New retinoid analogs from δ-pyronene, a natural synthon

Article abstract of DOI:10.1002/(SICI)1099-0690(199906)1999:6<1489::AID-EJOC1489>3.0.CO;2-1

δ-Pyronene (1), a readily available terpenic synthon, is an excellent raw material for the preparation of numerous terpenic intermediates. Original retinoid analogs such as 'iso'-retinyl acetate (5), 'iso'-retinal (6) and ethyl 'iso' retinoate (7), in which the cyclogeranyl moiety is functionalized in an unusual position, were prepared from δ-pyronene.

Full text of DOI:10.1002/(SICI)1099-0690(199906)1999:6<1489::AID-EJOC1489>3.0.CO;2-1

FULL PAPER
New Retinoid Analogs from δ-Pyronene, a Natural Synthon
[a]
[a]
[a]
[b]
´ ´
Frederic Lambertin, Martin Wende, Marie Jeanne Quirin, Martine Taran,
and Bernard Delmond*[a]
Keywords: δ-Pyronene / Terpenoids / Retinoids / Wittig reactions
δ-Pyronene (1), a readily available terpenic synthon, is an
excellent raw material for the preparation of numerous
terpenic intermediates. Original retinoid analogs such as
“iso”-retinyl acetate (5), “iso”-retinal (6) and ethyl “iso”-
retinoate (7), in which the cyclogeranyl moiety is
functionalized in an unusual position, were prepared from
δ-pyronene.
Introduction
The authors have recently reported[1Ϫ5] on the efficient
use of δ-pyronene (1), a terpenic synthon, in order to obtain
new terpenoids with a cyclogeranyl skeleton bearing a func-
tionalized side chain in an unusual position. Thus, for ex-
ample, “iso”-β-ionone (3) has been prepared[5] using “iso”-
β-cyclogeranyl iodide (2), which is itself derived from δ-py-
ronene (1) in an excellent yield (see Scheme 1).
Scheme 2. Retrosynthetic analysis for the obtention of “iso”-reti-
noids 5Ϫ7
C15 ؉ C5 Coupling
Coupling of “iso”-β-cyclogeranyl iodide (2) with the di-
Scheme 1. δ-Pyronene (1), precursor of “iso”-β-cyclogeranyl deriva- anion prepared from the corresponding hydroxy sulfoxide,
13,[9] afforded the C15 hydroxy sulfoxide 9 in a yield of 57%.
tives 2 and 3
This compound was refluxed in a toluene solution in the
Retinoids are the subject of much interest[6] due to their
essential role in wide-ranging biological functions and ther-
apies, e.g. the vision process, the treatment of skin disorders
and more recently cancer prevention and therapy. Many
natural or modified retinoids have also been synthesized
and biologicaly evaluated for use in these applications (der-
matology, oncology, etc.).
In this paper, the authors report on the use of δ-pyronene
(1), as a precursor of the new retinoid analogs (“iso”-retino-
ids[7]) 5Ϫ7, following coupling reactions via the C10 and
C15 intermediates 2 and 4, respectively (Scheme 2).
The homologation steps were based on the Wittig reac-
tion[8] between the cyclic phosphonium salts 8 and 10 ob-
tained from the same precursor, “iso”-β-cyclogeranyl iodide
(2), and linear aldehydic units 16, 17 and 19, prepared from
isoprene (11) (see Experimental Section, Scheme 6).
presence of potassium carbonate to give “iso”-vinyl-β-ionol
(4) (83% yield), with an (E) configuration with respect to
the newly formed double bond (see Scheme 3).
This new compound can be considered as an analog of
vinyl-β-ionol, which is an important intermediate in the
synthesis of retinoids.[10] Quantitative treatment of 4 with
triphenylphosphane hydrobromide led to the phosphonium
bromide 10.
The aldehyde 17, coupled (EtONa, 1 equiv.) with the
phosphonium salt 10 gave “iso”-retinyl acetate (5) in a yield
of 69%, corresponding to an approximately 1:1 mixture of
(E) and (Z) isomers with respect to the C-4ϪC-5 double
bond (see Scheme 4).
In a similar way, the coupling of the aldehyde 16 with the
phosphorane derived from phosphonium bromide 10 with
sodium ethoxide was realized. After acidic deprotection and
the addition of hydroquinone, a yield of 64% of “iso”-reti-
nal (6) as the only (all-E) isomer was obtained.
