12-Substituted-13,14-dihydroretinols designed for affinity labeling of retinol binding- and processing proteins

Article abstract of DOI:10.1016/j.tet.2004.06.116

All-trans- and 11-cis-retinol derivatives substituted with various electron-withdrawing groups at C₁₂ were designed to be affinity labels for retinol binding and processing proteins. Unlike other non-selective highly reactive affinity labels, these compounds carry a Michael acceptor type substitution at C₁₂ of the polyene chain. Therefore, they are expected to be highly selective towards such proteins that have a nucleophilic residue near the C₁₁ position of their retinol ligand. The synthetic route for these compounds is based on the Emmons-Horner reaction of a C15 aldehyde with an appropriate phosphonate bearing the desired electron-withdrawing group to be incorporated at the C₁₂ position of the retinol skeleton. Graphical abstract

Full text of DOI:10.1016/j.tet.2004.06.116

Tetrahedron 60 (2004) 8093–8102
12-Substituted-13,14-dihydroretinols designed for affinity labeling
of retinol binding- and processing proteins
*
Revital Yefidoff and Amnon Albeck
The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel
Received 22 March 2004; revised 7 June 2004; accepted 24 June 2004
Available online 29 July 2004
Abstract—All-trans- and 11-cis-retinol derivatives substituted with various electron-withdrawing groups at C12 were designed to be affinity
labels for retinol binding and processing proteins. Unlike other non-selective highly reactive affinity labels, these compounds carry a Michael
acceptor type substitution at C12 of the polyene chain. Therefore, they are expected to be highly selective towards such proteins that have a
nucleophilic residue near the C11 position of their retinol ligand. The synthetic route for these compounds is based on the Emmons–Horner
reaction of a C15 aldehyde with an appropriate phosphonate bearing the desired electron-withdrawing group to be incorporated at the C12
position of the retinol skeleton.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
RBPs, a major disadvantage when attempting to tag a
specific minor constituent protein.6a
Retinoids and their metabolites are essential for many
physiological processes such as vision, gene transcription,
cell proliferation and differentiation, hormone level regu-
lation, immune function and morphogenesis.1 The regu-
lation of these processes is mediated via retinoid-binding
proteins (RBP). RBP range from a variety of retinoid-
processing and metabolizing enzymes via retinoid recep-
tors, to different transport proteins designed to protect and
transfer these sensitive and lipophilic compounds to their
cell target, as well as mediators of retinoid action.2 RBP can
be found as soluble proteins both intra- and extracellularly,
while others are present as integral membrane-bound minor
constituents. The multiplicity of retinoid isomers and
chemical forms (alcohols, aldehydes, acids and esters)
requires different protein structures and binding sites, in
order to bind the appropriate ligand with high selectivity and
affinity.
In a previous study, we synthesized a set of 13-substituted-
13,14-dihydroretinols as potential affinity labels of retinol-
binding proteins.8 Most of these compounds were found to
be not stable enough for biological studies. Thus, the present
paper describes the design and synthesis of a family of
stable 12-substituted all-trans- and 11-cis-retinol deriva-
tives (Fig. 1) that would act as mild, highly specific affinity
labels for retinol-binding proteins containing a nucleophilic
residue in the binding pocket of the protein. One specific
target in mind was the enzyme trans retinyl ester
isomerohydrolase, which has been postulated to carry out
its catalytic activity via a nucleophilic attack at the substrate
C
11 position.1a,9
Affinity labeling has been used as a tool in the study of these
proteins’ structure and function and for their isolation and
purification. Most of the affinity labels of various RBPs
were synthetic retinoids bearing highly reactive functional
groups such as azide,3 diazirene,3a,4 allyl bromide,5
haloketone and ester6 or diazoketone and ester.3a,4a,b,7 As
such, they lack the specificity within the large family of
Keywords: Retinol analogs; Retinol binding proteins; trans Retinyl ester
isomerohydrolase; Affinity labeling; Michael acceptors.
* Corresponding author. Tel.: C972-3-5318862; fax: C972-3-5351250;
e-mail: albecka@mail.biu.ac.il
Figure 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.116

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R. Yefidoff, A. Albeck / Tetrahedron 60 (2004) 8093–8102
2. Results and discussion
2.1. Design of the C12-substituted retinol analogs
Substitution of an electron-withdrawing group at C12 of the
retinol polyene skeleton can efficiently render the C11
position an electrophilic core of the molecule, yielding an
electrophilic retinoid of a Michael acceptor type (Fig. 2).
