Stereoselective synthesis of all-trans-, (13Z)- and (9-nor)-retinoic acids via Stille reaction

Article abstract of DOI:10.1055/s-1999-2531

Stereoselective construction of retinoic acid and certain analogues were achieved through two successive Stille reactions. First, the coupling of (E)- 1,2-bis(tributylstannyl)ethene and (Z)- or (E)-tributylstannyl 3-iodoalk-2- enoates was performed followed by iododestannylation. The second step involved another vinyltin which was synthesised by stannylmetallation of the Negishi dienyne derived from β-ionone.

Full text of DOI:10.1055/s-1999-2531

LETTER
141
Stereoselective Synthesis of All-trans-, (13Z)- and (9-nor)-Retinoic Acids via
Stille Reaction
Jérôme Thibonnet,a Mohamed Abarbri,a Alain Duchêne,a* Jean-Luc Parrainb*
a Laboratoire de Physicochimie des Interfaces et des Milieux Réactionnels, Faculté des Sciences de Tours, Parc de Grandmont,
37200 Tours, France
b Laboratoire de Synthèse Organique associé au CNRS (ESA 6009), Faculté des Sciences de Saint Jérôme,
13397 Marseille Cedex 20, France
E-mail: jl.parrain@lso.u-3mrs.fr
Received 5 October 1998
Abstract: Stereoselective construction of retinoic acid and certain
analogues were achieved through two successive Stille reactions.
First, the coupling of (E)-1,2-bis(tributylstannyl)ethene and (Z)- or
(E)-tributylstannyl 3-iodoalk-2-enoates was performed followed by
iododestannylation. The second step involved another vinyltin
which was synthesised by stannylmetallation of the Negishi di-
enyne derived from b-ionone.
Key words: retinoic acids, Stille cross-coupling reaction, vinyltin
reagents, (E)-1,2-bis(tributylstannyl)ethene, iodovinylic substitu-
tion.
Scheme 1
Retinoids are metabolites, derivatives and synthetic ana-
logues of vitamin A. They bind to and activate nuclear re-
tinoid receptors which function as ligand-dependent
transcription factors.1 All-trans-retinoic acid (ATRA),
(13Z)-retinoic acid (13-cis-RA)2 and other retinoids are
known to modulate proliferation and differentiation of a
variety of cell types through activation of their intracellu-
lar retinoid receptors. These receptors are divided into two
distinct classes, retinoic acid receptors (RARs) and retin-
oid X receptors (RXRs) which have retinoic acids as
ligands.3 Several members of this class are in use for the
treatment of dermatological diseases and certain can-
cers.4,5 The search for new methods of stereocontrolled
synthesis is therefore of current interest. Among these,
transition metal catalysed cross coupling6 represents an
interesting alternative to Wittig7 or sulphone-based8 olefi-
nation. In connection with our ongoing work on the Stille
reaction9 using substrates bearing an unprotected acid
function,10 we decided to develop direct and flexible
routes yielding retinoic acid and analogues. We describe
here the synthesis of all-trans-, (13Z)- and (9-nor)-retino-
ic acids.11
anocuprate (Lipshutz reagent)13 at -78 °C in the presence
of methanol (10 eq.)14 yielded (7E,9E)-dienylstannane 3a
mixed with the internal vinylstannane 3a’15 (3a/3a’ = 75/
25). Fortunately, we found that this ratio could be in-
creased to 92/8 when the reaction was performed at
-90 °C.
Scheme 2
To obtain trisubstituted vinylstannane 3b, dienyne 2 was
treated with 1.1 equivalent of Lipshutz reagent in THF to
yield the intermediate vinylcuprate which was trapped
with an excess of methyl iodide (10 eq.) in the presence of
HMPA (4 eq.). In this case, the reaction occurred with a
high regioselectivity (up to 92/8 in favour to the terminal
vinylstannane). Iododestannylation of 3a and 3b with io-
dine in ether at low temperature gave quantitatively the
corresponding vinyliodides but these were unfortunately
found to be very unstable and totally decomposed during
the purification on column chromatography.6h We there-
fore chose to use vinyltin reagents rather than vinyliodides
for the final step of synthesis.
Our retrosynthetic strategy (Scheme 1) is based on the
coupling of two building blocks A and B and starts from
commercially available and inexpensive b-ionone and
tetrolic acid.
In order to minimize the number of protection and depro-
tection steps, we planned a method of synthesis without
protection of the acid function. The synthesis of fragment
A (Scheme 2) began with b-ionone 1 which was converted
to dienyne 2 and provided 80% yield (after distillation)
according to the reliable Negishi procedure.12 Treatment
of 2 with 1.1 equivalent of lithium butyltributylstannylcy-
Synlett 1999, No. 1, 141–143 ISSN 0936-5214 © Thieme Stuttgart · New York