[a]
´ ´
´
Laboratoire de Chimie des Substances Vegetales, Universite
Bordeaux 1,
´
351, cours de la Liberation, F-33405 Talence Cedex, France
Fax: (internat.) ϩ 33-5/56846422
C10 ؉ C10 Coupling
E-Mail: b.delmond@ipin.u-bordeaux.fr
[b]
´
Unite dЈEnseignement et de Recherche des Sciences Pharmaceu-
“iso“-β-Cyclogeranyl iodide (2) was used as the precursor
of cyclic C10 phosphonium iodide 8 (see Scheme 3). Genera-
´
tiques, Universite Bordeaux II,
´
146, rue Leo Saignat, F-33076 Bordeaux Cedex, France
Eur. J. Org. Chem. 1999, 1489Ϫ1494
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0606Ϫ1489 $ 17.50ϩ.50/0
1489

F. Lambertin, M. Wende, M. J. Quirin, M. Taran, B. Delmond
FULL PAPER
“iso”-Retinyl Acetate (5) (Table 1)
From the unambiguous assignment of the triplet signal at
δ ϭ 5.64 (2-H), we observed COSY crosspeaks with methyl
singlets at δ ϭ 1.91 and 1.94 that may be assigned to CH3-
10 methyl groups. The COSY spectrum revealed two three-
spin systems, involving 4-H, 5-H and 6-H resonances. The
signals (dd) at δ ϭ 6.39 and 6.67 correspond to the 5-H
proton for each isomer; the former is correlated with the
protons resonating at δ ϭ 5.88 and 6.59 and the latter with
the protons resonating at δ ϭ 6.18 and 6.27.
The HMBC spectrum showed a long-range correlation
between CH3-10 proton signals at δ ϭ 1.91 and 1.94 and
carbon (CH) resonances at δ ϭ 136.1 and 132.3, respec-
tively, which were therefore assigned to CH-4. Those latter
1
carbon resonances can be associated, by a H-13C HMQC
experiment, with the proton resonances at δ ϭ 6.27 and
5.88; as a consequence, the assignments of 6-H vinylic pro-
ton at δ ϭ 6.18 and 6.59 were straightforward. The δ ϭ
1.99 and 1.96 signals were established for CH3-11 methyl
groups from the COSY spectrum, which exhibited corre-
lation peaks with 6-H proton resonances at δ ϭ 6.18 and
6.59.
Scheme 3. Preparation of phosphonium salts 8 and 10; reagents
and conditions: (a) PPh3, Et2O; (b) 13, nBuLi (2 equiv.), THF,
Ϫ78°C; (c) K2CO3, toluene, reflux; (d) PPh3/HBr, MeOH
1
Table 1. H- and 13C-NMR chemical shifts assignments of (all-E)-
and (4Z)-“iso”-retinyl acetate 5
Scheme 4. C15 ϩ C5 coupling
tion of the corresponding phosphorane with nBuLi at 0°C,
followed by the addition of the linear C10 formyl ester 19
provided a 70% yield of polyene isomers. Treatment of this
mixture with iodine gave ethyl “iso”-retinoate (7) as a mix-
ture of four isomers, from which the two major components
[(all-E) isomer (61%), (2Z,6E) isomer (31%)] were charac-
terized by NMR analysis (see Scheme 5).
Scheme 5. C10 ϩ C10 coupling
NMR Analysis
1
The complete H- and 13C-NMR chemical shift assign-
ments of “iso”-retinyl acetate (5) [(all-E) and (4Z) isomers]
and (all-E)-“iso”-retinal (6) were deduced from 2-D tech-
niques such as COSY 1H1H,[11] 1H-detected one-bond (CH)
heteronuclear multiple quantum coherence (HMQC),[12]
and long-range multi-bond (CH) heteronuclear connec-
tivity (HMBC).[13]
1490
Eur. J. Org. Chem. 1999, 1489Ϫ1494

New Retinoid Analogs from δ-Pyronene, a Natural Synthon
FULL PAPER
By means of an HMBC experiment, multi-bond corre-
At this stage, the assignments of CH-6 (δH ϭ 6.23, δC ϭ
lations were also detected from CH3-11 proton signals to 130.0) became unambiguous. In a similar approach, the
carbon (CH) resonances at δ ϭ 131.7 and 131.5, and thus CH3 proton resonance at δ ϭ 2.03 was assigned to CH3-
assigned to C-8. Thereby, the remaining vinylic proton sig- 11 from the observed correlation peaks with three carbon
nals at δ ϭ 6.75 and 6.77 were assigned to 9-H.
resonances at δ ϭ 130.0 (CH-6), 141.9 (C) and 130.5 (CH).
The assignments of sp2 quaternary carbon atoms were As a consequence, these two latter carbon resonances may
obtained from the analysis of long-range-correlation res- be assigned to C-7 and CH-8, respectively.
ponses over two and three bonds using the HMBC tech-
niques. The quaternary carbon resonances at δ ϭ 139.0 and
3
139.6 were assigned to C-3 from J connectivities with a 1-
Conclusion
H proton (δ ϭ 4.75) and 2J connectivities with CH3-10 pro-
tons. The C-7 quaternary carbon atoms correspond to sig-
nals at δ ϭ 137.5 and 138.5 which correlate long-range
(2JCH) with CH3-11 proton signals at δ ϭ 1.99 and 1.96,
respectively. Furthermore, the HMBC spectrum revealed
3JCH connectivities from the gem-dimethyl proton signals
(δ ϭ 1.07) to sp2-quaternary carbon atoms at δ ϭ 141.6
and 141.7(C-2Ј).
These results showed that δ-pyronene, easily available
from myrcene, is a particularly efficient new terpenic syn-
thon, allowing a synthetic approach to retinoid analogs.
