A pericyclic cascade to the stereocontrolled synthesis of 9-cis- retinoids

Article abstract of DOI:10.1021/jo991757f

A domino reaction that is pericyclic in nature is thought to be triggered upon treatment of alkenynol 10 with arylsulfenyl chlorides. The process comprises an ordered sequence of sigmatropic rearrangements: a reversible [2,3]-allyl sulfenate to allyl sulfoxide shift, followed by a [2,3]-propargyl sulfenate to allenyl sulfoxide rearrangement, and last a stereodifferentiating [1,5]-sigmatropic hydrogen migration leading to polyene 13. The occurrence of the C7 to C11 hydrogen migration has been demonstrated by labeling experiments. The double diastereoselection of the [1,5]- sigmatropic hydrogen shift to afford a single isomer of the final polyene 13 is thought to arise from a combination of the electronic effect of the sulfoxide at one terminus, and the steric effect imparted by the bulky trimethylcyclohexenyl substituent at the other terminus. The overall process thus constitutes a stereoselective synthesis of an E,Z,Z-triene fragment from an alkenynol and, in particular, a retinoid with the 7E,9Z,11Z,13E configuration on the conjugated polyenic side chain. Application of this method to the synthesis of retinoids, including labeled analogues, is straightforward.

Full text of DOI:10.1021/jo991757f

2696
J . Org. Chem. 2000, 65, 2696-2705
A P er icyclic Ca sca d e to th e Ster eocon tr olled Syn th esis of
9-cis-Retin oid s
Beatriz Iglesias, Alicia Torrado, and Angel R. de Lera*
Departamento de Quı´mica Fı´sica e Quı´mica Orga´nica, Universidade de Vigo, 36200 Vigo, Spain
Susana Lo´pez
Departamento de Quı´mica Orga´nica, Universidade de Santiago de Compostela, 15706 Santiago, Spain
Received November 10, 1999
A domino reaction that is pericyclic in nature is thought to be triggered upon treatment of alkenynol
10 with arylsulfenyl chlorides. The process comprises an ordered sequence of sigmatropic
rearrangements: a reversible [2,3]-allyl sulfenate to allyl sulfoxide shift, followed by a [2,3]-propargyl
sulfenate to allenyl sulfoxide rearrangement, and last a stereodifferentiating [1,5]-sigmatropic
hydrogen migration leading to polyene 13. The occurrence of the C7 to C11 hydrogen migration
has been demonstrated by labeling experiments. The double diastereoselection of the [1,5]-
sigmatropic hydrogen shift to afford a single isomer of the final polyene 13 is thought to arise from
a combination of the electronic effect of the sulfoxide at one terminus, and the steric effect imparted
by the bulky trimethylcyclohexenyl substituent at the other terminus. The overall process thus
constitutes a stereoselective synthesis of an E,Z,Z-triene fragment from an alkenynol and, in
particular, a retinoid with the 7E,9Z,11Z,13E configuration on the conjugated polyenic side chain.
Application of this method to the synthesis of retinoids, including labeled analogues, is straight-
forward.
In tr od u ction
chemists. The thermally induced suprafacial [1,5]-sig-
matropic hydrogen shift of vinylallenes (model transfor-
mation 1 f 2) has been extensively studied by Okamura
in elegant approaches to the triene and pentaene conju-
gated systems of vitamin D analogues (3 f 4) and 11-
cis-retinoids (5 f 6, Scheme 1).3 In the case of compound
5 the pericyclic nature of the [1,5]-hydrogen shift ensures
the Z geometry of the central double bond, but control
over the geometry of the ensuing polyene terminus in 6
could not be achieved. Intense efforts have been directed
toward finding substituents with the ability to influence
the stereochemical course of the rearrangement at the
termini of the conjugated system in order to fully realize
the synthetic benefit of stereocontrolled polyene synthesis
via [1,5]-H shifts. In this regard, Okamura discovered
that the sulfoxide group not only accelerated the [1,5]-
sigmatropic hydrogen shift of vinylallene sulfoxides, but
also directed the migrating hydrogen anti to its location.4
Upon treatment of propargylic alcohols 7 with PhSCl, the
intermediate vinylallene sulfoxides 8 stereoselectively
provided triene sulfoxides 9 (Scheme 1) regardless of the
size of the R group, by a [1,5]-H migration that is,
however, inconsequential for the geometry of the terminal
Sequential transformations constitute important syn-
thetic strategies for the construction of complex molecules
from simple precursors.1 In particular, transformations
that arise as a consequence of functionality introduced
by a previous fragmentation, bond formation or rear-
rangement, termed tandem, domino, or cascade reactions,
are powerful bond-forming reaction sequences that also
enjoy the added benefit of being atom-economical.1a
A
systematic classification of domino processes has been
proposed and is based on the type of chemical reaction
involved in the first and subsequent step of the global
sequence.1a Most of the pericyclic-pericyclic tandem
processes described in the literature have been mainly
based on the venerable Diels-Alder and Claisen rear-
rangements, as well as their variants, as the key func-
tional group-forming steps. The exploitation of the full
synthetic potential inherent in pericyclic processes, in-
cluding the high diastereoselectivities predicted by the
Woodward-Hoffmann rules, has yet to be fully realized.1
In this regard, the [1,j]-H subset of sigmatropic rear-
rangements is one of the least exploited pericyclic reac-
tions from the synthetic perspective. This neglect is
perhaps due to the fact that both [1,5]-H and [1,7]-H
migrations entail polyene isomerization processes. When
the polyene includes a cumulene bond (in particular an
allene bond),2 the gain in complexity, for example the
extended conjugation of the resulting polyene, is remark-
able, and this finding has not escaped the attention of
(2) For reviews on allenes, see (a) The Chemistry of Ketenes, Allenes
and Related Compounds, Patai, S., Ed.; J ohn Wiley & Sons: New York,
1980; Part II. (b) Landor, S. R. The Chemistry of the Allenes; Academic
Press: New York, 1982. (c) Okamura, W. H. Acc. Chem. Res. 1983,
16, 81-88. (d) Schuster, H. F.; Coppola, G. M. Allenes in Organic
Synthesis; Wiley-Interscience: New York, 1984. (e) Pasto, D. J .
Tetrahedron 1984, 40, 2805-2827. (f) Bruneau, C.; Dixneuf, P. Allenes
and Cumulenes. In Comprehensive Organic Funcional Group Trans-
formations; Katritzky, A. R., Meth-Cohn, O., Rees, C., Roberts, S., Eds.;
Pergamon Press: Oxford, 1995; Volume 1, Chapter 1.20, pp 953-995.
(3) (a) Reference 2c. (b) Zhu, G.-D.; Okamura, W. H. Chem. Rev.
1995, 95, 1877-1952.
* Corresponding author. Phone: + (34) 986 812316. Fax: + (34)
986 812382. e-mail: qolera@uvigo.es.
(1) (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993,
32, 131-163. (b) Tietze, L. F. Chem. Rev. 1996, 96, 115-136. (c) Parson,
P. J .; Penkett, C. S.; Shell, A. J . Chem. Rev. 1996, 96, 195-206. (c)
Bunce, R. A. Tetrahedron 1995, 51, 13103-13159.
(4) (a) Okamura, W. H.; Shen, G. Y.; Tapia, R. J . Am. Chem. Soc.
1986, 108, 5018-5019. (b) Shen, G. Y.; Tapia, R.; Okamura, W. H. J .
Am. Chem. Soc. 1987, 109, 7499-7505.
10.1021/jo991757f CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/30/2000

Stereocontrolled Synthesis of 9-cis-Retinoids
J . Org. Chem., Vol. 65, No. 9, 2000 2697
Sch em e 1
Sch em e 2
group at one of the termini experiencing cyclization (from
E/Z 86:14 for 12, R′ ) CH2OH to E/Z > 99:1 for 12, R′ )
CHO).
Within this context,5 we became interested in the study
of the effect that heteroatoms attached to the internal
position (C4 in 11, vide infra) might have on the thermal
behavior of divinylallenes. In a preliminary communica-
tion we described the unprecedented isomerization of
alkenynol 10 to polyene 13a upon treatment with phe-
nylsulfenyl chloride and Et3N (Scheme 2), which was
suspected to involve a divinylallene sulfoxide.7 We report
here a detailed mechanistic study of this remarkable
approach to 9-cis-retinoic acid,8 the native ligand of the
RXR nuclear receptors,9 and its extension to the stereo-
controlled synthesis of retinoids with 9Z geometry. This
process takes advantage of the directing effect of the
phenylsulfoxide group to control double-bond geometry
in a [1,5]-sigmatropic hydrogen shift.
Resu lts a n d Discu ssion
Treatment of a solution of known alcohol 10 (obtained
in two steps from â-ionone)10 in THF/Et3N with freshly
prepared11 phenylsulfenyl chloride at -78 °C and stirring
of the mixture for 1 h at -78 °C and then for 1 h at
ambient temperature gave compound 13a in 61% yield
after chromatographic purification on silica gel impreg-
nated with Et3N. The polyenic nature of the product was
suggested, in comparison to 10, by the increase in the
number of signals in the vinyl region and the absence of
olefin. However, other sulfur substituents (PhS, PhO2S)
that also accelerate the rearrangement failed to induce
stereoselectivity on the sulfoxide-substituted olefin ge-
ometry in 9.