The C13–C14 bond in the synthetic retinol analogs is
saturated, in contrast to the native ligand. This prevents
cross-conjugation to the 12-substituted electron-withdrawing
group, thus, increasing its electrophilicity. In addition, in the
context of the trans retinyl ester isomerohydrolase, the
saturated C13–C14 bond prevents the natural isomerization
from taking place, ensuring that the C12-substituted
compounds are not substrates for the enzyme.
Figure 3.
Both 13-de-methyl and 13-methyl analogs were prepared,
since this substitution may affect the isomeric distribution of
the new synthetic 12-substituted retinol analogs. The 13-de-
methyl analogs are expected to exhibit higher stability of
their 11-cis isomer, relative to the corresponding 13-methyl
counterparts (see below). This is especially relevant taking
into account the fact that the 11-cis isomer of retinoids is
of high biological importance. Thus, both the all-trans and
the 11-cis isomers of the various new compounds were
synthesized.
cyano phosphonate 7) or triethyl phosphonoacetate (yield-
ing ester phosphonate 11), respectively.
The corresponding methylated analogs 10 and 14 were
prepared from 1,3-butanediol by protection of the primary
alcohol (yielding also some secondary alcohol protection),
substitution of the free secondary hydroxyl with iodide (9
and 13)12 and condensation with the appropriate phos-
phonates. The condensation on the secondary alkyl iodides
was more difficult and required drastic conditions: 55–60 8C
for 5 days in the presence of HMPA in dry THF.
Since many 13-demethyl retinoids are biologically active10
or bind their biological target,11 the omission of this methyl
in some of the new affinity label compounds should not
prohibit their activity.
Phosphonates 10 and 14 have a few chiral centers, only one
of which will remain in the corresponding final products.
They were both synthesized as a mixture of diastereomers.
These compounds are quite rigid, in respect to their C3–C4
bond. Their relative configurations and conformations were
determined by the 3JH,H and 3JP,C coupling constants in the
1H and 13C NMR spectra. While the ester phosphonate 14
was present in solution as a mixture of both the anti and
the gauche conformations (in both diastereomers), both
diastereomers of the cyano phosphonate 10 were present
mainly in the gauche conformation, without any significant
contribution from the anti conformation (Fig. 4). This is
probably due to the very small size of the cyano substituent.
2.2. Synthesis
A convergent strategy for the synthesis of the 12-substituted
retinol analogs 1–6 was employed, based on the assembly of
two fragments, the all-trans isomer of the C15 aldehyde 15
and an appropriate four-carbon chain phosphonate, via the
Emmons–Horner condensation (Fig. 3). The phosphonates
contain the precursors of the electron-withdrawing group
functionalities.
2.2.1. Preparation of the phosphonate units. Four differ-
ent phosphonates were prepared for the synthesis of the six
12-substituted retinol analogs by a common synthetic
strategy, i.e. condensation of an O-protected halo alcohol
with an appropriate phosphonate bearing the desired
substituent (Scheme 1).
2.2.2. Condensation. The synthesis of the 12-substituted
retinol analogs from C15 aldehyde 1513 and the appropriate
phosphonates is described in Scheme 2. All the conden-
sation reactions between aldehyde 15 and the different
phosphonates, as well as all subsequent reactions were
carried out under dim red light, in order to avoid undesired
isomerizations along the polyene skeleton.
Thus, 3-bromopropanol protected either with tert-butyldi-
methylsilyl or with tetrahydropyran was condensed with the
sodium salt of diethyl cyanomethylphosphonate (producing
The Emmons–Horner condensation between all-trans
Figure 2.

R. Yefidoff, A. Albeck / Tetrahedron 60 (2004) 8093–8102
8095
Scheme 1. Reagents and conditions: (a) (EtO)2P(O)CH2CN, NaH, dry THF/HMPA. (b) I2, PPh3, imidazole, CH2Cl2. (c) (EtO)2P(O)CH2CO2Et, NaH, dry
THF/HMPA.
aldehyde 15 and either phosphonate 7 or 11 readily
produced a mixture of two isomers about the newly formed
C11–C12 double bond of 16 and 20: 11-Z (will be referred to
as ‘all-trans’ in respect to the full length retinol skeleton)
and 11-E (11-cis in the retinol terminology) (Scheme 2).
