Enantioselective synthesis of all of the stereoisomers of (E)-13,14-dihydroxyretinol (DHR)

Article abstract of DOI:10.1016/j.tetasy.2004.01.019

The Stille cross-coupling of trienyliodide 4 and E-alkenylstannanes 5, derived from enantioenriched diols obtained by a Sharpless asymmetric dihydroxylation (SAD), provides a convergent route to all stereoisomers of 13,14-dihydroxyretinol (DHR), an immuno

Full text of DOI:10.1016/j.tetasy.2004.01.019

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 839–846
Enantioselective synthesis of all of the stereoisomers of
(E)-13,14-dihydroxyretinol (DHR)
Susana Alvarez, Rosana Alvarez and Angel R. de Lera*
Departamento de Quꢀımica Orgꢀanica, Universidade de Vigo, 36200 Vigo, Spain
Received 3 December 2003; accepted 14 January 2004
Abstract—The Stille cross-coupling of trienyliodide 4 and E-alkenylstannanes 5, derived from enantioenriched diols obtained by a
Sharpless asymmetric dihydroxylation (SAD), provides a convergent route to all stereoisomers of 13,14-dihydroxyretinol (DHR), an
immunomodulator derived from vitamin A.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
synthetic pathways that cause structural changes to
retinolꢀs functional group (oxidation level) or side-chain
(double bond geometry, positional shifts involving
allylic hydrogens and olefin oxidation). (14R)-14-Hy-
droxy-4,14-retroretinol 2 (14-HRR)4 and dihydroxyret-
inol 3 (DHR),5 the only vitamin A metabolites with
additional hydroxyl groups on the side-chain, stimulate
B-cell proliferation and T-cell activation. In vitro studies
Vitamin A (retinol 1, Fig. 1)1 serves as a prohormone in
cells and organs, generating a diverse range of meta-
bolites that regulate fundamental physiological pro-
cesses including vision,2 cell differentiation, cell
proliferation and apoptosis,3 development and immu-
nity. These intracellular mediators arise through bio-
14
4
9
OH
13
OH
OH
1 retinol (vitamin A)
2 (14R)-14-hydroxy-4,14-retroretinol
Me OH
HO Me
OH
OH
OH
OH
3 (13S,14R)-13,14-dihydroxyretinol
3 (13R,14R)-13,14-dihydroxyretinol
HO Me
Me OH
OH
OH
OH
OH
3 (13S,14S)-13,14-dihydroxyretinol
3 (13R,14S)-13,14-dihydroxyretinol
Figure 1. Retinol and its side-chain hydroxylated metabolites.
* Corresponding author. Tel.: +34-986-812316; fax: +34-986-812556; e-mail: qolera@uvigo.es
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.019

840
S. Alvarez et al. / Tetrahedron: Asymmetry 15 (2004) 839–846
3
using the 5/2 lymphoblastic cell line fed with H-retinol
proved the biogenetic relationship between vitamin A 1
and DHR 3.6 Interestingly, attempts to correlate bio-
synthetically DHR 3 and 14-HRR 2 in the same cell line
proved unsuccessful, suggesting that both metabolites
are independent end-points of retinol metabolism. An
elusive 13,14-epoxyretinol might be the common pre-
cursor of both 2 and 3.6;7a
ation (SAD)11 of precursors 7 to enforce enantiofacial
differentiation. The diversity-oriented combination of
protected enynol isomers (Z)-7 and (E)-7 with pseudo-
enantiomeric AD-mix a and AD-mix b reagents to
obtain each of the four stereoisomers of target 3 is
reported herein.
Only one report on the non-stereoselective preparation
of (13R,14R)-3 and (13S,14R)-3, which uses D-glycer-
2. Results and discussion
aldehyde acetonide as a chiral pool starting material,
has so far been published.5;7 On the other hand, Corey
reported direct dihydroxylation of vitamin A acetate en
route to metabolite 2. This method afforded a 10:1 ratio
of the primary to secondary acetate of (13S,14S)-3, due
to scrambling by acetyl O,O-migration. The formation
of the mixture was, however, inconsequential since the
syntheses of 2 was completed by acetylation to give the
14,15-diacetate, dehydration, and saponification.7c
Benzyl ethers 7a and p-methoxyphenyl ethers 7b
(derived from (E)- and (Z)-enynols by benzylation or
Mitsunobu-type ether formation, respectively)12 were
reported by Tietze to afford the highest eeꢀs in the
dihydroxylation reaction using AD-mix a. Hence, these
derivatives were selected to carry out our study. How-
ever, having obtained the desired skeleton, the protect-
ing groups13 proved to be quite robust and the more
forcing conditions required, were incompatible with the
stability of the final polyenic product. Among the base-
labile protecting groups13 the p-methoxybenzoates 7c
(prepared in high yields by stirring (E)- and (Z)-enynols
with p-anisoyl chloride and Et3N in CH2Cl2 at room
temperature),14 were selected because of their superior
performance in SAD, relative to alcohols or ethers.15
As part of our research concerned with the chemistry
and biology of retinoids,8 we required access to all DHR
stereoisomers for immunomodulation studies. In our
attempts to synthesize these target molecules, we set out
to overcome some of the limitations of the existing
route.5 We envisioned that the preparation of 3 (Fig. 2)
could be achieved through the combination of two
powerful synthetic processes: (i) a metal-catalyzed cross-
coupling9 (a Stille reaction)10 between stereodefined
building-blocks 4 and 5 to control polyene geometry and
(ii) the Sharpless enantioselective catalytic dihydroxyl-
The yields and enantiomeric excesses for the dihydr-
oxylation of enynols 7 are shown in Table 1. Analogues
7c were first reacted with commercial AD-mix a and
AD-mix b under standard reaction conditions (t-BuOH/
H2O, 4 ꢁC), but significant amounts of starting material
(up to 50%) were recovered after stirring for 48 h. We
did however find that mixing the individual components
of the SAD cocktail prior to running the reaction
ensured completion of the dihydroxylation in the same
period of time (Scheme 1).16 According to the work of
Sharpless17 (Z)-trisubstituted enynes lead generally to
lower eeꢀs relative to the (E)-isomers. Strikingly,
p-methoxybenzoate (Z-7c afforded the lowest ee
(56%) when treated with the components of AD-mix a
(entry 1).18
I
HO Me
4
+
OH
OH
Me
OH
HO
3
Bu3Sn
OR
5
Two procedures for organostannane formation starting
from alkynes, namely stannnylcupration/protonolysis19
and palladium-catalyzed hydrostannation,20 were then
surveyed for the preparation of the alkenylstannanes
(Scheme 2). The latter method [(n-Bu3SnH,
PdCl2(PPh3)2, THF, 23 ꢁC]19 afforded alkenylstannanes
Me
6 OH
OR
HO
a, R = Bn
H
b, R = PMP
c, R = p-MeOBz
OR
(Z)-7 or (E)-7
Figure 2.