The synthesis of 11-cis-retinoids (5 f 6) depicted in
Scheme 1 is one of the relatively few existing studies on
the pericyclic reactions of divinylallenes that have olefins
of differing substitution patterns on either side of the
allene. We have recently reported that bulky substituents
at the allene unit are capable of influencing the regio-
and stereoselectivity of the electrocyclic ring closure of
divinylallenes 11 to functionalized alkylidenecyclobutenes
12 (Scheme 2).5 The torquoselectivity,6 i.e., the stereose-
lectivity arising from a preferred mode of rotation of
substituents during electrocyclization (indicated as C6-
inward for 11), was mainly steric in nature and was
enhanced by the presence of an electron-withdrawing
1
signals due to the methylene at C7 of 10 in the H NMR
spectrum of 13a . Extensive NOE experiments suggested
the 7E,9Z,11Z,13E geometry for the conjugated polyene
structure shown in 13a . The Z geometry about the C11-
C12 double bond was unequivocally established after
(7) de Lera, A. R.; Castro, A.; Torrado, A.; Lo´pez, S. Tetrahedron
Lett. 1998, 39, 4575-4578.
(8) For details on the nomenclature and numbering of retinoids,
see: IUPAC-IUB J oint Commission on Biochemical Nomenclature
(J CBN). Eur. J . Biochem. 1982, 129, 1-5. Note that the cis and trans
notations are used for the geometry of the polyene side chain,
regardless of the substituents.
(9) For reviews on biological implications of 9-cis-retinoic acid, see
(a) Evans, R. M. Science 1988, 240, 889-895. (b) Mangelsdorf, D. A.;
Evans, R. M. Cell 1995, 83, 841-850. (c) Rosen, J .; Day, A.; J ones, T.
K.; J ones, E. T. T.; Nadzan, A. M.; Stein, R. B. J . Med. Chem. 1995,
38, 4855-4874.
(5) (a) Garc´ıa Rey, J .; Rodr´ıguez, J .; de Lera, A. R. Tetrahedron Lett.
1993, 34, 6293-6296. (b) Lo´pez, S.; Garc´ıa Rey, J .; Rodr´ıguez, J .; de
Lera, A. R. Tetrahedron Lett. 1995, 36, 4669-4672. (c) Lo´pez, S.;
Rodr´ıguez, J .; Garc´ıa Rey, J .; de Lera, A. R. J . Am. Chem. Soc. 1996,
118, 1881-1891. (d) de Lera, A. R.; Torrado, A., Garc´ıa Rey, J .; Lo´pez,
S. Tetrahedron Lett. 1997, 38, 7421-7424. (e) de Lera, A. R.; Garc´ıa
Rey, J .; Hrovat, D. A.; Iglesias, B.; Lo´pez, S. Tetrahedron Lett. 1997,
38, 7425-7428.
(10) Isler, O.; Huber, W.; Ronco, A.; Kofler, M. Helv. Chim. Acta
1947, 30, 1911-1927.
(11) Barrett, A. G. M.; Dhanak, D.; Graboski, G. G.; Taylor, S. J .
Org. Synth. 1990, 68, 8-13.
(6) Dolbier, W. R., J r.; Koroniak, H.; Houk, K. N.; Sheu, C. Acc.
Chem. Res. 1996, 29, 471-477.

2698 J . Org. Chem., Vol. 65, No. 9, 2000
Iglesias et al.
Sch em e 3a
ester 18, which is the primary derivative of 10 formed
upon treatment with phenylsulfenyl chloride (Scheme 5).
A further insight into the mechanism of the overall
transformation is provided by analysis of the configura-
tion of the product. Both the facile [2,3]-sigmatropic
rearrangement of propargylic sulfenates to allenyl sul-
foxides16 and the aforementioned effect of the allenyl
sulfoxide on the kinetics and stereodifferentiation of the
[1,5]-H shift4 are key factors suggesting the involvement
of allenyl sulfoxide 19 in the overall conversion. Given
the rate-accelerating effect, as well as the control of facial
selectivity imparted by the sulfoxide group in [1,5]-
sigmatropic hydrogen migrations of vinylallene phenyl
sulfoxides,4 which directs the migrating hydrogen anti,
the geometries of the C9-C10 (Z) and C11-C12 (Z)
double bonds of 13a can be properly justified (Scheme
5). Moreover, the severe steric interactions imparted by
the bulky trimethylcyclohexenyl group at the migration
origin would favor the transition state leading stereose-
lectively to the C7-C8 E geometry. However, for the
system to accommodate the [1,5]-H shift, an isomeriza-
tion of the 8E to the 8Z geometry in 19 would be required,
and this stereochemical issue will be addressed subse-
quently.
a
(a) t-BuLi, MeLi, MeOH, THF, -78 °C, 67%. (b) n-Bu4NF,
THF, 25 °C, 93%. (c) Ag2O, MnO2, MeOH, 1 M NaOH, 60 °C, 72%.
Sch em e 4
To corroborate the presumed involvement of a C7 to
C11 [1,5]-sigmatropic hydrogen migration, we turned our
attention to the analysis of the reaction product arising
from the isotopologous C7-dideuterated enynol, 10-C7-
d2. Propargylic alcohol 10-C7-d2, with the desired label
at C7,8 was prepared as shown in Scheme 6. Incorpora-
tion of deuterium into commercially available 2-(2,2,6-
trimethylcyclohexenyl)ethanal (20) with NaH in D2O/
Pyr17 was followed by Horner-Emmons condensation
with diethyl 1-(ethoxycarbonyl)ethanephosphonate to
provide ester 21 in 73% yield as a 62:38 mixture of E/Z
isomers, which were separated by chromatography.
DIBAL-H reduction of 21 afforded quantitatively allylic
alcohol 22, and oxidation of the latter with activated
MnO2 provided dideuterated aldehyde 23 in 89% yield.
Finally, condensation of aldehyde 23 and the acetylenic
anion originating from treatment of enyne 245c with
n-BuLi provided the desired target 10-C7-d2 in 75% yield.
Subjecting alkenynol 10-C7-d2 to the appropriate reac-
tion conditions afforded a polyenic sulfoxide in 77% yield.
1H NMR analysis of this compound showed a high level
of isotope incorporation at C11, and quantification pro-
vided a value of 95% label at this position, which further
attests to the postulated C7 to C11 [1,5]-H shift (Scheme
5) through the mediation of the dideuterated divinylal-
lene sulfoxide 19-C7-d2.
stereoselective desulfuration, using a modification12 of
Okamura’s procedure13 (t-BuLi, MeLi,12 MeOH, THF,
-78 °C, 67%), and spectroscopic analysis of the product
14 (Scheme 3). Additional evidence for the structure of
13a came from deprotection of 14 (TBAF, 25 °C) to
provide 9-cis-retinol 1514 (93% yield) and oxidation of 15
with Ag2O/MnO2/MeOH15 to yield 9-cis-retinoic acid 16
(72% yield).
Reaction of 10 with p-nitrophenylsulfenyl chloride
likewise provided compound 13b (79% yield) together
with a second product, which was easily identified as silyl
ether 17 (15% yield). The use of o-nitrophenylsulfenyl
chloride gave instead compound 17 as the major compo-
nent (60%) together with pentaene 13c (40%). The silyl
ether of 11,12-didehydroretinol 17 most likely arises by
vinylogous elimination of the 10-arylsulfenate group
derived from 10 (see 18, Scheme 5), a process favored
when the NO2 substituent slows down the alternative
pathway leading to 13b,c through steric and inductive
effects (Scheme 4).
If a [1,5]-sigmatropic hydrogen migration was indeed
operating in the overall sequence 10 f 13a , and the
vinylallene sulfoxide intermediate (8E)-19 lacks the cis
geometry required for such a shift, the isomerization of
(8E)-19 to (8Z)-19 under the reaction conditions is a
prerequisite for the success of the entire sequence
(Scheme 5). Among the thermal noncatalyzed mecha-
nisms known to produce double bond isomerization,18 the
first to be considered was a reversible allylic rearrange-
The overall transformation 10 f 13 involves the
unprecedented one-step synthesis of stereodefined tet-
raenes (ignoring the cyclohexenyl double bond) from
alkenynols and is presumed to originate from sulfenate
(12) Neef, G.; Eder, U.; Seeger, A. Tetrahedron Lett. 1980, 21, 903-
906.
(13) (a) Theobald, P. G.; Okamura, W. H. J . Org. Chem. 1990, 55,
741-750. (b) Theobald, P. G.; Okamura, W. H. Tetrahedron Lett. 1987,
28, 6565-6568. (c) Park. G.; Okamura, W. H. Synth. Commun. 1991,
21, 1047-1054.
(14) Liu, R. S. H.; Asato, A. E. Tetrahedron 1984, 40, 1931-1969.
(15) Liebman, A. A.; Burger, W.; Malarek, D. H.; Serico, L.; Muccino,
R. R.; Perry, C. W.; Choudhry, S. C. J . Labeled Compound Radiopharm.
1989, 28, 525-541.
(16) (a) Horner, L.; Binder, V. Liebigs Ann. Chem. 1972, 757, 33-
68. (b) VanRheenen, V.; Shephard, K. P. J . Org. Chem. 1979, 44, 1582-
1584. (c) Cutting, I.; Parsons, P. J . Tetrahedron Lett. 1983, 24, 4463-
4464. See also ref 4.
(17) Fransen, M. R.; Palings, I.; Lugtenburg, J .; J ansen, P. A. A.;
Groenendijk, G. W. T. Recueil Trav. Chim. Pays-Bas 1980, 99, 384-
391.