These compounds, having a skeleton in which the polyenic
side-chain was linked to the cyclogeranyl moiety in an un-
usual position, represent a new type of retinoid with poten-
tial for biological uses.
From the measured H,H coupling constants J4,5 the pres-
ence of an (all-E) isomer (J4,5 ϭ 15.6 Hz) and a (4Z) isomer
(J4,5 ϭ 12 Hz) were unambiguously identified. Taking into
account the observed values for C-11 methyl carbon reson-
ances (δ ഠ 13), the C-6ϪC-7 double bond in each isomer
can be assigned to an (E) configuration.
Experimental Section
General: All reactions were performed under nitrogen; air- and
moisture-sensitive compounds were introduced by syringe or can-
nula through a rubber septum to the reaction vessel. Solvents were
freshly distilled prior to use. Ϫ H and 13C NMR: Bruker AC 250
1
“iso”-Retinal (6) (Table 2)
(250 MHz for 1H and 62.89 MHz for 13C) or Bruker DPX 400
(400 MHz for 1H and 100.61 MHz for 13C), CD3Cl solution,
chemical shifts expressed downfield from tetramethylsilane (TMS),
multiplicities in 13C NMR of the different carbon atoms were deter-
mined using the DEPT sequences and J-Mod experiments. Ϫ IR:
PerkinϪElmer 683, either neat or as a film on sodium chloride
plates. Ϫ High-resolution mass spectra (HRMS): VG Micromass
16F (10000 resolution), 70 eV. Ϫ Flash chromatography: Merck al-
umina and Kieselgel 60, 60Ϫ200 µm. The standard workup means
that the organic layers were washed with satd. sodium chloride
aqueous solution (brine), dried with anhydrous magnesium sulfate,
filtered and concentrated in vacuo.
1
The ethylenic proton area of the H-NMR spectrum of
“iso”-retinal (6) exhibited five doublets and a multiplet at
δ ϭ 7.13, corresponding to the 5-H proton. From the
COSY spectrum, the aldehyde proton 1-H (δ ϭ 10.08)
showed a correlation peak with the proton resonance at δ ϭ
5.96 which can be assigned to 2-H.
After associating proton and carbon resonances by an
HMQC experiment, the CH3-proton resonance at δ ϭ 2.31
was assigned to CH3-10 from a long-range correlation peak
in the HMBC spectrum with the C-2 carbon resonance (δ ϭ
128.8). The 10-H proton resonance also exhibited a corre-
lation with a carbon resonance at δ ϭ 154.9 (C) and 134.3
(CH), which were therefore assigned to C-3 and C-4, respec-
tively.
Preparation of the Linear Aldehyde Units 16, 17, and 19 (Scheme 6)
2-Methyl-1-(phenylsulfinyl)-3-buten-2-ol (13): Isoprene (11) (12.5
mL, 0.125 mol) was added to a suspension of N-bromosuccinim-
ide[14] (25.5 g, 0.14 mol) in a mixture of acetone/water (50:10, 120
mL) at 0°C. The reaction mixture was stirred for 15 h at room
temp., then extracted with Et2O. The combined organic layers were
washed with satd. aqueous sodium bicarbonate, dried (MgSO4),
and concentrated under vacuo to give 19.4 g (94% yield) of a mix-
ture of bromhydrines which was used without purification. Thio-
phenol (7.2 mL, 70 mmol) was added to a suspension of 95% so-
dium hydride (1.77 g, 70 mmol) in DMF (70 mL) at 0°C. After 1
h of stirring at ambient temp., bromohydrines (10.7 g, 65 mmol)
were added at 0°C. The reaction was allowed to warm to room
temp., then stirred for 15 h. after which it was poured into ice/
water, extracted with CHCl3, and treated by the standard workup.
The residue was purified by chromatography on silica gel (petro-
leum ether/ether, 90:10) to give 12 (7.36 g, 58% yield).[15] Ϫ Sodium
metaperiodate (4.41 g, 21 mmol) in water (40 mL) was added to a
solution of hydroxy sulfide 12 (4 g, 21 mmol) in tert-butyl alcohol
(100 mL), After 15 h of stirring at room temp., the reaction was
quenched by the addition of water, and extracted with CHCl3 fol-
lowed by the standard workup. The white solid obtained was puri-
1
Table 2. H- and 13C-NMR chemical shift assignments of (all-E)-
“iso”-retinal 6
Eur. J. Org. Chem. 1999, 1489Ϫ1494
1491

F. Lambertin, M. Wende, M. J. Quirin, M. Taran, B. Delmond
FULL PAPER
1
yield 16 (323 mg, 58% yield). Ϫ H NMR: δ ϭ 1.79 (s, 3 H), 3.32
(s, 6 H), 5.21 (d, 1 H, 4-H), 6.32 (d, 1 H, 3-H), 9.50 (s, 1 H, CHO).
Ϫ
13C NMR: δ ϭ 18.3 (CH3), 52.7 (OCH3), 99.3 (C-4), 142.4 (C-
2), 146.9 (C-3), 194.8 (C-1).
