Synthesis of new 9-methylene analogs of retinoids

Article abstract of DOI:10.1080/00397910500187688

We report herein a series of syntheses that provides diverse structural modifications of the side-chain of retinoids to obtain new compounds with potential use in anticancer therapy. Starting from a β-methylenealdehyde synthon, we have synthesized a series of new 9-methylene-13-desmethyl-14-methyl analogs and a series of 9-methylene-11-desmethyl trienic homologs. For the first series, the condensation of the C-15 β-methylenealdehyde with the anion of ethyl 4-(diethoxyphosphoryl)-2E-methylbut-2-enoate led to the 7E,11E,13E-ester. This gave the desired aldehyde by a reduction into the corresponding alcohol (DIBAL-H) and subsequent oxidation by MnO₂. For the second series, the reaction of the C-15 β-methylenealdehyde with the anions of ethyl diethoxyphosphorylacetate, diethyl cyanomethylphosphonate, or diethyl 2-oxopropylphosphonate led to the C-17 ester, the C-17 nitrile, and the C-18 ketone, respectively. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500187688

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Synthesis of New 9‐Methylene
Analogs of Retinoids
Alain Valla a , Zo Andriamialisoa a , Dominique
Cartier a , Roger Labia a & Pierre Potier b
a Chimie et Biologie des Substances Naturelles FRE
2125 CNRS 6 , Quimper, France
b Institut de Chimie des Substances Naturelles, UPR
2301 CNRS , Gif‐sur‐Yvette Cedex, France
Published online: 18 Aug 2006.
To cite this article: Alain Valla , Zo Andriamialisoa , Dominique Cartier , Roger Labia
& Pierre Potier (2005) Synthesis of New 9‐Methylene Analogs of Retinoids, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:18, 2363-2369
To link to this article: http://dx.doi.org/10.1080/00397910500187688
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Synthetic Communicationsw, 35: 2363–2369, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500187688
Synthesis of New 9-Methylene Analogs
of Retinoids
Alain Valla, Zo Andriamialisoa, Dominique Cartier,
and Roger Labia
Chimie et Biologie des Substances Naturelles FRE 2125 CNRS 6,
Quimper, France
Pierre Potier
Institut de Chimie des Substances Naturelles, UPR 2301 CNRS,
Gif-sur-Yvette Cedex, France
Abstract: We report herein a series of syntheses that provides diverse structural modi-
fications of the side-chain of retinoids to obtain new compounds with potential use in
anticancer therapy. Starting from a b-methylenealdehyde synthon, we have synthe-
sized a series of new 9-methylene-13-desmethyl-14-methyl analogs and a series of
9-methylene-11-desmethyl trienic homologs. For the first series, the condensation of
the C-15 b-methylenealdehyde with the anion of ethyl 4-(diethoxyphosphoryl)-2E-
methylbut-2-enoate led to the 7E,11E,13E-ester. This gave the desired aldehyde by a
reduction into the corresponding alcohol (DIBAL-H) and subsequent oxidation by
MnO2. For the second series, the reaction of the C-15 b-methylenealdehyde with the
anions of ethyl diethoxyphosphorylacetate, diethyl cyanomethylphosphonate, or
diethyl 2-oxopropylphosphonate led to the C-17 ester, the C-17 nitrile, and the C-18
ketone, respectively.
Keywords: b-Methylenealdehyde, retinoic acid analogs, retinoids
Retinoic acids (all E and 9Z), metabolites of retinol, act as ligands of small
molecular hormones that regulate the gene transcription through the activation
Received in Poland April 29, 2005
Address correspondence to Alain Valla, Laboratoire de Chimie et Biologie des
´
Substances Naturelles FRE 2125 CNRS, 6, rue de l’Universite 29000, Quimper,
France. E-mail: alain.valla@cegetel.net
2363

