Stereoselective synthesis of trienoic acids: Synthesis of retinoic acids and analogues

Article abstract of DOI:10.1055/s-2006-950201

Stereoselective construction of conjugated trienoic acids was achieved through two successive Stille reactions, the first step consisting of the coupling of (E)-1,2-bis(tributylstannyl)ethene and tributylstannyl (Z)- or (E)-3-iodoalk-2-enoates. Two different routes were used for the second step: (1) cross-coupling of the stannyldienoic acid reagents and vinyl iodides, or (2) cross-coupling of vinylstannane reagents and the tributylstannyl 5-iodopenta-2,4-dienoates generated by iododestannylation of stannyldienes. Vinylstannanes synthesized by stannylmetalation of the Negishi dienyne derived from β- or α-ionone and safranal thus provided access to stereodefined retinoic acids. Some retinoid and yne analogues were also prepared by Sonogashira coupling. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950201

FEATURE ARTICLE
2951
Stereoselective Synthesis of Trienoic Acids: Synthesis of Retinoic Acids and
Analogues
Synthesis of Retinoic
A
o
c
ids
a
nd An
h
alogues amed Abarbri,a Jean-Luc Parrain,b Alain Duchêne,a Jérôme Thibonnet*a
a
Laboratoire de Synthèse et Physicochimie Organique et Thérapeutique, EA 3857, Faculté des Sciences de Tours, Parc de Grandmont,
37200 Tours, France
Fax +33(2)47367073; E-mail: jerome.thibonnet@univ-tours.fr
Laboratoire de Synthèse par Voie Organométallique, UMR CNRS 6178, Case postale D12, Faculté des Sciences de Saint Jérôme, Avenue
Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
b
Received 13 January 2006; revised 1 June 2006
coupling, and McMurry coupling. Linstrumelle et al. re-
ported the easy construction of these compounds by suc-
cessive Sonogashira-type reactions from (Z)- or (E)-
dichloroethene.9 Owing to its mild experimental condi-
Abstract: Stereoselective construction of conjugated trienoic acids
was achieved through two successive Stille reactions, the first step
consisting of the coupling of (E)-1,2-bis(tributylstannyl)ethene and
tributylstannyl (Z)- or (E)-3-iodoalk-2-enoates. Two different
routes were used for the second step: (1) cross-coupling of the stan- tions, the Stille cross-coupling reaction10 has also
nyldienoic acid reagents and vinyl iodides, or (2) cross-coupling of
emerged as a key step in various methods of total synthe-
sis of natural products such as leinamycin,11 macrolactin
vinylstannane reagents and the tributylstannyl 5-iodopenta-2,4-di-
enoates generated by iododestannylation of stannyldienes. Vinyl-
A,12 des-epoxy-rosaramycin,13 and limocrocin.14 In con-
stannanes synthesized by stannylmetalation of the Negishi dienyne
nection with our ongoing work15 on the Stille reaction for
derived from b- or a-ionone and safranal thus provided access to
stereodefined retinoic acids. Some retinoid and yne analogues were
also prepared by Sonogashira coupling.
which substrates bearing an unprotected acid function are
used, we wanted to develop direct and flexible routes
yielding retinoic acids and analogues. We describe here
the synthesis of all-trans-, (13Z)-, and (9-nor)-retinoic ac-
ids, and some retinoid and yne analogues derived from b-
or a-ionone and safranal.16,17 Our retrosynthesis strategy
(Scheme 1) is based on the coupling of two building
blocks A and B or C and starts from commercially avail-
able b- or a-ionone or safranal and alk-2-ynoic acids.
Key words: Stille reaction, cross-coupling, tin compounds, trienoic
acids, retinoic acids, polyenic acids
Introduction
Polyenic compounds with fixed configurations are found
in many natural products such as retinoids or polyenic
macrolides (e.g., mycoticin, roxatoxin). Retinoids are also
metabolites, derivatives, and synthetic analogues of vita-
min A. They bind to and activate nuclear retinoid recep-
tors, 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 mod-
ulate the proliferation and differentiation of a variety of
cell types through activation of their intracellular retinoid
receptors. These receptors are divided into two distinct
classes, the retinoic acid receptors (RARs, subtypes a, b,
and g) and the retinoid X receptors (RXRs, subtypes a, b,
and g), which have retinoic acids as ligands.3 Several
members of this class are used for the treatment of derma-
tological diseases and certain cancers.4,5 The search for
new methods of stereocontrolled synthesis is therefore of
current interest.
Results and Discussion
Stannylcupration of Alk-2-ynoic Acids
Over the last decade, functionalized vinylstannane re-
agents have emerged as valuable tools in organic synthe-
sis.18 Because of their wide range of reaction possibilities,
especially in vinyl transfer in palladium-catalyzed cross-
coupling, they have been used in key steps in total synthe-
sis.19–24
We planned to study the synthesis of a great number of vi-
nylstannanes and vinyl iodides bearing an unprotected
carboxylic acid function, as part of a program dealing with
the reactivity of unprotected iodovinylic acids and orga-
nometallic reagents under palladium-complex catalysis.15
We have previously studied the stannylmetalation of alk-
2-ynoic acids (Scheme 2)25–27 and found that the best re-
sults were obtained with the high-order cyanocuprate
(Bu3Sn)(Bu)CuLi·LiCN (2.3 equiv); this afforded fair
yields of the E-isomers.25,26 We obtained the same results
with 3-substituted alk-2-ynoic acids 1a–h, which were
transformed into vinylstannanes 2a–j and, after subse-
quent iodine treatment, into the corresponding 3-iodoalk-
2-enoic acids 3a–j (Scheme 2, Table 1). The reactions
proceeded with complete regio- and stereoselectivity in
each case. It should be noted that the same results were
In the past, conjugated polyenes have been constructed by
Wittig-type approaches,6 Peterson olefination, or sulfone-
based olefination (Julia coupling).7,8 Conjugated polyenes
can also be synthesized by several other methods such as
the Horner–Emmons reaction, the Stille approach, Suzuki
SYNTHESIS 2006, No. 17, pp 2951–2970
x
x.
x
x
.
2
0
0
6
Advanced online publication: 15.08.2006
DOI: 10.1055/s-2006-950201; Art ID: Z01406SS
© Georg Thieme Verlag Stuttgart · New York

2952
M. Abarbri et al.
FEATURE ARTICLE
obtained in the stannylmetalation of the corresponding that the addition of methanol (110 equiv) contributed to a
tributylstannyl esters 2a¢–j¢.
slight increase in the yields (4–7%).
Attempts to incorporate a methyl group by quenching the
vinylcopper intermediate with methyl iodide failed, even
in the presence of 30 equivalents hexamethylphosphor-
amide (this agrees with the results of the stannylcupration
of diethoxypropyne28). It should be noted that for iodine
quenching (entry 10), the reaction was only completed af-
ter 48 hours at 0 °C. As recently reported for the stannyl-
cupration in the presence of methanol,29 we also observed
Synthesis of Dienoic Acids
The synthesis of dienoic acids 4 by palladium-catalyzed
cross-coupling between 3-iodoalk-2-enoic acids 3 and vi-
nylstannanes was achieved as shown in Scheme 3. The
vinylstannanes were used with 3% bis(acetonitrile)di-
chloropalladium(II) in N,N-dimethylformamide as sol-
vent. The mild experimental conditions of the Stille cross-
Biographical Sketches
Mohamed Abarbri was the laboratory of Professor interests include new syn-
born in 1966 in Alhoceima Paul Knochel at the Univer- thetic methods, develop-
(Marocco). In 1995 he ob- sity of Marburg, he became ment of new organotin
tained his PhD in Chemistry lecturer (1996) and full pro- reagents, ultrasound chem-
at the University of Tours. fessor (2002) at the Univer- istry, and synthesis of per-
After postdoctoral studies in sity of Tours. His research fluoro compounds.
Jean-Luc Parrain obtained sity of Oxford, he joined the His research interests in-
his PhD in Chemistry in CNRS as Chargé de Recher- clude new catalytic reac-
1990 at the University of che at the laboratory of Or- tions toward new synthetic
Nantes (France) under the ganic Synthesis of the methods, development of
supervision of Professor University of Nantes. In new organotin and silicon
Jean-Paul Quintard. After 1995, he moved to the Uni- reagents, and total synthesis
postdoctoral studies in the versity of Marseille and was of natural compounds.
laboratory of Professor then appointed a CNRS di-
Steve Davies at the Univer- rector of research in 2001.
Alain Duchêne was born in the laboratory of Professor ests include new synthetic
Tours (France) in 1947. He Ryoji Noyori at the Univer- methods, development of
studied organic chemistry at sity of Nagoya (1992), he new organogermanium or
the Faculty of Sciences, was promoted to full profes- tin reagents, ultrasound
Bordeaux I University. Af- sor in 1997 at the University chemistry, and synthetic or-
ter postdoctoral studies in of Tours. His research inter- ganic materials.
Jérôme Thibonnet, born in After postdoctoral studies in (2000). He became lecturer
1971 in Joinville (France), the laboratory of Professor at the University of Tours in
received his PhD in 1999 Paul Knochel at the Univer- 2003. His research interests
from the University of sity of Munich, he joined the include new synthetic meth-
Tours where he worked on University of Aix-Marseille ods, development of new or-
the total synthesis of retin- III as Ingénieur de Recher- ganotin reagents, and total
oids under the supervision che at the laboratory of Pro- synthesis of natural com-
of Professor Alain Duchêne. fessor Maurice Santelli pounds.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Retinoic Acids and Analogues
2953
R1
O
R2
R1
O
OH
or
O
OH
R2
R1
M(X)
+
A
(X)M
OH
+
C
B
A
R1
M
+
OH
O
O
M
O
safranal
or α- or β-ionone
α- or β-ionone
Scheme 1 Retrosynthetic strategy for the preparation of retinoid acids from alk-2-ynoic acids and a- or b-ionone or safranal
Table 1 Yields in the Stannylcupration of 3-Substituted Alk-2-ynoic Acids
Entry
Starting material 1
R1
R2
H
H
H
H
H
H
H
H
D
I
Intermediate 2 Yield of 2a (%) Product 3
Yield of 3b (%)
1
2
1a
1b
1c
1d
1e
1f
H
2a
2b
2c
2d
2e
2f
65
63
68
64
72
62
55
72
60
45
3a15c
3b27
3c
58
56
60
57
66
59
51c
63
58
38
Me
3
Et
4
Pr
3d
5
(CH2)4Me
Ph
3e27
3f
6
7
1g
1h
1b
1b
TMS
MOM
Me
2g
2h
2i
3g
8
3h
9
3i
10
Me
2j
3j
a Conversion based on 1.
b Yields of isolated products 3 based on alkynoic acids 1.
c The desilylated product also formed (5–10%).
R1
R2
R2
coupling reaction resulted in good yields of dienoic acids
4a–j (Table 2).
OH
Bu3Sn
OX
I
OH
a, b, c
d
Surprisingly, cross-coupling between alkenoic acid 3h
and tributyl(vinyl)stannane gave cyclohexene 4k result-
ing from a Diels–Alder reaction between two molecules
of the expected dienoic acid (Scheme 4). We were unable
to reproduce this reaction with other iodoalkenoic acids
and tributyl(vinyl)stannane.
O
R1
O
R1
3a–j
O
X = H 2a–j
X = SnBu3 2a'–j'
1a–h
Scheme 2 Synthesis of 3-iodoalk-2-enoic acids by stannylcupration
of alk-2-ynoic acids. Reagents and conditions: (a) (Bu3Sn)(Bu)Cu-
Li·LiCN (2.3 equiv), THF, –78 °C, 1 h; (b) NH4Cl (R2 = H), D2O
(R2 = D), or I2 (R2 = I); (c) SiO2 (X = H), or no treatment
(X = SnBu3); (d) I2, Et2O.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

2954
M. Abarbri et al.
FEATURE ARTICLE
H(D)
Table 2 Yields of Alka-2,4-dienoic Acids Synthesized by Cross-
Coupling of 3-Iodoalk-2-enoic Acids with Vinylstannanes
R1
HI or DI 57%
(1.3 equiv)
R1
OH
OH
Entry Starting R1
R2
Product 4 Yield (%)
90 °C, 12 h
for R = Me
I
O
O
material 3
1a–h
5a–h
1
2
3b
3b
3b
3c
3c
3c
3c
3g
3g
3a
Me
Me
Me
Et
H
4a27
4b27
4c27
4d
74
65
68
77
82
84
62
76
75
82
Scheme 5 Synthesis of (Z)-3-iodoalk-2-enoic acids by hydro-
iodation of alk-2-ynoic acids
TMS
Ph
3
By a reaction similar to that described for acids 3 above,
cross-coupling of 3-stannylalk-2-enoates 2a¢ or 2b¢ with a
vinyl iodide or p-toluenesulfonyl chloride yielded alkeno-
ic acids 6a–c after deprotection of the carboxy function
(Scheme 6, Table 3).
4
H
5
Et
TMS
Ph
4e
6
Et
4f
Bu3Sn
OSnBu3
R2
OH
7
Et
CH2CH(OEt)2 4g
a, b
R1
O
R1
O
8
TMS
TMS
H
H
4h
4i
2a',b'
6a–c
9
TMS
TMS
Scheme 6 Palladium-catalyzed cross-coupling of 3-stannylalk-2-
enoates with organohalides. Reagents and conditions: (a) R2X (1.1
equiv), [PdCl2(NCMe)2] (5%), DMF, r.t., 3 h; (b) sat. KF, 1 M HCl.
10
4j
R1
O
R1
O
Synthesis of Dienynoic Acids and Trienoic Acids
SnBu3
R2
+
R2
OH
Attempts to use (E)-1,2-bis(tributylstannyl)ethene31 as vi-
nylstannylation reagent with acids 3 or 5 failed. However,
studies related to the synthesis of 4-arylbut-3-enoic acids
through the Stille approach showed that protection of the
carboxy function as a tributylstannyl ester group, for ex-
ample, resulted in a considerable increase in yield.15d,32
Stille coupling of 3-iodoalk-2-enoic acids 3 or 5 protected
as their tributyltin esters with (E)-1,2-bis(tributylstan-
nyl)ethene (1.1 equiv) in the presence of a catalytic
amount (5 mol%) of bis(acetonitrile)dichloropalladi-
um(II) stereospecifically provided stannylalkadienoates
7, with retention of the configurations of the two double
bonds (Scheme 7, Table 4).33 The reaction of (E)-1,2-
I
OH
3
4a–j
Scheme 3 Synthesis of alka-2,4-dienoic acids from 3-iodoalk-2-
enoic acids and vinylstannanes. Reagents and conditions:
[PdCl2(NCMe)2] (5%), DMF, r.t., 3 h.
The synthesis of (Z)-3-iodoalk-2-enoic acids 5, the coun-
terparts of (E)-acids 4, by hydroiodation of alk-2-ynoic
acids 1a–h with an aqueous solution of hydroiodic acid, as
well as the reactivity of acids 5 with vinylstannanes have
already been described (Scheme 5).15b,27,30
O
O
O
3h
COOH
COOH
COOH
Pd(II)
DMF
I
80%
COOH
+
COOH
SnBu3
O
O
4k
Scheme 4 Cross-coupling between an alkenoic acid and a vinylstannane followed by a Diels–Alder reaction between two product molecules
Table 3 Yields of Alkenoic Acids Synthesized by Cross-Coupling of 3-Stannylalk-2-enoates with Organohalides
Entry
1
Starting material 2 R1
R2X
Product 6
No
Yield (%)
62
COOH
2a¢
2b¢
H
6a
Cl
Cl
I
2
3
Me
TsCl
6b
6c
68
75
COOH
COOH
Ts
2a¢
H
COOH
2
I
HOOC
3
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Retinoic Acids and Analogues
2955
bis(tributylstannyl)ethene with iodovinylic esters (such as NOESY NMR experiment on 8d confirmed the retention
methyl or ethyl esters) under the same experimental con- of the Z-stereochemistry of the a double bond. When 0.5
ditions yielded products resulting from a double cross- equivalents of (E)-1,2-bis(tributylstannyl)ethene were
coupling reaction.34 Without stannyldienoates 7 being pu- used, only the bis-coupling product 8i formed (Table 4,
rified first, an iododestannylation reaction in diethyl ether entry 9).
at room temperature quantitatively yielded pure and un-
protected 5-iodoalka-2,4-dienoic acids 8, without isomer-
By a similar procedure, iododienoic acids 8a, 8b, or 8d
underwent cross-coupling with vinylstannanes, yielding
ization of the a double bond, and with retention of the
trienoic acids 9a–f (Scheme 8, Table 5). The coupling of
configuration of the second double bond (Scheme 7).
an tributyl(ethynyl)stannane also took place, giving di-
Bis-coupling products35 or tributylstannyl-substituted enynoic acid 9g in 79% yield and without polymerization
products36 were never observed when 1.1 equivalents of (Table 5, entry 7), again proving the mildness of these ex-
(E)-1,2-bis(tributylstannyl)ethene were used. The perimental conditions.