(E)-4-Acetoxy-2-methyl-2-butenal
(17):
K2HPO4
(1.32 g,
7.7 mmol), KH2PO4 (276 mg, 2 mmol) and sodium bromide
(80 mg, 0.77 mmol) were added to a solution of chloro acetate 14
(1.07 g, 6.5 mmol) in DMSO (8 mL). After stirring for 16 h at
80°C, the reaction mixture was poured into water (100 mL) and
extracted with CHCl3. The organic layers were washed with satd.
sodium chloride and dried (MgSO4). The evaporation of solvents
under reduced pressure provided a crude product which was puri-
fied by chromatography (silica gel). The elution with petroleum
ether/ether (60:40) gave 17 (532 mg, 58% yield).[18]
Ethyl 3,7-Dimethyl-8-oxo-2,4,6-octatrienoate (19):[20] The chloro al-
dehyde 15 (1.44 g, 1 mmol) was added at 0°C to an ethanol solu-
tion (5 mL) of the phosphonium salt (400 mg, 0.85 mmol) prepared
from ethyl 4-bromo-3-methyl-2-butenoate (EtONa/EtOH, 0°C).
The reaction mixture was stirred for 2 h and extracted with Et2O.
The combined organic layers were washed with 10% aqueous HCl,
satd. NaHCO3, satd. NaCl, dried (MgSO4) and concentrated to
give the C10 chloro ester 18 (120 mg, 55% yield) after chromatogra-
phy (silica gel, petroleum ether/ether, 92:8). K2HPO4 (201 mg,
1.15 mmol), KH2PO4 (42 mg, 0.31 mmol) and NaBr (12 mg,
0.115 mmol) were added to a solution of 18 (229 mg, 1 mmol) in
DMSO (8 mL) The solution was stirred for 18 h at 80°C, poured
into water (100 mL) and extracted with chloroform followed by the
standard workup. The residue purified by chromatography (silica
gel, petroleum ether/ether, 70:30) gave 19 (135 mg, 65% yield) as a
Scheme 6. Preparation of linear aldehydic units 16, 17 and 18; re-
agents and conditions: (a) NBS, acetone/H2O; (b) PhSNa, DMF;
(c) NaIO4, tBuOH/H2O; (d) tBuOCl, AcOH then CuSO4, H2SO4;
(e) DMSO, K2HPO4/KH2PO4, NaBr, 80°C; (f) Na2CO3, MeOH/
H2O; (g) PCC, CH2Cl2; (h) HC(OCH3)3, MeOH, APTS; (i) Ph3Pϭ
CHC(CH3)ϭCHCO2Et then I2
fied by chromatography (silica gel, petroleum ether/ether, 20:80)
and gave 13 (3.41 g, 79% yield).[16]
(E)-4,4-Dimethoxy-2-methyl-2-butenal (16): tert-Butyl hypo-
chlorite (17.3 g, 0.16 mol) was added at 0°C to a solution of iso-
prene (11) (13.6 g, 0.2 mol) in acetic acid (58 g, 0.96 mol).[17] The
reaction mixture was stirred for 1 h, hydrolyzed and extracted with
petroleum ether. The combined extracts were successively washed
with satd. NaHCO3 and satd. NaCl, and dried (MgSO4). The fil-
trate was concentrated under reduced pressure, dissolved in acetic
acid (60 mL), and treated with both copper sulfate (0.4 g, 2 mmol)
and sulfuric acid (0.4 g, 4 mmol). The resultant mixture was stirred
for 4 d at ambient temp., quenched by the addition of water and
extracted with ether. The standard workup gave (E)-4-chloro-3-
methyl-2-buten-1-ol acetate (14) (14.8 g, 86% yield).[18] Without
further purification this residue was dissolved in methanol (240
mL) and stirred for 5 h at 0°C in the presence of an aqueous solu-
tion (80 mL) of sodium carbonate (14.3 g, 135 mmol). The mixture
was filtered, concentrated and poured onto ice/water. The extrac-
tion with chloroform followed by a standard workup afforded a
crude product which was purified by chromatography (silica gel,
petroleum ether/ether, 60:40) to provide the chloro alcohol (9.05
g, 75% yield). The chloro alcohol (900 mg, 6.6 mmol) in dichloro-
methane (10 mL) was added at 0°C to a suspension of pyridinium
chlorochromate (2.2 g, 10.5 mmol) in dichloromethane (20 mL).