2364
A. Valla et al.
of the retinoic acid receptors (RARa, b, and g) and retinoid X receptors
(RXRa, b, and g). These receptors show major biological functions such as
cell differentiation, cell proliferation, and embryonic development. All
E-retinoic acid (ATRA), 13-cis-retinoic acid (13-cis-RA) and synthetic etreti-
nate have been used for treatment of skin diseases.[1–3] Retinoids are
compounds that regulate various physiological processes throughout embryo-
genesis, organogenesis, and homeostasis. Their differentiation and apoptosis-
inducing properties have shown strong utility for the treatment of carcinomas
and for cancer chemoprevention.[4–6]
Aromatic triethylenic compounds that have activity as antagonists for
retinoic acid receptors were described and their pharmaceutical compositions
patented.[7] Another process related to the syntheses of aromatic retinoid
antagonists for the manufacturing of a medicament for the treatment of osteo-
porosis and for use in the treatment of preneoplastic and neoplastic diseases.
They were also tested for retinoid receptor antagonist activity.[8]
In a recent work, we described the syntheses and the differentiation
and apoptosis-inducing potential of methylene and side-chain-modified
retinoids.[9] Taking into account these data and in connection with structure–
activity relationships of retinoids, a series of new 9-methylene-13-desmethyl-
14-methyl analogs and a series of 9-methylene-11-desmethyl trienic homologs
were synthesized. A b-methylenealdehyde synthon 1 (4E-3-methylene-5-
(2,6,6-trimethyl-1-cyclohexen-1-yl)-4-pentenal) was used for these syntheses,
which was previously reported for the syntheses of 13E and 13Z retinoids.[10]
The synthesis of the first series of analogs is described in Scheme 1.
Horner–Emmons reaction of 1 with the anion of ethyl 4-(diethoxypho-
sphoryl)-2E-methylbut-2-enoate (generated by sodium hydride) led to the
7E,11E,13E-ester 2 in 41% yield (after purification), with a regioselectivity
higher than 99% for the all E isomer. This latter was further reduced at
258C in toluene into the corresponding 7E,11E,13E-alcohol 3, using diisobu-
tylaluminium hydride (DIBAL-H, 1M in toluene). A convenient oxidation
with manganese dioxide in pentane at room temperature for 12 h led to the
7E,11E,13E-aldehyde 4 in 60% yield.
The second series of homologs is depicted in Scheme 2.
Scheme 1.

Synthesis of New 9-Methylene Analogs of Retinoids
2365
Scheme 2.
Horner–Emmons reaction of 1 with the anions of ethyl diethoxy-
phosphorylacetate, diethyl cyanomethylphosphonate, and diethyl 2-oxopro-
pylphosphonate led to the compounds 5–7 in satisfactory yields (51–67%).
For the syntheses of products 5 and 7, the regioselectivity for the production
of the 7E,9-methylene-11E isomer was higher than 99%.
During the synthesis of ketone 7, we also isolated a small amount (13%)
of a by-product: compound 8. This formation could be explained by an aldo-
lization reaction involving the anion of the ketone 7 and the b-methylenealde-
hyde 1 and catalyzed by the anion of the phosphonate (Scheme 3). This
reaction was not possible in the case of compounds 5 and 6 because their
phosphonate anions were extremely nucleophilic.
EXPERIMENTAL
1
All reactions were carried out under an argon atmosphere. H NMR spectra
were recorded at 400 MHz on a Bruker Avance DPX 400. Chemical shifts
are reported in ppm (d) relative to TMS. IR spectra were run on a Bruker
IF 55 spectrometer.
Scheme 3.

2366
A. Valla et al.
2. At 2608C, 6.6 g of ethyl 4-(diethoxyphosphoryl)-2-methylbut-2-enoate[11]
(10.1 mmol) in 25 mL of 1,2-dimethoxyethane (DME) were slowly added to a
stirred suspension of 0.4 g of sodium hydride (10.1 mmol) in 20 mL of DME.