R1
O
R1
R1
O
c–e
a, b
COOH
I
OH
I
Bu3Sn
OSnBu3
R2
8a–h
R2
3 or 5
R2
7a–d
Scheme 7 Synthesis of 5-iodoalka-2,4-dienoic acids by palladium-catalyzed cross-coupling. Reagents and conditions: (a) Bu3SnOMe, Et2O,
r.t.; (b) (E)-Bu3SnCH=CHSnBu3 (1.1 equiv), [PdCl2(NCMe)2] (5%), DMF, r.t., 3–5 h; (c) I2, Et2O, r.t.; (d) sat. KF; (e) 0.1 M HCl.
Table 4 Yields of 5-Iodoalka-2,4-dienoic Acids Synthesized by Cross-Coupling of 3-Iodoalk-2-enoic Acids with (E)-1,2-Bis(tributylstan-
nyl)ethene Followed by Iododestannylation
Entry
R1
R2
Starting material
Product 8
No
Yielda (%)
3 or 5
1
2
H
H
H
H
3a
5a
8a
8b
64
66
COOH
I
I
COOH
3
4
Me
Me
H
H
3b
5b
8c
70
69
COOH
I
I
8d
COOH
5
6
Me
Et
D
H
5i
8e
8f
74
70
D
I
I
COOH
3c
COOH
7
8
Pr
Pr
H
H
3d
5d
8g
8h
67
73
COOH
I
I
COOH
9
Me
H
5b
8ib
71
COOH
COOH
a Yield of Stille coupling with (E)-1,2-bis(tributylstannyl)ethene.
b Obtained when 0.5 equiv 1,2-bis(tributylstannyl)ethene was used.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

2956
M. Abarbri et al.
FEATURE ARTICLE
R2
R2
R1
R1
+
SnBu3
COOH
COOH
R3
R3
I
8a,b,d
9a–g
Scheme 8 Synthesis of trienoic acids by cross-coupling between iododienoic acids and vinylstannanes. Reagents and conditions: stannane
(1.2 equiv), [PdCl2(NCMe)2] (5%), DMF, r.t., 3 h.
Table 5 Yields of Trienoic Acids Synthesized by Cross-Coupling of Dienoic Acids with Vinyl- and Ethynylstannanes
Entry
Dienoic acid
Stannane
Product 9
No
9a
9b
Yield (%)
1
2
8a
8b
SnBu3
88
84
COOH
COOH
3
4
5
8d
8d
8d
9c
9d
9e
96
74
72
COOH
SnBu3
COOH
OEt
OEt
EtO
SnBu3
EtO
COOH
6
7
8d
8d
9f
86
79
SnBu3
Me3Si
Me3Si
COOH
9g
SnBu3
COOH
Cross-Coupling with Alkynes
Application to Retinoid Synthesis
We also investigated the synthesis of dienynoic acids 10 In view of the results we obtained in the synthesis of
(Scheme 9) from alkynes and iodoalkadienoic acids 8 un- trienoic and dienynoic acids, we planned to apply this
der Sonogashira conditions,37 using dichlorobis(triphen- strategy to the synthesis of retinoic acids and some ana-
ylphosphine)palladium(II), copper(I) iodide, butylamine, logues. For this, fragments B and C needed to be synthe-
and N,N-dimethylformamide as solvent at room tempera- sized (Scheme 1).
ture. We thus obtained the corresponding dienynoic acids
The synthesis of fragment B (12a–c) or C (13,14) began
10 in fair yields (Table 6).38 In all cases, Glaser coupling
with b-ionone (11a), a-ionone (11b) (Scheme 10), or sa-
(<5%) resulted in lower product yields. Protection of the
carboxy function was not necessary, and the configura-
tions of the two double bonds were unchanged. In addi-
franal (Scheme 11). Ionones 11a and 11b gave dienynes
12a and 12b in 80% yield (after distillation) by the reli-
able Negishi procedure (Scheme 10).40 Trienyne 12c was
tion, no cyclization to butenolides or a-pyrones
obtained from safranal by a method described by Wright
occurred.39
for the synthesis of conjugated en-1-ynes (Scheme 11).41
Treatment of dienynes 12 with 1.1 equivalents of the Lip-
shutz reagent [(Bu3Sn)(Bu)CuLi·LiCN] at –78 °C in the
presence of methanol (110 equiv) yielded (1E,3E)-dienyl-
stannanes 13 mixed with internal vinylstannanes 15a (13/
15a, 75:25) (Scheme 10). Fortunately, we found that this
ratio could be increased to 92:8 if the reaction was per-
formed at –90 °C, if the intermediate vinylcuprate was
trapped with an excess of methyl iodide (10 equiv) in the
presence of tetrahydrofuran. In this case, the reaction oc-
R1
R1
H
COOH
COOH
+
I
R2
R2
8b–d
10a–f
Scheme 9 Synthesis of dienynoic acids from alkynes and iodoalka-
dienoic acids. Reagents and conditions: alkyne (1.5 equiv),
[PdCl2(PPh3)2] (3%), CuI, BuNH2, DMF, r.t., 4 h.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Retinoic Acids and Analogues
2957
Table 6 Yields of Dienynoic Acids Synthesized by Cross-Coupling of Dienoic Acids with Alkynes
Entry
1
Dienoic acids R1
R2
Ph
Product 10
No
Yield (%)
75
8b
H
10a
Ph
COOH
COOH
2
3
8d
Me
Ph
10b
75
77
Ph
8d
Me
TMS
10c38
Me3Si
O
COOH
4
5
6
8d
8d
8c
Me
Me
Me
MOM
10d
10e
70
76
72
COOH
COOH
CH2SBn
GeBu3
BnS
10f38
COOH
Bu3Ge
curred in high regioselectivity, up to 92:8 in favor of the from stannane 14a and dienoic acid 8c, with tet-
terminal dienylstannane 14 (14/15b, 92:8) (Scheme 10).
rakis(triphenylphosphine)palladium as catalyst; this gave
all-trans-retinoic acid (16c) in poor yield, as already de-
scribed by Negishi.16a
Iododestannylation of 13 or 14 with iodine in diethyl ether
at low temperature quantitatively provided the corre-
sponding vinyl iodides, but these were unfortunately very
unstable and decomposed completely during purification
by column chromatography. We therefore chose to use vi-
nylstannane reagents 14 rather than vinyl iodides for the
final stage of the synthesis. It should be noted that these
vinylstannanes were used without any purification. Stille
coupling of 5-iodoalka-2,4-dienoic acids 8 with vinylstan-
nanes 14 in the presence of a catalytic amount (3%) of
bis(acetonitrile)dichloropalladium(II) stereoselectively
provided retinoids 16 in good to moderate yields
(Scheme 12, Table 7). Cross-coupling occurred with re-
tention of the configurations of the double bonds and no
decomposition products were observed. Synthesis of all-
trans-retinoic acid (16c) was also subsequently attempted
1.
Me3Si
PPh3Br–
O
LDA, THF, –5 °C
2. TBAF
H
12c
64%
Safranal
Scheme 11 Synthesis of a conjugated trienyne from safranal and an
alkyne
R
SnBu3
R = H; 13a,b
R = Me; 14a,b
terminal
b, c, d
a
O
+
SnBu3
R
R = H; 15a
R = Me; 15b
12a,b
11a,b
internal
Scheme 10 Synthesis of vinyl stannanes from a- and b-ionones. Reagents and conditions: 13a,b (R = H): (a) Negishi’s conditions: LDA,
–78 °C, 1 h, then (EtO)2POCl, –78 °C, 1 h, then LDA, –78 °C to –20 °C, 3 h, then HCl; (b) (Bu3Sn)(Bu)CuLi·LiCN, THF, MeOH, –90 °C;
(c) sat. NH4Cl. 14a,b (R = Me): (a) Negishi’s conditions; (b) (Bu3Sn)(Bu)CuLi·LiCN, THF, MeOH, –90 °C; (c) MeI (10 equiv), –90 °C
to 25 °C, 12 h; (d) sat. NH4Cl.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

2958
M. Abarbri et al.
FEATURE ARTICLE
Table 7 Yields of Retinoid Acids Synthesized by Cross-Coupling of Dienoic Acids with Vinylstannanes
Entry
1
Dienoic acids 8 R1
R2
H
Vinylstannanes 14
Product 16
Yielda (%)
55
8a
H
16a
SnBu3
14a
14a
2
3
4
5
8d
8c
8b
8d
Me
Me
H
H
H
H
H
16b
16c
16d
16e
70
73
45
55
14a
14a
Me
SnBu3
14b
a Yields after purification.
R1
Conclusion
SnBu3
COOH
+
I
We have investigated a new general route to both (Z,E,E)-
and (E,E,E)-conjugated trienoic acids and describe a new
stereoselective approach to the synthesis of retinoids,
starting from inexpensive materials and based on cross-
coupling reactions (Stille or Sonogashira reaction). In
contrast to the most frequently reported methods, the
method described here uses unprotected acids, thus saving
protection and deprotection steps.
R2
14a,b
8
R1
COOH
R2
16a–f
Scheme 12 Synthesis of retinoid acids. Reagents and conditions:
[PdCl2(NCMe)2] (3%), DMF, 25 °C, 3 h.
1H NMR spectra were recorded at 200 MHz or at 300 MHz on Bruk-
er AC200 and Bruker Avance DPX 300 spectrometers with CDCl3
used as solvent. The residual proton resonance of CDCl3 (dH = 7.25
ppm) was used as the internal reference. 13C NMR spectra were re-
corded at 50 MHz or 75 MHz on the same spectrometers with
CDCl3 used as solvent; the solvent peak at dC = 77.0 ppm was used
as the reference. EI mass spectra were measured at 70 eV by GC-
MS or direct introduction mode. The isotopic patterns are given for
120Sn (isotopic values 33%) in organotin fragments; this means that
the reported values (values in brackets) for organotin fragments
were only roughly one third of the correct value, taking into account
the 10 isotopes of tin compared with those of organic fragments.
Melting points are uncorrected. Standard column chromatography
was performed on Merck silica gel (60 Å, 230–400 mesh silica gel)
by flash column chromatography techniques. Analytical TLC was
conducted on Merck precoated silica gel 60 F254 plates. All reac-
tions were performed in oven-dried glassware under positive argon
pressure, unless otherwise noted. Reaction mixtures were stirred
magnetically. Et2O was dried and freshly distilled from sodium/
benzophenone. DMF was dried by distillation over CaH2 prior to
use. Acids 1a and 1b were prepared by a previously reported proce-
dure.42 4-Methoxybut-3-ynoic acid (1h) was prepared by carbon-
ation of 3-methoxypropynylmagnesium bromide. Other acids 1c–g
were purchased from commercial suppliers and used without puri-
fication. Tributyl(vinyl)stannane was prepared from vinylmagne-
sium bromide and bis(tributyltin) oxide.43 (E)-1-(Tributylstannyl)-
2-(trimethylsilyl)ethene was prepared by hydrostannation of (tri-
methylsilyl)acetylene.44 (E)-Tributyl(b-styryl)stannane was prepared
by hydrostannation of phenylacetylene.45 (E)-4,4-Diethoxy-1-
(tributylstannyl)but-1-ene was obtained by stannylmetalation of the
It is interesting that if a mixture of a vinylstannane 14 and
its positional isomer 15b was used, only the terminal re-
gioisomer 14 led to the desired coupling product.
Cross-coupling of enynes 12a–c with iododienes 17 under
the same conditions as described before (cf. Scheme 9)
yielded didehydro retinoid acids 18 (Scheme 13, Table 8).
R1
a
COOR3
+
I
R2
17
R1
12a–c
COOR3
R2
R3 = H, t-Bu
18a–h
Scheme 13 Synthesis of didehydro retinoid acids by cross-coupling
of enynes with iododienes. Reagents and conditions: [PdCl2(PPh3)2]
(3%), CuI (3%), BuNH2, DMF, r.t., 4–5 h.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Retinoic Acids and Analogues
2959
Table 8 Yields of 9,10-Didehydro Retinoid Acids Synthesized by Cross-Coupling of Enynes with Iododienes
Entry
1
Diene
R1
H
R2
H
R3
H
Enyne
Product
Yielda (%)
70
17a
18a
12a
12a
2
3
4
5
6
17b
17c
17d
17e
17b
Me
Me
Et
H
D
H
H
H
H
18b
18c
18d
18e
18f
80
73
76
78
85
H
12a
12a
12a
H
Me
Me
t-Bu
H
12b
12b
7
8
17c
17b
Me
Me
D
H
H
H
18g
18h
76
72
12c
a Yields after purification.
homopropargylic acetal by (tributylstannyl)(methyl)magnesium in
the presence of CuCN.46 (Tributylstannyl)acetylene was prepared
from ethynyllithium–ethylenediamine complex and Bu3SnCl47.
Alkynes 12a and 12b were prepared by a method described by
Negishi.40
MS (EI, 70 eV): m/z (%) = 305 (36) [M+ – 57], 249 (57), 193 (48),
191 (48), 177 (11), 137 (21), 121 (21) [organotin fragments], 57
(23), 45 (10), 41 (100) [organic fragments].
(E)-3-(Tributylstannyl)but-2-enoic Acid (2b)
Yield: 63%; yellow oil.
Compounds 2 and 2¢ by Stannylcupration of Alk-2-ynoic Acids
1; General Procedure
IR (neat): 1689, 1597 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 7.2 Hz, 9 H), 0.98 (m,
6 H), 1.30–1.78 (m, 12 H), 2.46 (d, J = 1.7 Hz, JSn–H = 44 Hz, 3 H),
6.05 (q, J = 1.7 Hz, JSn–H = 63 Hz, 1 H), 10.70 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 9.3 (JSn–C = 335–321 Hz, 3 C),
13.5, 22.5 (JSn–C = 26 Hz), 27.2 (JSn–C = 57 Hz, 3 C), 28.8
(JSn–C = 20 Hz, 3 C), 127.5 (JSn–C = 36 Hz), 169.8 (JSn–C = 77 Hz),
173.5 (JSn–C = 318 Hz).
119Sn NMR (149 MHz, CDCl3): d = –32.6.
MS (EI, 70 eV): m/z (%) = 319 (43) [M+ – 57], 263 (56), 207 (46),
177 (22), 137 (37), 121 (30) [organotin fragments], 85 (23), 69 (18),
67 (17), 55 (11), 41 (100), 39 (54) [organic fragments].
(Bu3Sn)(Bu)CuLi·LiCN was prepared by the general route outlined
by Lipshutz.48 CuCN (1.8 g, 20.17 mmol) was suspended in freshly
distilled THF (60 mL), and the mixture was cooled at –78 °C and
treated with 1.6 M BuLi in hexane (25.2 mL, 40.35 mmol). The
mixture was allowed to react for 15 min, and then Bu3SnH (10.85
mL, 40.35 mmol) was added dropwise. After the mixture had stirred
for 10 min at –78 °C, the 3-substituted alk-2-ynoic acid 1 (8.77
mmol) diluted in THF (10 mL) was added, and the reaction was al-
lowed to proceed for 1 h. The reaction mixture was quenched with
sat. NH4Cl soln at –78 °C and diluted with Et2O. The organic layer
was separated, washed with brine (30 mL), and dried over MgSO4.
After the solvent had been removed by rotary evaporation, purifica-
tion of the residue by column chromatography (silica gel, PE–Et2O,
50:50, then CH2Cl2) gave 2.
(E)-3-(Tributylstannyl)pent-2-enoic Acid (2c)
Yield: 68%; yellow oil.
(E)-3-(Tributylstannyl)acrylic Acid (2a)
Yield: 65%; yellow oil.
IR (neat): 1690, 1624, 1570 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.93 (t, J = 7.2 Hz, 9 H), 1.02 (m,
6 H), 1.23–1.62 (m, 12 H), 6.36 (d, J = 19.4 Hz, JSn–H = 54–51 Hz,
1 H), 7.93 (d, J = 19.4 Hz, JSn–H = 58 Hz, 1 H), 10.70 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 9.6 (JSn–C = 335–351 Hz, 3 C),
13.5, 27.1 (JSn–C = 57–55 Hz, 3 C), 28.8 (JSn–C = 21 Hz, 3 C), 135.6
(JSn–C = 13 Hz), 156.4 (JSn–C = 292–283 Hz), 169.6 (JSn–C = 69 Hz).
