Efficient synthesis of 11-cis-retinoids

Article abstract of DOI:10.1002/(SICI)1521-3765(19990401)5:4<1172::AID-CHEM1172>3.0.CO;2-Q

The light sensitivity and unstable nature of 11-cis-retinoids makes them ideal visual chromophores in nature. The synthesis of 11-cis-retinal analogues is of paramount importance in bioorganic studies of rhodopsin, the photoreceptor of the visual transduction pathway, but the instability of 11- cis-retinoids complicates their synthesis and there is no general synthetic route. Common strategies to the cis geometry have failed in the case of 11- cis-retinoids, and most often low yields and complex isomeric mixtures are obtained. Herein we report an efficient, general, and mild preparation of 11- cis-retinoids by semi-hydrogenation of 11-yne-retinoid precursors with Cu/Ag- activated zinc dust.

Full text of DOI:10.1002/(SICI)1521-3765(19990401)5:4<1172::AID-CHEM1172>3.0.CO;2-Q

FULL PAPER
Efficient Synthesis of 11-cis-Retinoids
Babak Borhan, María L. Souto, Joann M. Um, Bishan Zhou, and Koji Nakanishi*[a]
Abstract: The light sensitivity and unstable nature of 11-cis-retinoids makes them
ideal visual chromophores in nature. The synthesis of 11-cis-retinal analogues is of
paramount importance in bioorganic studies of rhodopsin, the photoreceptor of the
visual transduction pathway, but the instability of 11-cis-retinoids complicates their
synthesis and there is no general synthetic route. Common strategies to the cis
geometry have failed in the case of 11-cis-retinoids, and most often low yields and
complex isomeric mixtures are obtained. Herein we report an efficient, general, and
mild preparation of 11-cis-retinoids by semi-hydrogenation of 11-yne-retinoid
precursors with Cu/Ag-activated zinc dust.
Keywords: 11-cis-retinoids
mophores enynes hydrogena-
tions retinal analogues zinc
reductions
´ chro-
´
´
´
´
bonds survive. Most schemes geared towards the introduction
of the 11-cis geometry (especially those close to the end of the
synthetic scheme) have either failed or resulted in low yields
with formation of complex isomeric mixtures.[9±15] In addition,
the more common photoisomerization strategy of all-trans-
retinoids and subsequent HPLC purification of the 11-cis
isomer is not compatible with analogues that contain light-
sensitive functional groups. Moreover, in some cases it has
been difficult to separate by chromatography the isomeric
mixture of retinals obtained from photoisomerization. The
unusual difficulty encountered in generating the 11-cis
geometry is probably associated with the steric hindrance
between 10-H and 13-Me, which leads to a nonplanar
conformation which could isomerize easily to relieve stress
under most experimental conditions.[1, 16±18] Very recently,
Uenishi et al. have developed an elegant synthesis of 11-cis-
retinal itself based on the Suzuki coupling of the C12 ± C13
bond.[19] The preparation of 11-cis-retinal analogues with a
photolabile group, such as 1, has also been accomplished by
enzymatic isomerization of all-trans precursors by means of
retinochrome isolated from the visual cells of cephalopods.[20]
Although efficient, this method is unsuitable for securing
relatively large quantities of compound. We have therefore
focused on the chemical synthesis of the 11-cis-retinoids. Here
we report an efficient, nonphotochemical preparation of 11-
cis-retinoids by zinc-mediated semi-hydrogenation of 11-yne-
retinoid precursors.
Introduction
Visual transduction is initiated by photoisomerization of the
11-cis-retinal chromophore to all-trans-retinal, which in turn
leads to a series of conformational changes in rhodopsin, and
eventually results in the enzymatic cascade responsible for
vision.[1±3] Although the initial and final states of the
chromophore/opsin interactions have been clarified to a
considerable degree,[4±8] the nature of the discrete intermedi-
ates along the transduction pathway remains uncertain on a
molecular structural basis. One of our main objectives is to
study this by tracing the changes in chromophore/receptor
interactions with photoaffinity analogues such as the tritiated
1. We could thus elucidate the position of the b-ionone ring
with relation to the protein by identification of the cross-
linked sites. A general synthetic method yielding 11-cis-
retinoids, as well as analogues with photolabile moieties such
as 1, would greatly facilitate bioorganic studies of rhodopsin.