Minor amounts of the 9-cis isomer of 20 were also isolated.
Deprotection and separation of the isomers afforded the all-
trans and the 11-cis isomers of retinol analogs 1 and 5,
respectively.
phosphonates with aldehyde 15 produced mainly the all-
trans isomer of 17 and 21, with only minor amounts of the
11-cis isomer. Thus, the introduction of Me-20 indeed
fulfilled the expectation of stabilizing the all-trans isomer
due to increased steric repulsion in the 11-cis isomer. The
all-trans and 11-cis isomers of the final products, 12-cyano-
13,14-dihydroretinol 2 and 12-carbethoxy-13,14-dihydro-
retinol 6, were readily obtained by mild deprotection of 17
and 21, respectively.
The isolation and purification of some of the all-trans-
retinol analogs was problematic due to unconstrained
isomerization about the C11–C12 double bond. We therefore
decided to re-introduce the Me-20 group to the retinol
analogs. This should decrease the rate of isomerization,
owing to steric hindrance between H-10 and the Me-20
group in the 11-cis isomer.14 Furthermore, re-introduction
of the methyl group to C13 makes these 12-substituted
retinol analogs better mimics of the native substrate of the
enzyme.
During the synthesis of 21, the basic conditions of the
Emmons–Horner reaction promoted some dimerization of
aldehyde 15 by the Robinson annulation reaction.15
Cyano intermediates 16 and 17 were also used for the
synthesis of the 12-formyl retinol analogs 3 and 4,
respectively. In order to produce separately each isomer,
the subsequent reduction of the nitrile group and deprotec-
tion were carried out separately for each isomer of 16 and
17. DIBAL-H reduction followed by removal of the silyl
protecting group successfully furnished the desired products
12-formyl-13-demethyl-13,14-dihydroretinol 3 and 12-
formyl-13,14-dihydroretinol 4. The above procedure pre-
served the isomeric integrity of the starting materials 11-cis
16, 11-cis 17 and all-trans 17. However, similar treatment
of all-trans 16 yielded a mixture of all-trans and 11-cis
O-protected-12-formyl retinol 18, even when all reactions
and workups were carried out in the dark at 4 8C.
Deprotection of all-trans 18 again produced a mixture of
all-trans and 11-cis 3, along with some 9-cis product. The
best results (a 1:1 mixture of all-trans: 11-cis) were obtained
when the aldehyde reduction product was subjected to
deprotection immediately, without any purification step.
These results demonstrate once again the stabilizing effect
Thus, the 13-methyl substituted analogs were synthesized
similarly, starting with phosphonates 10 and 14, which carry
both the nitrile and ester functionalities, respectively, and
the future Me-20 groups. The condensation reaction of the
Figure 4.

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R. Yefidoff, A. Albeck / Tetrahedron 60 (2004) 8093–8102
Scheme 2. Reagents and conditions: (a) NaH, dry THF. (b) Bu4NCFK, dry THF. (c) (i) DIBAL-H, hexane, K78 8C. (ii) SiO2/H2O, ether. (d) PPTS, EtOH,
55 8C.
of the 13-methyl substitution on the all-trans isomer of the
retinol analogs.
standard), unless otherwise indicated. 31P NMR spectra
were recorded at 81 MHz in CDCl3 (85% H3PO4 as an
1
external reference). H NMR assignments were supported
The chemical stability of aldehyde derivatives 3 and 4, both
in terms of isomerization and degradation, was poor. Only
when kept dry at K20 8C, was the 11-cis isomer stable
against isomerization for several months. The all-trans-
isomer was much more labile. Nitriles 1 and 2 and esters 5
and 6 were quite stable under argon atmosphere at 20 8C.