Table 1. SAD of protected enynols 7c (Scheme 1)
Entry
Enyne
AD-mixa
Yield (%)b
Ee (%)c
Ee (%)d
Diol 6e
1
2
3
4
(Z)-7c
(Z)-7c
(E)-7c
(E)-7c
a
b
a
b
82
78
74
75
56
82
86
89
87
95
96
94
(2S,3R)-6
(2R,3S)-6
(2S,3S)-6
(2R,3R)-6
a Components of the AD-mix reagent in t-BuOH/H2O, 4 ꢁC, 48 h.
b Isolated product; average of three runs.
c The ee (%) was determined by chiral HPLC (Daicel Chiralcel OD-H, 15 cm · 0.46 cm) on the crude, unpurified reaction samples; average of three
runs.
d The ee (%) was determined by chiral HPLC after purification by chromatography and crystallization (hexane/CH2Cl2).
e Absolute configuration of the major enantiomer assigned tentatively by application of the Sharpless mnemonic.

S. Alvarez et al. / Tetrahedron: Asymmetry 15 (2004) 839–846
841
AD-mix β
t-BuOH:H2O, 4 ºC
OR
AD-mix α
t-BuOH:H2O, 4 ºC
(Z)-7c, R = p-MeOBz
Me
HO
OH
OH
Me
OR
OR
OH
(2S,3R)-6
(2R,3S)-6
OH
Me
Me
HO
OR
OR
OH
OH
(2S,3S)-6
(2R,3R)-6
AD-mix α
t-BuOH:H2O, 4 ºC
AD-mix β
t-BuOH:H2O, 4 ºC
OR
(E)-7c, R = p-MeOBz
Scheme 1.
8
OHC
I
PPh3Br
nBuLi, THF
9
-78 ºC, 60%
I
HO Me
4
+
Table 2
OR
OH
Me
OH
HO
Bu3Sn
OR
10, R = p-MeOBz
LiOH
THF/H2O
5
3, R = H
5, R = p-MeOBz
Me
OH
HO
Table 2
OR
n-Bu3SnH, PdCl2(PPh3)2
6, R = p-MeOBz
THF, 23 ºC
Scheme 2.
5 from the corresponding monoprotected triols in
slightly higher yields (Table 2). A series of alkenyl-
stannanes were subsequently coupled to trienyliodide 4.
Compound 4, generally obtained by zirconium-assisted
carboalumination–iodination starting from the dienyne
derived from b-ionone, is a common building block in
Table 2. Yield (%) and enantiomeric excess (ee%) of the synthetic sequence starting from dihydroxylated enynols 6 (Scheme 2)
Configuration
5 (%)a
10 (%)b
Configuration
Ee 10 (%)c
3 (%)d
(2S,3R)-6
(2R,3R)-6
(2R,3S)-6
(2S,3S)-6
60
50
80
61
73
75
77
75
(13R,14S)-10
(13R,14R)-10
(13S,14R)-10
(13S,14S)-10
88
94
96
94
85
95
99
95
a n-Bu3SnH, PdCl2(PPh3)2, THF, 25 ꢁC.
b (PhCN)2PdCl2, i-Pr2NEt, THF/DMF, 50 ꢁC.
c Determined by chiral HPLC (Daicel Chiralcel OD-H, 15 cm · 0.46 cm).
d LiOH, THF/H2O, 25 ꢁC.

842
S. Alvarez et al. / Tetrahedron: Asymmetry 15 (2004) 839–846
retinoid synthesis.21 An alternative preparation that
avoids the use of pyrophoric Me3Al is the Wittig reac-
tion between known aldehyde 822 and the phosphonium
salt 9,23 a process that furnishes 4 in comparable yield
(Scheme 2).
spectra were recorded on a HP5989A spectrophoto-
meter using MeOH as solvent. Absorption maxima are
reported in nm. Low-resolution mass spectra were taken
on a HP59970 instrument operating at 70 eV. High-
resolution mass spectra were taken on a VG Autospec
M instrument.
The selection of Stille reaction conditions was guided by
our previous experience in the synthesis of vitamin A
and related polyenes.8 The use of (PhCN)2PdCl2 in the
4.2. Preparation of p-methoxybenzoates
€
presence of Hunigꢀs base and a mixture of DMF/THF at
4.2.1. General procedure
50 ꢁC24 offered slightly better yields than Farinaꢀs con-
ditions (Pd2dba3, AsPh3, NMP).25 The yields for the
purified polyenes are given in Table 2 along with the
enantiomeric purity of 10, as determined by chiral
HPLC. Lastly, the stereoisomeric p-methoxybenzoates
10 were smoothly hydrolyzed by treatment with LiOH
in THF/H2O to provide triols 3 in high yields (Table 2).
The enantiomeric excess of the final product 3 was
inferred to be equal to that determined for the precursor
4.2.1.1. (E)-3-Methylpent-2-en-4-in-1-yl p-methoxy-
benzoate (E)-7c. A solution of p-methoxybenzoyl chlo-
ride (10.64 g, 62.34 mmol) in CH2Cl2 (100 mL) was
added to a solution of (E)-3-methylpent-2-en-4-in-1-ol
(2.0 g, 20.82 mmol) and Et3N (28.9 mL, 208.2 mmol) in
CH2Cl2 (100 mL). The reaction mixture was stirred for
1 h at 25 ꢁC and the solvent was evaporated. The residue
was purified by column chromatography (silica gel,
90:10 hexane/EtOAc) to afford 6.32 g (95%) of a white
solid (mp 44–46 ꢁC/hexane/EtOAc). 1H NMR
(400.13 MHz, CDCl3): d 7.98 (d, J ¼ 8:9 Hz, 2H), 6.90
(d, J ¼ 8:9 Hz, 2H), 6.12 (t, J ¼ 6:9 Hz, 1H), 4.85 (d,
J ¼ 6:9 Hz, 2H), 3.85 (s, 3H), 2.87 (s, 1H), 1.92 (s, 3H)
ppm. 13C NMR (100.68 MHz, CDCl3): d 166.1 (s), 163.4
(s), 132.2 (d), 131.7 (d, 2·), 122.4 (s), 122.0 (s), 113.6 (d,
2·), 85.5 (s), 75.9 (d), 60.6 (t), 55.4 (q), 17.6 (q) ppm. FT-
IR (NaCl): t 3291 (m, CBC), 2924 (m, C–H), 1711 (s,
C@O), 1606 (s) cmꢀ1. MS (FABþ): m=z (%) 232 (Mþ+2,
8), 231 (71), 230 (Mþ+1, 86), 164 (8), 154 (22), 153 (100).