The phosphonate was synthesized by an Arbusov reaction between the
bromide (or chloride) compound and triethylphosphite at 1608C. After
20 min at 2608C, 2 g of b-methyleneacetaldehyde (9.2 mmol) in 25 mL of
DME were added, and the mixture was warmed to rt. After purification of
the crude product (4.8 g) by column chromatography (SiO2, cyclohexane/
dichloromethane 60/40), the ester 2 was obtained as yellow oil (1.23 g, 41%).
1
IR (film cm21): 1717, 1601. H NMR (CDCl3): 7.22 (d, 1H, J ¼ 11.2,
C13-H); 6.45 (dd, 1H, J ¼ 15.1, J ¼ 11.2, C12-H); 6.19 (dt, 1H, J ¼ 15.1,
J ¼ 6.6, C11-H); 6.15 and 6.07 (2d, 2H, J ¼ 16.1, C7-H and C8-H); 5.05 and
4.98 (2s, 2H, C9-CH2); 4.22 (q, 2H, J ¼ 7.2, CO2CH2CH3); 3.18 (d, 2H,
J ¼ 6.6, C10-H); 2.01 (t, 2H, J ¼ 6.1, C4-H); 1.94 (1s, 3H, C14-CH3); 1.70 (1s,
3H, C5-CH3); 1.62 (m, 2H, C3-H); 1.46 (m, 2H, C2-H); 1.32 (t, 3H, J ¼ 7.2,
CO2CH2CH3); 1.00 (s, 6H, C1-CH3). 13C NMR (CDCl3): 168.5 (C15); 143.9,
137.3, 129.1, and 125.6 (C1, C2, C9 and C14); 139.9, 138.0, 134.2, 128.0, and
127.2 (C7, C8, C11, C12, and C13); 115.4 (C9-CH2); 60.4 (CO2CH2CH3); 39.3,
36.0, 32.7, and 19.1 (C3, C4, C5, and C10); 34.1 (C6); 28.7, 21.5, 14.2, and
12.5 (C2-CH3, C6-CH3, C14-CH3; and CO2CH2CH3). Anal. calcd. for
C22H32O2: C, 80.44; H, 9.82; O, 9.74. Found: C, 80.22; H, 9.98; O, 9.80.
3. At 258C, 0.46 g (1.4 mmol) of the preceding ester in 15 mL of toluene
were reduced by 2.5 mL (2.8 mmol) of diisobutylaluminium hydride (DIBAL-
H) in 5 mL of toluene. After quenching with an aqueous solution of 1 M
NH4Cl and the usual workup, the oily product (0.39 g) was purified by
column chromatography (SiO2, dichloromethane) to furnish the alcohol 3 as
yellow oil (0.28 g, 70%).
IR (film cm21): 3363. 1H NMR (CDCl3): 6.36 (dd, 1H, J ¼ 15.0,
J ¼ 10.9, C12-H); 6.17 and 6.07 (2d, 2H, J ¼ 16.3, C7-H and C8-H); 6.08
(d, 1H, J ¼ 10.9, C13-H); 5.81 (dt, 1H, J ¼ 15.0, J ¼ 6.7, C11-H); 5.01 and
4.96 (2s, 2H, C9-CH2); 4.07 (s, 2H, C15-H); 3.10 (d, 2H, J ¼ 6.7, C10-H);
2.01 (t, 2H, J ¼ 6.2, C4-H); 1.79 and 1.70 (2s, 6H, C5-CH3 and C14-CH3);
1.62 (m, 2H, C3-H); 1.47 (m, 2H, C2-H); 1.01 (s, 6H, C1-CH3). 13C NMR
(CDCl3): 144.8, 137.4, 135.2, and 128.9 (C1, C5, C9, and C14); 134.4, 132.0,
127.7, 127.2, and 124.9 (C7, C8, C11, C12, and C13); 114.8 (C9-CH2); 68.5
(C15); 39.4, 35.7, 32.7, and 19.1 (C4, C3, C2, and C10); 34.1 (C1); 28.7,
21.5, and 14.0 (C5-CH3, C1-CH3, and C14-CH3). Anal. calcd. for C20H30O:
C, 83.86; H, 10.56; O, 5.59. Found: C, 83.59; H, 10.71; O, 5.70.