(18) Sonnet, P. E. Tetrahedron 1980, 36, 557-604.

Stereocontrolled Synthesis of 9-cis-Retinoids
J . Org. Chem., Vol. 65, No. 9, 2000 2699
Sch em e 5
Sch em e 6a
vinylallenyl sulfoxide 28 was thermodynamically favored.
However, methyl substitution might alter the course of
the rearrangement ([2,3]-propargylic vs [2,3]-allylic). The
allyl sulfoxides 27 were the exclusive or major products
(i.e., when R1 ) CH3, R2 ) R3 ) R4 ) H, a 4:1 27/28
mixture was obtained) starting from the monomethylated
alkenynols, whereas the presence of a terminal dimethy-
lated double bond (R1 ) R2 ) CH3) led only to vinyallene
sulfoxides 28 (Scheme 7).
In keeping with these observations, alkenynol 29
(Scheme 8), which was obtained in 87% yield by addition
of the alkynyl anion derived from 24 to acrolein, was
treated with PhSCl under the standard reaction condi-
tions to afford a single product. This compound showed
a characteristic trans coupling pattern (J ) 15.6 Hz) in
the vinylic region, together with two groups of signals
resonating at 3.55 and 3.63 ppm characteristic of an
allylic sulfoxide, in its 1H NMR spectrum. These spec-
troscopic data suggested structure (E)-31 for the primary
[2,3]-allylic rearrangement product, a situation that is
in agreement with the behavior exhibited by simple
systems such as 26. Signals due to a minor (<10%)
a
(a) NaH, pyridine, D2O, 25 °C (repeat three times), 99%; (b)
diethyl 1-(ethoxycarbonyl)ethanephosphonate, n-BuLi, THF, -78
°C, then 25 °C, 73%; (c) DIBAL-H, THF, 0 °C, 99%; (d) MnO2,
CH2Cl2, 25 °C, 89%; (e) n-BuLi, 24, then 23, 1.5 h at -78 °C, then
25 °C, 75%; (f) PhSCl, Et3N, THF, -78 °C, then 25 °C, 1 h, 77%.
ment19 of the primary product, i.e., sulfenate ester to allyl
sulfoxide, since [2,3] shifts of that nature generally have
low activation energies.20 Indeed, Okamura and van
Krutchen had previously isolated the allyl sulfoxide 27
upon treatment of the simple alkenynols 25 (R1 ) R2 )
R3 ) R4 ) H) with PhSCl.21 Interestingly, although the
geometry of the double bond in the primary product 27
is E, heating a benzene solution of (E)-27 (R1 ) R2 ) R3
) R4 ) H) afforded a mixture of (E)-27, (Z)-27 and
vinylallene sulfoxide 28. This observation led to the
conclusion that the allyl sulfenate to allyl sulfoxide
rearrangement (26 f 27) was reversible in that case; the
allyl sulfoxides 27 were the kinetic products, whereas the
1
compound were also present in the H NMR spectrum,
and these increased in intensity upon standing. More-
over, heating a solution of (E)-31 in C6D6 to 50 °C in a
sealed tube cleanly led to an equilibrium mixture consist-
ing of (E)-31 and its (Z)-31 isomer in a 1:2 ratio after 25
h, the same ratio observed upon heating the isolated (Z)-
31 under the same conditions. At higher temperatures
(80 °C) complex mixtures were obtained from which the
desired vinylallene sulfoxide could not be isolated. How-
ever, in independent experiments, indirect support for
the formation of a vinylallene by [2,3]-propargylic rear-
rangement was based on the observation that treatment
of 10 or acetal 3322 with Ph2PCl/Et3N23 afforded alle-
(19) (a) Bickart, P.; Carson, F. W.; J acobus, J .; Miller, E. G.; Mislow,
K. J . Am. Chem. Soc. 1968, 90, 4869-4875. (b) Tang, R.; Mislow, K.
J . Am. Chem. Soc. 1970, 92, 2100-2103. (c) J ones-Hertzog, D. K.;
J orgensen, W. L. J . Org. Chem. 1995, 60, 6682-6683. (d) Evans, D.
A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147-155. (e) Hoffmann,
R. W. Angew. Chem., Int. Ed. Engl. 1979, 18, 563-572. (f) J ones-
Hertzog, D. K.; J orgensen, W. L. J . Am. Chem. Soc. 1995, 117, 9077-
9078. (g) Amaudrut, J .; Pasto, D. J ., Wiest, O. J . Org. Chem. 1998, 63,
6061-6064.
(20) Burnier, J . S.; J orgensen, W. L. J . Org. Chem. 1984, 49, 3001-
3020.
(21) van Kruchten, E. M. G. A.; Okamura, W. H. Tetrahedron Lett.
1982, 23, 1019-1023.
(22) Acetal 33 was prepared following the general synthetic scheme
previously described,5 starting from the corresponding acetal derived
from known 3-methylpent-4-yn-2-enal (Derguini, F.; Nakanishi, K.;
Balogh-Nair, V. Tetrahedron Lett. 1979, 4899-4502).
(23) (a) Nicolaou, K. C.; Maligres, P.; Shin, J .; de Leon, E.; Rideout,
D. J . Am. Chem. Soc. 1990, 112, 7825-7826. (b) Grissom, J . W.;
Klingberg, D.; Huang, D.; Slattery, B. J . J . Org. Chem. 1997, 62, 603-
626.

2700 J . Org. Chem., Vol. 65, No. 9, 2000
Iglesias et al.
Sch em e 7
Sch em e 8
Sch em e 9
Supported by the experiments described above, a
detailed mechanism can be proposed for the isomerization
of alkenynol 10 to TBDMS-protected 9-cis-12-phenyl-
sulfinylretinol 13a . The sequence of events in this domino
reaction includes reversible19 [2,3]-sigmatropic shift of
allyl sulfenate ester (E)-18 to allyl sulfoxide 35 (with
concomitant double bond isomerization arising from
conformer 35′),19,20 followed by propargylic sulfenate to
vinylallene sulfoxide rearrangement16,21 from (Z)-1826 to
provide (Z)-19 and, finally, irreversible doubly stereose-
lective [1,5]-sigmatropic hydrogen migration to 13a
(Scheme 10). Although vinylallene sulfoxide (Z)-19 could
not be isolated due to the facile [1,5]-H rearrangement
induced by the sulfoxide group, its involvement was
inferred from the stereoselective generation of the C11-
C12 Z olefin geometry as well as by the isolation of
allenylphosphine oxides 32 and 34 described above. The
facile (-78 °C) conversion of 10 to 13a without the
isolation of intermediates 35 and 19 stands in contrast
to their isolation in simple systems (Schemes 8 and 9).
It is likely that the sterically bulky ring additionally
contributes to the acceleration of both the reversible [2,3]-
allylic as well as the [2,3]-propargylic rearrangements.
The unprecedented cascade of sigmatropic rearrange-
ments described in Scheme 10 allows the highly stereo-
nylphosphine oxides 32 and 34, respectively (Scheme 9).24
From (E)-vinylallene sulfoxide (E)-19 (Scheme 10), how-
ever, an alternative mechanistic proposal of electrocyclic
nature was also considered. The electrocyclic ring-closure
of dienes (vinylallenes) followed by electrocyclic ring-
opening of cyclobutenes (alkylidenecyclobutenes) in the
same conrotatory sense could also account for the double-
bond isomerization, which might even profit from the
torquoelectronic effects of the substituents.6 We were,
however, unable to demonstrate by NMR the involvement
of alkylidenecyclobutenes upon heating simple vinylal-
lene sulfoxides at high temperatures.25
The thermal behavior of the model systems depicted
in Scheme 7 led us to postulate the likely formation of
vinylallene sulfoxides by rearrangement of allyl propar-
gylic sulfenate esters and, by inference, their mediation
in the rearrangement of 10 to 13a , a hypothesis awaiting
further confirmation.
(26) A referee suggested that interception of the Z-allyl alcohol (Z)-
10 by displacement of the allylsulfoxide 35′ to allylsulfenate (Z)-18
equilibrium (Scheme 10) with a thiopile might constitute additional
support for the proposed mechanism. However when, in separate
experiments, excess P(OMe)3 was added to a reaction flask containing
10 and PhSCl (Et3N, CH2Cl2, -78 °C) after 15, 30, and 60 min reaction
time, a mixture of (E)-10 and 13a was obtained in all cases with no
detectable presence of isomer (Z)-10.
(24) Allenyl phosphine oxides 32 and 34 were thermally stable, and
they could be recovered unaltered after heating to 140 °C in C6D6 (1H
NMR monitoring), thus providing evidence of the rate-retarding effect
of a heteroatom at C4 on the electrocyclization of these model
divinylallenes compared to analogues (Scheme 2) in which a t-Bu is
present at the same position.
(25) T. Costas, unpublished.