The resultant reaction was kept at 0°C for an additional 90 min,
1
1:1 mixture of (2E)/(2Z) isomers. Ϫ H NMR [(2E)]: δ ϭ 1.28 (t,
3 H, CH3CH2), 1.90 (s, 3 H, 9-H), 2.35 (s, 3 H, 10-H), 4.18 (q, 2
H, CH3CH2), 5.93 (s, 1 H, 2-H), 6.65 (d, 1 H, J4,5 ϭ 15.6 Hz, 4-
H), 6.92Ϫ6.99 (m, 2 H, 5-H and 6-H), 9.48 (s, 1 H, CHO). Ϫ 13C
NMR: δ ϭ 9.7 (C-9), 13.7 (C-10), 14.2(CH3CH2), 60.1 (CH3CH2),
123.3 (C-2), 128.3 (C-5), 139.9 (C-7), 143.6 (C-4), 147.9 (C-6), 150.5
1
(C-3), 166.4 (C-1), 194.7 (C-8). Ϫ H NMR [(2Z)]: δ ϭ 1.28 (t, 3
H, CH3CH2), 1.90 (s, 3 H, 9-H), 2.09 (s, 3 H, 10-H), 4.18 (q, 2 H,
CH3CH2), 5.84 (s, 1 H, 2-H), 8.16 (d, 1 H, J4,5 ϭ 15.6 Hz, 4-H),
6.92Ϫ6.96 (m, 2 H, H-5 and 6-H), 9.48 (s, 1 H, CHO). Ϫ 13C
NMR: δ ϭ 9.8 (C-9), 14.2 (CH3CH2), 20.6 (C-10), 60.1 (CH3CH2),
121.1 (C-2), 129.2 (C-5), 137.3 (C-4), 139.8 (C-7), 147.1 (C-6), 149.0
(C-3), 165.8 (C-1), 194.5 (C-8).
C15 ؉ C5 Coupling
“iso”-Vinyl-β-ionol (4): n-Butyllithium (4.9 mL of a 2.5  solution
in hexane) was added at Ϫ78°C to a solution of 13 (1.28 g,
then filtered through a short alumina column. Elution with ether 6.1 mmol) in THF (50 mL). After the solution was stirred for
gave 4-chloro-3-methyl-2-butenal (15) (800 mg, 90% yield)[19] as a
mixture of (E)/(Z) stereoisomers. Trimethyl orthoformate (8 mL)
and p-toluenesulfonic acid (160 mg, 0.9 mmol) were added to the
15 min, a solution of “iso”-β-cyclogeranyl iodide (2) (1.45 g,
5.5 mmol) in THF (10 mL) was added. The reaction mixture was
kept at Ϫ78°C for 15 h, poured in ice/water, acidified with 10%
chloro aldehyde 15 (1.072 g, 9 mmol) in a solution of methanol (8 aqueous HCl and extracted with ether, followed by the standard
mL). After stirring for 18 h at room temp., the solution was hy-
drolyzed with satd. NaHCO3, extracted with ether and treated by
workup. Purification by chromatography (silica gel, petroleum
ether/ether, 50:50) provided C15 hydroxy sulfoxide 9 (1.05 g, 57%
the standard workup. Further purification by chromatography on yield). A solution of 9 (660 mg, 1.91 mmol) in toluene (10 mL) was
silica gel, eluting with petroleum ether/ether (90:10) gave the refluxed in the presence of potassium carbonate (905 mg) for 72 h.
chloro acetal (968 mg, 65% yield). K2HPO4 (845 mg, 4.86 mmol), After stirring and evaporation of toluene, the mixture was purified
KH2PO4 (177 mg, 1.31 mmol) and sodium bromide (50 mg,
0.49 mmol) were added to a solution of the chloro acetal (628 mg,
by chromatography on deactivated alumina. Elution with petro-
leum ether/ether (90:10) gave 4 (350 mg, 83% yield). Ϫ IR: ν˜ ϭ
1
3.8 mmol) in DMSO (20 mL). This mixture was stirred at 80°C 3384 cmϪ1 (OH). Ϫ H NMR: δ ϭ 1.02 (s, 6 H), 1.41 (s, 3 H, 6-
for 20 h, poured into water (100 mL) and extracted with chloro-
H), 1.76 (s,
3
H, 7Ј-H), 5.07Ϫ5.26 (m,
2
H,
form. The standard workup afforded a residue which was purified CH2ϭ), 5.68 (m, 1 H, J4,5 ϭ 15.9 Hz, 4-H), 6.68 (m, 1 H, J4,5
ϭ
by chromatography (silica gel, petroleum ether/ether, 80:20) to
1492
15.9 Hz, 5-H), 5.94Ϫ6.05 (m, 1 H, CHϭ). Ϫ 13C NMR: δ ϭ 13.6
Eur. J. Org. Chem. 1999, 1489Ϫ1494

New Retinoid Analogs from δ-Pyronene, a Natural Synthon
(C-7Ј), 19.0 (C-5Ј), 26.6 (C-6Ј), 27.9 (C-8Ј and C-9Ј), 28.3 (C-6),
FULL PAPER
(d, 1 H, 8-H), 6.35 (d, 1 H, 6-H), 6.73 (d, 1 H, J8,9 ϭ 15 Hz), 6.90
35.4 (C-3Ј), 39.2 (C-4Ј), 73.6 (C-3), 111.9 (C-1), 126.5 (C-1Ј), 127.2 (dd, 1 H, J4,5 ϭ 16 Hz; J5,6 ϭ 12 Hz, 5-H), 7.71 (d, 1 H, J4,5
ϭ
(C-5), 132.5 (C-4), 140.8 (C-2Ј), 144.3 (C-2). Ϫ HRMS (C15H24O): 16 Hz, 4-H). Ϫ 13C NMR [(all-E)]: δ ϭ 13.1 (C-11), 13.8 (C-10),
calcd. 220.1827; found 220.1824.