HRMS (FABþ): calcd for C14H15O3 (Mþ+1), 231.1021;
found, 231.1023.
p-methoxybenzoate 10, since
decomposition on the chiral HPLC column.
3 suffered extensive
3. Conclusion
In summary, SAD of protected enynols, palladium-
catalyzed hydrostannation and Stille cross-coupling
have been optimized in a synthetic sequence that afford
every stereoisomer of DHR 3 with high enantiomeric
purity after deprotection. Notably, the power of the
Stille reaction for C–C bond formation in the presence
of multiple free hydroxy groups should be highlighted.26
4.2.1.2. (Z)-3-Methylpent-2-en-4-in-1-yl p-methoxy-
benzoate (Z)-7c. Following the general procedure, the
title compound was obtained from (Z)-3-methylpent-2-
en-4-in-1-ol in 89% as a white solid (mp 40–42 ꢁC/hex-
ane/EtOAc) after purification by column chromatogra-
phy (silica gel, 90:10 hexane/EtOAc). 1H NMR
(400.13 MHz, CDCl3): d 7.97 (d, J ¼ 8:7 Hz, 2H), 6.87
(d, J ¼ 8:7 Hz, 2H), 5.96 (t, J ¼ 6:7 Hz, 1H), 4.96 (d,
J ¼ 6:7 Hz, 2H), 3.83 (s, 3H), 3.20 (s, 1H), 1.91 (s,
3H) ppm. 13C NMR (100.68 MHz, CDCl3): d 166.1 (s),
163.3 (s), 132.5 (d), 131.6 (d, 2·), 122.5 (s), 122.0 (s),
113.6 (d, 2·), 82.9 (s), 81.4 (d), 63.04 (t), 55.4 (q), 21.9
(q) ppm. FT-IR (NaCl): t 3291 (m, CBC), 2927 (m, C–
H), 2361 (m), 1711 (s, C@O) cmꢀ1. MS (FABþ): m=z (%)
232 (Mþ+2, 6), 231 (Mþ+1, 48), 230 (Mþ, 48), 155 (28),
1543 (100). HRMS (FABþ): calcd for C14H15O3
(Mþ+1), 231.1021; found, 231.1025.
4. Experimental
4.1. General
All reactions were performed in an argon atmosphere.
The solvents were dried and distilled under argon.
HPLC grade solvents were used for the HPLC purifi-
cation. 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 Merck silica gel 60 particle size (0.040–
0.063 lm). Optical rotations were recorded on an
1
Autopol IV polarimeter at the sodium D line. H and
13C magnetic resonance spectra (NMR) were recorded
on Bruker AMX 400 [400 MHz (100 MHz for 13C)].
Fourier transform spectrometers and chemical shifts are
expressed in parts per million ðdÞ relative to tetrameth-
ylsilane (TMS, 0 ppm) or chloroform (CHCl3, 7.24 ppm
4.3. Sharpless asymmetric dihydroxylation
4.3.1. General procedure
4.3.1.1. (2S,3R)-2,3-Dihydroxy-3-methylpent-4-yn-1-yl
p-methoxybenzoate (2S,3R)-6. A solution of (Z)-3-
methylpent-2-en-4-in-1-yl p-methoxybenzoate Z-7c
(1.0 g, 4.35 mmol) in t-BuOH/H2O (6 mL, 1:1, v/v) was
added to an emulsion of K3Fe(CN)6 (4.29 g,
1
for H and 77.00 ppm for 13C) as an internal reference.
13C multiplicities (s, singlet; d, doublet; t, triplet; q,
quartet) were assigned with the aid of the DEPT pulse
sequence. Infrared spectra (IR) were obtained on a
MIDAC Prospect Model FT-IR spectrophotometer.
Absorptions are recorded in wavenumbers (cmꢀ1). UV
13.05 mmol),
K2CO3
(1.80 g,
13.05 mmol),
(DHQ)2PHAL (0.033 g, 0.044 mmol), K2OsO4 Æ 2H2O
(0.008 g, 0.022 mmol) and MeSO2NH2 (0.45 g,

S. Alvarez et al. / Tetrahedron: Asymmetry 15 (2004) 839–846
843
25
the crude; 94% ee after purification) ½aꢁ ¼ þ29:9 (c
4.78 mmol) in tBuOH/H2O (6 mL, 1:1, v/v). The mixture
was stirred at 5 ꢁC, for 48 h, Na2SO3 (0.34 g) was added
and the stirring maintained at 25 ꢁC for 1 h. The mixture
was extracted with CH2Cl2 (3·) and the organic layers
washed with 1 M NaOH (3·), dried and concentrated.
The residue was purified by column chromatography
(silica gel, 65:35 hexane/EtOAc) and recrystallization to
afford 0.945 g (82%) of a white solid (mp 80–82 ꢁC/
CH2Cl2/hexane) (56% ee on the crude; 87% ee after
D
1.27, MeOH).
4.4. Palladium-catalyzed hydrostannation
4.4.1. General procedure
4.4.1.1. (2S,3R,4E)-2,3-Dihydroxy-3-methyl-5-(tri-n-
butylstannyl)-pent-4-yn-1-yl-p-methoxybenzoate (2S,3R)-
5. Bu3SnH (0.4 mL, 1.52 mmol) was added to a solution
of (2S,3R)-2,3-dihydroxy-3-methylpent-4-yn-1-yl p-
methoxybenzoate (2S, 3R)-6 (0.2 g, 0.76 mmol) and
PdCl2(PPh3)2 (0.006 g, 0.015 mmol) in THF (20 mL).
The reaction was stirred for 10 min and the solvent
evaporated. The residue was purified by column chro-
matography (silica gel, 67:30:3 hexane/EtOAc/Et3N) to
1
crystallization). H NMR (400.13 MHz, CDCl3): d 7.99
(d, J ¼ 7:5 Hz, 2H), 6.91 (d, J ¼ 7:5 Hz, 2H), 4.59 (dd,
J ¼ 12:1, 3.1 Hz, 1H), 4.52 (dd, J ¼ 12:1, 7.4 Hz, 1H),
3.86 (m, 4H), 3.01 (s, 1H), 2.95 (d, J ¼ 6:3 Hz, 1H), 2.51
(s, 1H), 1.57 (s, 3H) ppm. 13C NMR (100.13 MHz,
CDCl3): d 167.1 (s), 163.9 (s), 132.0 (d, 2·), 122.2 (s),
113.9 (d, 2·), 84.4 (s), 76.4 (d), 74.0 (s), 69.4 (d), 66.3 (t),
55.7 (q), 26.2 (q) ppm. FT-IR (NaCl): t 3418 (w, –OH),
2923 (m, CH@), 1708 (s, C@O), 1258 (s) cmꢀ1. MS
(FABþ): m=z (%) 266 (Mþ+2, 14), 265 (Mþ+1, 100), 247
(16), 195 (34), 154 (13). HRMS (FABþ): calcd for
C14H17O5 (Mþ+1), 265.1076; found, 265.1079. Anal.