4. Alcohol 3 (0.25 g, 0.9 mmol) in 5 mL of pentane was oxidized by 0.78 g
(9 mmol) of manganese dioxide in 5 mL of pentane at rt for 12 h. After purifi-
cation of the oily product (0.22 g) by column chromatography (SiO2, dichlor-
omethane), the aldehyde 4 was obtained as yellow oil (0.17 g, 68%).
IR (film cm21): 1683, 1635. 1H NMR (CDCl3): 9.45 (s, 1H, C15-H); 6.88
(d, 1H, J ¼ 11.2, C13-H); 6.63 (dd, 1H, J ¼ 15.1, J ¼ 11.2, C12-H); 6.35 (dt,
1H, J ¼ 15.1, J ¼ 6.7, C11-H); 6.15 and 6.08 (2d, 2H, J ¼ 16.6, C7-H and

Synthesis of New 9-Methylene Analogs of Retinoids
2367
C8-H); 5.09 and 5.00 (2s, 2H, C9-CH2); 3.24 (d, 2H, J ¼ 6.7, C10-H); 2.01
(t, 2H, J ¼ 6.3, C4-H); 1.85 and 1.70 (2s, 6H, C5-CH3 and C14-CH3); 1.62
(m, 2H, C3-H); 1.46 (m, 2H, C2-H); 0.99 (s, 6H, C1-CH3). 13C NMR
(CDCl3): 195.0 (C15); 148.7, 142.7, 134.0, 128.3, and 126.9 (C7, C8, C11,
C12, and C13); 143.4, 137.2, 136.3, and 129.3 (C6, C5, C9, and C14); 115.8
(C9-CH2); 39.3, 36.2, 32.7, and 19.1 (C4, C3, C2, and C10); 34.1 (C1); 28.7,
21.5, and 9.3 (C5-CH3, C1-CH3, and C14-CH3). Anal. calcd. for C20H28O:
C, 84.45; H, 9.92; O, 5.62. Found: C, 84.21; H, 10.03; O, 5.76.
5. At 08C, 3.5 g (15.6 mmol) of ethyl diethoxyphosphorylacetate in
20 mL of 1,2-dimethoxyethane (DME) were slowly added to a stirred suspen-
sion of 0.57 g of sodium hydride (14.2 mmol) in 20 mL of DME. After 1 h at
08C, the solution was cooled to 258C and 3.1 g (14.2 mmol) of 1 in 20 mL of
DME were added, and the mixture was warmed to rt. The crude reaction was
quenched with a aqueous solution of ammonium chloride. After extraction
with ether and the usual workup, the crude product (3.9 g) was purified by
column chromatography (SiO2, dichloromethane 60/40) to give the ester 5 as
yellow oil (2.46 g, 60%).
IR (film cm21): 1722. 1H NMR (CDCl3): 7.08 (dt, 1H, J ¼ 15.6, J ¼ 6.6,
C11-H); 6.11 and 6.06 (2d, 2H, J ¼ 16.5, C7-H and C8-H); 5.91 (d, 1H,
J ¼ 15.6, C12-H); 5.08 and 4.98 (2s, 2H, C9-CH2); 4.21 (q, 2H, J ¼ 7.1,
CO2CH2CH3); 3.18 (d, 2H, J ¼ 6.6, C10-H); 2.01 (t, 2H, J ¼ 6.3, C4-H);
1.70 (s, 3H, C5-CH3); 1.63 (m, 2H, C3-H); 1.48 (m, 2H, C2-H); 1.29 (t, 3H,
J ¼ 7.1, CO2CH2CH3); 1.00 (s, 6H, C1-CH3). 13C NMR (CDCl3): 166.4
(C13); 146.6, 133.9, 128.3, and 122.5 (C7, C8, C11, and C12); 142.7, 137.2,
and 129.2 (C6, C5, and C9); 116.0 (C9-CH2); 60.1 (CO2CH2CH3); 39.3,
35.0, 32.7, and 19.1 (C4, C3, C5, and C10); 34.1 (C1); 28.7, 21.5, and 14.1
(C5-CH3, C1-CH3, and CO2CH2CH3). Anal. calcd. for C19H28O2: C, 79.12;
H, 9.78; O, 11.09. Found: C, 78.99; H, 9.98; O, 11.03.