13.9 (C-7Ј), 14.4 (CH3CH2Ϫ), 19.1 (C-5Ј), 26.5 (C-6Ј), 28.0 (C-8Ј
and C-9Ј), 35.8 (C-3Ј), 39.2 (C-4Ј), 59.7 (CH3CH2), 118.6 (C-2),
127.9 (C-1Ј), 129.1 (C-9), 130.1 (C-6), 131.0 (C-8), 131.1 (C-5),
135.1 (C-4), 140.2 (C-7), 142.3 (C-2Ј), 152.8 (C-3), 167.2 (CO2Et).
“iso”-Retinyl Acetate (5): A solution of triphenylphosphane hydro-
bromide (587 mg, 1.82 mmol) in methanol (5 mL) was added to
“iso”-vinyl-β-ionol (4) (400 mg, 1.82 mmol) in a methanol solution
(10 mL). The mixture was stirred for 48 h at room temp., concen-
trated under vacuo and washed with ether to afford the phos-
phonium salt 10 (950 mg, 99% yield). Sodium ethoxide (88 mg,
1.14 mmol) in ethanol (2 mL), was added at Ϫ15°C to a solution
of 10 (725 mg, 1.14 mmol) in dry ethanol (10 mL). After the mix-
ture was stirred for 15 min at this temp., it was treated with the
aldehyde acetate 17 (263 mg, 1.85 mmol). The resultant reaction
was kept at Ϫ15°C for 1 additional h. The reaction mixture was
allowed to warm to ambient temp. and hydrolyzed. Extraction with
ether was followed by a standard workup. Further purification of
the residue by chromatography (silica gel, petroleum ether/ether,
95:5) gave a 50:50 mixture [(4E)/(4Z)] of 5 (260 mg, 69% yield). Ϫ
1H and 13C NMR: see Table 1. Ϫ HRMS (C22H32O2): calcd.
328.2402; found 328.2407.
Ϫ
13C NMR (2Z): δ ϭ 13.1 (C-11), 13.9 (C-7Ј), 14.4 (CH3CH2),
19.1 (C-5Ј), 21.0 (C-10), 26.5 (C-6Ј), 28.0 (C-8Ј and C-9Ј), 35.8 (C-
3Ј), 39.2 (C-4Ј), 59.7 (CH3CH2), 116.5 (C-2), 128.0 (C-1Ј), 129.1
(C-9), 129.3 (C-4), 130.1 (C-6), 131.0 (C-8), 132.3 (C-5), 140.4 (C-
4), 142.4 (C-2Ј), 151.1 (C-3), 166.5 (CO2Et).
Acknowledgments
We thank the Centre d’Etudes Structurales et d’Analyse des Mol-
´
ecules Organiques (Bordeaux 1 University), and in particular M.
Petraud, B. Barbe (NMR spectra) and G. Bourgeois, C. Vitry
(mass spectra).
“iso”-Retinal (6): Sodium ethoxide (68 mg, 1 mmol) in ethanol
solution was added at 0°C to a solution of the phosphonium salt
10 (627 mg, 1 mmol) in dry ethanol (8 mL), and the mixture was
stirred at Ϫ10°C for 15 min. The reaction mixture was treated with
the aldehyde acetal 16 (173 mg, 1.2 mmol) at Ϫ10°C for 1 h, hy-
drolyzed with 10% HCl and extracted with ether. The combined
organic layers were washed with satd. NaHCO3, satd. NaCl, dried
(MgSO4) and concentrated in vacuo. The residue was purified by
chromatography on silica gel, eluting with petroleum ether/ether
(80:20) to give the (all-E) isomer of 6 (183 mg, 64% yield) which,
to be stabilized, was kept in ether solution with hydroquinone (0.5
equiv.). Ϫ 1H and 13C NMR: see Table 2. Ϫ HRMS (C20H28O):
calcd. 285.2218; found 285.2208.
[1]
D. Serramedan, F. Marc, M. Pereyre, C. Filliatre, P. Chabardes,
B. Delmond, Tetrahedron Lett. 1992, 33, 4457Ϫ4460.
[2]
F. Marc, B. Soulet, D. Serramedan, B. Delmond, Tetrahedron
1994, 50, 3381Ϫ3388.
[3]
M. J. Quirin, M. Taran, B. Delmond, Can. J. Chem. 1996, 74,
1852Ϫ1856.
[4]
B. Boulin, B. Arreguy-San Miguel, B. Delmond, Tetrahedron
1998, 54, 2753Ϫ2762.
[5]
M. J. Quirin, M. Taran, B. Delmond, Synth. Commun. 1995,
25, 3339Ϫ3345.