1
afford 0.204 g (60%) of an oil. H NMR (400.13 MHz,
CDCl3): d 7.95 (d, J ¼ 8:8 Hz, 2H), 6.87 (d, J ¼ 8:8 Hz,
2H), 6.28 (d, J ¼ 19:5 Hz, 2JSn–H ¼ 34:5 Hz, 1H), 6.04 (d,
3
J ¼ 19:5 Hz, JSn–H ¼ 32:5 Hz, 1H), 4.43 (dd, J ¼ 11:9,
2.8 Hz, 1H), 4.27 (dd, J ¼ 11:9, 7.6 Hz, 1H), 3.8–3.7 (m,
1H), 3.82 (s, 3H), 3.03 (s, 1H), 2.45 (s, 1H), 1.5–1.4 (m,
6H), 1.35 (s, 3H), 1.2–1.0 (m, 12H), 1.0–0.7 (m,
Calcd for C14H17: C, 63.61; H, 6.14. Found C, 63.64; H,
25
D
6.25. ½aꢁ ¼ ꢀ25:6 (c 0.42, MeOH).
9H) ppm. 13C NMR (100 MHz, CDCl3): d 165.7 (s),
1
162.5 (s), 148.7 (d), 130.7 (d, 2·), 126.4 (d, JSn–C
¼
2
174:2 Hz), 121.2 (s), 112.6 (d, 2·), 74.8 (d, JSn–C
26:5 Hz), 65.4 (t), 59.4 (s), 54.4 (q), 28.1 (t), 26.2 (t,
¼
4.3.1.2. (2R,3S)-2,3-Dihydroxy-3-methylpent-4-yn-1-yl
p-methoxybenzoate (2R,3S)-6. Following the general
procedure for the SAD (AD-mix b, method B), the title
compound was obtained in 78% yield as a white solid
after purification by column chromatography (silica gel,
1
2JSn–C ¼ 27.3 Hz), 23.9 (q), 12.7 (q), 8.4 (t, JSn–C
¼
164:63 Hz) ppm. MS (FABþ): m=z (%) 555 (Mþ+1, 9),
539 (24), 501 (21), 500 (25), 499 (100), 498 (42), 497 (76),
494 (41), 385 (32), 383 (24), 289 (20), 153 (33). HRMS
65:35 hexane/EtOAc) and recrystallization (82% ee on
(FABþ): calcd for C26H45O5116Sn (M+Hþ), 555.2283;
25
D
25
D
the crude; 95% ee after purification). ½aꢁ ¼ þ32:9 (c
found, 555.2289. ½aꢁ ¼ ꢀ14:8 (c 0.027, MeOH).
0.37, MeOH).
4.4.1.2. (2R,3S,4E)-2,3-Dihydroxy-3-methyl-5-(tri-n-
butylstannyl)-pent-4-yn-1-yl-p-methoxybenzoate (2R,3S)-
5. Following the general procedure for hydrostannation
with palladium, the title compound was obtained in 80%
yield as a yellow oil after purification by column chro-
4.3.1.3. (2S,3S)-2,3-Dihydroxy-3-methylpent-4-yn-1-yl
p-methoxybenzoate (2S,3S)-6. Following the general
procedure for the SAD (AD-mix a, method B), the title
compound was obtained in 74% yield as a white solid
after purification by column chromatography (silica gel,
65:35 hexane/EtOAc) and recrystallization (86% ee on
the crude; 96% ee after purification) (mp 80–82 ꢁC/
CH2Cl2/hexane). 1H NMR (400.13 MHz, CDCl3): d 7.99
(d, J ¼ 6:7 Hz, 2H), 6.90 (d, J ¼ 6:7 Hz, 2H), 4.55 (dd,
J ¼ 2:9, 2.2 Hz, 1H), 4.50 (dd, J ¼ 6:9, 2.5 Hz, 1H), 4.5–
4.4 (m, 2H), 3.86 (s, 3H), 2.87 (s, 2H), 2.47 (s, 1H), 1.56
(d, J ¼ 2:2 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3):
d 167.4 (s), 164.1 (s), 132.4 (d, 2·), 122.4 (s), 114.1 (d,
2·), 85.3 (s), 76.2 (d), 73.9 (s), 69.6 (d), 65.7 (t), 55.9 (q),
25.6 (q) ppm. FT-IR (NaCl): t 3421 (w, OH), 2924 (m,
C–H), 1696 (s), 1606 (f, C@O) cmꢀ1. MS (FABþ): m=z
(%) 265 (Mþ+1, 6), 264 (Mþ, 71), 164 (8), 154 (13), 153
(100). HRMS (FABþ): calcd for C14H17O5 (Mþ+1),
matography (silica gel, 67:30:3 hexane/EtOAc/Et3N).
25
D
½aꢁ ¼ þ20:8 (c 0.24, MeOH).
4.4.1.3. (2S,3S,4E)-2,3-Dihydroxy-3-methyl-5-(tri-n-
butylstannyl)-pent-4-yn-1-yl-p-methoxybenzoate (2S,3S)-
5. Following the general procedure for hydrostannation
with palladium, the title compound was obtained in 61%
yield as a yellow oil after purification by column chro-
matography (silica gel, 67:30:3 hexane/EtOAc/Et3N). 1H
NMR (400.13 MHz, CDCl3): d 7.95 (d, J ¼ 9:1 Hz, 2H),
2
6.87 (d, J ¼ 9:1 Hz, 2H), 6.28 (d, J ¼ 19:5 Hz, JSnH
¼
32:8 Hz, 1H), 6.06 (d, J ¼ 19:5 Hz, 3JSnH ¼ 33:1 Hz, 1H),
4.42 (dd, J ¼ 11:9, 2.8 Hz, 1H), 4.27 (dd, J ¼ 11:9,
7.6 Hz, 1H), 3.8–3.7 (m, 1H), 3.80 (s, 3H), 1.5–1.4 (m,
6H), 1.31 (s, 3H), 1.2–1.1 (m, 12H), 0.9-0.7 (m,
265.1076; found, 265.1066. Anal. Calcd for C14H17: C,
25
D
63.61; H, 6.14. Found C, 63.71; H, 6.13. ½aꢁ ¼ ꢀ28:7 (c
0.74, MeOH).