6. Using the same procedure, starting from 1.5 g (6.9 mmol) of 1 and 1.34
(7.6 mmol) of diethyl cyanomethylphosphonate, the crude mixture (1.55 g)
was purified by column chromatography (SiO2, dichloromethane/cyclo-
hexane 50/50) to provide 1.1 g (67%) of the nitrile 6, as a mixture of two
isomers 11E and 11Z (70/30).
1
11E isomer: IR (film cm21): 2221. H NMR (CDCl3): 6.85 (dt, 1H,
J ¼ 16.3, J ¼ 6.3, C11-H); 6.05 (s, 2H, C7-H and C8-H); 5.43 (d, 1H,
J ¼ 16.3, C12-H); 5.13 and 4.98 (2s, 2H, C9-CH2); 3.20 (d, 2H, J ¼ 6.3,
C10-H); 2.01 (t, 2H, J ¼ 6.4, C4-H); 1.68 (s, 3H, C5-CH3); 1.62 (m, 2H,
C3-H); 1.46 (m, 2H, C2-H); 1.00 (s, 6H, C1-CH3). 13C NMR (CDCl3): 153.3,
133.3, 128.6, and 100.8 (C7, C8, C11, and C12); 141.4, 136.9, 129.7, and 117.3
(C6, C5, C9, and C13); 116.8 (C9-CH2); 39.2, 35.9, 32.7, and 19.1 (C4, C3, C2,
and C10); 34.1 (C1); 28.7 and 21.5 (C5-CH3 and C1-CH3). Anal. calcd. for
C17H23N: C, 84.59; H, 9.60; N, 5.80. Found: C, 84.32; H, 9.88; N, 5.80.
1
11Z isomer: IR (film cm21): 2220. H NMR (CDCl3): 6.58 (dt, 1H,
J ¼ 10.9, J ¼ 7.4, C11-H); 6.16 and 6.07 (2d, 2H, J ¼ 17.0, C7-H and C8-H);
5.45 (d, 1H, J ¼ 10.9, C12-H); 5.08 and 5.00 (2s, 2H, C9-CH2); 3.40 (d, 2H,

2368
A. Valla et al.
J ¼ 7.4, C10-H); 2.02 (t, 2H, J ¼ 6.2, C4-H); 1.70 (s, 3H, C5-CH3); 1.63 (m, 2H,
C3-H); 1.48 (m, 2H, C2-H); 1.02 (s, 6H, C1-CH3). 13C NMR (CDCl3): 152.9,
133.7, 128.3, and 100.2 (C7, C8, C11, and C12); 142.0, 137.0, 129.6, and 115.7
(C6, C5, C9, and C13); 116.0 (C9-CH2); 39.3, 34.7, 32.8, and 19.1 (C4, C3, C2,
and C10); 34.1 (C1); 28.7 and 21.5 (C5-CH3 and C1-CH3). Anal. calcd. for
C17H23N: C, 84.59; H, 9.60; N, 5.80. Found: C, 84.34; H, 9.81; N, 5.85.
7. Analogously, at 2108C, with 6 g (27.5 mmol) of 1 and 5.88 g
(27.5 mmol) of diethyl 2-oxopropylphosphonate, the crude mixture (7.1 g)
was purified by column chromatography (SiO2, dichloromethane) to give
the ketone 7 as yellow oil (3.52 g, 51%). A more polar fraction was constituted
by the compound 8 as yellow oil (0.85 g, 13%).