[6]
[6a]
For general monographs, see:
M. B. Sporn, A. B. Roberts,
D. S. Goodman (Eds.), The Retinoids, vol. 1 and 2, Academic
[6b]
Press, Orlando, 1984. Ϫ
M. B. Sporn, A. B. Roberts, D. S.
Goodman (Eds.), The Retinoids: Biology, Chemistry and Medi-
[6c]
cine, 2nd ed., Raven Press, New York, 1994. Ϫ
M. I. Daw-
son, W. H. Okamura (Eds.), Chemistry and Biology of Synthetic
Retinoids, CRC Press, Boca Raton, 1990. Ϫ [6d] L. Packer (Ed.),
C10 ؉ C10 Coupling
Methods in Enzymology, Academic Press, New York, 1990,
[6e]
vol.89, part A. Ϫ
L. Packer (Ed.), Methods in Enzymology,
Ethyl “iso”-Retinoate (7):
A solution of triphenylphosphane
Academic Press, New York, 1991, vol. 90, part B.
By analogy with usual retinoids, these new derivatives were
named “iso”-retinoids. With the taken numbering scheme, the
systematic name for “iso”-retinal 7 is thus (all-E)-3,7-dimethyl-
9-(2Ј,3Ј,3Ј-trimethyl-1Ј-cyclohexen-1Ј-yl)-2,4,6,8-nonatetraen-1-
al.
[7]
[8]
(19.3 g, 73 mmol) in anhydrous ether (50 mL) was added to “iso”-
β-cyclogeranyl iodide (2) (12 g, 58 mmol). After 4 h of stirring at
room temp., filtration and washing with ether, the Wittig salt 8 was
afforded (27.2 g, 87% yield). n-Butyllithium (0.35 mL of a 2.5 
solution in hexane) was added at 0°C to 8 (416 mg, 0.8 mmol) in
a THF solution (20 mL). After the mixture had been stirred for
15 min, it was treated with the aldehyde ester 19 (165 mg,
0.8 mmol) in THF solution (5 mL). The resultant reaction mixture
was kept 12 h at ambient temp., quenched with 10% HCl and ex-
tracted with Et2O. The organic layers were washed with satd.
NaHCO3, satd. NaCl and dried (MgSO4). The solvent was evapo-
rated to give a residue which was chromatographed (silica gel,
petroleum ether/ether, 92:8). The crude product was dissolved in
petroleum ether (5 mL) and stirred at room temp. for 2 h with
iodine (1 mg) in the dark. The reaction mixture was washed with
sodium thiosulfate and dried (MgSO4). The solvent was removed
For a review on utilizations of Wittig and related reactions in
[8a]
natural products synthesis, see:
H. Pommer, P. C. Thieme,
[8b]
Top. Curr. Chem. 1983, 109, 165Ϫ188. Ϫ
B. E. Maryanoff,
[8c]
A. B. Reitz, Chem. Rev. 1989, 89, 863Ϫ927. Ϫ
E. Vedejs,
[8d]
M. J. Peterson, Top. Stereochem. 1994, 21, 1Ϫ157. Ϫ
K. C.
Nicolaou, M. W. Harter, J. L. Gunzner, A. Nadin, Liebigs Ann.
[8e]
1997, 1283Ϫ1301. Ϫ
25, 73Ϫ253.
W. S. Wadsworth, Org. React. 1977,
[9]
P. J. R. Nederlof, M. T. Moolenaar, E. R. De Waard, H. O.
Huisman, Tetrahedron 1977, 33, 579Ϫ580.
[10] [10a]
W. Oroshnik, A. D. Mebane, J. Am. Chem. Soc. 1949, 71,
[10b]
2062Ϫ2065. Ϫ
H. Pommer, Angew. Chem. 1960, 72,
M. Julia, D. Arnould, Bull. Soc. Chim. Fr.
[10c]
811Ϫ819. Ϫ
1973, 746Ϫ750. Ϫ [10d] H. Pommer, A. Nurrenbach, Pure Appl.
[10e]
Chem. 1975, 43, 527Ϫ551. Ϫ
Chem. 1976, 47, 173Ϫ181. Ϫ
S. M. Makin, Pure Appl.
1
[10f]
in vacuo to give 7 as a mixture of two major isomers: Ϫ H NMR
G. L. Olson, H. C. Cheung,
[(all-E)]: δ ϭ 0.97 (s, 6 H), 1.21 (t, 3 H, CH3CH2), 1.41 (m, 2 H,
4Ј-H), 1.59 (m, 2 H, 5Ј-H), 1.75 (s, 3 H, 7Ј-H), 1.93 (s, 3 H, 11-H),
2.11 (m, 2 H, 6Ј-H), 2.28 (s, 3 H, 10-H), 4.09 (q, 2 H, CH3CH2),
5.69 (s, 1 H, 2-H), 5.96 (d, 1 H, 6-H), 6.08 (d, 1 H, 8-H), 6.30 (d,
K. D. Morgan, C. Neukom, G. Saucy, J. Org. Chem. 1976, 41,
3287Ϫ3293. Ϫ [10g] P. S. Manchand, M. Rosenberger, G. Saucy,
P. A. Wehrli, H. Wong, L. Chambers, M. P. Ferro, W. Jackson,
[10h]
Helv. Chim. Acta 1976, 59, 387Ϫ396. Ϫ
P. S. Manchand,
H. Wong, J.F. Blount, J .Org. Chem. 1978, 43, 4769Ϫ4774. Ϫ
[10i]