Stereocontrolled Synthesis of 9-cis-Retinoids
J . Org. Chem., Vol. 65, No. 9, 2000 2701
Sch em e 10
Sch em e 11a
a
(a) ClCH2CO2Me, MeOH, MeONa, 0 °C, then 25 °C, 58%; (b) n-BuLi, 24, then 37, 1.5 h at -78 °C, then 25 °C, 56%; (c) PhSCl, Et3N,
THF, -78 °C, then 25 °C, 1 h, 40%; (d) t-BuLi, MeLi, MeOH, THF, -78 °C, 73%; (e) n-Bu4NF, THF, 25 °C; (f) Ag2O, MnO2, MeOH, 1 M
NaOH, 60 °C, 53% (two steps).
selective generation of the C7-C12 triene fragment of
9-cis-retinoids in a one-pot reaction starting from alk-
enynol 10. The complete control of the side-chain geom-
etry of 9-cis-retinoids can be extended to the preparation
of ring-modified 9-cis-retinoids, according to the general
scheme indicated for the parent compound 9-cis-retinoic
acid 16 (Scheme 2 and Scheme 3). As an example of an
application, the synthesis of the (9Z)-4,6-retroretinoic8
acid 42 was undertaken. Darzen’s glycidic acid condensa-
tion10 of racemic R-ionone 36 led to unsaturated aldehyde
37 in 58% yield. Alkenynol 38 was obtained in 56% yield
by addition of the lithium anion derived from 24 to
aldehyde 37. The key sequence of pericyclic reactions
afforded, as anticipated from the results described above,
the protected 9-cis-12-arylsulfinyl-4,6-retroretinol 39 (40%).
Stereospecific sulfoxide reduction provided 40 in 73%
yield, and this step was followed by elaboration of the
final carboxylic acid 42 through deprotection of 40
(TBAF) followed by oxidation of alcohol 41 with Ag2O/
MnO2 in a combined yield of 53% (Scheme 11).
In conclusion, it has been shown that retinoids with
the 9-cis geometry are accessible in one step from enynol
10. The mechanism is another example of a pericyclic
domino reaction, in which the product of the first thermal
transformation serves as a starting material for the
subsequent step(s) of the same overall transformation.
In contrast to other pericyclic cascades described in the
literature, our sequence does not build complexity, but

2702 J . Org. Chem., Vol. 65, No. 9, 2000
Iglesias et al.
Sch em e 12a
Et3N (0.90 mL, 6.50 mmol). After stirring for 15 min, a solution
of phenylsulfenyl chloride (0.94 g, 6.50 mmol) in THF (20 mL)
was added. The resulting orange solution was stirred at -78
°C for 1 h and at 25 °C for an additional 1 h. Saturated aqueous
Na2CO3 was added, and the aqueous layer was extracted with
ether (3×). The combined organic layers were washed with
H2O (3×) and brine (3×), dried (Na2SO4), and evaporated. The
residue was purified by flash chromatography on silica gel (90:
8:2 hexane/EtOAc/Et3N) to provide 0.69 g (61%) of sulfoxide
13a as a yellow oil. 1H NMR (400 MHz, CDCl3) δ -0.01 (s,
6H), 0.85 (s, 9H), 1.05 (s, 6H), 1.4-1.6 (m, 4H), 1.61 (d, J )
0.9 Hz, 3H), 1.75 (s, 3H), 1.83 (s, 3H), 2.04 (t, J ) 6.0 Hz, 2H),
4.15 (m, 2H), 5.66 (tq, J ) 6.0, 0.9 Hz, 1H), 6.39 (d, J ) 16.0
Hz, 1H), 6.67 (d, J ) 16.0 Hz, 1H), 6.89 (d, J ) 12.1 Hz, 1H),
7.12 (d, J ) 12.1 Hz, 1H), 7.4-7.6 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ -4.8 (2×), 17.3, 18.7, 19.6, 21.8, 22.3, 26.3 (3×), 29.4
(2×), 33.5, 34.6, 39.9, 60.7, 121.6, 124.7 (2×), 129.1 (2×), 129.3,
129.9, 131.1, 131.4, 132.0, 132.3, 133.4, 138.3, 142.0, 144.1,
144.2; UV (MeOH) λmax 234, 334 nm; HRMS calcd for C32H48O2-
SSi 524.3144, found 524.3141.
ter t-Bu tyld im eth ylsilyl (7E,9Z,11E,13E)-Retin yl Eth er
(14). Gen er a l P r oced u r e for th e Desu lfu r a tion Rea ction .
To a cooled (-78 °C) stirred solution of sulfoxide 13a (0.20 g,
0.39 mmol) in THF (20 mL) containing MeOH (0.05 mL, 1.22
mmol), was added, dropwise, MeLi (0.06 mL, 1.6 M in Et2O,
0.10 mmol) followed by t-BuLi (1.03 mL, 1.7 M in pentane,
1.76 mmol) using a syringe pump at a rate of 2.1 mL/h, and
the resulting mixture was stirred for 10 min at -78 °C. MeOH
(10 mL) and H2O (10 mL) were added, and the mixture was
allowed to reach 25 °C. The aqueous layer was extracted with
Et2O (3×), and the combined organic layers were washed with
H2O (2×) and brine (2×), dried (Na2SO4), and evaporated.
Purification by chromatography on neutral alumina (2.4%
H2O) (100% hexane) afforded 0.10 g (67%) of 9-cis-retinyl ether
14. 1H NMR (400 MHz, C6D6) δ 0.06 (s, 6H), 0.99 (s, 9H), 1.11
(s, 6H), 1.4-1.6 (m, 4H), 1.58 (s, 3H), 1.82 (s, 3H), 1.9-2.0 (m,
2H), 1.93 (s, 3H), 4.26 (d, J ) 6.3 Hz, 2H), 5.77 (t, J ) 6.3 Hz,
1H), 6.07 (d, J ) 11.3 Hz, 1H), 6.29 (d, J ) 15.0 Hz, 1H), 6.32
(d, J ) 16.0 Hz, 1H), 6.92 (dd, J ) 15.0, 11.3 Hz, 1H), 7.04 (d,
J ) 16.0 Hz, 1H); 13C NMR (100 MHz, C6D6) δ -4.8 (2×), 12.8,
18.7, 19.8, 21.1, 22.4, 26.4 (3×), 29.3 (2×), 33.4, 34.7, 39.9, 60.7,
123.7, 129.6, 130.2, 131.1, 132.8, 134.3, 135.0, 137.0, 137.1,
a
(a) t-BuLi, MeLi, MeOH, THF, -78 °C, 77%; (b) t-BuLi, MeLi,
MeOD, THF, -78 °C, 63%; (c) n-Bu4NF, THF, 25 °C, 65-67%.
provides stereochemically defined polyenes from precur-
sors that are not fully conjugated. In a more fundamental
sense, the reaction could be described as a doubly
stereoselective [1,5]-sigmatropic hydrogen shift. Whereas
the “sulfoxide effect”4 secures the 11Z geometry of 13,
the exclusive formation of the 7E geometry is most likely
ascribed to the severe steric hindrance enforced by the
highly substituted cyclohexenyl ring.
Given the paucity of stereocontrolled methods for the
synthesis of retinoids with the 9Z geometry,27 as well as
the increasing importance of these geometric isomers in
vision studies28 and as ligands of the RXR subfamily of
nuclear receptors,9 the pericyclic cascade described here
should find application in retinoid research. The potential
utility of these compounds as biological tools may be
enhanced by incorporation of labels in the stereoselective
reduction step. As an additional application, the synthe-
sis of C7,C11-dideuterated-retinol 15-C7,C11-d2 and C7,-
C11,C12-trideuterated-retinol 15-C7,C11,C12-d3 is shown
in Scheme 12.
138.8; UV (MeOH) λmax 254, 322 nm; HRMS calcd for C26H44
OSi 400.3161, found 400.3156.
-
(7E,9Z,11E,13E)-Retin ol (15). Gen er a l P r oced u r e for
th e Dep r otection of Silyl Eth er s. TBAF (0.30 mL, 1 M in
THF, 0.30 mmol) was added to a solution of retinyl ether 14
(0.10 g, 0.25 mmol) in THF (4.2 mL). After stirring at 25 °C
for 1.5 h, the mixture was poured over saturated NaHCO3,
and it was extracted with Et2O (3×). The combined organic
layers were washed with saturated NaHCO3 (2×), dried (Na2-
SO4) and evaporated. Purification by chromatography (SiO2,
77:20:3 hexane/AcOEt/Et3N) afforded 0.06 g (93%) of 9-cis-
retinol 15.14 1H NMR (400 MHz, C6D6) δ 1.22 (s, 6H), 1.4-1.6
(m, 4H), 1.64 (s, 3H), 1.93 (s, 3H), 2.0-2.1 (m, 2H), 2.05 (s,
3H), 4.10 (d, J ) 6.6 Hz, 2H), 5.73 (t, J ) 6.6 Hz, 1H), 6.20 (d,
J ) 11.3 Hz, 1H), 6.37 (d, J ) 15.0 Hz, 1H), 6.43 (d, J ) 16.1
Hz, 1H), 7.03 (dd, J ) 15.0, 11.3 Hz, 1H), 7.14 (d, J ) 16.1
Hz, 1H).
(7E,9Z,11E,13E)-Retin oic Acid (16). Gen er a l P r oced u r e
for th e Oxid a tion of P r im a r y Alcoh ols to Ca r boxylic
Acid s. A solution of 9-cis-retinol 15 (0.05 g, 0.17 mmol) in dry
MeOH (3.5 mL) was added to a suspension of activated MnO2
(0.09 g, 1.05 mmol) and Ag2O (0.24 g, 1.05 mmol) in a mixture
of H2O (4.9 mL), MeOH (4.9 mL) and 1 M NaOH (0.87 mL) at
60 °C, under an Ar atmosphere. After stirring at 60 °C for 2
h, the mixture was cooled to 25 °C and filtered through Celite
into a flask contaning ice-cooled H2O (2.3 mL), CH2Cl2 (11.4
mL), and 3 M H3PO4 (1.25 mL). The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (3×). The
combined organic layers were washed with H2O containing
brine (0.08 mL/mL H2O), dried (Na2SO4), and evaporated.