11
10
13
N2
1
O
CTO
The synthesis of 11-cis-retinal analogues is complicated by
their unusual instability to light and temperature, and by their
facile isomerization under conditions which most Z double
[a] Prof. K. Nakanishi, Dr. B. Borhan, Dr. M. L. Souto, J. M. Um, B. Zhou
Department of Chemistry
Results and Discussion
Columbia University, New York
New York 10027 (USA)
Although numerous synthetic routes (summarized in
Scheme 1) were pursued to prepare 11-cis-retinoids, none of
them gave satisfactory results.
Fax: (‡1)21-2932-8273
E-mail: kn5@columbia.edu
1172
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1172±1175
Reaction of
Scheme 1(d):
b. HWE Olefination
(Using ylide with 11-cis geometry)
mixed high-order cuprates (ob-
tained from cis-vinyl iodide 3)
with a,b-unsaturated acetylenic
esters was also unsuccessful and
led to complex mixtures of
products.
P
OR
e. Semi-hydrogenation of acetylene
11
9
12
13
c. Stille coupling
In order to pursue the syn-
thesis of 11-cis-retinoids by the
semi-hydrogenation of 11-yne
precursors, straightfoward syn-
theses of 10a, 10b, 11a, and
11b were first performed
(Scheme 3). 4-Hydroxy-b-ion-
one, readily prepared from b-
ionone (6a),[24] was protected
with triethylsilyl chloride to
afford 6b. Subsequent HWE
OR
OR
OR
CHO
Me3Sn
ClZn
a. HWE Olefination
(Yielding cis-C11 geometry)
4
5
P
d. Michael-type, high-order cuprate addition
OR
Cu•Me2S•LiBr
CO2Et
OTES
Scheme 1. Synthetic schemes used in the preparation of 11-cis-retinoids (TES ˆ triethylsilyl).
Scheme 1(a): The Wittig and Horner± Wadsworth ± Emmons
(HWE) reactions illustrated in Scheme 1(a) were performed
to generate the 11-cis geometry from unstabilized ylides and
bis(trifluoroethyl) phosphonates; however, at best they gave a
mixture of isomers with no more than 25% of 11-cis.[21, 22]
Although it is possible that the initial product of the Wittig
reaction is predominantly cis, it seems likely that the product
would isomerize to the trans isomer under basic reaction
conditions.
coupling with dimethyl (3-trimethylsilyl-2-propynyl)phospho-
nate[25] yielded the alkyne 7b (97%; 5:1 E:Z at C9).
Deprotection of both silyl groups with tetrabutylammonium
fluoride (TBAF) gave the terminal acetylene 8b. Palladium
coupling of 8b with vinyl iodide 9[26] proceeded with complete
stereochemical retention to yield the 11-yne precursor 10b
(91%).
Semi-hydrogenation of 10b was attempted with different
reducing systems [Scheme 1(e)]. Heterogeneous catalytic
systems such as the Lindlar catalyst gave variable results
which depended on the level of catalyst ꢂpoisoningꢁ with
additives such as pyridine, quinoline, 2,2'-(ethylenedithio)-
diethanol, and also on the modified Lindlar catalyst (prepared
with different co-metals such as Mn2‡, Ba2‡, and Ni2‡).[27] In
these cases, the catalyst was either weakened to the extent
that it did not reduce the triple bond or reduced the C5 and/or
C13 double bonds at the same rate, or faster, than the triple
bond of the 11-yne. Presumably, the electron density of the
Scheme 1(b): Formation of the 9-ene via ylides which contain
the 11-cis geometry was also fruitless, presumably because of
similar isomerization to the trans isomer.