IR (neat): 1686, 1628, 1180 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.87 (t, J = 7.1 Hz, 9 H), 0.94 (m,
6 H), 1.02 (t, J = 7.5 Hz, 3 H), 1.20–1.60 (m, 12 H), 2.87 (qd,
J = 7.5, 1.1 Hz, JSn–H = 56 Hz, 2 H), 5.92 (t, J = 1.1 Hz, JSn–H = 65–
62 Hz, 1 H), 10.75 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 9.9 (JSn–C = 334–319 Hz, 3 C),
13.5, 13.8 (JSn–C = 10.5 Hz), 27.2 (JSn–C = 58 Hz, 3 C), 28.5
(JSn–C = 25 Hz), 28.8 (JSn–C = 20 Hz, 3 C), 126.5 (JSn–C = 35.5 Hz),
169.6 (JSn–C = 82 Hz), 177 (JSn–C = 319 Hz).
119Sn NMR (149 MHz, CDCl3): d = –33.6.
119Sn NMR (149 MHz, CDCl3): d = –45.5.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

2960
M. Abarbri et al.
FEATURE ARTICLE
MS (EI, 70 eV): m/z (%) = 333 (100) [M+ – 57], 277 (76), 221 (57),
219 (54), 137 (29), 121 (22) [organotin fragments], 99 (10), 81 (21),
41 (15) [organic fragments].
1H NMR (200 MHz, CDCl3): d = 0.87 (t, J = 7.2 Hz, 9 H), 0.86–
0.96 (m, 6 H), 1.23–1.51 (m, 12 H), 3.35 (s, 3 H), 4.54 (d, J = 2.7
Hz, JSn–H = 29–24 Hz, 2 H), 5.93 (t, J = 2.7 Hz, JSn–H = 59 Hz, 1 H),
10.8 (br s, 1 H).
(E)-3-(Tributylstannyl)hex-2-enoic Acid (2d)
Yield: 64%; yellow oil.
IR (neat): 1690, 1595, 1240 cm–1.
13C NMR (50 MHz, CDCl3): d = 10.8 (JSn–C = 335–351 Hz, 3 C),
13.6 (3 C), 27.1 (JSn–C = 59 Hz, 3 C), 29 (JSn–C = 20 Hz, 3 C), 58,
76.3 (JSn–C = 21 Hz), 123.2 (JSn–C = 26 Hz), 169.6 (JSn–C = 74 Hz),
181 (JSn–C = 322 Hz).
1H NMR (200 MHz, CDCl3): d = 0.86 (t, J = 7.2 Hz, 9 H), 0.92 (m,
9 H), 1.15–1.66 (m, 14 H), 2.84 (t, J = 7.1 Hz, JSn–H = 57 Hz, 2 H),
5.95 (t, J = 1 Hz, JSn–H = 65.8–63.4 Hz, 1 H), 9.80 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 10 (JSn–C = 318–333 Hz, 3 C), 13.5
(3 C), 14, 22.8 (JSn–C = 10 Hz), 27.2 (JSn–C = 55.5–58.7 Hz, 3 C),
28.8 (JSn–C = 20 Hz, 3 C), 37.2 (JSn–C = 24.3 Hz), 127 (JSn–C = 35
Hz), 169.8 (JSn–C = 80.5–83.8 Hz), 177.5 (JSn–C = 309.5–324.2 Hz).
MS (EI, 70 eV): m/z (%) = 347 [M+ – 57] (100), 291 (50), 235 (49),
177 (26), 137 (20), 121 (15) [organotin fragments], 95 (21), 57 (10),
41 (17) [organic fragments].
119Sn NMR (149 MHz, CDCl3): d = –33.3.
MS (EI, 70 eV): m/z (%) = 349 (45) [M+ – 57], 317 (100), 273 (19),
261 (17), 235 (17), 203 (15), 177 (52), 121 (19) [organotin frag-
ments], 57 (25), 55 (13), 43 (12), 41 (72), 39 (38) [organic frag-
ments].
(E)-3-(Tributylstannyl)[2-2H]but-2-enoic Acid (2i)
Yield: 60%; yellow oil.
IR (neat): 2238, 1689, 1598 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 7.2 Hz, 9 H), 0.95–
0.98 (m, 6 H), 1.30–1.78 (m, 12 H), 2.22 (s, JSn–H = 38 Hz, 3 H),
10.35 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 9.3 (JSn–C = 335–321 Hz, 3 C),
13.4 (3 C), 22.5 (JSn–C = 25 Hz), 27.2 (JSn–C = 58 Hz, 3 C), 28.8
(JSn–C = 21 Hz, 3 C), 124.2 (t, JC–D = 26 Hz), 169.8 (JSn–C = 76 Hz),
173.5 (JSn–C = 318 Hz).
(E)-3-(Tributylstannyl)oct-2-enoic Acid (2e)
Yield: 72%; yellow oil.
IR (neat): 3400–2500, 1690, 1595, 1240 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.87 (t, J = 7.1 Hz, 9 H), 0.95 (m,
9 H), 1.20–1.62 (m, 18 H), 2.85 (br t, J = 7.4 Hz, JSn–H = 57 Hz, 2
H), 5.94 (br s, JSn–H = 66–63.6 Hz, 1 H), 11.90 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 10 (JSn–C = 333.3–318.4 Hz, 3 C),
13.4 (3 C), 13.8, 22.3, 27.2 (JSn–C = 50–51 Hz, 3 C), 28.8 (JSn–C = 20
Hz, 3 C), 29.1 (JSn–C = 10 Hz), 31.7, 35.3 (JSn–C = 24 Hz), 127
(JSn–C = 34 Hz), 169.7 (JSn–C = 83 Hz), 178.2 (JSn–C = 342–320 Hz).
MS (EI, 70 eV): m/z (%) = 320 (43) [M+ – 57], 264 (56), 208 (46),
177 (21), 137 (37), 121 (23) [organotin fragments], 57 (14), 55 (14),
43 (26), 41 (100), 39 (37) [organic fragments].
(Z)-2-Iodo-3-(tributylstannyl)but-2-enoic Acid (2j)
Yield: 45%; yellow oil.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 7.1 Hz, 9 H), 0.92–
0.95 (m, 6 H), 1.24–1.69 (m, 12 H), 2.23 (s, JSn–H = 38 Hz, 3 H),
11.3 (br s, 1 H).
119Sn NMR (149 MHz, CDCl3): d = –34.0.
MS (EI, 70 eV): m/z (%) = 375 (100) [M+ – 57], 319 (33), 263 (28),
177 (27), 137 (21), 121 (15) [organotin fragments], 95 (19), 81 (13),
55 (11), 41 (18) [organic fragments].
(E)-3-Phenyl-3-(tributylstannyl)acrylic Acid (2f)
Yield: 62%; yellow oil.
IR (neat): 3076, 3059, 3018, 1695, 1604 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.92 (t, J = 7.2 Hz, 9 H), 0.95 (m,
6 H), 1.24–1.69 (m, 12 H), 6.17 (s, JSn–H = 58–56 Hz, 1 H), 6.94–
7.01 (m, 2 H, Ar), 7.15–7.36 (m, 3 H, Ar), 11.20 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 11.9 (JSn–C = 342–327 Hz, 3 C),
13.5 (3 C), 25.1 (JSn–C = 20.4 Hz), 27.2 (JSn–C = 60 Hz, 3 C), 28.7
(JSn–C = 20 Hz, 3 C), 93.1 (JSn–C = 23 Hz), 168.6 (JSn–C = 72 Hz),
172.6 (JSn–C = 278 Hz).
Tributylstannyl (E)-3-(Tributylstannyl)but-2-enoate (2b¢)
Yield: 76%; yellow oil.
13C NMR (50 MHz, CDCl3): d = 10.2 (JSn–C = 335–321 Hz, 3 C),
13.5 (3 C), 27.1 (JSn–C = 59–56 Hz, 3 C), 28.7 (JSn–C = 20.5 Hz, 3 C),
124.4 (JSn–C = 60 Hz, 2 C), 125.9, 127.4 (JSn–C = 35 Hz), 128 (2 C),
144 (JSn–C = 18 Hz), 170 (JSn–C = 68.9 Hz), 173.1 (JSn–C = 290 Hz).
MS (EI, 70 eV): m/z (%) = 381 (12) [M+ – 57], 269 (100), 267 (74),
213 (45), 177 (28), 155 (33) [organotin fragments], 147 (76), 103
(39), 102 (19), 91 (24), 77 (37), 57 (39), 51 (33), 41 (56), 39 (26)
[organic fragments].
IR (neat): 1599, 1543, 1525 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.89–1.66 (m, 54 H), 2.37 (d,
J = 1.8 Hz, JSn–H = 47 Hz, 3 H), 6.06 (q, J = 1.8 Hz, JSn–H = 66 Hz,
1 H).
13C NMR (50 MHz, CDCl3): d = 9.2 (JSn–C = 333–317 Hz, 3 C),
13.5 (6 C), 16.3 (JSn–C = 361–344 Hz, 3 C), 22.0 (JSn–C = 30 Hz),
26.9 (JSn–C = 67–63 Hz, 3 C), 27.2 (JSn–C =& nbsp;58–55 Hz, 3 C),
27.8 (JSn–C = 20 Hz, 3 C), 28.9 (JSn–C = 20 Hz, 3 C), 130.1
(JSn–C = 32 Hz), 164.1 (JSn–C = 348–333 Hz), 170.3 (JSn–C = 79 Hz).
(E)-3-(Tributylstannyl)-3-(trimethylsilyl)acrylic Acid (2g)
Yield: 55%; yellow oil.
119Sn NMR (149 MHz, CDCl3): d = –35.5, 100.1.
1H NMR (200 MHz, CDCl3): d = 0.13 (s, 9 H), 0.95 (t, J = 7.2 Hz,
9 H), 0.96–1.05 (m, 6 H), 1.23–1.63 (m, 12 H), 8.23 (s, JSn–H = 70
Hz, 1 H), 10.7 (br s, 1 H).
MS (EI, 70 eV): m/z (%) = 609 (29) [M+ – 57], 319 (16), 317 (13),
291 (14), 247 (16), 235 (31), 177 (49) [organotin fragments], 57
(45), 42 (14), 41 (100), 39 (42) [organic fragments].
13C NMR (50 MHz, CDCl3): d = –1.4 (3 C), 9.6 (JSn–C = 334–352
Hz, 3 C), 13.4 (3 C), 27.2 (JSn–C = 57–55 Hz, 3 C), 29 (JSn–C = 21
Hz, 3 C), 138.2 (JSn–C = 13 Hz), 164.2 (JSn–C = 293–284 Hz), 169.8
(JSn–C = 67 Hz).
Tributylstannyl (E)-3-Phenyl-3-(tributylstannyl)acrylate (2f¢)
Yield: 73%; white crystals; mp 56–58 °C.
IR (neat): 3076, 3059, 1695, 1604, 1234, 908 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.85–1.70 (m, 54 H), 6.15 (s,
JSn–H = 59–56 Hz, 1 H), 6.94–7.02 (m, 2 H, Ar), 7.15–7.36 (m, 3 H,
Ar).
(E)-4-Methoxy-3-(tributylstannyl)but-2-enoic Acid (2h)
Yield: 72%; yellow oil.
IR (neat): 1685, 1600, 1235, 1110 cm–1.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Retinoic Acids and Analogues
2961
13C NMR (50 MHz, CDCl3): d = 10.2 (JSn–C = 335–321 Hz, 3 C),
13.5 (6 C), 17.4 (JSn–C = 337–322 Hz, 3 C), 26.8 (JSn–C = 65–61 Hz,
3 C), 27.1 (JSn–C = 59–56 Hz, 3 C), 27.7 (JSn–C = 24–22 Hz, 3 C),
28.7 (JSn–C = 20.5 Hz, 3 C), 124.4 (JSn–C = 60 Hz, 2 C), 125.9, 127.4
(JSn–C = 35 Hz), 127.9 (2 C), 144 (JSn–C = 18 Hz), 168 (JSn–C = 69
Hz), 172 (JSn–C = 290 Hz).
MS (EI, 70 eV): m/z (%) = 669 (5) [M+ – 57], 381 (100), 267(18),
177 (28), 121 (10) [organotin fragments], 147 (12), 137 (19), 77
(12), 69 (16), 41 (16) [organic fragments].
MS (EI, 70 eV): m/z (%) = 270 (29) [M+], 255 (28), 185 (23), 127
(16), 75 (100), 73 (63), 45 (46), 44 (12), 43 (77).
(E)-3-Iodo-4-methoxybut-2-enoic Acid (3h)
Yield: 63%; colorless oil.
IR (neat): 3084, 1689, 1604, 1242, 1114 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.41 (s, 3 H), 4.58 (d, J = 1.6 Hz,
2 H), 6.92 (t, J = 1.6 Hz, 1 H), 10.5 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 58.0, 73, 130.6, 131.8, 168.5.
MS (EI, 70 eV): m/z (%) = 242 (2) [M+], 115 (100), 87 (24), 69 (26),
45 (31), 39 (49).
3-Iodoalk-2-enoic Acids 3 by Iododestannylation of Acids 2;
General Procedure
Vinylstannane 2 (12 mmol) in freshly distilled Et2O (30 mL) was
cooled to 0 °C and treated with a soln of I2 (3.5 g, 14 mmol) in Et2O
(30 mL). The mixture was allowed to react for 2 h at r.t., and then
washed with 0.5 M Na2S2O3 (20 mL) to eliminate excess I2. The
mixture was then hydrolyzed with sat. aq KF (25 mL) and acetone
(25 mL) to remove all the tributyltin salts that had formed. After
vigorous stirring for 3 h, the reaction mixture was filtered and
washed with H2O (2 × 15 mL). The aqueous layer was acidified
with 1 M HCl soln and extracted with Et2O (3 × 25 mL), and the or-
ganic soln was washed with brine (2 × 15 mL). After usual treat-
ment, the crude acid 3 was purified by crystallization (PE–Et2O,
90:10).
(E)-3-Iodo[2-2H]but-2-enoic Acid (3i)
Yield: 58%; white crystals; mp 71–73 °C.
IR (KBr): 2287, 1674, 1601, 1263 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.04 (s, 3 H), 10 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 32, 124.5, 131.4 (t, JC–D = 25 Hz),
169.6.
MS (EI, 70 eV): m/z (%) = 213 (8) [M+], 127 (14), 86 (100), 45 (26),
43 (41), 41 (34), 40 (99), 39 (93).
(Z)-2,3-Diiodobut-2-enoic Acid (3j)
Yield: 38%; white crystals; mp 71–73 °C.
(E)-3-Iodopent-2-enoic Acid (3c)
IR (neat): 3043, 2955, 2801, 2620, 1676, 1559, 1264, 1086 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.00 (s, 3 H), 7.00 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 33.6, 98, 127.3, 169.
MS (EI, 70 eV): m/z (%) = 338 (7) [M+], 254 (16), 211 (42), 127
(18), 45 (10), 39 (100), 38 (32).
Yield: 60%; colorless oil.
IR (neat): 3068, 2921, 2851, 2712, 2617, 1692, 1608, 1237 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.18 (t, J = 7.4 Hz, 3 H), 3.17 (qd,
J = 7.4, 0.7 Hz, 2 H), 6.68 (t, J = 0.7 Hz, 1 H), 11 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.3, 35.5, 130, 135.4, 168.7.
MS (EI, 70 eV): m/z (%) = 226 [M+] (1), 127 (6), 99 (100), 71 (16),
53 (41), 45 (11), 43 (61).
Alka-2,4-dienoic Acids 4 by Cross-Coupling of Acids 3 with
Vinylstannanes; General Procedure
[PdCl2(NCMe)2] (129 mg, 0.5 mmol) was added to a DMF soln (15
mL) of acid 3 (10 mmol) and the appropriate vinylstannane (12
mmol) in a 50-mL flask. The mixture was stirred for 6 h at 25 °C,
then hydrolyzed with a 1 M soln of KF (25 mL) and acetone (25
mL) to precipitate the Bu3SnI that had formed. After strongly stir-
ring for 2 h, the reaction mixture was filtered, washed with a 0.1 M
HCl soln (2 × 15 mL) and extracted with Et2O (3 × 20 mL). After
usual workup, the crude acid 4 was purified by crystallization (PE–
Et2O, 95:5).
(E)-3-Iodohex-2-enoic Acid (3d)
Yield: 57%; colorless oil.
IR (neat): 3067, 2964, 2932, 2729, 2617, 1697, 1604, 1248 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.00 (t, J = 7.3 Hz, 3 H), 1.66
(sext, J = 7.3 Hz, 2 H), 3.14 (t, J = 7.3 Hz, 2 H), 6.74 (s, 1 H), 11.8
(br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 12.7, 23, 43, 130.7, 133.9, 169.3.
MS (EI, 70 eV): m/z (%) = 240 (1) [M+], 113 (100), 95 (27), 69 (14),
67 (38), 45 (23), 43 (34), 41 (74), 39 (60).
(E)-3-Ethylpenta-2,4-dienoic Acid (4d)
Yield: 77%; colorless oil.