142
J. Thibonnet et al.
LETTER
Fragment B was obtained from tetrolic acid 4, which was It is interesting to note that, starting from the mixtures of
converted into pure (E)-vinyliodide 5 by stannylcupration vinylstannanes 3 and their internal isomers, only the ter-
reaction and iodine treatment of the generated vinylstan- minal regioisomers led to the desired coupling products.
nane,16 while (Z)-5 was more classically obtained by hy-
droiodination with an aqueous solution of hydroiodic
acid.17
Scheme 3
In conclusion, we have described a new stereoselective
approach to the synthesis of retinoids starting from inex-
pensive materials and based on the Stille reaction. In con-
trast to the most frequently mentioned methods, the
method described here uses unprotected acids, thus avoid-
ing protection and deprotection steps.21
Stille coupling of b-iodovinylic acids (E)- and (Z)-5 (ini-
tially protected as the corresponding tributyltin esters)
with (E)-1,2-bis(tributylstannyl)ethene (1.1 eq.)18 in the
presence of a catalytic amount (5%) of dichlorobis
(acetonitrile)palladium(II), stereospecifically provided
dienyltins with retention of the configuration of the two
double bonds in fair yields. Subsequent iododestannyla-
tion of the dienyltin adducts in ether at room temperature
yielded quantitatively pure dienyliodide acids (E)- and
(Z)-6.19
Acknowledgement
We thank CNRS and MESR for providing financial support, the
"Service d’analyse chimique du vivant de Tours" for recording
NMR and mass spectra, and the "Conseil Régional de la Région
Centre" for awarding a fellowship to one of us (J.T.).
References and Notes
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(2) The traditional retinoid numbering system is being used in the
text when referring to ATRA. The IUPAC nomenclature is
used in the typical procedure.
Scheme 4
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Shudo, K. Chem. Pharm. Bull. 1994, 42, 2575. (b) Wada, A.;
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Finally, Stille coupling of iodovinylic acid 6 with vinyl-
stannanes 3a and b in the presence of a catalytic amount
(3%) of dichlorobis(acetonitrile)palladium(II) stereo-
selectively provided retinoids 7a-d, with good to moder-
ate yields.20 Crosscoupling occurred with retention of the
configuration of the double bonds and no degradation
products were observed. The results are summarised in
Table 1. A subsequent attempt was run with 3b, (E)-6 and
tetrakis(triphenylphosphine)palladium as catalyst which
provided a poor yield of ATRA 7c as already described by
Negishi.6a
Scheme 5
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LETTER
All-trans, (13Z)- and (9-nor)-Retinoic Acids via Stille Reaction
143
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(20) Typical procedure: To a DMF solution (15 mL), 3b (1.20 g,
2.52 mmol) and (2Z,4E)-5-iodo-3-methylpent-2,4-dienoic
acid (Z)-6 (0.5 g, 2.1 mmol), 16 mg (0.063 mmol, 3%) of
dichlorobis(acetonitrile)palladium(II) were added. The mix-
ture was stirred for 3h at 25°C before the reaction mixture was
washed with a saturated solution of ammonium chloride (2x15
mL) and extracted with diethyl ether (3x30 mL). After the
usual workup, the crude (2Z,4E,6E,8E)-3,7-dimethyl-9-
(2',6',6'-trimethyl-1'-cyclohex-1'-enyl)nona-2,4,6,8-tetra-
enoic acid 7d was purified by column chromatography (petro-
leum ether/ ether: 95/5 then 70/30) and crystallisation in ether.
yield: 70%. Orange crystals; m.p. = 161 °C [m.p.(lit.) = 162-
164 °C]; IR: 3062, 2956, 2921, 2851, 2581, 1682, 1605, 1562,
1276, 1225; Raman: 1594, 1163; 1H NMR (400 MHz)
(CDCl3) d(ppm): 1.01 (6H, s), 1.43-1.47 (2H, m), 1.58-1.61
(2H, m), 1.70 (3H, s), 1.98 (3H, s), 2.01 (2H, t, J = 5.7 Hz),
2.08 (3H, s), 5.64 (1H, s), 6.15 (1H, d, J = 16.0 Hz), 6.25 (1H,
d, J = 11 Hz), 6.27 (1H, d, J = 16.0 Hz), 7.01 (1H, dd, J = 15.2
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C
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(15)
NMR: 12.8, 19.1, 21.1, 21.6, 28.8 (2C), 33, 34.1, 39.5, 115.7,
128.7, 129, 130.2, 132.8, 137.2, 137.5, 138.7, 140.3, 153.5,
172; MS: m/z = 300 (M.+, 41), 285 (95), 239 (66), 197 (16),
185 (11), 143 (11), 133 (13), 129 (24), 99 (11), 89 (54), 88
(70), 87 (35), 85 (16), 73 (46), 72 (15), 71 (13), 61 (12), 60
(28), 59 (13), 58 (63), 57 (39), 45 (100), 44 (43).
(21) We also found that the use of acids instead of ester analogues
greatly improved the purification steps for the elimination of
tributyltin byproducts or impurities.
Synlett 1999, No. 1, 141–143 ISSN 0936-5214 © Thieme Stuttgart · New York