CHO
Ph3PCH2I I
I
nBuLi / THF / -78˚C
3
2
OTES
OTES
Scheme 2. Synthesis of the cis-vinyl iodide 3.
Br
TMS
HP(O)(OMe)2
NaHMDS/THF
Scheme 1(c): Compound 3 was
obtained from aldehyde 2 by
Storkꢁs preparation of cis-vinyl
iodides (Scheme 2).[23] Stille-
type couplings of the C12 ± C13
bond with iodide 3 and the
vinyl ± tin 4 or vinyl ± zinc 5
electrophiles were attempted,
but none of the desired 11-cis-
retinoid was isolated from these
reactions (performed under var-
ious conditions with different
sources of Pd2‡ and Pd0). The
products obtained were mostly
mixtures of different trans iso-
mers. In addition, evidence for
dimerization of the starting vi-
nyl iodide 3 was noted in mass-
TMS
O
P
TMS
nBu4NF
THF
(MeO)2
O
nBuLi/THF
6a, R=H
7a, R=H (99%)
7b, R=OTES (97%)
R
6b, R=OTES
R
CH2OTBS
(Ph3P)4Pd/CuI/iPrNH2
OTBS
9
I
R
10a, R=H (91%)
10b, R=OH (91%)
R
1. iBuMgCl/Cp2TiCl2
2. I2/-78˚ C
3. TBS-Cl
8a, R=H (99%)
8b, R=OH (98%)
OH
CH2OH
nBu4NF
THF
11a, R=H (99%)
11b, R=OH (97%)
R
Scheme 3. Synthesis of the 11-yne precursors 11a and 11b (TMS ˆ trimethylsilyl, TBS ˆ tert-butyldimethylsilyl,
NaHMDS ˆ sodium bis(trimethylsilyl)amide).
spectral studies.
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1173

K. Nakanishi et al.
FULL PAPER
triple bond within the polyene system is not appreciably
greater than that of the C5 and C13 double bonds, and
therefore we were not able to refine the hydrogenation power
of the catalyst and thus selectively reduce the acetylene. Other
systems such as nickel boride bound to borohydride exchange
resin[28] and homogeneous catalytic systems[29] also failed to
yield the desired 11-cis-ene.
retinoids 10b, 11a, and 11b (with free hydroxyl(s) either at C4
or in the side-chain) were reduced successfully. It is possible
that in these cases the free hydroxyl(s) coordinate to the
activated zinc and thus facilitate the reduction. It is also
interesting to note that for substrates with unprotected 15-
hydroxyl groups (11a and 11b), reduction proceeds with
lower stereoselectivity.
In contrast to the attempted conversions outlined above,
the following conditions finally gave satisfactory results. Zinc-
mediated semi-hydrogenation of acetylenic compounds has
been reported, but in most cases a-branched acetylenes are
not reduced or are reduced at low yields with elevated
temperatures (unsuitable for retinoid synthesis).[30, 31] How-
ever, reduction of 11-yne precursor 10b with Cu/Ag-activated
Zn dust in methanol/water at room temperature proceeded
surprisingly smoothly to form the desired 11-cis-retinoid 12
with 100% cis stereoselectivity in high yield (Scheme 4).
Removal of the TBS group from 12 with TBAF gave 11-cis-4-
hydroxyretinol (13b), accompanied by 5 ± 15% isomerization
of the polyene stereochemistry (presumably either by addi-
tion ± elimination of fluoride anion or because of the basicity
of the reagent). However, this was minimized when the
reaction was performed at 08C. As shown in Scheme 5, semi-
In conclusion, an efficient and general synthesis of 11-cis-
retinoids has been achieved by the activated-zinc reduction of
11-yne-retinoid precursors. The mild and selective nature of
this reduction system should allow the synthesis of a variety of
11-cis-retinoids. The production of [3H-15]-11-cis-3-diazo-4-
oxo-retinal (1) from the 4-oxo-analogue 14b, together with
photoaffinity results, will be reported in due course.