by COSY and NOESY experiments, while 13C NMR
assignments were supported by distortionless enhancement
by polarization transfer (DEPT), heteronuclear multiple
quantum correlation (HMQC) and heteronuclear multiple
bond connectivity (HMBC) experiments. J values are given
in Hz. The NMR signals are assigned according to the atom
numbering of the retinoid skeleton (Fig. 1). All-trans, 11-cis
or 9-cis configurations refer to the configuration of the
retinol skeleton. UV spectra were recorded on a diode array
spectrophotometer in dichloromethane. Mass spectra were
recorded in DCI mode with methane, unless otherwise
stated. TLC was performed on E. Merck 0.2 mm precoated
silica gel F-254 plates, and viewed by UV light and
vanillin.16 Chromatography refers to flash column
chromatography,17 carried out on silica gel 60 (230–400
mesh ASTM, E. Merck). Anhydrous solvents were dried
and freshly distilled: THF and diethyl ether (referred to as
ether) from sodium/benzophenone, CH2Cl2 from CaCl2 and
3. Conclusions
In this paper we present the design and synthesis of a family
of retinol analogs substituted at C12 with electron with-
drawing groups as potential selective affinity labels for
retinol binding- and processing proteins. Both 11-cis and
all-trans isomers of aldehyde, cyano and ester substituted
retinol analogs and 13-demethyl retinol analogs were
prepared via an efficient convergent procedure, based on
Emmons–Horner condensation reaction between C15 alde-
hyde and an appropriate phosphonate unit bearing the
desired C12 functional group. These compounds are now
being tested as inhibitors of the enzyme trans retinyl ester
isomerohydrolase.
˚
DMF from 4 A molecular sieves.
4.2. Synthesis
1-tert-Butyldimethylsilanyloxy-3-butanol 818 and C15 alde-
hyde 1513b were prepared as previously described.
4. Experimental
4.1. General
4.2.1. Diethyl 4-tert-butyldimethylsilanyloxy-1-cyano-
butyl phosphonate (7). General procedure A. Diethyl
cyanomethylphosphonate (7.7 g, 0.04 mol), was added
dropwise to a suspension of NaH (80% in mineral oil,
1.42 g) and NaI (0.5 g) in dry THF (120 mL) and HMPA
(20 mL) under Ar atmosphere. After full consumption of
NaH, 1-(tert-butyldimethylsilanyloxy)-3-bromopropane
All operations involving synthesis and manipulation of full-
length retinoids were performed under dim red light. 1H and
13C NMR spectra were recorded at 300 or 600, and 75 or
150 MHz, respectively, in CDCl3 (TMS as an internal

R. Yefidoff, A. Albeck / Tetrahedron 60 (2004) 8093–8102
8097
(5.0 g, 0.022 mol) was added and the reaction mixture was
stirred at rt for 3 days. The solvent was evaporated and the
residue was dissolved in ether and washed twice with water.
The organic phase was dried (MgSO4), filtered and
evaporated. Chromatography (CHCl3: ether, 1:3) afforded
the product as colorless oil (40% yield). 1H NMR d 4.23 (m,
JZ7.2 Hz, 4H, CH2OP), 3.70 (ddd, JZ10.5, 5.5, 5.1 Hz,
1H, H-4), 3.64 (ddd, JZ10.5, 6.5, 5.0 Hz, 1H, H-4), 3.04
(ddd, JZ23.4, 10.5, 4.8 Hz, 1H, H-1), 2.12–1.79 and 1.73–
1.64 (m, 4H, H-2, H-3), 1.38 (m, 6H, Me), 0.89 (s, 9H,
t-Bu), 0.05 (s, 6H, SiMe2). 13C NMR d 116.2 (d, JZ9.1 Hz,
CN), 63.8 (d, JZ7.0 Hz, COP), 63.5 (d, JZ6.9 Hz, COP),
61.7 (C-4), 30.3 (d, JZ11.9 Hz, C-3), 29.7 (d, JZ143.8 Hz,
C-1), 25.7 (t-Bu), 24.0 (d, JZ4.2 Hz, C-2), 18.1 (C-t-Bu),
16.2 (d, JZ5.6 Hz, 2!Me), K5.6 (C–Si). 31P NMR d 18.8.
HRMS m/z calcd for C16H35NO4SiP (MHC) 364.2073,
found 364.2053.