12H) ppm. 13C NMR (100 MHz, CDCl3): d 167.5 (s),
1
164.2 (s), 151.5 (d), 132.5 (d, 2·), 128.4 (d, JSn–C
¼
4
4.3.1.4. (2R,3R)-2,3-Dihydroxy-3-methylpent-4-yn-1-
yl p-methoxybenzoate (2R,3R)-6. Following the general
procedure for the SAD (AD-mix b, method B) the title
compound was obtained in 75% yield as a white solid
after purification by column chromatography (silica gel,
65:35 hexane/EtOAc) and recrystallization (89% ee on
174:3 Hz), 122.9 (s), 114.4 (d, 2·), 76.2 (d, JSn–C
27:3 Hz), 66.6 (t), 61.2 (s), 56.1 (q), 29.7 (t), 27.9 (t,
¼
1
2JSn–C ¼ 27:3 Hz), 23.7 (q), 14.9 (q), 10.2 (t, JSn–C
¼
164:6 Hz) ppm. MS (FABþ): m=z (%) 555 (Mþ+1, 13),
501 (30), 500 (2), 499 (100), 497 (60), 494 (40), 385 (20),
289 (50), 153 (33). HRMS (FABþ): calcd

844
S. Alvarez et al. / Tetrahedron: Asymmetry 15 (2004) 839–846
for C26H45O5116Sn (M+Hþ), 555.2266; found, 555.2260.
½aꢁ ¼ ꢀ24:9 (c 0.15, MeOH).
4.5.1.2. (13S,14R)-13,14-Dihydroxyretinol p-meth-
oxybenzoate (13S,14R)-10. Following the general pro-
cedure for Stille coupling, the title compound was
obtained (75%) as a solid after purification by column
25
D
chromatography (silica gel, 80:30 hexane/EtOAc) (96%
ee). ½aꢁ ¼ þ27:7 (c 0.018, MeOH).
4.4.1.4. (2R,3R,4E)-2,3-Dihydroxy-3-methyl-5-(tri-n-
butylstannyl)-pent-4-yn-1-yl-p-methoxybenzoate (2R,3R)-
5. Following the general procedure for hydrostannation
with palladium, the title compound was obtained in 50%
yield as a yellow oil after purification by column chro-
25
D
4.5.1.3. (13S,14S)-13,14-Dihydroxyretinol p-methoxy-
benzoate (13S,14S)-10. Following the general procedure
for Stille coupling, the title compound was obtained
(75%) as a solid after purification by column chroma-
matography (silica gel, 67:30:3 hexane/EtOAc/Et3N).
25
D
½aꢁ ¼ þ12:5 (c 0.008, MeOH).
1
tography (silica gel, 70:30 hexane/EtOAc) (94% ee). H
NMR (400.13 MHz, CDCl3): d 7.95 (d, J ¼ 8:9 Hz, 2H),
6.87 (d, J ¼ 9:1 Hz, 2H), 6.72 (dd, J ¼ 15:3, 11.2 Hz,
1H), 6.13 (d, J ¼ 16:0 Hz, 1H), 6.02 (d, J ¼ 15:8 Hz,
1H), 5.99 (d, J ¼ 10:0 Hz, 1H), 5.75 (d, J ¼ 15:3 Hz,
1H), 4.46 (dd, J ¼ 11:9, 3.1 Hz, 1H), 4.29 (dd, J ¼ 11:9,
7.6 Hz, 1H), 3.82 (s, 3H), 3.9–3.8 (m, 1H), 2.74 (s, 2H),
2.0–1.9 (m, 2H), 1.91 (s, 3H), 1.67 (s, 3H), 1.6–1.5 (m,
2H), 1.54 (s, 3H), 1.5–1.3 (m, 2H), 0.98 (m, 6H) ppm.
13C NMR (100.68 MHz, CDCl3): d 166.8 (s), 163.6 (s),
137.8 (s), 137.4 (d), 137.1 (s), 136.5 (d), 131.8 (d, 2·),
129.2 (s), 126.7 (d), 127.2 (d), 126.2 (d), 122.1 (s), 113.7
(d, 2·), 76.3 (s), 74.4 (d), 66.3 (t), 55.4 (q), 39.6 (t), 34.2
(s), 32.9 (t), 28.9 (q), 25.5 (q), 21.7 (q), 19.3 (t), 12.7
4.4.2.
2-[(1E,3E)-4-Iodo-3-methylbuta-1,3-dien-1-yl]-
1,3,3-trimethylcyclohex-1-ene 4. n-BuLi (4.6 mL, 1.5 M
en hexane, 7.02 mmol) was added to a suspension of
phosphonium salt 9 (3.0 g, 6.26 mmol) in THF (72 mL)
at )30 ꢁC, and the mixture stirred for 20 min at )30 ꢁC,
and for 40 min at )78 ꢁC. A solution of iodide 8 (1.37 g,
7.02 mmol) in THF (24 mL) was then added. After 3 h
stirring, H2O (15 mL) was added and the mixture ex-
tracted with hexane (3·). The organic layers were dried
and the solvent evaporated. The residue was purified by
column chromatography (alumina, hexane) to afford
1.16 g (60%) of a yellow oil.27
(q) ppm. UV (MeOH): kmax 258 (11,000), 201
25
(11,500) nm. ½aꢁ ¼ ꢀ16:6 (c 0.036, MeOH). MS (EIþ):
D
m=z (%) 454 (Mþ, 10), 259 (30), 152 (30), 135 (100), 92
(11), 76 (30) HRMS (EIþ): calcd for C28H38O5,
454.2710; found, 454.2708.
4.5. Stille coupling
4.5.1. General procedure
4.5.1.1. (13R,14S)-13,14-Dihydroxyretinol p-methoxy-
benzoate (13R,14S)-10. To a solution of 2-[(1E, 3E)-
4-iodo-3-methylbuta-1,3-dien-1-yl]-1,3,3-trimethylcyclo-
hex-1-ene 4 (0.066 g, 0.208 mmol) in DMF (3.3 mL) was
added a solution of (2S, 3R, 4E)-1-benzyloxy-5-(tri-n-
butylstannyl)-3-methylpent-2-en-2,3-diol (2S, 3R)-5
(0.050 g, 0.270 mmol) in THF (3.3 mL), (PhCN)2PdCl2
(0.024 g, 0.062 mmol) and i-Pr2NEt (0.042 mL,
1.08 mmol). The mixture was stirred at 50 ꢁC for 4 h.