Experimental Section
All purchased chemicals were obtained from Aldrich. The solvents used in
the reactions were freshly distilled to dryness and used under an argon
atmosphere. 1H NMR spectra were obtained on a Bruker DMX500
instrument and the residual protic solvent (CDCl3 or C6D6) was used as
internal reference. 13C NMR was recorded at 75 MHz on a Bruker
DMX300 instrument. Low-resolution and high-resolution FAB mass
spectra were measured on a JEOL
JMS-DX303 HF mass spectrometer
with a glycerol matrix and Xe ionizing
11
CH2OTBS
Zn(Cu/Ag)
gas. Flash column chromatography
was performed with ICN silica gel
MeOH/H2O
(32 ± 63 mesh). The reactions of com-
pounds with more than 3 conjugated
double bonds were perfomed in the
dark room with minimal red lighting
(photographic safety lamps). 11-cis-
OH
CH2OTBS
12 (93%)
100% 11-cis-stereochemistry
OH
10b
Scheme 4. Semi-hydrogenation of the 11-yne precursor 10b over activated Zn.
Retinoids are unstable compounds and must be stored in absolute darkness.
They isomerize easily in the presence of trace acids. We have found that
they can be stored very well as frozen solutions in benzene at 788C.
hydrogenation of 11b (obtained by deprotection of 10b) with
activated Zn also occurred efficiently to produce 13b, mainly
as the 11-cis isomer (>95%). Double oxidation of 11-cis-4-
hydroxyretinol (13b) with manganese dioxide[32] provided 11-
cis-4-oxo-retinal (14b).
Compound 7b: Dimethyl (3-trimethylsilyl-2-propynyl)phosphonate[25]
(2.3 g, 10.5 mmol) in anhydrous THF (50 mL) at 08C under argon was
treated with nBuLi (10.5 mmol) to give a red solution. The ice-bath was
removed and the reaction mixture was stirred at room temperature for
15 min, after which time 6b[24] (1.7 g, 5.28 mmol) in anhydrous THF (5 mL)
was added. The mixture was stirred for an additional 3 h, and was then
quenched with aqueous NH4Cl and extracted with Et2O (2 Â ). The
combined organic phases were washed with saturated NaCl and dried over
anhydrous Na2SO4. The product was purified by column chromatography
Synthesis of 11-cis-retinal (14a), the natural chromophore,
was accomplished similarly from the b-ionone (6a) via the 11-
yne retinoid 11a (Scheme 3). Efficient reduction of the 11-yne
gave Z:E selectivity of 13:1 at C11 (Scheme 5),[33] and was
followed by oxidation of 11-cis-retinol with tetrapropylam-
monium perruthenate (TPAP)/4-methylmorpholine N-oxide
(NMO)[34] to form the 11-cis-retinal (14a) in quantitative
yield. (The same reaction with manganese dioxide resulted in
lower yield.) Attempts to reduce 10a were futile and the
starting material was recovered. Since the low solubility of
10a could be the cause of its lack of reactivity, the reduction
was carried out in various solvent systems such as THF/water,
DMF/water, 2-propanol/THF/water, and tert-butyl alcohol/
water, but none was successful. On the other hand, the 11-yne-
1
(hexanes/EtOAc, 4:1) to yield 7b (2.14 g, 97%; 5:1 E:Z at C9). H NMR
(500 MHz, CDCl3): d ˆ 0.21 (s, 9H), 0.64 (dd, 6H, J ˆ 7.9, 15.9 Hz), 0.98 (t,
9H, J ˆ 7.9 Hz), 1.00 (s, 3H), 1.02 (s, 3H), 1.38 (m, 1H), 1.64 (m, 2H), 1.72
(s, 3H), 1.82 (m, 1H), 2.05 (s, 3H), 4.04 (t, 1H, J ˆ 5.5 Hz), 5.44 (s, 1H), 6.09
(d, 1H, J ˆ 16.1 Hz), 6.21 (d, 1H, J ˆ 16.1 Hz). Compound 7b was not
characterized further and was used directly in the following reaction.