and 2-(3-bromopropoxy)-tetrahydropyran (0.5 g, 2.2 mmol)
in dry THF (8 mL) at rt for 2 days. Chromatography
(n-hexane/ether 1:1) afforded the product (a diastereomeric
mixture) as colo0rless oil (65% yield). 1H NMR d 4.57 (t, JZ
3.3 Hz, 1H, H-2 ), 4.18 (m, 6H, CH2OCO and CH2OP), 3.84
(ddd, JZ11.4, 7.8, 3.6 Hz, 1H, H-60), 3.74 (m, 1H, H-5),
3.48 (m, 1H, H-60), 3.38 (m, 1H, H-5), 3.00 (ddd, JZ22.5,
10.5, 4.5 Hz, 1H, H-2), 2.1–1.5 (m, 10H, H-3, H-4, H-30,
H-40, H-50), 1.34 and 1.33 (t, JZ7.2 Hz, 3H, phosphonate-
Me), 1.29 (t, JZ7.2 Hz, 3H, ester-Me). 13C NMR d 169.0
(d, JZ4.5 Hz, C-1), 98.6 and 98.5 (C-20), 66.5 and 66.4 (C-
60), 62.5 (d, JZ6.6 Hz, COP), 62.4 (d, JZ6.8 Hz, COP),
62.0 (C-5), 61.2 (CH2OCO), 45.33 and 45.30 (d, JZ
131.3 Hz, C-2), 30.5 (C-30), 28.2 (d, JZ14.5 Hz, C-4), 28.1
(d, JZ14.8 Hz, C-4), 25.3 (C-50), 23.89 and 23.86 (d, JZ
4.8 Hz, C-3), 19.3 (C-40), 16.2 (d, JZ5.4 Hz, phosphonate-
Me), 14.0 (ester-Me). 31P NMR d 23.3. HRMS m/z calcd for
C11H24O6P (MHC-THP) 283.1311, found 283.1317, calcd for
C11H22O5P (MHCKTHP-H2O) 265.1146, found 265.1148.
4.2.2. tert-Butyl-3-iodobutoxy dimethylsilane (9). General
procedure B. 8 (3.0 g, 0.015 mol) in dry CH2Cl2 (16 mL)
was added to a solution of triphenylphosphine (5.9 g,
0.022 mol), imidazole (1.6 g, 0.023 mol) and iodine (5.7 g,
0.022 mol) in dry CH2Cl2 (60 mL). After 3 h at rt, the
solvent was evaporated. The residue was triturated with
n-hexane and the organic phase was washed with sat.
Na2S2O3, dried (MgSO4), filtered and evaporated to give 9
4.2.5. 1-(Tetrahydropyran-2-yloxy)-3-butanol (12).19 1,3-
Dihydroxybutane (1.0 g, 11 mmol), 3,4-dihydro-2H-pyran
(1.0 g, 12 mmol) and catalytic amount of PPTS (0.28 g,
1.1 mmol) were stirred in dry CH2Cl2 (25 mL) at rt for 4 h.
Evaporation and chromatography (n-hexane/ether 1:1 and
then 3:1) afforded the product 12 (about 1:1 diastereomeric
mixture) as colorless oil (45% yield), along with some
1
as colorless oil (95% yield). H NMR d 4.35 (dqd, JZ9.6,
1
6.9, 4.5 Hz, 1H, H-3), 3.76 (ddd, JZ10.5, 5.7, 4.5 Hz, 1H,
H-1), 3.65 (ddd, JZ10.2, 8.1, 4.8 Hz, 1H, H-1), 1.99 (ddt,
JZ14.7, 9.6, 4.8 Hz, 1H, H-2), 1.97 (d, JZ6.9 Hz, 3H,
Me-4), 1.79 (dddd, JZ18.6, 8.1, 5.4, 4.5 Hz, 1H, H-2), 0.91
(s, 9H, t-Bu), 0.08 and 0.07 (s, 3H, SiMe). 13C NMR d 68.2
(C-3), 62.7 (C-1), 39.9 (C-2), 25.8 (t-Bu), 23.3 (C-4), 18.1
(C-t-Bu), K5.6 (C–Si). MS (CI/ isobutane) m/z 315 (MHC),
257 (MHCKt-Bu).
3-protected (5%) byproduct. H NMR d 4.50 and 4.49 (t,
JZ4.5 Hz, 1H, H-20), 3.87, 3.78 and 3.55–3.39 (m, 5H, H-1,
H-3, H-60), 3.16 (s, 1H, OH), 1.63 and 1.44 (m, 8H, H-2,
H-30, H-40, H-50), 1.11 (d, JZ6.3 Hz, 3H, Me-4). 13C NMR
d 98.8 and 98.6 (C-20), 66.8 and 66.2 (C-3), 65.7 and 65.6
(C-1), 62.04 and 61.9 (C-60), 38.1 and 38.0 (C-2), 30.5 and
30.3 (C-3 ;), 25.1 (C-50), 23.12 and 23.07 (C-4), 19.4 and
19.2 (C-40). HRMS m/z calcd for C9H17O3 ((MKH)C)
173.1178, found 173.1183.