Purification by chromatography (SiO2, 95:5 CH2Cl2/MeOH)
afforded 0.04 g (72%) of retinoic acid 16.26 1H NMR (400 MHz,
CDCl3) δ 1.05 (s, 6H), 1.5-1.7 (m, 4H), 1.76 (s, 3H), 2.02 (s,
Exp er im en ta l Section
Gen er a l. Solvents were dried according to published meth-
ods and distilled before use. HPLC grade solvents were used
for the HPLC purification. All other reagents were commercial
compounds of the highest purity available. Analytical thin-
layer chromatography (TLC) was performed using Merck silica
gel (60 F-254) plates (0.25 mm) precoated with a fluorescent
indicator. Column chromatography was performed using Mer-
ck silica gel 60 (particle size 0.040-0.063 µm). All operations
involving synthesis and/or manipulation of retinoids were done
under subdued light.
ter t-Bu t yld im et h ylsilyl (7E,9Z,11Z,13E)-12-(P h en yl-
su lfin yl)r etin yl Eth er (13a ). Gen er a l P r oced u r e for th e
Rea ction of P r op a r gyl Alcoh ols w ith P h en ylsu lfen yl
Ch lor id e. To a cooled (-78 °C) solution of propargyl alcohol
105c (0.90 g, 2.16 mmol) in THF (40 mL) was added, dropwise,
(27) (a) Bennani, Y. L. J . Org. Chem. 1996, 61, 3542-3544. (b)
Bennani, Y. L.; Boehm, M. F. J . Org. Chem. 1995, 60, 1195-1200. (c)
Wada, A.; Hiraishi, S.; Takamura, N.; Date, T.; Aoe, K.; Ito, M. J . Org.
Chem. 1997, 62, 4343-4348. (d) Pazos, Y.; de Lera, A. R. Tetrahedron
Lett. 1999, 40, 8287-8290.
(28) For recent reviews, see: (a) Corson, D. W.; Crouch, R. K.
Photochem. Photobiol. 1996, 64, 595-600. (b) Crouch, R. K.; Chader,
G. J .; Wiggert, B.; Pepperberg, D. R. Photochem. Photobiol. 1996, 64,
613-621.

Stereocontrolled Synthesis of 9-cis-Retinoids
J . Org. Chem., Vol. 65, No. 9, 2000 2703
3H), 2.06 (t, J ) 6.4 Hz, 2H), 2.36 (s, 3H), 5.81 (s, 1H), 6.07 (d,
J ) 11.2 Hz, 1H), 6.26 (d, J ) 15.0 Hz, 1H), 6.29 (d, J ) 15.8
Hz, 1H), 6.66 (d, J ) 15.8 Hz, 1H), 7.13 (dd, J ) 15.0, 11.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 19.2, 20.9, 21.9,
29.0 (2×), 33.0, 34.2, 39.4, 117.2, 127.9, 129.4, 130.2, 130.5,
130.6, 134.2, 137.9, 139.0, 155.3, 170.8; IR (NaCl) υ 3600-
3100 (br, O-H), 1679 (s, CdO) cm-1; UV (MeOH) λmax 340 nm;
HRMS calcd for C20H28O2 300.2089, found 300.2103.
calcd for C16H24D2O2 252.2058, found 252.2065. Da ta for (Z)-
21: 1H NMR (400 MHz, CDCl3) δ 0.96 (s, 6H), 1.32 (t, J ) 7.1
Hz, 3H), 1.4-1.5 (m, 2H), 1.5-1.6 (m, 2H), 1.60 (s, 3H), 1.89
(d, J ) 1.3 Hz, 3H), 1.93 (t, J ) 6.2 Hz, 2H), 4.23 (q, J ) 7.1
Hz, 2H), 5.81 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.3, 19.4,
19.6, 20.5, 28.1 (2×), 28.3, 32.7, 34.9, 39.6, 59.9, 125.5, 128.2,
136.1, 144.9, 168.0; IR (NaCl) υ 1714 (s, CdO) cm-1; HRMS
calcd for C16H24D2O2 252.2058, found 252.2055.
ter t-Bu t yld im et h ylsilyl (7E,9Z,11Z,13E)-12-(4-Nit r o-
p h en ylsu lfin yl)r et in yl E t h er (13b ) a n d ter t-Bu t yld i-
m et h ylsilyl (7E,9E,13E)-11,12-Did eh yd r or et in yl E t h er
(17). In accordance to the general procedure described above,
the reaction of propargyl alcohol 10 (0.05 g, 0.12 mmol) with
p-nitrophenylsulfenyl chloride (0.07 g, 0.36 mmol) provided
0.05 g (79%) of sulfoxide 13b as a yellow oil and 7 mg (15%) of
product 17. (See Supporting Information for 13b characteriza-
tion data). Da ta for 17: 1H NMR (250 MHz, CDCl3) δ -0.09
(s, 6H), 0.91 (s, 9H), 1.01 (s, 6H), 1.4-1.6 (m, 4H), 1.69 (s, 3H),
1.84 (s, 3H), 1.9-2.0 (m, 2H), 2.05 (s, 3H), 4.27 (d, J ) 6.4 Hz,
2H), 5.52 (s, 1H), 5.92 (t, J ) 6.4 Hz, 1H), 6.09 (d, J ) 16.3
Hz, 1H), 6.25 (d, J ) 16.3 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ -5.2 (2×), 15.0, 17.7, 18.3, 19.2, 21.6, 25.9 (3×), 28.9 (2×),
33.0, 34.2, 39.6, 60.1, 86.2, 98.9, 108.7, 119.4, 129.3, 130.0,
135.6, 136.1, 137.6, 147.1; UV (MeOH) λmax 318 nm; HRMS
calcd for C26H42OSi 398.3005, found 398.3001.
(2E)-4,4-Dideu ter o-2-m eth yl-4-(2,6,6-tr im eth ylcycloh ex-
1-en -1-yl)bu t-2-en -1-ol (22). To a cooled (0 °C) solution of
ethyl ester (E)-21 (0.14 g, 0.55 mmol) in THF (3 mL) was added
DIBAL-H (1.60 mL, 1.0 M in toluene, 1.60 mmol). After stirring
at 0 °C for 3 h, H2O was added and the mixture was extracted
with Et2O (5x). The combined organic layers were washed with
a saturated aqueous NaHCO3 solution, H2O, and brine, dried
(Na2SO4), and evaporated. Purification of the residue by
chromatography (SiO2, 85:15 hexane/ethyl acetate) afforded
1
0.12 g (99.9%) of alcohol 22 (>95% D) as a clear oil. H NMR
(400 MHz, CDCl3) δ 0.97 (s, 6H), 1.4-1.5 (m, 2H), 1.54 (s, 3H),
1.5-1.6 (m, 2H), 1.72 (d, J ) 1.1 Hz, 3H), 1.92 (t, J ) 6.1 Hz,
2H), 3.99 (d, J ) 5.5 Hz, 2H), 5.26 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.7, 19.5, 19.6, 26.3, 28.2 (2×), 32.8, 34.8, 39.7, 68.9,
127.3, 127.8, 133.0, 136.1; IR (NaCl) υ 3600-3100 (br, OH)
cm-1; HRMS calcd for C14H22D2O 210.1953, found 210.1958.
(2E)-4,4-Dideu ter o-2-m eth yl-4-(2,6,6-tr im eth ylcycloh ex-
1-en -1-yl)bu t-2-en a l (23). To a solution of alcohol 22 (0.26 g,
1.24 mmol) in CH2Cl2 (5 mL) was added MnO2 (1.72 g, 19.81
mmol), and the mixture was stirred at 25 °C for 3 h. It was
then filtered through Celite, and the solvent was evaporated.
Purification by chromatography (SiO2, 98:2 hexane/ethyl
acetate) afforded 0.23 g (89%) of aldehyde 23 (95% D) as a
clear oil. 1H NMR (400 MHz, CDCl3) δ 0.99 (s, 6H), 1.4-1.5
(m, 2H), 1.54 (s, 3H), 1.5-1.6 (m, 2H), 1.81 (d, J ) 1.1 Hz,
3H), 1.96 (t, J ) 6.2 Hz, 2H), 6.34 (s, 1H), 9.38 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 9.15, 19.3, 19.7, 27.8, 28.1 (2×), 32.8,
34.8, 39.4, 129.7, 134.2, 138.0, 155.8, 195.1; IR (NaCl) υ 1690
(s, CdO) cm-1; HRMS calcd for C14H20D2O 208.1796, found
208.1797.
Author: J ust one 3× for C-13 NMR shift at 25.9 ppm for
compound above?
ter t-Bu t yld im et h ylsilyl (7E,9Z,11Z,13E)-12-(2-Nit r o-
p h en ylsu lfin yl)r et in yl E t h er (13c) a n d ter t-Bu t yld i-
m et h ylsilyl (7E,9E,13E)-11,12-Did eh yd r or et in yl E t h er
(17). In accordance to the general procedure described above,
the reaction of propargyl alcohol 10 (0.05 g, 0.12 mmol) with
o-nitrophenylsulfenyl chloride (0.07 g, 0.36 mmol) provided
0.03 g (40%) of sulfoxide 13c as a yellow oil and 0.03 g (60%)
of 17. (See Supporting Information for 13c characterization
data).