IR (neat): 3094, 1687, 1626, 1601, 1284, 1236 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.15 (t, J = 7.5 Hz, 3 H), 2.85 (q,
J = 7.5 Hz, 2 H), 5.47 (d, J = 10.8 Hz, 1 H), 5.73 (d, J = 17.4 Hz, 1
H), 5.80 (s, 1 H), 6.38 (dd, J = 10.8, 17.4 Hz, 1 H), 10.65 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 14, 20.4, 118.1, 120, 138.4, 160.5,
172.
MS (EI, 70 eV): m/z (%) = 126 (95) [M+], 125 (41), 111 (67), 97
(54), 83 (30), 69 (35), 55 (58), 53 (77), 45 (30), 43 (54), 41 (75), 39
(100), 38 (15).
(E)-3-Iodo-3-phenylacrylic Acid (3f)
Yield: 59%; white crystals; mp 184–186 °C.
IR (KBr): 3077, 2954, 2818, 1691, 1616, 1587, 1150 cm–1.
1H NMR (200 MHz, acetone-d6): d = 6.88 (s, 1 H), 7.34 (br s, 5 H,
Ar), 10.48 (br s, 1 H).
13C NMR (50 MHz, acetone-d6): d = 116.2, 127.5 (2 C), 127.7,
128.8 (2 C), 132.7, 142.5, 163.6.
MS (EI, 70 eV): m/z (%) = 274 (1) [M+], 103 (24), 102 (100), 77
(12), 51 (11), 44 (38).
(E)-3-Iodo-3-(trimethylsilyl)acrylic Acid (3g)
Yield: 51%; pale yellow crystals; mp 103–105 °C.
IR (KBr): 3077, 2783, 2573, 1698, 1587, 1207 cm–1.
(2E,4E)-3-Ethyl-5-(trimethylsilyl)penta-2,4-dienoic Acid (4e)
Yield: 82%; yellow crystals; mp 57–59 °C.
IR (KBr): 3072, 1689, 1612, 1576, 1286, 1248 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.30 (s, 9 H), 7.04 (s, 1 H), 10.50
1H NMR (200 MHz, CDCl3): d = 0.16 (9 H, s), 1.12 (t, J = 7.5 Hz,
3 H), 2.85 (q, J = 7.5 Hz, 2 H), 5.81 (s, 1 H), 6.44 (d, J = 19.2 Hz, 1
H), 6.54 (d, J = 19.2 Hz, 1 H), 10.40 (br s, 1 H).
(br s, 1 H).
13C NMR (50 MHz, CDCl3): d = –1.67 (3 C), 130, 133.8, 169.1.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

2962
M. Abarbri et al.
FEATURE ARTICLE
13C NMR (50 MHz, CDCl3): d = –1.6 (JSi–C = 53 Hz, 3 C), 14, 20.3,
118.3, 137.2 (JSi–C = 63 Hz), 144.8, 161.2, 172.3.
MS (EI, 70 eV): m/z (%) = 87 (10), 71 (100), 57 (18), 45 (10), 43
(63), 39 (25).
MS (EI, 70 eV): m/z (%) = 198 (5) [M+], 183 (23), 169 (9), 125 (98),
75 (100), 73 (31), 59 (24), 45 (30), 43 (21).
6-[(Z)-2-Carboxy-1-(methoxymethyl)vinyl]-2-(methoxymeth-
yl)cyclohex-2-ene-1-carboxylic Acid (4k)
Yield: 80%; colorless oil.
IR (neat): 1709, 1687, 1633, 1322, 1257, 1087 cm–1.
(2E,4E)-3-Ethyl-5-phenylpenta-2,4-dienoic Acid (4f)
Yield: 84%; colorless oil.
IR (neat): 3450, 3086, 3032, 1684, 1599, 1240 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.62 (m, 1 H), 2.15–2.34 (m, 3 H),
3.07–3.13 (m, 1 H), 3.28–3.33 (m, 3 H), 3.37–3.40 (m, 3 H), 3.56
(d, J = 5.3 Hz, 1 H), 3.90 (s, 1 H), 4.48 (d, J = 15.3 Hz, 1 H), 4.91
(d, J = 15.8 Hz, 1 H), 5.73 (s, 1 H), 6.03 (br s, 1 H), 10.2 (br s, 2 H).
13C NMR (50 MHz, CDCl3): d = 20.9, 24.9, 38.5, 45.5, 57.5, 58.5,
70.1, 75.9, 115.8, 128.9, 131, 163.2, 170.8, 178.1.
1H NMR (200 MHz, CDCl3): d = 1.24 (t, J = 7.5 Hz, 3 H), 3.00 (q,
J = 7.5 Hz, 2 H), 5.93 (s, 1 H), 6.79 (d, J = 16.2 Hz, 1 H), 7.34 (d,
J = 16.2 Hz, 1 H), 7.35–7.46 (m, 3 H, Ar), 7.51–7.56 (m, 2 H, Ar),
8.90 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.1, 20.9, 117.8, 127 (2 C), 128.7
(3 C), 130.1, 134.5, 136.2, 161.0, 171.7.
MS (EI, 70 eV): m/z (%) = 179 (13), 131 (14), 129 (16), 115 (17),
93 (14), 91 (50), 77 (19), 69 (10), 67 (10), 65 (16), 55 (18), 53 (19),
45 (100), 44 (19), 43 (23), 41 (35), 39 (30).
MS (EI, 70 eV): m/z (%) = 202 (14) [M+], 157 (39), 141 (29), 129
(100), 128 (39), 115 (32), 78 (15), 77 (33), 51 (32), 45 (11), 39 (27).
Alk-2-enoic Acids 6 by Cross-Coupling of Organohalides with
Alk-2-enoates 2a¢ or 2b¢
(2E,4E)-7,7-Diethoxy-3-ethylhepta-2,4-dienoic Acid (4g)
Yield: 62%; pale yellow crystals; mp 49–51 °C.
IR (KBr): 3086, 3030, 1685, 1637, 1599, 1236 cm–1.
These reactions were performed according to a previously reported
method.32
1H NMR (200 MHz, CDCl3): d = 1.14 (t, J = 7.5 Hz, 3 H), 1.25 (t,
J = 7.0 Hz, 6 H), 2.56 (br t, J = 5.7 Hz, 2 H), 2.85 (q, J = 7.5 Hz, 2
H), 3.56 (dq, J = 9.3, 7.0 Hz, 2 H), 3.71 (dq, J = 9.3, 7.0 Hz, 2 H),
4.59 (t, J = 5.6 Hz, 1 H), 5.72 (s, 1 H), 6.12 (d, J = 15.8 Hz, 1 H),
6.20 (dt, J = 15.8, 5.6 Hz, 1 H), 10.4 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.0, 15.2 (2 C), 20.9, 37.7, 61.4
(2 C), 102, 116.3, 132.1, 134.2, 161, 171.1.
(2E,4E)-5-Chloropenta-2,4-dienoic Acid (6a)
Yield: 62%; colorless oil.
IR (neat): 3140, 3070, 1680, 1625, 1160 cm–1.
1H NMR (200 MHz, acetone-d6): d = 6.05 (d, J = 15.3 Hz, 1 H),
6.80 (dd, J = 13.0, 11.2 Hz, 1 H), 7.01 (d, J = 13.0 Hz, 1 H), 7.33
(dd, J = 15.3, 11.2 Hz, 1 H), 9.50 (br s, 1 H).
13C NMR (50 MHz, acetone-d6): d = 122.4, 128.8, 131.8, 140.2,
166.8.
MS (EI, 70 eV): m/z (%) = 197 (3) [M+ – 45], 103 (59), 79 (15), 77
(11), 75 (68), 47 (100), 43 (12).
MS (EI, 70 eV): m/z (%) = 132 (19) [M+], 97 (100), 87 (16), 79 (91),
69 (33), 61 (33).
(Z)-3-(Trimethylsilyl)penta-2,4-dienoic Acid (4h)
Yield: 76%; yellow oil.
IR (neat): 3080–2570, 1688, 1620, 1170 cm–1.
(E)-3-(p-Tolylsulfonyl)but-2-enoic Acid (6b)
1H NMR (200 MHz, CDCl3): d = 0.28 (s, 9 H), 5.47 (m, J = 11.1
Hz, 1 H), 5.53 (m, J = 18 Hz, 1 H), 6.07 (d, J = 1.2 Hz, 1 H), 7.62
(ddd, J = 18, 11.2, 1.2 Hz, 1 H), 9.80 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = –0.68 (3 C), 121.8, 126, 135.6,
161.7, 170.8.
MS (EI, 70 eV): m/z (%) = 170 (20) [M+], 155 (26), 111 (48), 75
(83), 73 (100), 52 (55), 45 (49), 43 (29).
Yield: 68%; yellow crystals; mp 87–89 °C.
IR (KBr): 3200–2600, 1675, 1620, 1600, 1145 cm–1.
1H NMR (200 MHz, acetone-d6): d = 2.24 (s, 3 H), 2.42 (s, 3 H),
6.90 (s, 1 H), 7.34 (d, J = 8 Hz, 2 H), 7.73 (d, J = 8 Hz, 2 H), 9.2 (br
s, 1 H).
13C NMR (50 MHz, acetone-d6): d = 17.5, 25.8, 130.4, 133.7 (2 C),
135.3 (2 C), 139.9, 150.5, 158.8, 169.8.
(2Z,4E)-3,5-Bis(trimethylsilyl)penta-2,4-dienoic Acid (4i)
Yield: 75%; yellow oil.
IR (neat): 3075–2560, 1684, 1627, 1180 cm–1.
(2E,4E,6E)-Octa-2,4,6-trienedioic Acid (6c)
Yield: 75%; yellow crystals; mp 110–112 °C.
IR (KBr): 3400–2500, 1698, 1670, 1623, 1012 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.16 (s, 9 H), 0.26 (s, 9 H), 6.05
(dd, J = 1.2, 0.5 Hz, 1 H), 6.17 (dd, J = 19.6, 0.5 Hz, 1 H), 7.74 (dd,
J = 19.6, 1.2 Hz, 1 H), 9.50 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = –1.62 (JSi–C = 52 Hz, 3 C), –0.62
(JSi–C = 51 Hz, 3 C), 125.2, 139.1, 142.7, 163.5, 170.5.
MS (EI, 70 eV): m/z (%) = 242 (3) [M+], 169 (100), 152 (17), 133
(15), 75 (35), 73 (79), 45 (43).
1H NMR (200 MHz, DMSO-d6): d = 6.08 (d, J = 8 Hz, 2 H), 6.87
(dd, J = 8, 2.2 Hz, 2 H), 7.27 (ddd, J = 15, 8, 2.2 Hz, 2 H), 12.5 (br
s, 2 H)
13C NMR (50 MHz, DMSO-d6): d = 126.4 (2 C), 138.1 (2 C), 143.8
(2 C) 168.3 (2 C).
MS (EI, 70 eV): m/z (%) = 168 (50) [M+], 122 (100), 94 (49), 79
(49), 77 (89), 66 (58), 55 (57), 51 (83), 45 (68), 41 (79).
(2E,4E)-5-(Trimethylsilyl)penta-2,4-dienoic Acid (4j)
Yield: 82%; yellow oil.
IR (neat): 3425–2553, 1687, 1624, 1575, 1246, 1016 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.16 (s, 9 H), 5.92 (d, J = 15.3 Hz,
1 H), 6.45 (d, J = 18.3 Hz, 1 H), 6.68 (dd, J = 18.3, 10.1 Hz, 1 H),
7.35 (dd, J = 15.3, 10.1 Hz, 1 H), 8.0 (1 H, s).
13C NMR (50 MHz, CDCl3): d = –1.8, 120.5, 140.8, 146.6, 148.4,
172.3.
Alka-2,4-dienoates 7 by Cross-Coupling of Acids 3 or 5 with
(E)-1,2-Bis(tributylstannyl)ethene; General Procedure
A dry 250-mL two-necked flask, flushed with argon, was charged
with a soln of the tributyltin iodocarboxylate derivative of 3 or 5 (10
mmol) in DMF (50 mL) and [PdCl2(NCMe)2] (52 mg, 2 mol%).
When the soln had become pale yellow, it was cooled to 0 °C, and
(E)-1,2-bis(tributylstannyl)ethene (7.27 g, 12 mmol) was added.
When the reaction had reached completion (after stirring at 25 °C
for 6 h, the soln had become dark, and the end of the reaction was
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Retinoic Acids and Analogues
2963
checked by 1H NMR spectroscopy), a 0.5 M soln of KF (30 mL) and
EtOAc (50 mL) were added to precipitate the Bu3SnI that had
formed. The reaction mixture was filtered through Celite and ex-
tracted with Et2O (3 × 30 mL). The organic phase was washed with
brine (2 × 15 mL) and dried (MgSO4). Removal of the solvents un-
der reduced pressure yielded 7, which was further purified by col-
umn chromatography (silica gel, PE–Et2O, 95:5).
(2Z,4E)-Tributylstannyl-5-tributylstannyl-3-methylpenta-2,4-
dienoate (7d)
Yield: 69%; yellow oil.
IR (neat): 2957, 2923, 2854, 2871, 1644, 1561, 1516 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.92 (t, J = 7 Hz, 9 H), 0.94 (t,
J = 7 Hz, 9 H), 1.26–1.66 (m, 36 H), 2.00 (s, 3 H), 5.81 (s, 1 H), 6.70
(d, J = 19.5 Hz, JSn–H = 64 Hz, 1 H), 7.97 (d, J = 19.5 Hz, JSn–H = 65
Hz, 1 H).
(2E,4E)-Tributylstannyl-5-tributylstannylpenta-2,4-dienoate
13C NMR (50 MHz, CDCl3): d = 9.4 (JSn–C = 331–349 Hz, 3 C),
13.5 (6 C), 16.4 (JSn–C = 342.4–359 Hz, 3 C), 20.1, 26.9 (JSn–C = 63–
66 Hz, 3 C), 27.2 (JSn–C = 53–56 Hz, 3 C), 27.8 (JSn–C = 20 Hz, 3 C),
29 (JSn–C = 21 Hz, 3 C), 119, 137 (JSn–C = 348–364 Hz), 143.6
(JSn–C = 12 Hz), 148, 172.
MS (EI, 70 eV): m/z (%) = 633 (21) [M+ – 57], 401 (6), 235 (25),
233 (36), 177 (54) [organotin fragments], 57 (90), 41 (100), 39 (21)
[organic fragments].
(7a)
Yield: 64%; yellow oil.
IR (neat): 2957, 2923, 2852, 1631, 1571, 1532, 1387 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.95 (t, J = 7.1 Hz, 18 H), 1.32–
1.66 (m, 36 H), 5.88 (d, J = 15.2 Hz, 1 H), 6.63 (d, J = 18.6 Hz, 1
H), 6.77 (dd, J = 18.6, 9 Hz, JSn–H = 74 Hz, 1 H), 7.16 (dd, J = 15.2,
9 Hz, JSn–H = 55 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 9.5 (JSn–C = 332–349 Hz, 3 C),
13.5 (6 C), 16.3 (JSn–C = 343–360 Hz, 3 C), 26.3 (JSn–C = 54 Hz, 3
C), 26.6 (JSn–C = 60 Hz, 3 C), 27.7 (JSn–C = 20.5 Hz, 3 C), 28.9
(JSn–C = 19 Hz, 3 C), 121.6, 144.6, 145, 145.6, 172.5.
119Sn NMR (149 MHz, CDCl3): d = –43.6, 98.8.
5-Iodopenta-2,4-dienoic Acids 8 by Iododestannylation of
Dienoates 7; General Procedure
Acids 8 were prepared from dienoates 7 by the general procedure
MS (EI, 70 eV): m/z (%) = 621 (26) [M+ – 57], 291 (47), 235 (52),
177 (81), 121 (25) [organotin fragments], 57 (21), 56 (17), 43 (15),
41 (100), 39 (39) [organic fragments].
described above for the synthesis of acids 3.
(2E,4E)-5-Iodopenta-2,4-dienoic Acid (8a)
Yield: 64%; colorless oil.
IR (neat): 3058, 1673, 1623, 1231 cm–1.
1H NMR (200 MHz, CDCl3): d = 6.05 (d, J = 15.2 Hz, 1 H), 7.17–
7.47 (m, 3 H), 8.35 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 90.6, 122.4, 143, 143.3, 167.8.
MS (EI, 70 eV): m/z (%) = 224 (44) [M+], 127 (10), 97 (67), 69 (29),
(2Z,4E)-Tributylstannyl-5-tributylstannylpenta-2,4-dienoate
(7b)
Yield: 66%; yellow oil.
IR (neat): 2957, 2924, 2852, 1632, 1619, 1561, 1527, 1262 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.85–1.01 (m, 18 H), 1.25–1.74
(m, 36 H), 5.66 (d, J = 11.3 Hz, 1 H), 6.24 (dd, J = 11.3, 10.5 Hz, 1
H), 6.67 (d, J = 18.7 Hz, JSn–H = 38 Hz, 1 H), 7.80 (dd, J = 18.7,
10.5 Hz, JSn–H = 83–64 Hz, 1 H).
51 (81), 45 (26), 41 (100), 39 (38).
