Synthesis of isomeric 1,4-[13C]2-labeled 2-ethoxycarbonyl-1,4-diphenylbutadienes

Article abstract of DOI:10.1016/S0040-4039(00)02021-9

The 1,4-bis-¹³C-labeled isomeric compounds (Z,E)- and (E,E)-2-ethoxycarbonyl-1,4-diphenylbutadiene have been synthesized by two different methods. A double Horner-Wadsworth-Emmons (HWE) strategy was employed for the synthesis of the Z,E isomer. On the other hand, synthesis of the E,E isomer was achieved by Baylis-Hillman reaction of benzaldehyde with ethyl acrylate and subsequent rearrangement, followed by Wittig olefination with benzaldehyde. The routes provide stereoselective access to labeled compounds in good yields.

Full text of DOI:10.1016/S0040-4039(00)02021-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 619–621
Synthesis of isomeric 1,4-[13C]2-labeled
2-ethoxycarbonyl-1,4-diphenylbutadienes
Rachael M. Crist, Pulgam Veera Reddy and Babak Borhan*
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
Received 13 October 2000; accepted 25 October 2000
Abstract—The 1,4-bis-13C-labeled isomeric compounds (Z,E)- and (E,E)-2-ethoxycarbonyl-1,4-diphenylbutadiene have been
synthesized by two different methods. A double Horner–Wadsworth–Emmons (HWE) strategy was employed for the synthesis of
the Z,E isomer. On the other hand, synthesis of the E,E isomer was achieved by Baylis–Hillman reaction of benzaldehyde with
ethyl acrylate and subsequent rearrangement, followed by Wittig olefination with benzaldehyde. These routes provide stereoselec-
tive access to labeled compounds in good yields. © 2001 Elsevier Science Ltd. All rights reserved.
Retinal binding proteins have been the focus of many
investigators, their importance in visual transduction,
gene regulation control, and onset of diseases has been
well documented.1 They have also been used as models
for studying protein–substrate interactions. Wavelength
regulation exhibited by various rhodopsin pigments in
the eye is a remarkable example of the consequences of
protein–substrate interactions.2,3 A single chromophore,
namely 11-cis-retinal, bound to different rhodopsins is
tuned to absorb at various wavelengths, which allows
for the perception of color. These interactions provide a
simple and elegant platform to study protein–substrate
interactions.
cause different degrees of torsional twisting of the
single bonds, thus causing different degrees of conjuga-
tion and ultimately different wavelength maxima.4 We
are interested in studying retinal conformational differ-
ences in different rhodopsin pigments by the binding of
bis-13C-labeled retinal such as 11,14-[13C]2-11-cis-retinal
(1) (for examining the degree of C12/C13 twisting).
Solid state NMR techniques will be used to probe the
degree of single bond twisting within the polyene as it is
bound to different rhodopsin proteins.5,6
It has been suggested that conformational and/or
stereoelectronic effects control wavelength regulation
exhibited by different rhodopsins.2,3 With regards to the
unbound chromophore, steric interactions of the C5-
CH3/H8 and C13-CH3/H10 in 11-cis-retinal (1) force
dihedral twists of the C6/C7 and C12/C13 single bonds,
respectively. However, unique environments within the
retinal binding site of each rhodopsin pigment may
To first establish the solid state NMR conditions and
probe the limitations in sensitivity and accuracy for the
measurement of dihedral angles with bis-13C-labeled
substrates, we have synthesized two isomers of 2-
ethoxycarbonyl-1,4-diphenylbutadiene to serve as
model compounds (Z,E isomer 2, and E,E isomer 3).
These two molecules contain the same olefinic labeling
pattern as the proposed 11-cis-retinal (1), i.e. 1,4-[13C]2-
labels. The isomeric phenyl group at C1 of 2 and 3 lead
to different torsional twists within the C2/C3 single
bond. We have performed conformational analyses of
Keywords: 1,2,4-trisubstituted-butadienes; HWE reactions; stable
radiolabeled synthesis.
* Corresponding author. Tel.: 517-355-9715 x 138; fax: 517-353-1793;
e-mail: borhan@cem.msu.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02021-9