Compound 8b: Acetylene 7b (1.7 g, 4.1 mmol) in solution in THF (20 mL)
was treated with nBu4NF (16.4 mL, 1M in THF, 16.35 mmol) and then
stirred at room temperature for 2 h. The mixture was quenched with
aqueous NH4Cl and extracted with Et2O (2 Â ). The combined organic
phases were washed with saturated NaCl and dried over anhydrous
Na2SO4. The product was purified by
column chromatography (hexanes/
11
11
EtOAc, 3:1) to yield 8b (929 mg,
Zn(Cu/Ag)
98%). 1H NMR (500 MHz, CDCl3):
d ˆ 1.00 (s, 3H), 1.03 (s, 3H), 1.43 (m,
1H), 1.63 (m, 1H), 1.70 (m, 1H), 1.74
[Ox]
11a, R=H
11b, R=OH
iPrOH/H2O
CH2OH
R
CHO
R
13a, R=H (85%)
13b, R=OH (70%)
14a, R=H (quant.)
14b, R=O (75%)
(s, 3H), 1.90 (m, 1H), 2.07 (s, 3H), 3.30
(d, 1H, J ˆ 2.3 Hz), 4.00 (t, 1H, J ˆ
4.6 Hz), 5.43 (s, 1H), 6.11 (d, 1H, J ˆ
16.1 Hz), 6.23 (d, 1H, J ˆ 16.1 Hz);
Scheme 5. Synthesis of 11-cis-retinoids. Oxidation of 13a !14a was accomplished with TPAP/NMO, whereas
oxidation of 13b !14b used MnO2.
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11-cis-Retinoids Synthesis
1172±1175
13C NMR (75 MHz, CDCl3): d ˆ 15.0, 18.5, 27.4, 28.4, 29.0, 34.4, 34.7, 70.1,
82.1, 83.9, 108.3, 129.3, 130.4, 136.1, 141.3, 148.8; C16H22O: calcd 230.1671;
found 230.1678 (HRMS).
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Ed. Engl. 1990, 29, 461 ± 480.
[4] K. Nakanishi, H. Zhang, K. A. Lerro, S. Takekuma, T. Yamamoto,
T. H. Lien, L. Sastry, D. J. Baek, C. Moquin-Pattey, M. F. Boehm, F.
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Gawinowicz, K. Nakanishi, J. Am. Chem. Soc. 1994, 116, 10165 ±
10173.
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15769.
[7] D. L. Farrens, C. Altenbach, K. Yang, W. L. Hubbell, H. G. Khorana,
Science 1996, 274, 768 ± 770.
[8] S. P. Sheikh, T. A. Zvyaga, O. Lichtarge, T. P. Sakmar, H. R. Bourne,
Nature 1996, 383, 347 ± 350.
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[10] A. Wada, Y. Tanaka, N. Fujioka, M. Ito, Bioorg. Med. Chem. Lett.
1996, 6, 2049 ± 2052.
[11] M. B. Sporn, A. B. Roberts, D. S. Goodman, The Retinoids: Biology,
Chemistry, and Medicine, Raven, New York, 1994.
[12] A. Hosoda, T. Taguchi, Y. Kobayashi, Tetrahedron Lett. 1987, 28, 65 ±
68.