2,2-Did eu t er o-2-(2,6,6-t r im et h ylcycloh ex-1-en -1-yl)e-
th a n a l (20-C2-d 2). A solution of 2-(2,6,6-trimethylcyclohex-
1-en-1-yl)ethanal (2.50 g, 12.05 mmol) in pyridine (14 mL)
containing D2O (6.50 mL, 0.36 mol) was added, dropwise, to a
suspension of NaH (46 mg, 1.81 mmol) in pyridine (4 mL).
After stirring at 25 °C for 2 h, the final mixture was extracted
with CH2Cl2 (3×). The combined organic layers were washed
with H2O, dried (Na2SO4), and evaporated. The whole process
was repeated twice more, until the complete disappearance of
the starting material was confirmed by 1H NMR, finally
isolating 2.02 g (99.9%) of dideuterated aldehyde 20-C2-d2 (>
95% D). 1H NMR (400 MHz, CDCl3) δ 0.98 (s, 6H), 1.4-1.5
(m, 2H), 1.58 (s, 3H), 1.5-1.6 (m, 2H), 2.02 (t, J ) 6.1 Hz,
2H), 9.53 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 19.3, 20.1,
28.0 (2×), 32.8, 34.5, 39.1, 43.1, 128.3, 132.5, 201.4; IR (NaCl)
υ 1720 (s, CdO) cm-1; HRMS calcd for C11H16D2O 168.1483,
found 168.1482.
Eth yl (2E)-4,4-Did eu ter o-2-m eth yl-4-(2,6,6-tr im eth yl-
cycloh ex-1-en -1-yl)bu t-2-en oa te ((E)-21) a n d Eth yl (2Z)-
4,4-Did eu ter o-2-m eth yl-4-(2,6,6-tr im eth ylcycloh ex-1-en -
1-yl)bu t-2-en oa te ((Z)-21). To a cooled (-78 °C) solution of
diethyl 1-(ethoxycarbonyl)ethanephosphonate (0.94 g, 3.93
mmol) in THF (7 mL) was added n-BuLi (1.50 mL, 2.93 M in
hexane, 4.28 mmol). After stirring at -78 °C for 30 min, a
solution of aldehyde 20 (0.60 g, 3.57 mmol) in THF (4 mL)
was added, and the final mixture was stirred at -78 °C for 3
h and at 25 °C for an additional 2 h. A 0.5 M HCl solution
was then added until neutral pH was reached, and the mixture
was extracted with Et2O (3×). The combined organic layers
were washed with H2O and brine, dried (Na2SO4), and
evaporated. Purification by chromatography (SiO2, 97:3 hex-
ane/ethyl acetate) afforded 0.41 g of (E)-21 (95% D) and 0.25
g of (Z)-21 (>95% D) (73% overall yield). Da ta for (E)-21: 1H
NMR (400 MHz, CDCl3) δ 0.97 (s, 6H), 1.30 (t, J ) 7.1 Hz,
3H), 1.4-1.5 (m, 2H), 1.53 (s, 3H), 1.5-1.6 (m, 2H), 1.89 (d, J
) 1.3 Hz, 3H), 1.94 (t, J ) 6.2 Hz, 2H), 4.18 (q, J ) 7.1 Hz,
2H), 6.60 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 12.4, 14.2,
19.4, 19.7, 27.4, 28.1 (2×), 32.8, 34.8, 39.4, 60.3, 126.1, 129.1,
134.6, 143.3, 168.3; IR (NaCl) υ 1710 (s, CdO) cm-1; HRMS
(2E,7E)-9-[(ter t-Bu tyld im eth ylsilyl)oxy]-1,1-d id eu ter o-
3,7-d im et h yl-1-(2,6,6-t r im et h ylcycloh ex-1-en -1-yl)n on a -
2,7-d ien -5-yn -4-ol (10-C7-d 2). Gen er a l P r oced u r e for th e
P r ep a r a tion of P r op a r gylic Alcoh ols. To a cooled (-78 °C)
solution of alkyne 24 (0.12 g, 0.58 mmol) in THF (2 mL) was
added, dropwise, n-BuLi (0.25 mL, 2.36 M in hexane, 0.58
mmol). After stirring at -78 °C for 15 min and at 0 °C for 20
min, the mixture was cooled to -78 °C, and a solution of
aldehyde 23 (0.11 g, 0.53 mmol) in THF (2 mL) was then
added. After stirring at -78 °C for 1.5 h, a saturated aqueous
NH4Cl solution was added and stirring at 25 °C was continued
for 10 min. The mixture was then extracted with Et2O (3×).
The combined organic layers were washed with brine, dried
(Na2SO4), and evaporated. Purification by chromatography
(SiO2, 93:7 hexane/ethyl acetate) afforded 0.17 g (75%) of
propargylic alcohol 10-C7-d2 (>95% D). 1H NMR (400 MHz,
CDCl3) δ 0.06 (s, 6H), 0.89 (s, 9H), 0.96 (s, 3H), 0.97 (s, 3H),
1.4-1.6 (m, 4H), 1.53 (s, 3H), 1.77 (d, J ) 1.4 Hz, 3H), 1.80 (d,
J ) 1.1 Hz, 3H), 1.91 (t, J ) 6.1 Hz, 2H), 4.24 (dq, J ) 6.2, 0.6
Hz, 2H), 4.84 (d, J ) 5.6 Hz, 1H), 5.43 (s, 1H), 5.91 (tq, J )
6.2, 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ -5.2 (2×), 12.1,
17.4, 18.2, 19.4, 19.6, 25.8 (3×), 26.4, 28.2 (2×), 32.8, 34.7, 39.6,
59.8, 68.4, 86.1, 87.9, 118.1, 128.1, 128.8, 132.6, 135.6, 137.0;
IR (NaCl) υ 3600-3100 (br, OH) cm-1; HRMS calcd for
C
26H42D2O2Si 418.3236, found 418.3221.
ter t-Bu tyldim eth ylsilyl (7E,9Z,11Z,13E)-7,11-Dideu ter o-
12-(p h en ylsu lfin yl)r etin yl Eth er (13a -C7,C11-d 2). In ac-
cordance to the general procedure described above, reaction
of propargylic alcohol 10-C7-d2 (0.15 g, 0.36 mmol) with Et3N
(0.15 mL, 1.08 mmol) and phenylsulfenyl chloride (0.16 g, 1.08
mmol) in THF (9 mL) provided, after purification by chroma-
tography (SiO2, 96:3:1 hexane/ethyl acetate/Et3N), 0.15 g (77%)
of retinyl ether 13a -C7,C11-d2 (95% D). An analytical sample
for characterization was further purified by chromatography
on Al2O3 (4.8% H2O) (95:5 hexane/ethyl acetate). 1H NMR (400
MHz, CDCl3) δ -0.01 (s, 6H), 0.84 (s, 9H), 1.04 (s, 6H), 1.4-
1.6 (m, 4H), 1.61 (s, 3H), 1.74 (s, 3H), 2.04 (t, J ) 6.1 Hz, 2H),

2704 J . Org. Chem., Vol. 65, No. 9, 2000
Iglesias et al.
2.07 (d, J ) 0.8 Hz, 3H), 4.1-4.2 (m, 2H), 5.66 (tq, J ) 6.0,
1.3 Hz, 1H), 6.65 (s, 1H), 6.88 (s, 1H), 7.4-7.6 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ -5.2 (2×), 16.8, 18.2, 19.1, 21.3,
21.9, 25.9 (3×), 29.0 (2×), 33.1, 34.2, 39.4, 60.2, 121.1, 124.2
(2×), 128.5, 128.8 (2×), 129.8, 130.7, 131.0, 132.9, 137.7, 141.6,
143.6 (2×); HRMS calcd for C32H46D2O2SSi 526.3270, found
526.3262.
alcohol 33 (0.24 g, 0.70 mmol) with Et3N (0.29 mL, 2.10 mmol)
and chlorodiphenylphosphine (0.25 mL, 2.10 mmol) provided
1
0.28 g (77%) of allene 34. H NMR (400 MHz, CDCl3) δ 0.85
(s, 3H), 0.93 (s, 3H), 1.4-1.6 (m, 4H), 1.43 (s, 3H), 1.49 (s, 3H),
1.90 (t, J ) 6.2 Hz, 2H), 1.93 (s, 3H), 2.67 (br s, 2H), 3.8-3.9
(m, 2×, 4H), 5.04 (br t, 1H), 5.56 (d, J ) 6.4 Hz, 1H), 5.85 (d,
4J H-P ) 10.4 Hz, 1H), 6.12 (d, J ) 6.4 Hz, 1H), 7.4-7.5 (m,
6H), 7.6-7.7 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 14.9, 18.1
(3J C-P ) 5.0 Hz), 20.4, 20.7, 28.7, 29.1, 29.3, 33.8, 35.8, 40.6,
65.7 (2×), 101.3, 104.5 (3J C-P ) 13.2 Hz), 107.2 (1J C-P ) 99.7
Hz), 126.6 (3J C-P ) 7.0 Hz), 129.1 (3J C-P ) 13.0 Hz), 129.3
(3J C-P ) 3.9 Hz), 132.5 (2J C-P ) 9.9 Hz), 132.6 (4J C-P ) 5.8
Hz), 132.7, 133.0, 133.9, 135.1, 136.7, 214.2 (2J C-P ) 5.9 Hz);
IR (NaCl) υ 1900 (w, CdCdC) cm-1; UV (MeOH) λmax 224, 246
nm; HRMS calcd for C34H41O3P 528.2793, found 528.2782.