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R. M. Crist et al. / Tetrahedron Letters 42 (2001) 619–621
these molecules and have determined the theoretical
dihedral angles between the olefinic planes (dihedral
angles between C1ꢀC2ꢀC3ꢀC4) for each compound. As
illustrated in Fig. 1, the planes defined by the two
olefins in the Z,E isomer 2 are twisted by about 20°.
However, the same two planes in the E,E isomer 3 are
twisted by 41°.
oxidized promptly with mCPBA to yield the syn-elimi-
nated product 6 in high yield. The olefinic carbons in 6
are the unlabeled carbons C2 and C3 in the final
product. The double HWE reaction at these two carbon
centers with 13C-carbonyl-labeled benzaldehyde would
deliver the 1,4-bis-13C-labeled compounds. The double
HWE reaction was initiated by the 1,4 addition of
diethylphosphite anion to obtain the bis-phosphate 7.
Deprotonation of 7 with s-BuLi and addition of labeled
benzaldehyde delivered intermediate 8, which was
treated with another equivalent of s-BuLi and labeled
benzaldehyde to deliver a 6:1 isomeric mixture of 2:3 in
39% yield over the latter steps. The Z,E isomer 2 was
purified by HPLC.9
Herein, we report two simple and straightforward
schemes for the stereospecific synthesis of 2 and 3.
Strategies for synthesis of similar compounds have been
reported previously.7,8 However, we required a proce-
dure that would deliver the 1,4-bis-labeled butadienes
from readily available and inexpensive 13C-labeled pre-
cursors. The labeled carbons are incorporated from
benzaldehyde in all cases, thus allowing the schemes to
be modified to obtain different 1,4-substituted butadi-
enes by changing the carbonyl species.
Our attempts at a one pot synthesis from 6“2 by
utilizing the enolate generated after the Michael addi-
tion of diethylphosphite with 6 for the subsequent
HWE reactions produced low yields of the desired final
compound and was not reproducible. It was therefore
necessary to isolate 7 and proceed forward. The bis-
olefination of 7 allows for the introduction of commer-
cially available 13C-labeled carbonyl compounds such
as benzaldehyde or other ketones or aldehydes as the
The Z,E isomer 2 was synthesized by employing a
double Horner–Wadsworth–Emmons (HWE) strategy
(Scheme 1) in a similar fashion, which was reported by
Minami et al.8 Selenation of triethyl-2-phosphonopro-
pionate (4) proceeded smoothly to furnish 5, which was
Figure 1. Structures 2 and 3 were minimized (MacroModel, version 7.0) to obtain the most stable conformation. The Z,E isomer
2 exhibits a 20° dihedral twist of the single bond which connects the olefinic planes. The E,E isomers exhibits a 41° dihedral twist
of the same bond.
Scheme 1.