Compound 10b: Vinyl iodide 9[26] (268 mg, 0.86 mmol) was dissolved in
iPrNH2 (3 mL), and tetrakis(triphenylphosphine)palladium (8.2 mg,
0.007 mmol) was then added. The solution was stirred at room temperature
for 5 min, following which CuI (1.4 mg, 0.007 mmol) was added. After
5 min, acetylene 8b (165 mg, 0.70 mmol) was introduced, and the mixture
was stirred at room temperature for 3.5 h. The reaction was then quenched
by the removal of solvent under reduced pressure. The residue was
dissolved in Et2O, extracted with aqueous NH4Cl, washed with saturated
NaCl, and dried over anhydrous Na2SO4. The crude product was purified
by column chromatography (EtOAc/hexanes, 1:19) to yield 10b (271 mg,
91%). 1H NMR (500 MHz, CDCl3): d ˆ 0.08 (s, 6H), 0.91(s, 9H), 1.00 (s,
3H), 1.03 (s, 3H), 1.43 (m, 1H), 1.63 (m, 1H), 1.69 (m, 1H), 1.81 (s, 3H),
1.84 (s, 3H), 1.90 (m, 1H), 2.05 (s, 3H), 4.00 (dd, 1H, J ˆ 4.8, 5.0 Hz), 4.28
(d, 2H, J ˆ 6.2 Hz), 5.55 (s, 1H), 5.93 (t, 1H, J ˆ 6.2 Hz), 6.17 (d, 1H, J ˆ
16.1 Hz), 6.20 (d, 1H, J ˆ 16.1 Hz); 13C NMR (75 MHz, CDCl3): d ˆ 5.2,
15.0, 17.7, 18.3, 18.6, 25.9, 27.5, 28.5, 29.0, 34.5, 34.7, 42.8, 60.1, 69.9, 85.8,
99.2, 109.6, 119.2, 128.3, 130.4, 136.2, 136.5, 141.2, 146.5; C26H42O2Si: calcd
414.2954; found 414.2954 (HRMS).
[13] D. Mead, A. E. Asato, M. Denny, R. S. H. Liu, Y. Hanzawa, T.
Taguchi, A. Yamada, N. Kobayashi, A. Hosoda, Y. Kobayashi,
Tetrahedron Lett. 1987, 28, 259 ± 262.
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Chem. Soc. 1983, 105, 1626 ± 1631.
[16] D. Koch, W. Gärtner, Photochem. Photobiol. 1997, 65, 181 ± 186.
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burg, R. A. Mathies, Biochemistry 1996, 35, 16230 ± 16240.
[18] R. S. H. Liu, A. E. Asato, M. Denny, D. Mead, J. Am. Chem. Soc.
1984, 106, 8298 ± 8300.
[19] J. Uenishi, R. Kawahama, O. Yonemitsu, A. Wada, M. Ito, Angew.
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[20] B. Borhan, R. Kunz, A. Y. Wang, K. Nakanishi, N. Bojkova, K.
Yoshihara, J. Am. Chem. Soc. 1997, 119, 5758 ± 5759.
[21] K. C. Nicolaou, M. W. Härter, J. L. Gunzner, A. Nadin, Liebigs Ann./
Recueil 1997, 1283 ± 1301.
Compound 12: Activated Zn dust was prepared as described by Boland
et al.[30] Argon was bubbled through a suspension of Zn dust (10 g) in
distilled H2O (60 mL) for 15 min. Cu(OAc)2 (1 g) was added and the flask
was sealed immediately. The mixture was stirred vigorously for 15 min.
AgNO3 (1 g) was then added (exothermic reaction), and the solution was
stirred for 30 min. The activated Zn was then filtered as it was washed
successively with H2O, MeOH, acetone, and Et2O. The moist activated Zn
was transferred immediately to a flask of the reaction solvents (H2O,
20 mL; MeOH, 20 mL). Compound 10b (170 mg, 0.41 mmol) was added to
this mixture, which was then stirred at room temperature in the dark for
21 h. The Zn dust was filtered through Celite with Et2O and H2O. The
organic phases were separated, washed with saturated NaCl, and dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure to
1
yield 12 (159 mg, 93%) with 100% stereoselectivity. H NMR (500 MHz,
CDCl3): d ˆ 0.08 (s, 6H), 0.91 (s, 9H), 1.01 (s, 3H), 1.04 (s, 3H), 1.43 (m,
1H), 1.64 (m, 1H), 1.70 (m, 1H), 1.83 (s, 3H), 1.84 (s, 3H), 1.88 (m, 1H),
1.92 (s, 3H), 4.00 (t, 1H, J ˆ 4.6 Hz), 4.32 (d, 2H, J ˆ 6.3 Hz), 5.63 (t, 1H,
J ˆ 6.2 Hz), 5.89 (d, 1H, J ˆ 11.7 Hz), 6.13 (s, 2H), 6.32 (t, 1H, J ˆ 11.9 Hz),
6.57 (d, 1H, J ˆ 12.0 Hz); 13C NMR (75 MHz, CDCl3): d ˆ 5.1, 12.2, 17.2,
18.3, 18.6, 26.0, 27.5, 28.5, 29.1, 34.5, 34.8, 60.4, 70.2, 124.4, 125.7, 127.4, 129.5,
132.0, 133.5, 133.9, 136.3, 139.1, 142.0; C26H44O2Si: calcd 416.3110; found
416.3111 (HRMS).