13C NMR (50 MHz, CDCl3): d = 9.5 (JSn–C = 333–352 Hz, 3 C),
13.5 (6 C), 16.4 (JSn–C = 322–337 Hz, 3 C), 26.9 (JSn–C = 64 Hz, 3
C), 27.1 (JSn–C = 54 Hz, 3 C), 27.7 (JSn–C = 19 Hz, 3 C), 28.9
(JSn–C = 20 Hz, 3 C), 118.5, 143.0 (JSn–C = 13 Hz), 144.3 (JSn–C = 75
Hz), 144.7 (JSn–C = 346–361 Hz), 171.8.
Anal. Calcd for C5H5O2I: C, 26.81; H, 2.25. Found: C, 26.67; H,
2.22.
(2Z,4E)-5-Iodopenta-2,4-dienoic Acid (8b)
Yield: 66%; colorless oil.
IR (neat): 3074, 3036, 2754, 2587, 1678, 1609, 1556, 1233 cm–1.
119Sn NMR (149 MHz, CDCl3): d = –48.8, 103.2.
MS (EI, 70 eV): m/z (%) = 621 (54) [M+ – 57], 331 (24), 291 (41),
253 (24), 235 (64), 225 (24), 177 (100), 121 (35) [organotin frag-
ments], 57 (37), 55 (20) [organic fragments].
1H NMR (200 MHz, acetone-d6): d = 5.73 (d, J = 11.3 Hz, 1 H),
6.60 (dd, J = 12, 11.3 Hz, 1 H), 7.06 (d, J = 14.6 Hz, 1 H), 8.41 (dd,
J = 14.6, 12 Hz, 1 H), 10.20 (br s, 1 H).
13C NMR (50 MHz, acetone-d6): d = 92.8, 116.5, 141.2, 144.9,
(2E,4E)-Tributylstannyl-5-tributylstannyl-3-methylpenta-2,4-
dienoate (7c)
Yield: 70%; yellow oil.
170.9.
MS (EI, 70 eV): m/z (%) = 224 (49) [M+], 127 (10), 97 (68), 52 (65),
51 (82), 45 (25), 41 (100), 39 (38).
IR (neat): 2957, 2924, 2874, 2853, 1613, 1566, 1523, 1375, 1075
cm–1.
1H NMR (200 MHz, CDCl3): d = 0.92 (t, J = 7 Hz, 9 H), 0.95 (t,
J = 7 Hz, 9 H), 1.29–1.67 (m, 36 H), 2.25 (d, J = 1 Hz, 3 H), 5.86
(s, 1 H), 6.61 (d, J = 19.3 Hz, JSn–H = 60–62 Hz, 1 H), 6.74 (d,
J = 19.3 Hz, JSn–H = 62–65 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 9.4 (JSn–C = 333–347 Hz, 3 C),
12.9, 13.5 (6 C), 16.3 (JSn–C = 342–360 Hz, 3 C), 27 (JSn–C = 63–66
Hz, 3 C), 27.1 (JSn–C = 53–56 Hz, 3 C), 27.7 (JSn–C = 20 Hz, 3 C),
28.9 (JSn–C = 21 Hz, 3 C), 121.4, 135.5 (JSn–C = 347–363 Hz), 149.6
(JSn–C = 11 Hz), 150, 173.
Anal. Calcd for C5H5O2I: C, 26.81; H, 2.25. Found: C, 26.52; H,
2.38.
(2E,4E)-5-Iodo-3-methylpenta-2,4-dienoic Acid (8c)
Yield: 64%; yellow crystals; mp 125–127 °C.
IR (KBr): 3065, 2955, 2924, 1678, 1614, 1190, 1269, 1190 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.29 (d, J = 0.5 Hz, 3 H), 5.92 (q,
J = 0.5 Hz, 1 H), 7.19 (d, J = 14.8 Hz, 1 H), 7.3 (d, J = 14.8 Hz, 1
H), 10.40 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 12.9, 85.2, 120.8, 148.8, 151.7,
167.3.
119Sn NMR (149 MHz, CDCl3): d = –45.0, 100.6.
MS (EI, 70 eV): m/z (%) = 238 (11) [M+], 127 (10), 111 (100), 66
(17), 65 (25), 55 (59), 45 (12), 43 (20), 41 (17), 39 (77).
MS (EI, 70 eV): m/z (%) = 633 (11) [M+ – 57], 345 (16), 291 (15),
233 (38), 177 (48), 121 (15) [organotin fragments], 57 (62), 56 (17),
55 (16), 44 (14), 43 (17), 41 (100), 39 (47) [organic fragments].
Anal. Calcd for C6H7O2I: C, 30.27; H, 2.96. Found: C, 30.07; H,
3.04.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

2964
M. Abarbri et al.
FEATURE ARTICLE
(2Z,4E)-5-Iodo-3-methylpenta-2,4-dienoic Acid (8d)
Yield: 69%; yellow crystals; mp 133–135 °C.
MS (EI, 70 eV): m/z (%) = 266 (8) [M+], 139 (100), 128 (18), 127
(10), 110 (15), 79 (12), 77 (14), 55 (11), 53 (10), 51 (14).
IR (KBr): 3475–2771, 1675, 1619, 1556, 1292, 1211 cm–1.
1H NMR (50 MHz, acetone-d6): d = 2.06 (s, 3 H), 5.72 (s, 1 H), 7.23
(d, J = 15.0 Hz, 1 H), 8.71 (d, J = 15.0 Hz, 1 H), 10.3 (br s, 1 H).
13C NMR (50 MHz, acetone-d6): d = 19.1, 87.2, 117.4, 142.3, 149.6,
166.
Anal. Calcd for C8H11O2I: C, 36.11; H, 4.17. Found: C, 35.93; H,
4.23.
(2Z,4E,6Z)-3,6-Dimethylocta-2,4,6-trienedioic Acid (8i)
Yield: 71%; colorless oil.
IR (neat): 3068–2600, 2361, 1675, 1620, 1556, 1284, 1211, 1170
cm–1.
1H NMR (200 MHz, CDCl3): d = 2.50 (s, 6 H), 6.01 (s 2 H), 6.78 (s,
2 H), 7.50 (br s, 2 H).
MS (EI, 70 eV): m/z (%) = 127 (8) [M+ – 111], 111 (100), 83 (13),
55 (45), 43 (19), 41 (13), 39 (59).
Anal. Calcd for C6H7O2I: C, 30.27; H, 2.96. Found: C, 29.84; H,
3.19.
13C NMR (50 MHz, CDCl3): d = 21.2, 119.4, 128.1, 150.2, 170.8.
(2Z,4E)-5-Iodo-3-methyl[2-2H]penta-2,4-dienoic Acid (8e)
Yield: 74%; yellow crystals; mp 189–191 °C.
MS (EI, 70 eV): m/z (%) = 196 (48) [M+], 153 (19), 152 (100), 107
(73), 67 (32), 45 (66), 44 (28), 41 (55), 39 (71).
IR (KBr): 3475–2771, 1676, 1619, 1556, 1292 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.0 (s, 3 H), 7.06 (d, J = 15 Hz, 1
H), 8.62 (d, J = 15.0 Hz, 1 H), 9.8 (br s, 1 H).
Trienoic Acids 9 by Cross-Coupling of Acids 8 with Vinylstan-
nanes; General Procedure
Acids 9 were prepared from acids 8 and vinylstannanes by the gen-
eral procedure described above for the synthesis of dienoic acids 4.
13C NMR (50 MHz, CDCl3): d = 21, 88.6, 117, 142.8, 152, 171.
MS (EI, 70 eV): m/z (%) = 239 (1) [M+], 127 (10), 112 (100), 111
(11), 84 (15), 67 (18), 66 (25), 56 (55), 43 (30), 40 (52), 39 (44).
(2E,4E)-Hepta-2,4,6-trienoic Acid (9a)
Yield: 88%; colorless oil.
IR (neat): 3400–2500, 1695, 1641, 1620, 1256 cm–1.
(2Z,4E)-5-Iodo-3-ethylpenta-2,4-dienoic Acid (8f)
1H NMR (200 MHz, CDCl3): d = 5.43 (d, J = 9.5 Hz, 1 H), 5.50 (d,
J = 16.5 Hz, 1 H), 5.95 (d, J = 15.3 Hz, 1 H), 6.32–6.72 (m, 3 H),
7.44 (dd, J = 15.3, 11.1 Hz, 1 H), 8.50 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 121.1 (2 C), 123.1, 130.7, 142.7,
147.2, 173.1.
MS (EI, 70 eV): m/z (%) = 124 (28) [M+], 79 (100), 53 (15), 52 (15),
45 (10), 39 (29).
Yield: 70%; colorless oil.
IR (neat): 3432, 3074, 1685, 1616, 1556, 1264, 1264 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.15 (t, J = 7.4 Hz, 3 H), 2.38 (q,
J = 7.4 Hz, 2 H), 5.67 (s, 1 H), 7.0 (d, J = 15.0 Hz, 1 H), 8.51 (d,
J = 15.0 Hz, 1 H), 11.3 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 13.5, 26.9, 87.6, 115.6, 141.9,
157.5, 171.3.
MS (EI, 70 eV): m/z (%) = 252 (2) [M+], 234 (10), 156 (10), 142
(12), 128 (71), 127 (67), 126 (16), 125 (100), 108 (15), 107 (19), 81
(11), 79 (32), 77 (20), 67 (11), 53 (12), 52 (12), 51 (14), 50 (12).
(2Z,4E)-Hepta-2,4,6-trienoic Acid (9b)
Yield: 84%; colorless oil.
IR (neat): 3300–2500, 1695, 1618, 1610, 1572, 1259 cm–1.
1H NMR (200 MHz, CDCl3): d = 5.40 (d, J = 9.1 Hz, 1 H), 5.49 (d,
J = 14.8 Hz, 1 H), 5.74 (d, J = 11.3 Hz, 1 H), 6.44–6.64 (m, 2 H),
6.76 (dd, J = 11.5, 11.3 Hz, 1 H), 7.55 (dd, J = 12.7, 11.5 Hz, 1 H),
10.40 (br s, 1 H).
Anal. Calcd for C7H9O2I: C, 33.36; H, 3.60. Found: C, 33.52; H,
3.51.
(2E,4E)-5-Iodo-3-propylpenta-2,4-dienoic Acid (8g)
Yield: 67%; colorless oil.
13C NMR (50 MHz, CDCl3): d = 117.5, 122.9, 129.5, 137.1, 143.5,
IR (neat): 3429, 3073, 2958, 2871, 1693, 1607, 1416, 1265, 1183,
948 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.98 (t, J = 7.4 Hz, 3 H), 1.52
(sext, J = 7.4 Hz, 2 H), 2.73 (t, J = 7.4 Hz, 2 H), 5.76 (s, 1 H), 6.99
(d, J = 15.0 Hz, 1 H), 7.51 (d, J = 15.0 Hz, 1 H), 11.3 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 14.6, 23.2, 29.7, 85.7, 119.2,
147.5, 158.7, 172.
147.3, 172.9.
MS (EI, 70 eV): m/z (%) = 124 (20) [M+], 79 (100), 78 (19), 51 (23),
39 (25).
(2Z,4E)-3-Methylhepta-2,4,6-trienoic Acid (9c)
Yield: 96%; yellow oil.
IR (neat): 3483, 3059, 3024, 2577, 1700, 1609, 1556, 1178 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.11 (d, J = 1.1 Hz, 3 H), 5.37 (dd,
J = 8.7, 2 Hz, 1 H), 5.48 (dd, J = 16.1, 2 Hz, 1 H), 5.77 (q, J = 1.1
Hz, 1 H), 6.56–6.69 (m, 2 H), 7.76 (d, J = 14.4 Hz, 1 H), 10.38 (br
s, 1 H).
MS (EI, 70 eV): m/z (%) = 266 (3) [M+], 237 (15), 221 (25), 139
(100), 128 (67), 127 61), 43 (48).
Anal. Calcd for C8H11O2I: C, 36.11; H, 4.17. Found: C, 35.93; H,
4.23.
13C NMR (50 MHz, CDCl3): d = 21.0, 116.9, 121.3, 129.8, 137,
(2Z,4E)-5-Iodo-3-propylpenta-2,4-dienoic Acid (8h)
Yield: 73%; colorless oil.
IR (neat): 3432, 3071, 1691, 1613, 1556, 1257, 957 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.97 (t, J = 7.5 Hz, 3 H), 1.57
(sext, J = 7.5 Hz, 2 H), 2.33 (td, J = 7.5, 1.0 Hz, 2 H), 5.68 (t, J = 1.0
Hz, 1 H), 7.05 (d, J = 15.0 Hz, 1 H), 8.52 (dd, J = 15.0, 1.0 Hz, 1
H), 11.3 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 8.4, 14.3, 36.2, 87.9, 116.5, 141.9,
156.1, 171.6.
137.1, 153, 171.8.
MS (EI, 70 eV): m/z (%) = 138 (22) [M+], 93 (100), 53 (14), 51 (18),
41 (20), 39 (41).
(2Z,4E)-3,7-Dimethylocta-2,4,6-trienoic Acid (9d)
Yield: 74%; yellow oil.
IR (neat): 3483, 3064, 3030, 1638, 1617, 1568 cm–1.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Retinoic Acids and Analogues
2965
1H NMR (200 MHz, CDCl3): d = 1.9 (s, 6 H), 2.12 (s, 3 H), 5.68 (s,
1 H), 6.11 (d, J = 10.7 Hz, 1 H), 6.9 (dd, J = 15.2, 10.7 Hz, 1 H),
7.65 (d, J = 15.2 Hz, 1 H), 10.8 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 18.6, 21.1, 26.4, 115.2, 125.9,
126.9, 133.1, 141.3, 154, 172.
(2Z,4E)-3-Methyl-7-phenylhepta-2,4-dien-6-ynoic Acid (10b)
Yield: 75%; yellow crystals; mp 169–171 °C.
IR (KBr): 3070, 2980, 2870, 2185, 1685, 1610, 1595, 1170 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.12 (s, 3 H), 5.76 (s, 1 H), 6.25
(d, J = 16 Hz, 1 H,), 7.31–7.3 (m, 3 H, Ar), 7.48–7.46 (m, 2 H, Ar),
8.1 (d, J = 16 Hz, 1 H), 9.6 (br s, 1 H).
MS (EI, 70 eV): m/z (%) = 166 (37) [M+], 121 (100), 107 (95), 105
(66), 93 (19), 43 (64), 41 (92), 40 (24), 39 (87).
13C NMR (100 MHz, CDCl3): d = 20.7, 89, 96, 116, 118, 123,
128.5, 128.8, 132, 137.7, 151.8, 171.4.
(2Z,4E,6E)-9,9-Diethoxy-3-methylnona-2,4,6-trienoic Acid (9e)
Yield: 72%; yellow oil.
IR (neat): 3450, 3063, 3028, 1671, 1662, 1640, 1607, 1247 cm–1.
MS (EI, 70 eV): m/z (%) = 212 (33) [M+], 197 (61), 165 (67), 115
(35), 105 (100), 83 (20), 77 (32), 39 (24).
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 7.0 Hz, 6 H), 2.07 (s,
3 H), 2.52 (t, J = 6.2 Hz, 2 H), 3.47–3.77 (m, 4 H), 4.57 (t, J = 6.2
Hz, 1 H), 5.7 (s, 1 H), 5.93 (dt, J = 15.1, 6.2 Hz, 1 H), 6.35 (dd,
J = 15.2, 10.5 Hz, 1 H), 6.65 (dd, J = 15, 10.5 Hz, 1 H), 7.67 (d,
J = 15.2 Hz, 1 H), 9.68 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 15.1 (2 C), 20.7, 37.4, 61.1 (2 C),
102, 116.2, 128.4, 132.8, 133.3, 135.6, 153, 171.3.
MS (EI, 70 eV): m/z (%) = 163 (4) [M+], 111 (95), 103 (92), 101
(26), 91 (11), 75 (64), 73 (43), 69 (28), 68 (14), 55 (18), 47 (94), 46
(17), 45 (95), 41 (58), 39 (60), 31 (100).
(2Z,4E)-3-Methyl-7-(trimethylsilyl)hepta-2,4-dien-6-ynoicAcid
(10c)
Yield: 77%; yellow crystals; mp 111–113 °C.
IR (KBr): 3100, 2985, 2875, 2200, 1690, 1615, 1170 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.25 (s, 9 H), 2.05 (d, J = 1 Hz, 3
H), 5.78 (q, J = 1 Hz, 1 H), 6.08 (d, J = 16 Hz, 1 H), 8.09 (d, J = 16
Hz, 1 H), 11.8 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 0.2 (JSi–C = 56 Hz, 3 C), 21, 102,
104, 116, 118, 119, 139, 152, 172.