1 H, 4-H), 6.73 (d, 1 H, J8,9 ϭ 15 Hz, 9-H), 6.92 (dd, 1 H, J4,5
ϭ
D. Arnould, P. Chabardes, G. Farge, M. Julia, Bull. Soc.
[10j]
16 Hz, J5,6 ϭ 12 Hz, 5-H). Ϫ 1H NMR (2Z): δ ϭ 0.97 (s, 6 H),
1.21 (t, 3 H, CH3CH2), 1.41 (m, 2 H, 4Ј-H), 1.59 (m, 2 H, 5Ј-H),
1.75 (s, 3 H, 7Ј-H), 1.93 (s, 3 H, 11-H), 1.98 (s, 3 H, 10-H), 2.11
(m, 2 H, 6Ј-H), 4.09 (q, 2 H, CH3CH2Ϫ), 5.55 (s, 1 H, 2-H), 6.11
Chim. Fr. 1985, 130Ϫ131. Ϫ
L. Duhamel, P. Duhamel, J.
[10k]
E. Ancel, Tetrahedron Lett. 1994, 35, 1209Ϫ1212. Ϫ
H.
Bienayme, C. Yezeguelian, Tetrahedron 1994, 50, 3389Ϫ3396.
[11] [11a]
N. Nagayama, A. Kumar, K. Wuthrich, R. R. Ernst, J.
[11b]
Magn. Reson. 1980, 40, 321Ϫ334. Ϫ
A. Bax, R. Freeman,
1493
Eur. J. Org. Chem. 1999, 1489Ϫ1494

F. Lambertin, M. Wende, M. J. Quirin, M. Taran, B. Delmond
FULL PAPER
[11c]
[15]
[16]
[17]
[18]
[19]
G. A. Morris, J. Magn. Reson. 1981, 42, 164Ϫ168. Ϫ
Bax, R. Freeman, J. Magn. Reson. 1981, 44, 542Ϫ561. Ϫ
A.
G. I. Zaitseva, V. M. AlЈ Bitskaya, Zh. Org. Chem. 1969, 5,
612Ϫ617; Chem. Abstr. 1969, 71, 21638.
[11d]
U. Piantini, O. W. Sorensen, R. R. Ernst, J. Am .Chem. Soc.
P. J. R. Nederlof, M. J. Moolenaar, E. R. de Waard, H. O.
Huisman, Tetrahedron Lett. 1976, 3175Ϫ3178.
W. Oroshnik, R. A. Mallory, J. Am. Chem. Soc. 1950, 72,
4608Ϫ4613.
[11e]
1982, 104, 6800Ϫ6801. Ϫ
A. J. Shaka, R. Freeman, J.
Magn. Reson. 1983, 51, 169Ϫ173.
[12] [12a]
L. J. Muller, J .Am. Chem. Soc. 1979, 101, 4481Ϫ4484. Ϫ
[12b]
A. Bax, R. H. Griffey, B. L. Hawkins, J. Magn. Reson.
J. H. Babler, M. J. Coghlam, M. Feng, P. Fries, J .Org. Chem.
1979, 44, 1716Ϫ1717.
[12c]
1983, 55, 301Ϫ315. Ϫ
M. R. Bendall, D. T. Pegg, D. M.
[12d]
Doddrell, J. Magn .Reson. 1983, 52, 81Ϫ117. Ϫ
Subramanian, J. Magn. Reson. 1986, 67, 565Ϫ569.
A. Bax, S.
R. J. Demur, Eur. Pat. Appl.1983, EP 82782; Chem. Abstr. 1983,
99, 175220.
[20] [20a]
[13] [13a]
A. Bax, M. F. Summers, J. Am. Chem. Soc. 1986, 108,
A. Wada, C. Tude, S. Hiraishi, Y. Tumala, T. Ohfusat, M.
[20b]
[13b]
2093Ϫ2094. Ϫ
M. F. Summers, L. G. Marzilli, A. Bax, J.
Ito, Synthesis 1995, 1107Ϫ1110. Ϫ
Chem. 1960, 22, 811Ϫ819.
H. Pommer, Angew.
Am. Chem. Soc. 1986, 108, 4285Ϫ4294.
[14] [14a]
E. J. Reist, I. G. Junka, B. R. Baker, J. Org. Chem. 1960,
Received November 2, 1998
[O98499]
[14b]
25, 1673Ϫ1674. Ϫ
P. A. Wehrli, B. Schaer, Synthesis 1977,
[14c]
649Ϫ650. Ϫ
G. Eletti-Bianchi, F. Centini, L. Re, J. Org
.Chem. 1976, 41, 1648Ϫ1649.
1494
Eur. J. Org. Chem. 1999, 1489Ϫ1494