[22] W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405 ± 4408.
[23] G. Stork, K. Zhao, Tetrahedron Lett. 1989, 30, 2173 ± 2174.
[24] H. B. Henbest, J. Chem. Soc. 1951, 1074 ± 1078.
[25] A. W. Gibson, G. R. Humphrey, D. J. Kennedy, S. H. B. Wright,
Synthesis 1991, 414 ± 416.
Compound 13a: Activated Zn dust was prepared as described above. The
activated Zn was transferred immediately into the reaction solvent of water
(2 mL) and iPrOH (2 mL). A solution of enyne 11a (14 mg, 0.05 mmol) in
iPrOH (2 mL) was added to this activated Zn suspension, and the mixture
was stirred at room temperature for 21 h. The Zn was then filtered through
Celite with Et2O and H2O. The organic phases were separated, washed with
saturated NaCl, and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure to yield 13a (12 mg, 85%; 13:1 Z:E at
C11). All spectroscopic measurements were consistent with reported
data.[15] 1H NMR (500 MHz, C6D6): d ˆ 1.09 (s, 6H), 1.46 (m, 2H), 1.57 (m,
2H), 1.66 (s, 3H), 1.73 (s, 3H), 1.86 (s, 3H), 1.92 (m, 2H), 3.94 (d, 1H, J ˆ
6.6 Hz), 5.69 (t, 1H, J ˆ 6.6 Hz), 5.87 (d, 1H, J ˆ 11.7 Hz), 6.29 (d, 1H, J ˆ
16.3 Hz), 6.35 (d, 1H, 16.3 Hz), 6.38 (t, 1H, J ˆ 11.9 Hz), 6.83 (d, 1H, J ˆ
12.1 Hz).
[26] The vinyl iodide 9 was obtained by reduction of 2-butyne-1-ol
mediated by titanocene dichloride (ref. [35]). Subsequent quenching
with iodine was followed by protection of the primary alcohol with
tributyldimethylsilyl chloride.
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639 ± 666.
[33] The reduction of 11a and 11b was much more sensitive to the quality
of the catalyst. Slight contamination such as trace acid led to isolation
of mostly trans-reduced product. To obtain good stereoselectivity, the
solvents used for preparation and washing of the zinc catalyst were of
highest purity. The catalyst was not allowed to dry in air during
preparation, and oxygen was excluded during the reduction. Interest-
ingly, the reduction of 10b is not as sensitive and is much more
forgiving, as it occurs with very high stereoselectivity.
[34] Y. S. Chauhan, R. A. S. Chandraratna, D. A. Miller, R. W. Kondrat, W.
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Acknowledgments
These studies were supported by NIH grant GM 34509 (KN), the
Ministerio de Educacion y Cultura of Spain (MLS), and an NSF-under-
graduate fellowship (JMU). The authors thank Nahada Allison for help
during her summer NSF-undergraduate fellowship.
Â
[1] K. Nakanishi, R. Crouch, Isr. J. Chem. 1995, 35, 253 ± 272.
[2] R. R. Rando, Chem. Biol. 1996, 3, 255 ± 262.
Received: July 10, 1998 [F1253]
Chem. Eur. J. 1999, 5, No. 4
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