(6E)-8-[(ter t-Bu tyld im eth ylsilyl)oxy]-6-m eth ylocta -1,6-
d ien -4-yn -3-ol (29). According to the general procedure
described above, the reaction of alkyne 24 (0.41 g, 1.96 mmol),
acrolein (0.10 g, 1.78 mmol), and n-BuLi (0.72 mL, 2.84 M in
hexane, 2.05 mmol) afforded, after purification by flash chro-
matography on silica gel (88:10:2 hexane/EtOAc/Et3N), 0.45 g
1
(87%) of alkenynol 29. H NMR (400 MHz, CDCl3) δ 0.07 (s,
6H), 0.89 (s, 9H), 1.79 (d, J ) 0.8 Hz, 3H), 4.25 (d, J ) 6.0 Hz,
2H), 5.00 (br s, 1H), 5.23 (d, J ) 10.1 Hz, 1H), 5.47 (d, J )
16.9 Hz, 1H), 5.95 (t, J ) 6.0 Hz, 1H), 6.00 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ -4.8 (2×), 18.0, 18.8, 26.3 (3×), 60.4, 64.0,
85.5, 89.0, 116.9, 118.3, 137.4, 138.1; IR (NaCl) υ 3600-3100
(br, O-H) cm-1; UV (MeOH) λmax 230 nm; HRMS calcd for
(2E)-2-Meth yl-4-(2,6,6-tr im eth ylcycloh ex-2-en -1-yl)bu t-
2-en a l (37). To a three-necked Morton flask equipped with a
mechanical stirrer and a solid addition funnel were added
R-ionone 36 (10.0 g, 52 mmol), methyl chloroacetate (12.25 mL,
0.14 mol), and MeOH (20 mL). The solution was cooled to -10
°C, and MeONa (9.6 g, 0.18 mol) was added in small portions
for 2 h. After stirring at 0 °C for 3 h, a solution of 15% NaOH
in MeOH (50 mL) was added and the resulting mixture was
stirred at 5 °C for 2 h, after which time it was allowed to reach
25 °C. Water was added (60 mL) and the final solution was
stirred for 30 min at 25 °C. The two layers were separated,
and the aqueous layer was extracted with Et2O (3×). The
combined organic layers were washed with water (3×), dried
(Na2SO4), filtered and evaporated. Purification by flash chro-
matography on silica gel (95:5 hexane/EtOAc) afforded 6.20 g
(58%) of aldehyde 37 as a clear yellow oil. 1H NMR (400 MHz,
CDCl3) δ 0.79 (s, 3H), 0.82 (s, 3H), 1.0-1.2 (m, 1H), 1.2-1.4
(m, 1H), 1.59 (d, J ) 1.8 Hz, 3H), 1.67 (d, J ) 1.1 Hz, 3H),
1.71 (br t, J ) 5.1 Hz, 1H), 1.8-2.0 (m, 2H), 2.38 (td, J ) 6.2,
0.9 Hz, 2H), 5.34 (br s, 1H), 6.50 (td, J ) 7.1, 1.3 Hz, 1H),
9.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 9.2, 22.8, 23.2, 27.4
(2×), 30.0, 31.5, 32.4, 49.2, 121.9, 134.5, 138.0, 155.8, 195.0;
HRMS calcd for C14H22O 206.1671, found 206.1667.
(2E,7E)-9-[(ter t-Bu tyld im eth ylsilyl)oxy]-3,7-d im eth yl-
1-(2,6,6-tr im eth ylcycloh ex-2-en -1-yl)n on a -2,7-d ien -5-yn -
4-ol (38). According to the general procedure described above,
the reaction of aldehyde 37 (0.5 g, 2.43 mmol), alkyne 24 (0.57
g, 2.70 mol), and n-BuLi (1.27 mL, 2.55 M in hexane, 3.24
mmol) in THF (8 mL), afforded, after flash chromatography
on silica gel (90:10 hexane/EtOAc), 0.56 g (56%) of propargylic
alcohol 38 as a yellow oil. (See Supporting Information for
characterization data).
ter t-Bu t yld im et h ylsilyl (7E,9Z,11Z,13E)-12-(P h en yl-
su lfin yl)-4,6-r etr or etin yl Eth er (39). Following the general
procedure described above, treatment of propargylic alcohol
38 (0.22 g, 0.53 mmol) with phenylsulfenyl chloride (0.23 g,
1.59 mmol) and Et3N (0.20 mL, 1.59 mmol) in THF (18 mL)
afforded, after flash chromatography on silica gel (93:6:1
hexane/EtOAc/Et3N), 0.11 g (40%) of sulfoxide 39. An analyti-
cal sample for characterization was purified by HPLC (85:15
hexane/EtOAc). (See Supporting Information for characteriza-
tion data).
ter t-Bu tyld im eth ylsilyl (7E,9Z,11E,13E)-4,6-r etr oReti-
n yl Eth er (40). Following the general procedure described
above, the reaction of sulfoxide 39 (0.03 g, 0.06 mmol) in THF
(4 mL) with MeOH (13 µL, 0.31 mmol), MeLi (40 µL, 1.6 M in
Et2O, 0.06 mmol), and tert-BuLi (0.36 mL, 1.7 M in pentane,
0.62 mmol) afforded, after purification by chromatography
(C18, 100% CH3CN), 0.02 g (73%) of silyl ether 40. (See
Supporting Information for characterization data).
(7E,9Z,11E,13E)-4,6-r etr oRetin oic Acid (42). Following
the general procedure described above, compound 40 (0.01 g,
0.03 mmol) was deprotected by treatment with TBAF (33 µL,
1.0 M in THF, 0.03 mmol) to afford alcohol 41. The residue
was immediately oxidized, according to the general procedure,
with MnO2 (14 mg, 0.16 mmol) and Ag2O (38 mg, 0.16 mmol)
to provide, after purification by chromatography (SiO2, 98:2
CH2Cl2/MeOH), 4 mg (53%) of carboxylic acid 42. (See Sup-
porting Information for characterization data).
C
15H26O2Si 266.1702, found 266.1696.
ter t-Bu t yld im et h ylsilyl (2E,6E)-6-Met h yl-1-(p h en yl-
su lfin yl)octa -2,6-d ien -4-yn -8-yl Eth er ((E)-31). In accor-
dance to the general procedure described above, the reaction
of Et3N (0.16 mL, 1.11 mmol), alkenynol 29 (0.10 g, 0.37 mmol),
and phenylsulfenyl chloride (0.16 g, 1.11 mmol) in THF (10
mL) afforded, after purification by flash chromatography (83:
15:2 hexane/EtOAc/Et3N), 0.12 g (89%) of sulfoxide (E)-31 as
a yellow oil. 1H NMR (400 MHz, CDCl3) δ 0.07 (s, 6H), 0.90 (s,
9H), 1.78 (d, J ) 1.2 Hz, 3H), 3.55 (ddd, J ) 12.8, 7.8, 0.8 Hz,
1H), 3.63 (ddd, J ) 12.8, 7.8, 0.8 Hz, 1H), 4.25 (d, J ) 6.2 Hz,
2H), 5.65 (d, J ) 15.6 Hz, 1H), 5.85 (dt, J ) 15.6, 7.8 Hz, 1H),
1
5.92 (td, J ) 6.3, 1.2 Hz, 1H), 7.5-7.6 (m, 5H); H NMR (400
MHz, C6D6) δ 0.00 (s, 6H), 0.93 (s, 9H), 1.62 (s, 3H), 2.85 (ddd,
J ) 12.8, 7.8, 1.1 Hz, 1H), 2.98 (ddd, J ) 12.8, 7.8, 1.1 Hz,
1H), 4.07 (d, J ) 6.2 Hz, 2H), 5.47 (d, J ) 15.7 Hz, 1H), 5.76
(dt, J ) 15.7, 7.8 Hz, 1H), 6.14 (td, J ) 6.2, 1.4 Hz, 1H), 6.9-
7.0 (m, 3H), 7.3-7.5 (dd, J ) 7.8, 2.3 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ -4.7 (2×), 17.9, 26.3 (3×), 38.0, 60.4, 60.9, 84.9,
94.2, 118.9, 124.7 (2×), 129.0, 129.5, 129.6 (2×), 131.8, 138.2,
142.9; UV (MeOH) λmax 278 nm; HRMS [M - t-Bu] calcd for
C17H21O2SSi 317.1032, found 317.1026. 1H NMR for (Z)-31 (400
MHz, C6D6) δ 0.01 (s, 6H), 0.94 (s, 9H), 1.60 (s, 3H), 3.47 (dd,
J ) 12.7, 7.8 Hz, 1H), 3.57 (dd, J ) 12.7, 7.8 Hz, 1H), 4.08 (d,
J ) 6.2 Hz, 2H), 5.5-5.6 (m, 2H), 6.00 (t, J ) 6.2 Hz, 1H),
7.0-7.2 (m, 3H), 7.44 (d, J ) 7.8 Hz, 2H).