R. M. Crist et al. / Tetrahedron Letters 42 (2001) 619–621
621
Scheme 2.
last step of the synthesis. In this manner, we can
introduce both labels at once at the end of the scheme.
This is desirable in the synthesis of labeled compounds
since there are no subsequent steps that would decrease
the yield of the labeled material.
Retinoids, 2nd ed.; Sporn, M. B.; Roberts, A. B.; Good-
man, D. S., Eds.; Raven Press: New York, 1994; pp.
443–520.
2. Kochendoerfer, G. G.; Wang, Z.; Oprian, D. D.;
Mathies, R. A. Biochemistry 1997, 36, 6577–6587.
3. Kochendoerfer, G. G.; Lin, S. W.; Sakmar, T. P.;
Mathies, R. A. TIBS 1999, 24, 300–305.
4. Blatz, P. E.; Liebman, P. A. Exp. Eye Res. 1973, 17,
573–580.
5. Weliky, D. P.; Tycko, R. J. Am. Chem. Soc. 1996, 118,
8487–8488.
6. Weliky, D. P.; Bennett, A. E.; Zvi, A.; Anglister, J.;
Steinbach, P. J.; Tycko, R. Nature Struct. Biol. 1999, 6,
141–145.
Synthesis of the E,E isomer 3 is illustrated in Scheme 2.
The Baylis–Hillman reaction between labeled benzalde-
hyde and ethyl acrylate proceeded smoothly to furnish
the allyl alcohol 9,10 which upon treatment with HBr in
concentrated sulfuric acid rearranged to yield the allyl
bromide 10 in excellent yield.11 As reported by Aggar-
wal and co-workers, we also noticed a substantial
decrease in reaction time required for the Baylis–Hill-
man reaction catalyzed by 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) (1 day) as compared to DABCO (7
days).12 Ylide 11 was obtained in quantitative yield
from the reaction of 10 with triphenylphosphine, which
was subsequently deprotonated and reacted with
labeled benzaldehyde to afford the desired E,E diene 3
in good yield and high isomeric purity (20:1 ratio of
3:2).13 Although we had to use the labeled benzalde-
hyde in the first step of the synthesis, we did not deem
this as a major problem since the yield of subsequent
reactions were high.
7. Bodalski, R.; Janecki, T. Synthesis 1989, 506–510.
8. Minami, T.; Tokumasu, S.; Hirao, I. Bull. Chem. Soc.
Jpn. 1985, 58, 2139–2140.
9. Compound 2 was purified by HPLC with a normal phase
column (Altex Ultra Sphere-Si) using a Perkin–Elmer
LC-75 system under isocratic conditions (2% EtOAc/Hex,
5 mL/min, detection at 325 nm). 1H NMR (300 MHz,
CDCl3): l 1.2 (3H, t, J=7.14 Hz); 4.34 (2H, q, J=7.14
1
Hz); 6.65 (1H, dd, J=16.5 Hz, JHC=156 Hz); 6.75 (1H,
1
d, JHC=155.2 Hz); 6.89 (1H, m); 7.2–7.5 (10H, m); 13C
NMR (75 MHz, CDCl3): l 13.9; 61.4; 126.6 (d, 3JCC=2.3
1
Hz); 127.4 (d, JCC=43.8 Hz); 128.0; 128.2; 128.3; 128.5
The stereoisomers 2 and 3 were characterized by one-
and two-dimensional NMR spectroscopy. The stereo-
chemistry of the olefinic bonds was confirmed by
NOESY. In particular, strong coupling of H1 and H3
protons was observed in 2, which was absent in 3. 13C
NMR analysis of the resulting 2 revealed doubly
enhanced signals at 132.7 and 131.0 ppm, while 3
displayed enhanced signals at 138.8 and 134.7 ppm,
corresponding to enriched C1 and C4 of the 1,3-butadi-
ene system.
(d, 2JCC=4.6 Hz); 128.7 (d, 2JCC=4.6 Hz); 131.0 (d,
3
1
3JCC=8.0 Hz); 132.7 (d, JCC=9.2 Hz); 134.2 (d, JCC
=
1
1
58.5 Hz); 135.4 (d, JCC=55.5 Hz); 136.7 (d, JCC=55.5
Hz); 168.9.
10. Fort, Y.; Berthe, M. C.; Caubere, P. Tetrahedron 1992,
48, 6371–6384.
11. Buchholz, R.; Hoffmann, H. M. R. Helv. Chim. Acta
1991, 74, 1213–1220.
12. Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311–
2312.
13. Compound 3 was purified by HPLC under the same
conditions as compound 2.9 1H NMR (500 MHz,
CDCl3): l 1.38 (3H, t, J=7 Hz); 4.35 (2H, q, J=7 Hz);
7.03 (1H, dd, J=3.3 Hz, 17 Hz); 7.20–7.48 (11H, m); 7.57
In conclusion, the present procedure provides a conve-
nient route to synthesize isomeric 1,4-substituted-buta-
dienes. The solid state NMR studies will be reported in
due course.
1
(1H, d, JHC=134 Hz); 13C NMR (75 MHz, CDCl3): l
1
14.5; 61.0; 121.6 (d, JCC=73.3 Hz); 126.7; 127.8; 128.4;
2
1
(d, JCC=4.6 Hz); 128.6; 128.7; 130.0 (d, JCC=70.9 Hz);
References
3
1
130.1; 134.7 (d, JCC=5.7 Hz); 135.5 (d, JCC=55.5 Hz);
137.5 (d, JCC=55.5 Hz); 138.8 (d, JCC=5.7 Hz); 167.5.
1
3
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