After addition of H2O, the mixture was saturated with
NaCl and extracted with CH2Cl2 (4·). The organic
layers were dried and the solvent evaporated. The resi-
due was purified by column chromatography (silica gel,
70:30 hexane/EtOAc) to afford 0.069 g (73%) of a solid
4.5.1.4. (13R,14R)-13,14-Dihydroxyretinol p-methoxy-
benzoate (13R,14R)-10. Following the general proce-
dure for Stille coupling, the title compound was
obtained (75%) as a solid after purification by column
chromatography (silica gel, 80:30 hexane/EtOAc) (94%
25
D
ee). ½aꢁ ¼ þ14:9 (c 0.003, MeOH).
4.6. Hydrolysis
4.6.1. General procedure
.
4.6.1.1. (13R,14S)-13,14-Dihydroxyretinol (13R,14S)-
3. LiOH Æ H2O (0.01 g, 0.220 mmol) was added to solu-
tion of (13R,14S)-10 (0.1 g, 0.220 mmol) in THF/H2O
(6 mL, 1:1, v/v). After stirring for 10 h, the mixture was
neutralized with a solution of 10% citric acid and then
extracted with EtOAc (3·). The organic layers were
dried and the solvent evaporated. The residue was
purified by column chromatography (silica gel, 60:40
1
(88% ee). H NMR (400.13 MHz, CDCl3): d 7.96 (d,
J ¼ 8:8 Hz, 1H), 6.88 (d, J ¼ 8:8 Hz, 1H), 6.72 (dd,
J ¼ 15:2, 11.3 Hz, 1H), 6.14 (d, J ¼ 15:7 Hz, 1H), 6.02
(d, J ¼ 15:7 Hz, 1H), 5.98 (d, J ¼ 11:3 Hz, 1H), 5.74 (d,
J ¼ 15:2 Hz, 1H), 4.46 (dd, J ¼ 12:2, 2.7 Hz, 1H), 4.3
(dd, J ¼ 12:7, 7.7 Hz, 1H), 3.83 (s, 3H), 3.9–3.8 (m, 1H),
2.39 (s, 1H), 2.0–1.9 (m, 2H), 1.98 (s, 1H), 1.91 (s, 3H),
1.67 (s, 3H), 1.6–1.5 (m, 2H), 1.55 (s, 3H), 1.5–1.4 (m,
2H), 0.99 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3): d
166.8 (s), 163.6 (s), 137.8 (s), 137.4 (s), 136.5 (d), 134.6
(d), 131.8 (d, 2·), 129.2 (d), 128.7 (s), 127.2 (d), 126.2
(d), 122.1 (s), 113.7 (d, 2·), 76.1 (d), 74.4 (s), 66.3 (t),
55.4 (q), 39.5 (t), 34.2 (t), 31.6 (s), 29.1 (q), 28.9 (q), 22.6
(q), 21.7 (t), 14.1 (q) ppm. UV (MeOH): kmax 290
(11,200) nm. MS (EIþ): m=z (%) 454 (Mþ, 2), 259 (34),
152 (20), 147 (11), 135 (100), 92 (11), 91 (10), 76 (20)
1
hexane/EtOAc) to afford 0.059 g (85%) as a solid. H
NMR (400.13 MHz, CDCl3): d 6.72 (dd, J ¼ 15:2,
11.3 Hz, 1H), 6.16 (d, J ¼ 16:0 Hz, 1H), 6.06 (d, J ¼
11:9 Hz, 1H), 6.05 (d, J ¼ 16:0 Hz, 1H), 6.05 (d, J ¼
15:2 Hz, 1H), 3.8–3.6 (m, 2H), 3.6–3.5 (m, 1H), 2.5–2.4
(m, 2OH), 2.0–1.9 (m, 2H), 1.937 (s, 3H), 1.68 (s, 3H),
1.7–1.6 (m, 2H), 1.5–1.4 (m, 2H), 1.33 (s, 3H), 1.00 (s,
6H) ppm.28 13C NMR (100.68 MHz, (CD3)2CO): d 140.5
(d), 139.9 (d), 139.1 (s), 136.1 (s), 132.07 (d), 130.3 (s),
127.7 (d), 126.4 (d), 79.5 (d), 76.3 (s), 65.2 (t), 41.3 (t),
35.9 (s), 34.5 (t), 30.3 (q), 26.8 (q), 22.9 (q), 21.0 (t), 13.7
(q). UV (MeOH): kmax 279 nm. MS (EIþ): m=z (%) 320
(Mþ, 1), 306 (15), 278 (19), 277 (49), 259 (18), 234 (20),
HRMS (EIþ): calcd for C28H38O5, 454.2719; found,
25
D
454.2703. ½aꢁ ¼ ꢀ22:7 (c 0.022, MeOH).

S. Alvarez et al. / Tetrahedron: Asymmetry 15 (2004) 839–846
845
Biochem. 1999, 68, 559; (b) Bourquet, W.; Germain, P.;
Gronemeyer, H. Trends Pharmacol. Sci. 2000, 21, 381.
€
4. Buck, J.; Derguini, F.; Levi, E.; Nakanishi, K.; Hammer-
ling, U. Science 1991, 254, 1654.
233 (17), 226 (11), 152 (12), 137 (13), 123 (15), 121 (13),
109 (13), 97 (18), 95 (32), 83 (15), 81 (36), 71 (18), 69
(100), 67 (16). HRMS (EIþ): calcd for C20 H32 O3,
25
D
320.2351; found, 320.2358. ½aꢁ ¼ þ9:9 (c 0.04, MeOH).
€
5. Derguini, F.; Nakanishi, K.; Hammerling, U.; Chua, R.;
Eppinger, T.; Levi, E.; Buck, J. J. Biol. Chem. 1995, 270,
18875, The naturally occurring DHR was shown to be a
5:4 mixture of (13R, 14R)-3 and (13S,14R)-3, but the
puzzling observation by Nakanishi et al. that the optical
activity of ꢁnaturalꢀ 3 was dependent on the concentration
of retinol added to the cell cultures (even becoming a
racemate at 10ꢀ5 M!) makes the actual configuration
uncertain.
4.6.1.2. (13S,14R)-13,14-Dihydroxyretinol (13S,14R)-
3. Following the general procedure for hydrolysis, the
title compound was obtained (99%) as a solid after
purification by column chromatography (silica gel, 60:40
25
D
hexane/EtOAc) ½aꢁ ¼ ꢀ13:3 (c 0.03, MeOH).