MS (EI, 70 eV): m/z (%) = 208 (13) [M+], 193 (54), 149 (27), 75
(100), 73 (19), 45 (44), 43 (37).
(2Z,4E,6E)-3-Methyl-7-(trimethylsilyl)hepta-2,4,6-trienoic
Acid (9f)
Yield: 86%; yellow oil.
IR (neat): 3159, 2959, 2929, 2680, 1680, 1657, 1605, 1261 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.15 (s, 9 H), 2.10 (s, 3 H), 5.76
(s, 1 H), 6.19 (d, J = 17.2 Hz, 1 H), 6.64 (dd, J = 14.6, 10.2 Hz, 1
H), 6.79 (dd, J = 17.2, 10.2 Hz, 1 H), 7.75 (d, J = 14.6 Hz, 1 H),
11.66 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = –1.5, 21, 117.5, 129.6, 138.8, 140,
143.9, 153.3, 171.4.
(2E,4E)-3-Methyl-7-(tributylgermyl)hepta-2,4-dien-6-ynoic
Acid (10f)
Yield: 72%; colorless oil.
IR (neat): 3100, 2980, 2875, 2200, 1690, 1615, 1170 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 7 Hz, 9 H), 1.5–1.34
(m, 18 H), 2.3 (s, 3 H), 5.86 (s, 1 H), 6.11 (d, J = 16 Hz, 1 H), 6.68
(d, J = 16 Hz, 1 H), 9.4 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 13.7, 14.2 (3 C), 14.5 (3 C), 26.5
(3 C), 27.8 (3 C), 101.5, 104.7, 116, 120, 144.3, 154, 172.
MS (EI, 70 eV): m/z (%) = 210 (2) [M+], 91 (10), 75 (100), 73 (41),
45 (19), 43 (16).
MS (EI, 70 eV): m/z (%) = 323 (22) [M+ – 56], 267 (20), 91 (44), 57
(23), 43 (11), 41 (100).
(2Z,4E)-3-Methylhepta-2,4-dien-6-ynoic Acid (9g)
Yield: 79%; colorless oil.
6-[(E)-But-1-en-3-ynyl]-1,5,5-trimethylcyclohexene (12b)
Compound 12b was prepared by a method described by Negishi.40
IR (neat): 3472, 3262, 2957, 2925, 1677, 1638, 1619, 1579, 1266
cm–1.
1H NMR (200 MHz, CDCl3): d = 2.07 (s, 3 H), 3.27 (s, 1 H), 5.81
(s, 1 H), 6.04 (d, J = 16.3 Hz, 1 H), 8.16 (d, J = 16.3 Hz, 1 H), 10.6
(br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 20.3, 82.9, 92.2, 114.7, 118.5,
139.4, 150.9, 170.
MS (EI, 70 eV): m/z (%) = 136 (39) [M+], 119 (10), 91 (82), 90 (20),
89 (17), 65 (78), 51 (45), 50 (43), 45 (26), 43 (14), 39 (100), 38 (24),
32 (29).
Yield: 86%; yellow oil.
IR (neat): 3300, 3200, 2100, 1633, 1608, 956 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.84 (s, 3 H), 0.89 (s, 3 H), 1.15–
1.44 (m, 2 H), 1.57 (m, 3 H), 1.98 (m, 2 H), 2.15 (d, J = 9.6 Hz, 1
H), 2.78 (dd, J = 2.2, 0.6 Hz, 1 H), 5.42 (m, 1 H), 5.43 (ddd,
J = 15.8, 2.2, 0.6 Hz, 1 H), 6.07 (ddd, J = 15.8, 9.6, 0.6 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 23.2, 23.4, 27.2, 28.0, 31.7, 32.7,
55.1, 76.6, 82.8, 110.3, 122.2, 133.0, 141.2.
MS (EI, 70 eV): m/z (%) = 174 (8) [M+], 159 (16), 118 (63), 117
(100), 115 (14), 103 (22), 91 (15).
Hepta-2,4-dien-6-ynoic Acids 10 by Cross-Coupling of Acids 8
with Alkynes; General Procedure
1-[(E)-But-1-en-3-ynyl]-2,6,6-trimethylcyclohexa-1,3-diene
(12c)
These reactions were performed according to a previously reported
method.38
A two-necked, 250-mL flask equipped with an argon bubbler, a
magnetic stirring bar, and a rubber septum was charged with tri-
phenyl[3-(trimethylsilyl)prop-2-ynyl]phosphonium bromide (21.5
g, 47 mmol) and dry THF (70 mL), and the flask was cooled with
an ice–water bath. Then, 1 M LDA in THF (50 mL, 50 mmol) was
added dropwise to this soln. The mixture was stirred for 1 h, and sa-
franal (4.05 g, 26.7 mmol) in dry THF (30 mL) was added at –5 °C,
after which stirring was continued for 15 h at 0 °C. The resulting
dark soln was quenched with sat. aq NH4Cl (50 mL) at 0 °C and ex-
tracted with Et2O (3 × 50 mL). The combined organic layers were
washed with brine (2 × 20 mL), dried (MgSO4), and concentrated in
(2Z,4E)-7-Phenylhepta-2,4-dien-6-ynoic Acid (10a)
Yield: 75%; colorless oil.
IR (neat): 3098, 2186, 1687, 1610, 1596, 1168 cm–1.
1H NMR (200 MHz, CDCl3): d = 5.82 (d, J = 11.3 Hz, 1 H), 6.24 (d,
J = 15.6 Hz, 1 H), 6.78 (t, J = 11.4 Hz, 1 H), 7.39–7.59 (m, 5 H), 8.0
(dd, J = 15.6, 11.4 Hz, 1 H), 11.1 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 89.0, 97.5, 118.7, 123.2, 128.9 (2
C), 129.7, 132.3, 133 (2 C), 137.3, 145.9, 172.2.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

2966
M. Abarbri et al.
FEATURE ARTICLE
vacuo. The crude product was diluted with an Et2O–PE mixture
(20:80; 100 mL), the insoluble material (Ph3PO) was removed by
filtration, and the solvent was evaporated. The residue was purified
by column chromatography (PE–Et2O, 90:10); this gave 1-[(E)-4-
(trimethylsilyl)but-1-en-3-ynyl]-2,6,6-trimethylcyclohexa-1,3-di-
ene.
J = 6.1 Hz, 2 H), 6.13 (m, 2 H), 6.18 (d, J = 18.9 Hz, JSn–H = 72 Hz,
1 H), 6.55 (ddd, J = 18.9, 7.1, 1.5 Hz, JSn–H = 61 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 9.8 (JSn–C = 328–343 Hz, 3 C),
13.5 (3 C), 19.2, 21.5, 27.3 (JSn–C = 50–64 Hz, 3 C), 28.8 (2 C), 29.1
(JSn–C = 20.0 Hz, 3 C), 33, 34.1, 39.7, 130.1, 129.4, 130.9
(JSn–C = 393–376 Hz, 1 C), 136.5 (JSn–C = 74 Hz, 1 C), 137.2, 147.7
(JSn–C = 9.3 Hz, 1 C).
1-[(E)-4-(Trimethylsilyl)but-1-en-3-ynyl]-2,6,6-trimethylcyclo-
hexa-1,3-diene
Yield: 5.1 g (78%); yellow oil.
IR (neat): 3050, 2970, 2150, 1260, 850 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.17 (s, 9 H), 0.98 (s, 6 H), 1.83
(s, 3 H), 2.03 (d, J = 3.9 Hz, 2 H), 5.57 (d, J = 16.5 Hz, 1 H), 5.69
(dt, J = 9.5, 3.9 Hz, 1 H), 5.80 (d, J = 9.5 Hz, 1 H), 6.60 (d, J = 16.5
Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = –0.1 (JSi–C = 46 Hz, 3 C), 20.1,
26.5 (2 C), 33.6, 39.7, 95.1, 104.9, 111.1, 126.1, 128.8, 129.5,
137.0, 140.5.
Stannanes 14a and 14b
After the stannylcuprate prepared from the corresponding alkyne 12
[as described above for the synthesis of compounds 13] had stirred
for 2 h at –90 °C, MeI (12.1 mL, 195 mmol) was added. The soln
was allowed to warm to 25 °C, and the mixture was stirred for 12 h.
The mixture was hydrolyzed with a sat. soln of NH4Cl and extracted
with Et2O (3 × 20 mL). The organic phases were washed with brine
and dried (MgSO4), and the solvents were removed under reduced
pressure. Compounds 14 were obtained contaminated with the cor-
responding internal isomers 15b (<10%), but were used without pu-
rification.
MS (EI, 70 eV): m/z (%) = 244 (18) [M+], 73 (100), 59 (15).
Tributyl[(1E,3E)-2-methyl-4-(2,6,6-trimethylcyclohex-1-
enyl)buta-1,3-dienyl]stannane (14a)
Yield: 78%; yellow oil.
1H NMR (200 MHz, CDCl3): d = 0.94 (t, J = 7.2 Hz, 9 H), 0.98 (m,
6 H), 1.07 (s, 6 H), 1.25–1.66 (m, 16 H), 1.75 (s, 3 H), 1.96 (s, 3 H),
2.05 (t, J = 6.0 Hz, 2 H), 5.88 (s, JSn–H = 68 Hz, 1 H), 6.06 (d,
J = 16.2 Hz, 1 H), 6.18 (d, J = 16.2 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 10.1 (JSn–C = 326–341 Hz, 3 C),
13.6 (3 C), 19.2, 20.5, 21.5, 27.3 (JSn–C = 50–63.7 Hz, 3 C), 28.8 (2
C), 29.1 (JSn–C = 20 Hz, 3 C), 32.9, 34.1, 39.5, 125.4, 128.6, 130.9
(JSn–C = 391–407 Hz, 1 C), 137.5, 138.7 (JSn–C = 71 Hz, 1 C), 150.8
(JSn–C = 29 Hz, 1 C).
MS (EI, 70 eV): m/z (%) = 423 (100) [M+ – 57], 311 (4), 309 (15),
235 (23), 209 (14), 207 (30), 193 (15), 179 (44), 177 (41), 123 (11),
121 (30) [organotin fragments], 189 (17), 181 (12), 133 (44), 131
(34), 107 (13), 105 (44), 93 (16), 91 (21), 81 (12), 79 (16), 77 (12),
69 (41), 62 (16), 55 (22), 48 (17), 43 (12), 41 (56), 40 (21), 39 (14),
31 (14) [organic fragments].
A 1 M soln of TBAF in THF (8.3 mL, 8.2 mmol) was added to a
soln of 1-[(E)-4-(trimethylsilyl)but-1-en-3-ynyl]-2,6,6-trimethyl-
cyclohexa-1,3-diene (1 g, 4.1 mmol) in dry THF (20 mL) at –5 °C,
and the mixture was stirred at r.t. for 2 h. The resulting dark soln
was quenched with sat. aq NH4Cl (10 mL) at 0 °C and extracted
with Et2O (3 × 20 mL). The combined organic layers were washed
with brine (2 × 15 mL), dried (MgSO4), and concentrated in vacuo.
Purification of the residue by column chromatography (PE–
Et2O, 95:5) gave 12c.
1-[(E)-but-1-en-3-ynyl]-2,6,6-trimethylcyclohexa-1,3-diene
(12c)
Yield: 0.58 g (82%); yellow oil.
IR (neat): 3320, 3055, 2980, 2120, 965 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.99 (s, 6 H), 1.83 (s, 3 H), 2.04
(d, J = 3.4 Hz, 2 H), 2.98 (d, J = 2.3 Hz, 1 H), 5.52 (dd, J = 16.5, 2.3
Hz, 1 H), 5.73 (dt, J = 9.8, 3.4 Hz, 1 H), 5.81 (d, J = 9.8 Hz, 1 H),
6.65 (d, J = 16.5 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 20.7, 27.2 (2 C), 34.3, 40.3, 78.6,
Tributyl[(1E,3E)-2-methyl-4-(2,6,6-trimethylcyclohex-2-
enyl)buta-1,3-dienyl]stannane (14b)
Yield: 83%; yellow oil.
1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 7.1 Hz, 9 H), 1.28–
1.58 (m, 29 H), 1.87 (s, 3 H), 2.00 (m, 2 H), 2.12 (d, J = 9.1 Hz, 1
H), 5.37 (dd, J = 15.6, 9.1 Hz, 1 H), 5.40 (m, 1 H), 5.80 (s,
JSn–H = 68 Hz, 1 H), 6.12 (d, J = 15.8 Hz, 1 H).
84.1, 110.8, 126.9, 129.5, 130.1, 137.5, 142.0.
MS (EI, 70 eV): m/z (%) = 172 (33) [M+], 157 (49), 143 (13), 142
(100), 141 (49), 129 (17), 128 (16), 115 (30), 91 (13), 77 (16), 65
(11), 63 (12), 51 (17), 41 (13), 39 (25).
Stannanes 13a and 13b; General Procedure
A soln of 1.6 M BuLi in hexane (24.3 mL, 39 mmol) was added
dropwise to a heterogeneous soln of CuCN (1.75 g, 19.5 mmol) in
THF (80 mL), at –78 °C, in a 100-mL four-necked flask flushed
with argon. After 10 min, Bu3SnH (10.5 mL, 39 mmol) was added;
the mixture became yellow and H2 evolved. The temperature of the
soln of was reduced to –90 °C, MeOH (100 equiv) and alkyne 12a
or 12b (2.61 g, 15 mmol) in THF (20 mL) were successively added
dropwise. After 2 h at –78 °C, the mixture was hydrolyzed with a
sat. NH4Cl soln and filtered through Celite. The aqueous phase was
extracted with Et2O (3 × 50 mL). The organic phases were com-
bined, washed with brine (2 × 20 mL), and dried (MgSO4), and the
solvents were evaporated to give vinylstannane 13.
13C NMR (50 MHz, CDCl3): d = 9.1 (JSn–C = 299–311 Hz, 3 C),
14.1 (3 C), 19.2, 23.4, 23.6, 27.7, 28.9 (JSn–C = 53 Hz, 3 C), 29.6
(JSn–C = 25 Hz, 3 C), 29.8, 32.2, 32.7, 55.0, 121.1, 130.1, 130.6,
137.5, 151.1.
(2Z,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-
enyl)nona-2,4,6,8-tetraenoic Acid (13-cis-Retinoic Acid) (16b);
Typical Procedure
[PdCl2(NCMe)2] (3%, 16 mg, 0.063 mmol) was added to a DMF
soln (15 mL) of 14a (1.20 g, 2.52 mmol) and 8d (0.5 g, 2.1 mmol)
in a 50-mL flask. The mixture was stirred for 3 h at 25 °C before be-
ing washed with a sat. soln of NH4Cl (2 × 15 mL) and extracted
with Et2O (3 × 30 mL). After the usual workup, the crude 16b was
purified by column chromatography (silica gel, PE–Et2O, 95:5, then
70:30) and crystallization (Et2O).
Tributyl[(1E,3E)-4-(2,6,6-trimethylcyclohex-1-enyl)buta-1,3-
dienyl]stannane (13a)
Yield: 85%; yellow oil.
1H NMR (200 MHz, CDCl3): d = 0.93 (t, J = 7.2 Hz, 9 H), 0.97 (m,
6 H), 1.07 (s, 6 H), 1.25–1.66 (m, 16 H), 1.75 (s, 3 H), 2.05 (t,
Yield: 70%; orange crystals; mp 161 °C (Lit. = 162–164 °C).
IR (KBr): 3264, 3062, 2956, 2921, 2851, 2581, 1682, 1605, 1562,
1276, 1225, 994 cm–1.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Retinoic Acids and Analogues
2967
1H NMR (400 MHz, CDCl3): d = 1.01 (s, 6 H), 1.43–1.47 (m, 2 H),
1.58–1.61 (m, 2 H), 1.70 (s, 3 H), 1.98 (s, 3 H), 2.01 (t, J = 5.7 Hz,
2 H), 2.08 (s, 3 H), 5.64 (s, 1 H), 6.15 (d, J = 16 Hz, 1 H), 6.25 (d,
J = 11 Hz, 1 H), 6.27 (d, J = 16 Hz, 1 H), 7.01 (dd, J = 15.2 Hz,
J = 11 Hz, 1 H), 7.73 (d, J = 15.2 Hz, 1 H), 10.7 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 12.8, 19.1, 21.1, 21.6, 28.8 (2 C),
33.0, 34.1, 39.5, 115.7, 128.7, 129.1, 130.0, 130.1, 132.9, 137.2,
137.5, 140.3, 153.5, 172.
MS (EI, 70 eV): m/z (%) = 300 (41) [M+], 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).