4.2.3. Diethyl 4-tert-Butyldimethylsilanyloxy-1-cyano-2-
methylbutyl phosphonate (10). Compound 10 was pre-
pared according to general procedure A with diethyl
cyanomethylphosphonate (5.7 g, 0.032 mol), NaH (60% in
mineral oil, 1.2 g) and 9 (5.4 g, 0.017 mol) in dry THF
(160 mL) and HMPA (24 mL) at 55 8C for 5 days.
Chromatography (hexane/ether 1:1) afforded the product
as a 2:1 diastereomeric mixture of colorless oil (75% yield,
4.2.6. 2-(3-Iodobutoxy)-tetrahydropyran (13). Compound
13 was prepared according to general procedure B with
triphenylphosphine (5.24 g, 0.02 mol), imidazole (1.36 g,
0.02 mol), iodine (5.1 g, 0.02 mol) in dry CH2Cl2 (27 mL)
and 12 (2.9 g, 0.017 mol, contaminated with about 10% of
the 3-protected isomer) in dry CH2Cl2 (13 mL). The
product, a 1:1 diastereomeric mixture contaminated by
17% of a 1:1 diastereomeric mixture of O-THP-1-iodo-3-
butanol, was obtained as colorless oil (52% overall yield).
1H NMR d 4.61 (t, JZ3.0 Hz, 1H, H-2), 4.59 (dd, JZ4.02,
2.7 Hz, 1H, H-2), 4.37 (dqd, JZ9.3, 6.9, 4.05 Hz, 1H, H-3 ),
4.35 (dqd, JZ10.8, 6.9, 4.5 Hz, 1H, H-3 ), 3.90 (m, 2H,
H-6, H-10), 3.85 (ddd, JZ12, 7, 3 Hz, 1H, H-6), 3.81 (dd0d,
JZ9.9, 7.8, 5.4 Hz, 1H, H-10), 3.52 (m, 3H, 2!H-6, H-1 ),
3.45 (ddd, JZ9.9, 8.1, 4.8 Hz, 1H, H-10), 2.08 (m, 1H,
H-20), 1.97 (d, JZ6.9 Hz, 3H, Me-40), 1.91 (m, 1H, H-20),
1.81 (m, 1H, H-4), 1.71 (m, 1H, H-3), 1.60–1.50 (m,
4H, H-3, H-4, 2!H-5,). 13C NMR d 99.4 and 98.4 (C-2),
67.1 and 66.8 (C-10), 62.5 and 62.00(C-6), 42.6 (C-20), 300.6
and 30.5 (C-3), 29.0 and 29.0 (C-4 ), 26.6 and 26.2 (C-3 ),
25.38 and 25.36 (C-5), 19.4 and 19.2 (C-4). MS (CI/NH3) m/
z 285 (MHC), 155 (MKHI). HRMS m/z calcd for C9H16O2I
(MKH) 283.0195, found 283.0196.
1
20% recovery of SM). H NMR d 4.23 (m, 4H, CH2OP),
3.70 (m, 2H, CH2-4), 3.39 (dd, JZ25.2, 3.0 Hz, 1H, H-1),
2.98 (dd, JZ24.6, 4.2 Hz, 1H, H-1), 2.39 and 2.10 (bm, 1H,
H-2), 1.62 (m, 2H, CH2-3), 1.38 (m, 6H, CH3CH2O), 1.22
(d, JZ6.9 Hz, 3H, 2-Me), 1.18 (dd, JZ6.9, 0.9 Hz, 3H,
2-Me), 0.89 (s, 9H, t-Bu), 0.05 (s, 6H, SiMe2). 13C NMR d
115.0 (d, JZ9.0 Hz, CN), 63.8, 63.7, 63.42 and 63.37 (d,
JZ6.7 Hz, COP), 60.7 and 60.1 (C-4), 38.4 (d, JZ13.5 Hz,
C-3), 36.9 (d, JZ143.2 Hz, C-1), 35.9 (d, JZ3.3 Hz, C-3),
35.2 (d, JZ143.2 Hz, C-1), 29.6 and 29.2 (d, JZ3.3 Hz,
C-2), 25.8 (t-Bu), 18.7 (d, JZ11.2 Hz, 2-Me), 18.1 (C-t-Bu),
17.2 (2-Me), 16.3 (d, JZ5.9 Hz, CH3CH2O), K5.4, K5.5,
K5.6 (C–Si). 31P NMR d 18.8 and 18.2. HRMS m/z calcd
for C16H35NO4PSi (MHC) 364.2073, found 364.2053.