4.6.1.3. (13S,14S)-13,14-Dihydroxyretinol (13S,14S)-
3. Following the general procedure for hydrolysis, the
title compound was obtained (95%) as a solid after
€
6. Korichneva, I.; Hammerling, U. J. Cell Sci. 1999, 112,
2521.
7. Three enantioselective syntheses of 14-HRR have been
purification by column chromatography (silica gel, 60:40
€
described: (a) Derguini, F.; Nakanishi, K.; Hammerling,
25
D
hexane/EtOAc). ½aꢁ ¼ þ14:3 (c 0.06, MeOH).
U.; Buck, J. Biochemistry 1994, 33, 623; (b) Nagai, M.;
Yoshimura, H.; Hibi, S.; Kikuchi, K.; Abe, S.; Asada, M.;
Yamauchi, T.; Hida, T.; Higashi, S.; Hishinuma, I.;
Yamanaka, T. Chem. Pharm. Bull. 1994, 42, 1545; (c)
4.6.1.4. (13R,14R)-13,14-Dihydroxyretinol (13R,14R)-
3. Following the general procedure for hydrolysis the
title compound was obtained (95%) as a solid after
purification by column chromatography (silica gel, 60:40
ꢀ
Corey, E. J.; Noe, M. C.; Guzman-Perez, A. Tetrahedron
Lett. 1995, 36, 4171.
8. (a) de Lera, A. R.; Domınguez, B.; Iglesias, B. J. Org.
ꢀ
Chem. 1998, 63, 4135; (b) Alvarez, R.; Iglesias, B.; Lopez,
1
hexane/EtOAc). H NMR (400.13 MHz, (CD3)2CO): d
ꢀ
S.; de Lera, A. R. Tetrahedron Lett. 1998, 39, 5659; (c)
6.73 (dd, J ¼ 15:2, 11.3 Hz, 1H), 6.16 (d, J ¼ 16:1 Hz,
1H), 6.12 (d, J ¼ 11:3 Hz, 1H), 6.09 (d, J ¼ 16:2 Hz,
1H), 5.92 (d, J ¼ 15:2 Hz, 1H), 3.87 (s, 1H, OH), 3.8-3.6
(m, 3H), 2.1–2.0 (m, 2H),1.91 (s, 3H), 1.68 (s, 3H), 1.7–
1.6 (m, 2H), 1.5–1.4 (m, 2H), 1.34 (s, 3H), 1.02 (s, 6H).28
1H NMR (400.13 MHz, CDCl3): d 6.74 (dd, J ¼ 15:2,
11.3 Hz, 1H), 6.15 (d, J ¼ 16:1 Hz, 1H), 6.07 (d, J ¼
12:2 Hz, 1H), 6.06 (d, J ¼ 16:1 Hz, 1H), 5.75 (d,
J ¼ 15:1 Hz, 1H), 3.78 (m, 2H), 3.6–3.5 (m, 1H), 2.6–2.4
(m, OH), 2.04 (s, 3H), 2.0–1.9 (m, 2H), 1.69 (s, 3H), 1.7–
1.6 (m, 2H), 1.5–1.4 (m, 2H), 1.01 (s, 6H) ppm.28 13C
NMR (100.68 MHz, CDCl3): d 137.8 (s), 137.4 (d), 136.6
(s), 136.4 (d), 129.5 (s), 128.5 (d), 127.3 (d), 126.2 (d),
76.4 (d), 74.9 (s), 63.0 (t), 39.6 (t), 34.2 (s), 33.0 (t), 29.0
(q, 2·), 24.0 (q), 21.7 (q), 19.3 (t), 12.7 (q). UV (MeOH):
kmax 289 nm. MS (EIþ): m=z (%) 259 (13), 256 (19), 137
(14), 129 (13), 97 (161), 95 (19), 93 (10), 85 (12), 83 (24),
82 (13), 72 (31), 71 (20), 70 (15), 69 (100). HRMS (EIþ):
ꢀ
Domınguez, B.; Iglesias, B.; de Lera, A. R. Tetrahedron
1999, 55, 15071; (d) Domınguez, B.; Pazos, Y.; de Lera, A.
ꢀ
R. J. Org. Chem. 2000, 65, 5917; (e) Pazos, Y.; Iglesias, B.;
de Lera, A. R. J. Org. Chem. 2001, 66, 8483; (f) Otero, M.
P.; Torrado, A.; Pazos, Y.; Sussman, F.; de Lera, A. R. J.
ꢀ
Org. Chem. 2002, 67, 5876; (g) Domınguez, B.; Vega, M.
J.; Sussman, F.; de Lera, A. R. Bioorg. Med. Chem. Lett.
2002, 12, 2607.
9. Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: New York, 1998.
10. (a) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771; (b) Stille,
J. K. Angew., Chem. Int. Ed. Engl. 1986, 25, 508; (c)
Mitchell, T. N. Synthesis 1992, 803; (d) Sato, T. In
Comprehensive Organometallic Chemistry II; Abel, E. W.,
Stone, F. G. A., Wilkinson, G., Eds.; Elsevier: Oxford,
1995; vol. 11, pp 355–387, Chapter 8; (e) Farina, V.; Roth,
G. P. In Advances in Metal-Organic Chemistry; Liebes-
kind, L. S., Ed.; JAI: New York, 1996; Vol. 5, pp 1–53;
(f) Farina, V. Pure Appl. Chem. 1996, 68, 73; (g) Farina,
V.; Krishnamurthy, V.; Scott, W. J. The Stille reaction.
Org. React. 1997, 50, 1; (h) Stanforth, S. P. Tetrahedron
1998, 54, 263; (i) Mitchell, N. T. In Ref. 10, Chapter 4, pp
167–202; (j) Farina, V.; Krishnamurthy, V. The Stille
Reaction; Wiley: New York, 1999; (k) Duncton, M. A. J.;
Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1235.
11. For selected reviews on the Sharpless asymmetric dihydr-
oxylation, see: (a) Finn, M. G.; Sharpless, K. B. Asymm.
Synth. 1985, 5, 247; (b) Rossiter, B. E. Asymm. Synth.
1985, 5, 194; (c) Sharpless, K. B. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 7, p 389; (d) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994,
94, 2483; (e) Becker, H.; Soler, M. A.; Sharpless, K. B.
Tetrahedron 1995, 51, 1345; (f) Johnson, R. A.; Sharpless,
K. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
2nd ed.; Wiley-VCH: New York, 2000; pp 357–398; (g)
calcd for C20H32O3, 320.2351; found, 320.2337.
25
D
½aꢁ ¼ ꢀ11:5 (c 0.026, MeOH).