Didehydro Retinoid Acids 18; General Procedure38
A soln of BuNH2 (1 mL, 10 mmol) and alkyne 12 (6.3 mmol) in
DMF (20 mL) was stirred under an argon atmosphere for 15 min at
r.t. Then acid 17 (217 mg, 4.2 mmol), [PdCl2(PPh3)2] (0.31 mmol),
and CuI (59 mg, 0.31 mmol) were added. After 4 h at r.t., the mix-
ture was poured into H2O (20 mL) and extracted with Et2O (3 × 25
mL); the organic phases were washed with a sat. soln of NH4Cl (3
× 10 mL) and dried (MgSO4). After the solvents had been evaporat-
ed under reduced pressure, the residue was purified by column chro-
matography (silica gel, hexane–Et2O, 30:70) or by crystallization
(Et2O).
(2Z,4E,8E)-9-(2,6,6-Trimethylcyclohex-1-enyl)nona-2,4,8-
trien-6-ynoic Acid (18a)
Yield: 70%; yellow oil.
IR (neat): 3090, 2990, 2882, 2190, 1685, 1505, 1175 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.06 (s, 6 H), 1.6–1.4 (m, 4 H),
1.73 (s, 3 H), 2.04 (t, J = 6 Hz, 2 H), 5.64 (dd, J = 16.2, 2.2 Hz, 1
H), 5.7 (d, J = 11 Hz, 1 H), 6.12 (d, J = 15.5, 1 H), 6.65–6.78 (m, 2
H), 7.85 (dd, J = 15.5, 11.7 Hz, 1 H), 10.08 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 19.5, 22, 29.3 (2 C), 33.7, 34.5, 40,
89.6, 98, 112, 118, 122, 133.3, 136.6, 137.5, 143.2, 146, 171.8.
(2E,4E,6E,8E)-7-Methyl-9-(2,6,6-trimethylcyclohex-1-
enyl)nona-2,4,6,8-tetraenoic Acid (All-trans-9-nor-retinoic Ac-
id) (16a)
Yield: 55%; colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.06 (s, 6 H), 1.45–1.49 (m, 2 H),
1.60–1.63 (m, 2 H), 1.75 (s, 3 H), 2.02 (s, 3 H), 2.07 (t, J = 5.7 Hz,
2 H), 5.90 (d, J = 15 Hz, 1 H), 6.17 (d, J = 15.9 Hz, 1 H), 6.20–6.30
(m, 2 H), 6.35 (d, J = 15.9 Hz, 1 H), 6.99 (dd, J = 15, 11.6 Hz, 1 H),
7.44 (dd, J = 14.9, 11.6 Hz, 1 H), 10.7 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 12.8, 19.1, 21.7, 28.8 (2 C), 33.0,
34.1, 39.4, 114.8, 127.4, 130.4, 131.7, 132.8, 134.9, 137.5, 138.6,
143.1, 147, 172.
MS (EI, 70 eV): m/z (%) = 270 (95) [M+], 255 (100), 209 (79), 183
(40), 165 (33), 155 (69), 141 (34), 91 (39), 55 (37), 41 (95).
(2Z,4E,8E)-3-Methyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-
2,4,8-trien-6-ynoic Acid (18b)
Yield: 80%; Yellow crystals; mp 114 °C.
IR (KBr): 3100, 2980, 2875, 2188, 1680, 1605, 1160 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.07 (s, 6 H), 1.67–1.64 (m, 4 H),
1.78 (s, 3 H), 2.00–2.03 (m, 2 H), 2.08 (s, 3 H), 5.68 (dd, J = 16, 2.3
Hz, 1 H), 5.76 (s, 1 H), 6.22 (dd, J = 16, 2.3 Hz, 1 H), 6.71 (d,
J = 16 Hz, 1 H), 8.05 (d, J = 16 Hz, 1 H), 9.1 (br s, 1 H).
(2Z,4E,6E,8E)-7-Methyl-9-(2,6,6-trimethylcyclohex-1-
enyl)nona-2,4,6,8-tetraenoic Acid [(13Z)-9-nor-Retinoic Acid)]
(16d)
Yield: 45%; colorless oil.
IR (neat): 3264, 3062, 2958, 2920, 2851, 1681, 1604, 1560, 1276,
1247 cm–1.
Raman-IR: 1592, 1161 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.07 (s, 6 H), 1.45–1.55 (m, 2 H),
1.60–1.70 (m, 2 H), 1.76 (s, 3 H), 2.04 (s, 3 H), 2.07 (t, J = 5.7 Hz,
2 H), 5.67 (d, J = 11.2 Hz, 1 H), 6.19 (d, J = 16 Hz, 1 H), 6.28 (d,
J = 11.8 Hz, 1 H), 6.37 (d, J = 16 Hz, 1 H), 6.82 (dd, J = 11.5, 11.2
Hz, 1 H), 6.96 (dd, J = 11.8, 14.6 Hz, 1 H), 7.56 (dd, J = 14.6, 11.5
Hz, 1 H), 9.52 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 19.4, 20.9, 22.1, 29.3 (2 C), 33.7,
34.5, 40, 89.3, 96.7, 112.1, 116.9, 118, 133, 137.2, 137.5, 142.7,
152.2, 171.7.
MS (EI, 70 eV): m/z (%) = 284 (53) [M+], 269 (100), 223 (68), 169
(52), 128 (27), 115 (27), 91 (36), 43 (32), 41 (76), 39 (38).
13C NMR (50 MHz, CDCl3): d = 12.7, 19.1, 21.6, 28.8 (2 C), 33.0,
34.1, 39.5, 114.6, 128.1, 129.4 (2 C), 130.3, 137.0, 139.1, 140.7,
143.1, 147.3, 171.8.
(2Z,4E,8E)-3-Methyl-9-(2,6,6-trimethylcyclohex-1-enyl)[2-
2H]nona-2,4,8-trien-6-ynoic Acid (18c)
Yield: 73%; yellow crystals; mp 135–137 °C.
IR: 3100, 2980, 2877, 2295, 2195,1690, 1605, 1155 cm–1.
(2Z,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-2-
enyl)nona-2,4,6,8-tetraenoic Acid (16e)
Yield: 55%; yellow crystals; mp 169–171 °C.
1H NMR (200 MHz, CDCl3): d = 0.81 (s, 3 H), 0.89 (s, 3 H), 1.17
(dt, J = 13.2, 4.7 Hz, 1 H), 1.44 (dt, J = 13.2, 8.1 Hz, 1 H), 1.57 (s,
3 H), 1.93 (s, 3 H), 2.01 (m, 2 H), 2.08 (s, 3 H), 2.18 (d, J = 9.4 Hz,
1 H), 5.41 (m, 1 H), 5.64 (dd, J = 15.3, 9.4 Hz, 1 H), 5.65 (br s, 1
H), 6.13 (d, J = 15.3 Hz, 1 H), 6.24 (d, J = 11.3 Hz, 1 H), 6.97 (dd,
J = 15.3, 11.3 Hz, 1 H), 7.73 (d, J = 15.3, 1 H), 11.5 (br s, 1 H).
1H NMR (400 MHz, CDCl3): d = 1.02 (s, 6 H), 1.61–1.42 (m, 4 H),
1.72 (s, 3 H), 2 (t, J = 4 Hz, 2 H), 2.02 (s, 3 H), 5.64 (dd, J = 16, 2
Hz, 1 H), 6.18 (dd, J = 16, 2 Hz, 1 H), 6.66 (d, J = 16 Hz, 1 H), 8.0
(d, J = 16 Hz, 1 H), 11 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 19, 20.6, 21.8, 29 (2 C), 33.4,
34.2, 39.7, 89.4, 96.4, 111.8, 116.6, 117.5 (t, JC–D = 27 Hz), 132.6,
137, 137.2, 142.4, 151.8, 170.6.
MS (EI, 70 eV): m/z (%) = 285 (56) [M+], 270 (100), 224 (65), 170
13C NMR (50 MHz, CDCl3): d = 13.4, 21.3, 23.1, 23.2, 27.1, 27.8,
31.7, 32.6, 54.9, 115.7, 121.2, 129.2, 129.8, 133.1, 133.4, 134.2,
135.9, 140.1, 153.7, 171.5.
MS (EI, 70 eV): m/z (%) = 256 (22) [M+ – 44], 200 (12), 185 (23),
159 (10), 157 (15), 149 (23), 145 (23), 143 (17), 134 (16), 133
(100), 132 (19), 131 (12), 129 (14), 122 (20), 121 (12), 120 (36),
119 (28), 117 (15), 115 (11), 107 (38), 106 (11), 105 (50), 94 (11),
93 (42), 92 (11), 91 (51), 81 (20), 79 (33), 77 (33), 69 (11), 67 (12),
65 (16), 55 (28), 53 (18), 43 (13), 41 (62), 39 (23).
(41), 129 (22), 91 (30), 55 (30), 45 (24), 43 (34), 41 (89).
(2Z,4E,8E)-3-Ethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-
2,4,8-trien-6-ynoic Acid (18d)
Yield: 76%; yellow crystals; mp 94–96 °C.
IR (KBr): 3095, 2980, 2878, 2185, 1685,1605, 1165 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.07 (s, 3 H), 1.19 (t, J = 7.4 Hz,
3 H), 1.6–1.47 (m, 4 H), 1.78 (s, 3 H), 2.06 (t, J = 6 Hz, 2 H), 2.45
(q, J = 7.4 Hz, 2 H), 5.7 (dd, J = 16, 2 Hz, 1 H), 5.75 (s, 1 H), 6.26
(dd, J = 16, 2.2 Hz, 1 H), 6.72 (d, J = 16 Hz, 1 H), 8.01 (d, J = 16
Hz, 1 H), 11.1 (s, 1 H).
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

2968
M. Abarbri et al.
FEATURE ARTICLE
13C NMR (50 MHz, CDCl3): d = 14, 19.5, 22.1, 27, 29.2 (2 C), 33.7,
34.5, 40, 90, 96.6, 112.2, 116.2, 116.4, 133, 136.4, 137.6, 142.7,
157.8, 172.
13C NMR (50 MHz, CDCl3): d = 20.4, 20.6, 26.8 (2 C), 34, 40, 90.7,
96.6, 111.2, 116.5, 117.8, 126.6, 129.6, 129.8, 137, 137.4, 140.5,
151, 171.
MS (EI, 70 eV): m/z (%) = 298 (39) [M+], 283 (97), 237 (63), 183
(31), 155 (29), 115 (47), 91 (40), 55 (38), 43 (42), 41 (100), 39 (42).
Acknowledgement
tert-Butyl (2Z,4E,8E)-3-Methyl-9-(2,6,6-trimethylcyclohex-1-
enyl)nona-2,4,8-trien-6-ynoate (18e)
Yield: 78%; yellow oil.
IR (neat): 3095, 2987, 2870, 2200, 1725, 1600, 1200 cm–1.
We thank CNRS and MRT for providing financial support, the ‘Ser-
vice d’analyse chimique du vivant de Tours’ for recording NMR
and mass spectra and ‘CRRMN Marseille’ for recording NMR
spectra.
1H NMR (400 MHz, CDCl3): d = 1.01 (s, 3 H), 1.41–1.45 (m, 2 H),
1.46 (s, 9 H), 1.54–1.60 (m, 2 H), 1.71 (s, 3 H), 1.94 (d, J = 1.3 Hz,
3 H), 2.0 (d, J = 6.3 Hz, 2 H), 5.60 (d, J = 1 Hz, 1 H), 5.61 (dd,
J = 15, 2.4 Hz, 1 H), 6.10 (dd, J = 16, 2.4 Hz, 1 H), 6.67 (d, J = 16
Hz, 1 H), 8.1 (d, J = 16 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 19.5, 20.6, 22.1, 28.7 (3 C), 29.2
(2 C), 33.7, 34.5, 40, 80.5, 89, 96, 112.3, 115.4, 120.7, 132.7, 137.5,
137.8, 142.2, 148.5, 165.9.
References
(1) (a) Orfanos, C. E.; Ehlert, R.; Gollnick, H. Drugs 1987, 34,
459. (b) Vokes, E. E.; Weichselbaum, R. R.; Lippman, S.
M.; Hong, W. K. New. Engl. J. Med. 1993, 328, 184.
(c) Dawson, M. I.; Okamura, W. H. Chemistry and Biology
of Synthetic Retinoids; CRC Press: Boca Raton, 1990.
(2) The traditional retinoid numbering system was used in the
text when all-trans-retinoic acid was referred to. The IUPAC
nomenclature was used in the experimental section.
(3) (a) Eyrolles, L.; Kawachi, E.; Kagechika, H.; Hashimoto, Y.;
Shudo, K. Chem. Pharm. Bull. 1994, 42, 2575. (b) Wada,
A.; Hiraishi, S.; Takamura, N.; Date, T.; Aoe, K.; Ito, M. J.
Org. Chem. 1997, 62, 4343.
MS (EI, 70 eV): m/z (%) = 340 (9) [M+], 284 (41), 269 (83), 239
(13), 215 (27), 115 (21), 57 (100), 43 (20), 41 (90), 39 (22).
(2Z,4E,8E)-3-Methyl-9-(2,6,6-trimethylcyclohex-2-enyl)nona-
2,4,8-trien-6-ynoic Acid (18f)
Yield: 85%; colorless oil.
(4) For the use of retinoids in cancer therapy, see: Smith, M. A.;
Parkinson, D. R.; Cheson, B. D.; Friedman, M. A. J. Clin.
Oncol. 1992, 10, 839.
(5) (a) Mangelsdorf, D. J.; Umesono, K.; Evans, R. M. The
Retinoids Receptors, In The Retinoids, 2nd ed.; Sporn, M.
B.; Roberts, A. B.; Goodman, D. S., Eds.; Raven Press: New
York, 1994, 319. (b) Leid, M.; Kastner, P.; Chambon, P.
Trends Biochem. Sci. 1992, 17, 427.
(6) (a) Babler, J. H.; Schlidt, S. A. Tetrahedron Lett. 1992, 33,
7697. (b) Wada, A.; Hiraishi, S.; Ito, M. Chem. Pharm. Bull.
1994, 42, 757. (c) Bennani, Y. L.; Moehm, M. F. J. Org.
Chem. 1995, 60, 1195. (d) Bennani, Y. L. J. Org. Chem.
1996, 61, 3542. (e) Wada, A.; Hiraishi, S.; Takamura, N.;
Date, T.; Aoe, K.; Ito, M. J. Org. Chem. 1997, 62, 4343.
(7) (a) Julia, M.; Badet, B.; Uguen, D.; Callipolitis, A. Bull. Soc.
Chim. Fr. 1976, 513. (b) Chabardes, P.; Decor, J. P.;
Varagnat, J. Tetrahedron 1977, 33, 2799. (c) Uneyama, K.;
Torii, S. Chem. Lett. 1977, 39.
IR (neat): 3100, 2983, 2870, 2190,1685, 1650, 1610, 1180 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.86 (s, 3 H), 0.9 (s, 3 H), 1.5–1.13
(m, 4 H), 1.58 (d, J = 1.6 Hz, 3 H), 1.98–2.01 (m, 2 H), 2.02 (d, J = 1
Hz, 3 H), 2.18 (d, J = 9 Hz, 1 H), 5.48 (br s, 1 H), 5.68 (dd, J = 15.8,
2.2 Hz, 1 H), 5.75 (br s, 1 H), 6.12 (dd, J = 15.8, 9 Hz, 1 H), 6.18
(dd, J = 16, 2.2 Hz, 1 H), 8.04 (d, J = 16 Hz, 1 H), 9.7 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 21, 23.3, 23.4, 27.3, 28, 31.7, 33,
55.5, 88, 96, 111, 116.8, 118, 122, 133, 137, 147.6, 152, 171.
MS (EI, 70 eV): m/z (%) = 284 (23) [M+], 183 (74), 169 (46), 167
(75), 155 (44), 153 (45), 141 (56), 128 (69), 122 (64), 115 (73), 105
(69), 91 (100), 43 (58), 41 (95).
(2Z,4E,8E)-3-Methyl-9-(2,6,6-trimethylcyclohex-2-enyl)[2-
2H]nona-2,4,8-trien-6-ynoic Acid (18g)
Yield: 76%; colorless oil.
IR (neat): 3090, 2985, 2880, 2300, 2190, 1685, 1600, 1160 cm–1.
(8) (a) Vedejs, E.; Bershas, J. P. Tetrahedron Lett. 1975, 16,
1359. (b) Simpkins, N. Sulphones in Organic Synthesis;
Pergamon: Oxford, 1993, 254–284. (c) Kelly, S. E. In
Comprehensive Organic Synthesis, Vol. 1; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, Chap. 3.
(9) Alami, M.; Crousse, B.; Linstrumelle, G.; Mambu, L.;
Larchevêque, M. Synlett 1993, 217; and references cited
therein.
(10) (a) Stille, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508.