ter t-Bu tyld im eth ylsilyl (8E,13E)-12-(Dip h en ylp h osp h i-
n oyl)-11,7-r etr or etin yl Eth er (32). Gen er a l P r oced u r e for
th e P r ep a r a tion of Allen ylp h osp h in e Oxid es. To a cooled
(-78 °C) solution of propargylic alcohol 10 (0.10 g, 0.24 mmol)
in THF (1.3 mL) was added, dropwise, Et3N (0.10 mL, 0.73
mmol), followed by chlorodiphenylphosphine (0.02 mL, 0.3
mmol). After stirring at -78 °C for 3 h and at 25 °C for an
additional 3 h, the solvent was evaporated. The residue was
purified by flash chromatography on silica gel (82:15:3 hexane/
EtOAc/Et3N) to provide, in order of elution, 0.07 g (70%) of
allene 32 as a colorless oil, and 0.03 g of unreacted starting
1
material. H NMR (400 MHz, CDCl3) δ -0.11 (s, 6H), 0.76 (s,
9H), 0.83 (s, 3H), 0.91 (s, 3H), 1.4-1.6 (m, 4H), 1.42 (s, 3H),
1.51 (s, 3H), 1.78 (s, 3H), 1.88 (t, J ) 6.1 Hz, 2H), 2.65 (br s,
4
2H), 4.21 (d, J ) 6.0 Hz, 2H), 5.00 (m, 1H), 5.80 (d, J H-P
)
10.5 Hz, 1H), 6.14 (t, J ) 6.0 Hz, 1H), 7.4-7.5 (m, 6H), 7.6-
7.7 (m, 4H); 13C NMR (100 MHz, CDCl3) δ -4.8 (2×), 14.3,
16.9, 17.0 (3J C-P ) 5.2 Hz), 18.6, 19.9, 20.1, 26.2 (3×), 28.1,
28.6, 28.8, 33.3, 35.3, 40.1, 60.9, 103.7 (3J C-P ) 13.5 Hz), 107.1
(1J C-P ) 101.3 Hz), 126.3 (3J C-P ) 7.1 Hz), 128.2 (3J C-P ) 7.0
Hz), 128.4 (3J C-P ) 9.0 Hz), 128.5, 128.6, 128.7 (3J C-P ) 9.0
Hz), 131.9, 132.0 (2J C-P ) 9.0 Hz, 2×), 132.0 (2J C-P ) 10.4 Hz,
2×), 132.7 (3J C-P ) 4.9 Hz), 132.8 (4J C-P ) 4.7 Hz), 133.8, 136.2,
213.0 (2J C-P ) 5.9 Hz); IR (NaCl) υ 1910 (w, CdCdC) cm-1
;
UV (MeOH) λmax 224, 246 nm; HRMS calcd for C38H53O2PSi
600.3552, found 600.3551.
(8E,13E)-14-[1,3]-Dioxola n -2-yl}-12-(d ip h en ylp h osp h i-
n oyl)-11,7-r etr or etin yl Eth er (34). In accordance to the
general procedure described above, treatment of propargylic

Stereocontrolled Synthesis of 9-cis-Retinoids
J . Org. Chem., Vol. 65, No. 9, 2000 2705
ter t-Bu tyld im eth ylsilyl (7E,9Z,11E,13E)-7,11-Did eu te-
r ior etin yl Eth er (14-C7,C11-d 2). According to the general
procedure described above, treatment of sulfoxide 13a -C7,C11-
d2 (0.05 g, 0.09 mmol) in THF (5 mL) with MeOH (18 µL, 0.45
mmol), MeLi (42 µL, 1.6 M in Et2O, 0.07 mmol), and tert-BuLi
(0.42 mL, 1.7 M in pentane, 0.71 mmol) afforded, after
purification by chromatography (SiO2, 99.6:0.4 hexane/Et3N),
0.03 g (77%) of retinyl ether 14-C7,C11-d2, which was im-
ethyl acetate, 43 min). 1H NMR (400 MHz, C6D6) δ 1.11 (s,
6H), 1.4-1.6 (m, 4H), 1.54 (s, 3H), 1.81 (s, 3H), 1.9-2.0 (m,
2H), 1.94 (s, 3H), 3.96 (d, J ) 6.6 Hz, 2H), 5.58 (t, J ) 6.6 Hz,
1H), 6.09 (s, 1H), 6.24 (s, 1H), 7.01 (s, 1H); 13C NMR (100 MHz,
C6D6) δ 12.4, 19.7, 20.8, 22.0, 29.2 (2×), 33.3, 34.5, 39.8, 59.4,
129.6, 129.8, 130.7, 131.8, 134.3, 135.9, 136.6, 138.5; IR (NaCl)
υ 3600-3100 (br, OH) cm-1; HRMS calcd for C20H28D2O
288.2422, found 288.2419.
1
mediately converted into the corresponding retinol. H NMR
(7E,9Z,11E,13E)-7,11,12-Tr id eu ter ior etin ol (15-C7,C11,-
C12-d 3). In accordance to the general procedure described
above, retinyl ether 14-C7,C11,C12-d3 (0.02 g, 0.06 mmol) in
THF (1.2 mL) was treated with TBAF (0.07 mL, 1.0 M in THF,
0.07 mmol) to afford, after purification by chromatography
(SiO2, 95:13:2 hexane/ethyl acetate/Et3N), 11 mg (67%) of
retinol 15-C7,C11,C12-d3 (95% D). A sample for characteriza-
tion was purified by HPLC (Prep Nova-Pak HR Silica [19 ×
(400 MHz, CDCl3) δ 0.08 (s, 6H), 0.91 (s, 9H), 1.04 (s, 6H),
1.5-1.7 (m, 4H), 1.75 (s, 3H), 1.80 (s, 3H), 1.96 (s, 3H), 2.04
(t, J ) 6.2 Hz, 2H), 4.35 (d, J ) 6.3 Hz, 2H), 5.60 (t, J ) 6.3
Hz, 1H), 6.00 (s, 1H), 6.22 (s, 1H), 6.63 (s, 1H);1H NMR (400
MHz, C6D6) δ 0.08 (s, 6H), 1.00 (s, 9H), 1.12 (s, 6H), 1.4-1.6
(m, 4H), 1.60 (s, 3H), 1.83 (s, 3H), 1.9 (m, 2H), 1.94 (s, 3H),
4.27 (d, J ) 6.3 Hz, 2H), 5.77 (t, J ) 6.3 Hz, 1H), 6.08 (s, 1H),
6.29 (s, 1H), 7.02 (s, 1H).
1
300 mm], 4 mL/min, 80:20 hexane/ethyl acetate, 44 min). H
ter t-Bu t yld im et h ylsilyl (7E,9Z,11E,13E)-7,11,12-Tr i-
d eu ter ior etin yl Eth er (14-C7,C11,C12-d 3). In accordance
to the general procedure described above, sulfoxide 13a -C7,-
C11-d2 (0.05 g, 0.09 mmol) in THF (5 mL) was treated with
CD3OD (18 µL, 0.44 mmol), MeLi (56 µL, 1.6 M in Et2O, 0.09
mmol), and tert-BuLi (0.42 mL, 1.7 M in pentane, 0.71 mmol)
to afford, after purification by chromatography (SiO2, 99.6:0.4
hexane/Et3N), 0.02 g (63%) of retinyl ether 14-C7,C11,C12-
d3, which was immediately converted into the corresponding
retinol.1H NMR (400 MHz, C6D6) δ 0.07 (s, 6H), 0.99 (s, 9H),
1.11 (s, 6H), 1.4-1.6 (m, 4H), 1.60 (d, J ) 0.4 Hz, 3H), 1.81 (s,
3H), 1.90 (m, 2H), 1.93 (d, J ) 0.7 Hz, 3H), 4.27 (d, J ) 6.4
Hz, 2H), 5.76 (t, J ) 6.4 Hz, 1H), 6.07 (s, 1H), 7.01 (s, 1H).
(7E,9Z,11E,13E)-7,11-Did eu ter ior etin ol (15-C7,C11-d 2).
In accordance to the general procedure described above, retinyl
ether 14-C7,C11-d2 (0.03 g, 0.06 mmol) in THF (1.3 mL) was
treated with TBAF (79 µL, 1.0 M in THF, 0.08 mmol) to afford,
after purification by chromatography (SiO2, 95:13:2 hexane/
ethyl acetate/Et3N), 12 mg (65%) of retinol 15-C7,C11-d2 (90%
D). A sample for characterization was purified by HPLC (Prep
Nova-Pak HR Silica [19 × 300 mm], 4 mL/min, 80:20 hexane/
NMR (400 MHz, C6D6) δ 1.18 (s, 6H), 1.4-1.6 (m, 4H), 1.61 (s,
3H), 1.88 (s, 3H), 1.9-2.0 (m, 5H), 4.03 (d, J ) 6.7 Hz, 2H),
5.64 (tq, J ) 6.7, 1.0 Hz, 1H), 6.15 (s, 1H), 7.06 (s, 1H); 13C
NMR (100 MHz, C6D6) δ 12.4, 19.6, 20.8, 22.0, 29.1 (2×), 33.2,
34.5, 39.8, 59.4, 129.5, 129.7, 130.7, 131.7, 134.3, 135.9, 138.5;
IR (NaCl) υ 3600-3100 (br, OH) cm-1; HRMS calcd for
C
20H27D3O 289.2485, found 289.2486.
Ack n ow led gm en t. We thank MEC (SAF98-1534),
Xunta de Galicia (grants XUGA30506B97 to A. R. de
L. and XUGA20905A98 to S. L.) for financial support,
and Dr. T. Mu´jica (University of La Laguna) and Mr.
A. Castro (University of Vigo) for help with preliminary
experiments in this area.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds described in the Experimental
Section. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O991757F