Acknowledgements
We thank the European Commission (RTD QLK3-
2002-02029 ꢁAnticancer Retinoidsꢀ), the Spanish Minis-
ꢀ
terio de Ciencia y Tecnologıa (Grant SAF01-3288;
Ramon y Cajal Research Contract to R.A.) and the
ꢀ
Xunta de Galicia (Grant PGIDIT02PXIC30108PN) for
financial support.
References and notes
1. For the nomenclature of retinoids, see: IUPAC-IUB Joint
Commission on Biochemical Nomenclature (JCBN). Eur.
J. Biochem. 1982, 129, 1.
~
Bolm, C.; Hildebrand, J. P.; Muniz, K. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; 2nd ed.; Wiley-
2. For recent reviews on vision, see: (a) Rando, R. R. Chem.
Rev. 2001, 101, 1881;(b)McBee, J.K.;Palczewski, K.;Baehr,
W.; Pepperberg, D. R. Prog. Retin. Eye Res. 2001, 20, 469.
3. For recent reviews on nuclear receptors, see: (a) Weath-
erman, R. V.; Fletterick, R. J.; Scanlan, T. S. Annu. Rev.
VCH: New York, 2000; pp 399–428.
€
12. (a) Tietze, L. F.; Gorlitzer, J. Synthesis 1996, 877; (b)
Tietze, L. F.; Gorlitzer, J. Liebigs Ann. Recueil 1997, 2221;
€
(c) The analogue of substrate 7a with a p-methoxybenzyl
group has also been reacted with AD-mix b, and the

846
S. Alvarez et al. / Tetrahedron: Asymmetry 15 (2004) 839–846
ꢀ
reported ee was 80%; Nakatani, K.; Okamoto, A.;
Matsuno, T.; Saito, I. J. Am. Chem. Soc. 1998, 120, 11219.
3592; (e) Fargeas, V.; Le Menez, P.; Berque, I.; Ardisson,
J.; Pancrazi, A. Tetrahedron 1996, 52, 6613; (f) Betzer,
J.-F.; Ardisson, J.; Lallemand, J.-Y.; Pancrazi, A. Tetra-
hedron Lett. 1997, 38, 2279; (g) Betzer, J.-F.; Muller,
B.; Pancrazi, A.; Prunet, J. J. Org. Chem. 1997, 62,
7768.
13. (a) Greene, T. W.; Wuts, P. G. Protective Groups in
Organic Synthesis; Wiley: New York, 1991; (b) Kocienski,
P. J. Protecting Groups; Thieme: Stuttgart, 1994.
14. Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetra-
hedron Lett. 1985, 26, 6291.
ꢀ
20. (a) Zhang, H. X.; Guibe, F. M.; Balavoine, G. J. Org.
ꢀ
15. (a) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am.
Chem. Soc. 1994, 116, 12109; (b) Corey, E. J.; Guzman-
ꢀ
Chem. 1990, 55, 1857; (b) Kikikawa, K.; Umekawa, H.;
Wada, F.; Matsuda, T. Chem. Rev. 1988, 88, 881; (c)
Smith, N. D.; Mancuso, J.; Lautens, M. Chem. Rev. 2000,
100, 3257.
ꢀ
ꢀ
Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1995, 117, 10805.
16. (a) Alternatively, a supplement of the oxidant and the
enantiopure dihydroquinine (DHQ) or dihydroquinidine
(DHQD) phthalazine ligands has been recommended to
speed up dihydroxylation of substrates that react slowly.
Byun, H.-S.; Kumar, E. R.; Bittman, R. J. Org. Chem.
1994, 59, 2630; (b) Kobayashi, Y.; William, A. D.;
Tokoro, Y. J. Org. Chem. 2001, 66, 7903.
21. (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am.
Chem. Soc. 1980, 102, 3298; (b) Negishi, E.; King, A. O.;
Tour, J. M. Org. Synth. 1985, 64, 44.
22. Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1
1990, 47.
23. Dawson, M. I.; Hobbs, P. D.; Chao, W. R. J. Med. Chem.
1981, 24, 1214.
€
17. (a) Jeong, K.-S.; Sjo, P.; Sharpless, K. B. Tetrahedron Lett.
1992, 33, 3833; (b) VanNieuwenhze, M. S.; Sharpless, K.
B. Tetrahedron Lett. 1994, 35, 843; (c) Sharpless, K. B.;
Amberg, W.; Beller, M.; Chen, M.; Hartung, J.; Kawa-
nami, Y.; Lubben, D.; Manoury, E.; Ogino, Y. J. Org.
Chem. 1991, 56, 4585.
24. Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813.
25. (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113,
9585; (b) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth,
G. P. J. Org. Chem. 1993, 58, 5434; (c) Farina, V.; Baker,
S. R.; Benigni, D. A.; Hauck, S. I.; Sapino, C. J. Org.
Chem. 1990, 55, 5833.
18. The structural factors underlying the modest ee in the
reaction of (Z)-7c with AD mix a are unclear at this
moment. We are attempting to gain a better understanding
of the structural factors that control the enantiofacial
differentiation of isomeric enynols using a combination of
experimental and theoretical models.
19. (a) Lipshutz, B. H.; Ellswoth, E. L.; Dimock, S. H.;
Reuter, D. C. Tetrahedron Lett. 1989, 30, 2065; (b)
Lipshutz, B. H.; Reuter, D. C. Tetrahedron Lett. 1989,
26. For other examples, see: (a) Kobayashi, Y.; Kato, N.;
Shimakazi, T.; Sato, F. Tetrahedron Lett. 1988, 29, 6297;
(b) Boyd, D. R.; Hand, M. V.; Sharma, N. D.; Chima, J.;
Dalton, H.; Sheldrake, G. N. J. Chem. Soc., Chem.
Commun. 1989, 616; (c) Kelly, T. R.; Li, Q.; Bhushan, V.
Tetrahedron Lett. 1990, 31, 161; (d) Nicolaou, K. C.;
Chakraborty, T. K.; Piscopio, A. D.; Minowa, N.;
Bertino, P. J. Am. Chem. Soc. 1993, 115, 4419.
27. (a) Negishi, E.; Owczarczyk, Z. Terahedron Lett. 1991, 32,
6683–6686; (b) Ling, R.; Yoshida, M.; Mariano, P. S. J.
Org. Chem. 1996, 61, 4439–4449.
ꢀ
30, 4617; (c) Le Menez, P.; Berque, I.; Fargeas, V.;
Ardisson, J.; Pancrazi, A. Synlett 1994, 998; (d) Le Menez,
ꢀ
P.; Fargeas, V.; Berque, I.; Poisson, J.; Ardisson, J.;
Lallemand, J.-Y.; Pancrazi, A. J. Org. Chem. 1995, 60,
28. 1H NMR is coincidental with that described in Ref. 5.