(b) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109,
813. (c) Mitchell, T. N. Synthesis 1992, 803. (d) Farina, V.
In Comprehensive Organometallic Chemistry II, Vol. 12;
Abel, E. W.; Stone, F. G.; Wilkinson, G., Eds.; Pergamon:
New York, 1995, Chap. 3.4, 161–241. (e) Farina, V.; Roth,
G. P. In Advances in Metal-Organic Chemistry, Vol. 5;
Liebeskind, L. S., Ed.; JAI Press: New York, 1996, 1–53.
(f) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React.
1997, 50, 1–652. (g) Farina, V.; Krishnamurthy, V. The
Stille Reaction; Wiley: New York, 1999.
1H NMR (200 MHz, CDCl3): d = 0.9 (s, 3 H), 0.95 (s, 3 H), 1.55–
1.19 (m, 2 H), 1.63 (d, J = 1.5 Hz, 3 H), 2.04–2.08 (m, 2 H), 2.06 (s,
3 H), 2.24 (d, J = 9.5 Hz, 1 H), 5.5 (br s, 1 H), 5.68 (dd, J = 15.7,
2.2 Hz, 1 H), 6.08 (dd, J = 15.7, 9.5 Hz, 1 H), 6.14 (dd, J = 16.2, 2.2
Hz, 1 H), 8.00 (d, J = 16.2 Hz), 10.5 (br s, 1 H).
13C NMR (50 MHz, CDCl3): d = 21, 23.3, 23.5, 27.3, 28, 31.8, 33,
55.5, 88, 95.7, 111, 116, 117 (t, JC–D = 27 Hz), 122, 133, 137, 147.6,
152, 171.5.
MS (EI, 70 eV): m/z (%) = 285 (10) [M+], 193 (35), 184 (23), 170
(23), 155 (27), 154 (28), 122 (35), 107 (43), 105 (41), 91 (43), 55
(44), 44 (39), 43 (75), 41 (100), 39 (51).
(2Z,4E,8E)-3-Methyl-9-(2,6,6-trimethylcyclohexa-1,3-di-
enyl)nona-2,4,8-trien-6-ynoic Acid (18h)
Yield: 72%; colorless oil.
IR (neat): 3102, 2985, 2871, 2189,1684, 1652, 1609, 1180 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.02 (s, 6 H), 1.87 (s, 3 H), 2.02
(s, 3 H), 2.05 (d, J = 5 Hz, 2 H), 5.71 (s, 1 H), 5.72–5.84 (m, 3 H),
6.17 (d, J = 15 Hz, 1 H), 6.66 (d, J = 16.3 Hz, 1 H), 8.03 (d, J = 16.3
Hz, 1 H).
(11) Pattenden, G.; Thom, S. M. Synlett 1993, 2883.
(12) Smith, A. B.; Ott, G. R. J. Am. Chem. Soc. 1996, 118, 13095.
(13) Le Menez, P.; Firmo, N.; Fargeas, V.; Ardisson, J.; Pancrazi,
A. Tetrahedron 1996, 52, 6613.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

FEATURE ARTICLE
Synthesis of Retinoic Acids and Analogues
2969
(14) Macdonald, G.; Lewis, N. J.; Taylor, R. J. K. Chem.
Commun. 1996, 2647.
(23) (a) Hibino, J. I.; Matsubara, S.; Morizawa, Y.; Oshima, K.;
Nozaki, H. Tetrahedron Lett. 1984, 25, 2151. (b) Cabezas,
J. A.; Oehlschlager, A. C. Synthesis 1994, 432. (c) Barbero,
A.; Cuadrado, P.; Fleming, I.; G onzalez, A. M.; Pulido, F.
J.; Rubio, R. J. Chem. Soc., Perkin Trans. 1 1993, 1657.
(d) Marek, I.; Alexakis, A.; Normant, J. F. Tetrahedron Lett.
1991, 32, 6337. (e) Beaudet, I.; Parrain, J.-L.; Quintard, J. P.
Tetrahedron Lett. 1991, 32, 6333. (f) Beaudet, I.; Launay,
V.; Parrain, J.-L.; Quintard, J. P. Tetrahedron Lett. 1995, 36,
389. (g) Stracker, E. C.; Zweifel, G. Tetrahedron Lett. 1991,
32, 3329.
(24) (a) Capella, L.; Degl’Innocenti, A.; Mordini, A.; Reginato,
G.; Ricci, A.; Seconi, G. Synthesis 1991, 1201. (b)Piers,E.;
Chong, J. M.; Morton, H. E. Tetrahedron 1989, 45, 363; and
references cited therein. (c) Marek, I.; Alexakis, A.;
Mangeney, P.; Normant, J. F. Bull. Soc. Chim. Fr. 1992, 129,
171. (d) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.;
Reuter, D. C. Tetrahedron Lett. 1989, 30, 2065. (e) Ricci,
A.; Blart, E.; Comes-Franchini, M.; Reginato, G.; Zani, P.
Pure Appl. Chem. 1996, 68, 679.
(25) (a) Piers, E.; Chong, J. M.; Keay, B. A. Tetrahedron Lett.
1985, 26, 6265. (b) Piers, E.; Wong, T.; Ellis, K. A. Can. J.
Chem. 1992, 70, 2058; and references cited therein.
(26) For preliminary work, see: Thibonnet, J.; Launay, V.;
Abarbri, M.; Duchêne, A.; Parrain, J.-L. Tetrahedron Lett.
1998, 39, 4277.
(27) Abarbri, M.; Thibonnet, J.; Parrain, J.-L.; Duchêne, A.
Synthesis 2002, 543.
(28) (a) Marek, I.; Alexakis, A.; Normant, J. F. Tetrahedron Lett.
1991, 32, 6337. (b) Beaudet, I.; Parrain, J.-L.; Quintard, J. P.
Tetrahedron Lett. 1991, 32, 6333.
(15) (a) Duchêne, A.; Abarbri, M.; Parrain, J.-L.; Kitamura, M.;
Noyori, R. Synlett 1994, 524. (b) Abarbri, M.; Parrain, J.-L.;
Duchêne, A. Tetrahedron Lett. 1995, 36, 2469. (c) Abarbri,
M.; Parrain, J.-L.; Cintrat, J.-C.; Duchêne, A. Synthesis
1996, 82. (d) Thibonnet, J.; Abarbri, M.; Parrain, J.-L.;
Duchêne, A. Tetrahedron Lett. 1996, 37, 7507.
(16) (a) Negishi, E. I.; Owczarczyk, Z. Tetrahedron Lett. 1991,
32, 6683. (b) de Lera, A. R.; Torrado, A.; Iglesias, B.;
Lopez, S. Tetrahedron Lett. 1992, 33, 6205. (c) Negishi, E.
I.; Ay, M.; Gulevich, Y. V.; Noda, Y. Tetrahedron Lett.
1993, 34, 1437. (d) Bienaymé, H.; Yezeguelian, C.
Tetrahedron 1994, 50, 3389. (e) Bienaymé, H. Tetrahedron
Lett. 1994, 35, 7383. (f) Torrado, A.; Lopez, S.; Alvarez, R.;
de Lera, A. R. Synthesis 1995, 285. (g) de Lera, A. R.;
Iglesias, B.; Rodriguez, J.; Alvarez, R.; Lopez, S.;
Villanueva, X.; Padros, E. J. Am. Chem. Soc. 1995, 117,
8220. (h) Torrado, A.; Iglesias, B.; Lopez, S.; de Lera, A. R.
Tetrahedron 1995, 51, 2435. (i) Bienaymé, H. Bull. Soc.
Chim. Fr. 1995, 132, 696.
(17) For recent syntheses of ATRA, 13-cis-RA, and retinoids,
see: (a) Aurell, M. J.; Ceita, L.; Mestres, R.; Parra, M.;
Tortaja, A. Tetrahedron 1995, 51, 3915. (b) de Lera, A. R.;
Castro, A.; Torrado, A.; Lopez, S. Tetrahedron Lett. 1998,
39, 4574. (c) Dominguez, B.; Iglesias, B.; de Lera, A. R. J.
Org. Chem. 1998, 63, 4135. (d) Uenishi, J.; Kawahama, R.;
Yonemitsu, O.; Wada, A.; Ito, M. Angew. Chem. Int. Ed.
1998, 37, 320. (e) Pazos, Y.; de Lera, A. R. Tetrahedron
Lett. 1999, 40, 8287. (f) Alvarez, R.; Iglesias, B.; de Lera,
A. R. Tetrahedron 1999, 55, 13779. (g) Dominguez, B.;
Iglesias, B.; de Lera, A. R. Tetrahedron 1999, 55, 15071.
(h) Borhan, B.; Souto, M.; Um, J.; Zhou, B.; Nakanishi, K.
Chem. Eur. J. 1999, 1172. (i) Wada, A.; Fujioka, N.;
Tanaka, Y.; Ito, M. J. Org. Chem. 2000, 65, 2438.
(j) Iglesias, B.; Torrado, A.; de Lera, A. R. J. Org. Chem.
2000, 65, 2696. (k) Dominguez, B.; Pazos, Y.; de Lera, A.
R. J. Org. Chem. 2000, 65, 5917. (l) Wada, A.; Fukunada,
K.; Ito, M. Synlett 2001, 800. (m) Pazos, Y.; Iglesias, B.; de
Lera, A. R. J. Org. Chem. 2001, 66, 8483. (n) Valla, A.;
Laurent, A.; Prat, V.; Andriamialisoa, Z.; Cartier, D.;
Giraud, M.; Labia, R.; Potier, P. Tetrahedron Lett. 2001, 42,
4795. (o) Valla, A.; Prat, V.; Laurent, A.; Andriamialisoa,
Z.; Giraud, M.; Labia, R.; Potier, P. Eur. J. Org. Chem. 2001,
1731. (p) Uenishi, J.; Matsui, K.; Wada, A. Tetrahedron
Lett. 2003, 44, 3093. (q) Cartier, D.; Valla, A.; Prat, V.;
Labia, R.; Le Guillou, R.; Potier, P. Tetrahedron Lett. 2003,
44, 5789. For a complete review on retinoid chemistry, see:
(r) Dominguez, B.; Alvarez, R.; de Lera, A. R. Org. Prep.
Proced. Int. 2003, 35, 239–306.
(29) Betzer, J. F.; Ardisson, J.; Lallemand, J. Y.; Pancrazi, A.
Tetrahedron Lett. 1997, 38, 2279.
(30) For the addition of hydrogen iodide to propiolic or tetrolic
acids, see: (a) Bowden, K.; Price, M. J. J. Chem. Soc. B
1970, 1466. (b) Chalcat, J. C.; Théron, F.; Vessière, R. C. R.
Acad. Sci., Ser. C 1971, 273, 763. (c) Zoller, T.; Uguen, D.
Tetrahedron Lett. 1998, 39, 6719. For the addition of
lithium halides to esters (or amides or nitriles), or
exclusively to propiolic acid and phenylpropiolic acid when
the LiX/AcOH/solvent/T °C system is used, see: (d)Ma, S.;
Lu, X. J. Chem. Soc., Chem. Commun. 1990, 1643. (e) Ma,
S.; Lu, X.; Li, Z. J. Org. Chem. 1992, 57, 709. (f) Meyer,
C.; Marek, I.; Normant, J. F. Synlett 1993, 386. (g) Piers,
E.; Wong, T.; Coish, P.; Rogers, C. Can. J. Chem. 1994, 72,
1816. (h) Luo, F.; Hseih, L. J. Chin. Chem. Soc. 1994, 41,
871. (i) Kotora, M.; Negishi, E.-I. Synthesis 1997, 121.
(31) To the best of our knowledge, (E)-1,2-bis(tributylstan-
nyl)ethene has generally been used in the Stille approach for
the synthesis of symmetrical bis-coupling products; for
examples, see: (a) Siesel, D. A.; Staley, S. W. Tetrahedron
Lett. 1993, 23, 3679. (b) Galarini, R.; Musco, A.; Pontellini,
R.; Bolognesi, A.; Destri, S. J. Chem. Soc., Chem. Commun.
1991, 364. (c) Zimmerman, E. K.; Stille, J. K.
(18) (a) Pereyre, M.; Quintard, J. P.; Rahm, A. Tin in Organic
Synthesis; Butterworths: London, 1987. (b) Davies, A. G.
Organotin Chemistry; Wiley-VCH: Weinheim, 1997.
(19) For example, see: McDermott, T. S.; Mortlock, A. A.;
Heathcock, C. H. J. Org. Chem. 1996, 61, 700.
Macromolecules 1985, 18, 321. Only few publications
describe the sequential use of (E)-1,2-bis(tributylstan-
nyl)ethene; for examples, see: (d) Haak, R. A.; Penning, T.
D.; Djuric, S. W.; Dziuba, J. A. Tetrahedron Lett. 1988, 29,
2783. (e) Barrett, A. G.; Edmunds, J. J.; Hendrix, J. A.;
Horita, K.; Parkinson, C. J. J. Chem. Soc., Chem. Commun.
1992, 1238.
(20) Leusink, A. J.; Budding, H. A. J. Organomet. Chem. 1968,
11, 533.
(21) (a) Miyake, H.; Yamamura, K. Chem. Lett. 1989, 981.
(b) Zhang, H. X.; Guibé, F.; Balavoine, G. J. Org. Chem.
1990, 55, 1857. (c) Asao, N.; Liu, J. X.; Sudoh, T.;
Yamamoto, Y. J. Org. Chem. 1996, 61, 4568.
(22) Matsubara, S.; Hibino, J. I.; Morizawa, Y.; Oshima, K.;
Nozaki, H. J. Organomet. Chem. 1985, 285, 163.
(32) Thibonnet, J.; Abarbri, M.; Parrain, J.-L.; Duchêne, A. Main
Group Metal Chemistry 1997, 20, 195.
(33) Compounds 7 are purified by column chromatography on
reversed-phase C18 silica gel.
(34) Thibonnet, J. PhD Thesis; University of Tours: France,
1999.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York

2970
M. Abarbri et al.
FEATURE ARTICLE
(35) Xiang, J. S.; Mahadevan, A.; Fuchs, P. L. J. Am. Chem. Soc.
1996, 118, 4284.
(36) Le Menez, P.; Firmo, N.; Fargeas, V.; Ardisson, J.; Pancrazi,
A. Synlett 1994, 998; under identical experimental
conditions, the reaction of (E)-1,2-bis(tributylstannyl)ethene
with a deconjugated isomer of 2a leads to 12% of
tributylstannyl transfer product (Scheme 14).
(39) Rousset, S.; Abarbri, M.; Thibonnet, J.; Duchêne, A.;
Parrain, J.-L. Synlett 1999, 701; and references cited therein.
(40) (a) Negishi, E.-I.; King, A. O.; Klima, W. L.; Patterson, W.;
Silveira, A. Jr. J. Org. Chem. 1980, 45, 2526. (b) Negishi,
E.-I.; King, A. O.; Tour, J. M. Org. Synth. 1986, 64, 44.
(41) Gibson, A. W.; Humphrey, G. R.; Kennedy, D. J.; Wright, S.
H. B. Synthesis 1991, 414.
(42) (a) Wolf, V. Chem. Ber. 1953, 86, 735. (b) Simmross, F.
M.; Weyersthal, P. Synthesis 1981, 72.
(43) (a) Seyferth, D.; Stone, F. G. A. J. Am. Chem. Soc. 1957, 79,
515. (b) Saihi, M. L.; Pereyre, M. Bull. Soc. Chim. Fr. 1977,
1251.
(44) Cunico, R. F.; Clayton, F. J. J. Org. Chem. 1976, 41, 1480.
(45) Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem. 1983,
48, 4634.
COOH 88%
SnBu3
Bu3Sn
Bu3Sn
+
COOSnBu3
I
PdCl2MeCN2 (3%),
DMF, 60 °C, 5 h
then KF sat. and
HCl (5N)
12%
COOH
Bu3Sn
76%
(46) (a) Beaudet, I.; Launay, V.; Parrain, J.-L.; Quintard, J. P.
Tetrahedron Lett. 1995, 36, 389. (b) Paulin-Launay, V.
PhD Thesis; University of Nantes: France, 1997.
(47) Renaldo, A. F.; Labadie, J. W.; Stille, J. K. Org. Synth. 1998,
67, 86.
(48) Lipshutz, B. H.; Ellsworth, E. L.; Dimock, S. H.; Reuter, D.
C. Tetrahedron Lett. 1989, 30, 2065.
Scheme 14 Reaction of (E)-1,2-bis(tributylstannyl)ethene with a
decongugated alkenoate
(37) Sonogashira, K. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley: New
York, 1998, 203–229.
(38) Abarbri, M.; Thibonnet, J.; Parain, J.-L.; Duchêne, A.
Tetrahedron Lett. 2002, 43, 4703.
Synthesis 2006, No. 17, 2951–2970 © Thieme Stuttgart · New York