobile phase,
4.30 min for its enantiomer), 16 has a retention time of 4.37 min (Chiracel OD-
H
column, 20% isopropanol in CO2 as mobile phase, 4.96 min for its
enantiomer), 18 has a retention time of 9.60 min (Chiracel AD column, 8%
ethanol in CO2 as mobile phase, 10.7 min for its enantiomer) and 19 has a
retention time of 20.6 min (Chiracel AD-H column, 10% ethanol in CO2 as
mobile phase, 25.5 min for its enantiomer).
9. Santagada, V.; Fiorino, F.; Severino, B.; Salvadori, S.; Lazarus, L. H.; Bryant, S. D.;
Caliendo, G. Tetrahedron Lett. 2001, 42, 3507.
20. Yields were not optimized. All compounds gave satisfactory spectroscopic
data consistent with the proposed structures. Data for selected compounds
14: 1H NMR (500 MHz, DMSO-d6) showed a mixture of rotamers doubling
most signals d ppm 3.02–3.16 (m, 2H) 3.50 and 3.55 (2s, 3H, OCH3, rotamers)
4.40–4.63 (2 d, J = 16.50 Hz, 1H, rotamers) 4.66–4.75 (2 d, J = 16.50 Hz, 1H,
rotamers) 4.85–5.19 (m, 5H), 6.80–6.86 (m, 1H), 6.90–6.97 (m, 1H), 7.08–7.15
(m, 1H), 7.25–7.52 (m, 10 H); MS (ES), 454 (M+Na)+ 15: 1H NMR (500 MHz,
chloroform-d) showed a mixture of rotamers doubling most signals d ppm
1.50 (s, 9H), 2.09 and 2.17 (s, 3H,) 3.08–3.28 (m, 2H) 3.52 and 3.59 (2s, 3H,
OCH3, rotamers) 4.48–4.57 (2 d, J = 17.20 Hz, 1H, rotamers) 4.79–4.95 (2 d,
J = 17.20 Hz, 1H, rotamers) 5.14–5.33 (m, 3H) 6.25 and 6.26 (2s, 1H,
rotamers), 6.90 (s, 1H) 7.28–7.46 (m, 5H), 7.62 (s, 1H); MS (ES), 477
(M+Na)+ 16: 1H NMR (500 MHz, chloroform-d) showed a mixture of rotamers
doubling most signals d ppm 1.53 (s, 9H), 2.09 and 2.14 (2s, 3H, rotamers)
3.06–3.31 (m, 2H) 3.57 and 3.63 (2s, 3H, OCH3, rotamers) 4.38–4.56 (2 d,
J = 16.94 Hz, 1H, rotamers) 4.78 (2 d, J = 16.94 Hz, 1H, rotamers) 4.97–5.07
(m, 1H) 5.14–5.35 (m, 2H) 6.28 (d, J = 10.99 Hz, 1H) 6.99 (dd, J = 8.24, 3.97 Hz,
1H) 7.29–7.56 (m, 5H); MS (ES), 453 (MꢀH)ꢀ 18: 1H NMR (300 MHz,
chloroform-d) showed a mixture of rotamers doubling most signals d ppm
3.04–3.27 (m, 2H) 3.57 and 3.61 (2s, 3H, OCH3, rotamers) 4.40–4.56 (2 d,
J = 16.94 Hz, 1H, rotamers) 4.65–4.75 (2 d, J = 16.94 Hz, 1H, rotamers) 4.97–
5.21 (m, 3H) 6.77–7.01 (m, 2H), 7.25–7.43 (m, 5H); 19: 1H NMR (500 MHz,
chloroform-d) showed a mixture of rotamers doubling most signals d ppm
3.22–3.44 (m, 2H), 3.57 and 3.64 (2s, 3H, OCH3, rotamers) 4.70 (d, J = 17.0 Hz,
1H) 4.93 (d, J = 17.0 Hz, 1H) 5.09–5.30 (m, 3H), 7.30–7.45 (m, 6H), 7.93–8.11
(m, 2H); MS (ES), 393 (M+Na)+.
10. Degnan, A. P.; Chaturvedula, P. V.; Conway, C. M.; Cook, D. A.; Davis, C. D.;
Denton, R.; Han, X.; Macci, R.; Mathais, N. R.; Moench, P.; Pin, S. S.; Ren, S. X.;
Schartman, R.; Signor, L. J.; Thalody, G.; Widmann, K. A.; Xu, C.; Macor, J. E.;
Dubowchik, G. M. J. Med. Chem. 2008, 51, 4858–4861.
11. (a) Heck, R. F. Org. React. 1982, 27, 345; (b) Crisp, G. T. Chem. Soc. Rev. 1998, 27,
427; (c) Jeffery, T. J. Chem. Commun. 1984, 1287.
12. For exceptionally mild catalysts for Heck reactions, see: Littke, A. F.; Fu, G. C. J.
Am. Chem. Soc. 2001, 123, 6989.
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observed H–C three-bond coupling constant (3J Hvinyl, Cmethyl
=
acetate carbonyl
10.9 Hz) for the (E) isomer of 5f is consistent with the trans-3JCOOR, H coupling.