IR (film cm21): 1674, 1699, 1625. 1H NMR (DMSO D-6): 6.91 (dt, 1H,
J ¼ 16.0, J ¼ 6.4, C11-H); 6.12 and 6.05 (2d, 2H, J ¼ 16.3, C7-H and C8-H);
6.08 (d, 1H, J ¼ 16.0, C12-H); 5.12 and 5.03 (2s, 2H, C9-CH2); 3.22 (d, 2H,
J ¼ 6.4, C10-H); 2.19 (s, 3H, C14-H); 1.97 (t, 2H, J ¼ 6.0, C4-H); 1.64
(s, 3H, C5-CH3); 1.56 (m, 2H, C3-H); 1.42 (m, 2H, C2-H); 0.95 (s, 6H,
C1-CH3). 13C NMR (CDCl3): 198.3 (C13); 145.9 (C11); 142.7, 137.1, and
129.4 (C6, C5, and C9); 133.8 and 128.4 (C7 and C8); 132.2 (C12); 116.1
(C9-CH2); 39.3 (C2); 35.3 (C10); 34.7 (C1); 32.7 (C4); 28.7 (C1-CH3); 26.8
(C14); 21.5 (C5-CH3); 19.1 (C3). Anal. calcd. for C18H26O: C, 83.67;
H, 10.14; O, 6.19 found: C, 83.42; H, 10.28; N, 6.30.
1
8. IR (film cm21): 3445, 1672, 1621. H NMR (CDCl3): 7.08 (dd, 1H,
J ¼ 16.0, J ¼ 8.0, C11-H); 6.20 (d, 1H, J ¼ 16.0, C12-H); 6.25, 6.12, 6.02,
0
0
and 6.01 (4d, 4H, J ¼ 16.4, C8 -H, C7 -H, C8-H, and C7-H); 5.24, 5.12,
0
5.07, and 5.03 (4s, 4H, C9-CH2, and C9 -CH2); 4.01 (m, 1H, C11-H); 3.37
(dd, 1H, J ¼ 8.0, C10-H); 2.73 (dd, 1H, J ¼ 13.8, J ¼ 3.2, C10-H); 2.30
(s, 3H, C13-CH3); 2.21 (dd, 1H, J ¼ 13.8, J ¼ 9.3, C10-H); 2.00 (t, 4H,
0
0
0
J ¼ 6.2, C4,4 -H); 1.66 (s, 6H, C5,5 -CH3); 1.60 (m, 4H, C3,3 -H); 1.45
(m, 4H, C2,2 -H); 0.99, 0.98, and 0.97 (3s, 12H, C1,1 -CH3). 13C NMR
(CDCl3): 198.5 (CO); 147.0 (C11); 145.4, 142.6, 137.1, 137.0, 129.7, and
0
0
0
129.4 (C9 , C6, C6 , and C5); 134.0, 133.8, 128.3, and 128.1 (C8 , C7 , C8,
0
0
0
0
and C7); 132.3 (C12); 117.0 and 115.7 (C9 -CH2 and C9-CH2); 70.9 (C11);
0
0
49.9 (C10); 39.2 (C2,2 ); 38.5 (C10 ); 34.0 (C1,1 ); 32.7 (C4,4 ); 28.7
0
0
0
0
0
(C1,1 -CH3); 26.9 (C13-CH3); 21.5 (C5,5 -CH3); 19.1 (C3,3 ). Anal. calcd. for
C33H48O2: C, 83.14; H, 10.15; O, 6.71. Found: C, 82.99; H, 10.23; N, 6.78.
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mediate C-15 b-methylenealdehyde. Tetrahedron 2000, 56, 7211–7215.
11. The ethyl 4-bromo-2-methylbut-2-enoate was synthesized by bromination of the
ethyl 2-methylbut-2-enoate with NBS. See Pattenden, G.; Weedon, B. C. L.
Carotenoids and related compounds. XVIII. Synthesis of cis- and cis, cis-
polyenes by reactions of the Wittig type. J. Chem. Soc. (C), 1968, 1984–1997.