4.2.4. Ethyl 2-diethoxyphosphoryl-5-(tetrahydropyran-
2-yloxy)-pentanoate (11). The product was obtained
according to general procedure A with triethyl phosphono-
acetate (1.0 g, 4.5 mmol), NaH (80% in mineral oil, 0.17 g)
4.2.7. Ethyl 2-diethoxyphosphoryl-3-methyl-5-(tetra-
hydropyran-2-yloxy)-pentanoate (14). Compound 14

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R. Yefidoff, A. Albeck / Tetrahedron 60 (2004) 8093–8102
was obtained according to general procedure A with triethyl
phosphonoacetate (4.9 g, 0.022 mol), NaH (80% in mineral
oil, 0.81 g) and 13 (2.5 g, 8.8 mmol, with 17% impurity of
the 3-protected isomer) in dry THF (40 mL) and HMPA
(10 mL) at 70 8C for 5 days. Chromatography (ether)
afforded the product as a diastereomeric mixture (colorless
4.2.9. O-TBS-12-cyano-13,14-dihydroretinol (17). Com-
pound 17 was prepared according to general procedure A
with phosphonate 10 (0.88 g, 2.4 mmol), NaH (60% in
mineral oil, 0.09 g) and aldehyde 15 (1.05 g, 4.8 mmol) at rt
for 3 days. The isomeric mixture (all-trans and 11-cis in a
9:1 ratio, and some 9-cis which was formed upon standing)
was purified by chromatography (hexane/ether 25:1),
1
oil, 066% yield). H NMR d 4.59 (dd, JZ4.5, 2.7 Hz, 1H,
1
H-2 ), 4.57 (dd, JZ4.1, 2.9 Hz, 1H, H-20), 4.20 (q, JZ
7.1 Hz, 2H, CH2OCO), 4.16 (m, 4H, CH2OP), 3.88 (m, 1H,
H-60), 3.80 (m, 1H, H-5), 3.52 (m, 1H, H-60), 3.42 (m, 1H,
H-5), 2.98 (dd, JZ21.3, 7.1 Hz, 1H, H-2), 2.96 (dd, JZ
21.2, 7.2 Hz, 1H, H-2), 2.85 (dd, JZ28.2, 5.3 Hz, 1H, H-2),
2.50 and 2.42 (m, 1H, H-3), 2.01 (m, 2H, H-4), 1.83 (m,
H-40), 1.70 (m, H-30), 1.6–1.5 (m, H-4, H-30, H-40, H-50),
1.33 (m, 3H, phosphonate-Me), 1.30 (t, JZ7.1 Hz, 3H,
ester-Me), 1.20 and 1.10 (d, JZ6.8 Hz, 3H, 3-Me). 13C
NMR d 169.0, 168.8 and 166.7 (d, JZ5.3 Hz, CO), 98.9,
98.8 and 98.6 (C-20), 65.2 and 64.80 (C-5), 63.6 and 62.8 (d,
JZ7 Hz, COP), 62.4 and 62.1 (C-6 ), 59.9 (CH2OCO), 51.1
and 51.0 (d, JZ134.5 Hz, C-2), 48.4 (d, JZ128.0 Hz, C-2),
47.6 (d, JZ131.6 Hz, C-2), 35.0 (d, JZ11.6 Hz, C-4), 34.9
(d, JZ11.3 Hz, C-4), 30.7 (C-30), 28.7 (d, JZ3.9 Hz, C-3),
25.5 (C-50), 22.6 (d, JZ6.6 Hz, 2-Me), 19.8 and 19.5 (C-40),
16.4 (d, JZ5.6 Hz, phosphonate-Me), 14.2 (ester-Me). 31P
NMR d 23.3. HRMS m/z calcd for C17H34O7P (MHC)
381.2042, found 381.1960.
yielding yellow oil in 58% yield. All-trans. H NMR d
6.99 (d, JZ11.7 Hz, 1H, H-11), 6.45 (d, JZ11.7 Hz, 1H,
H-10), 6.39 (d, JZ16.2 Hz, 1H, H-7), 6.21 (d, JZ16.2 Hz,
1H, H-8), 3.65 (dt, JZ10.2, 5.4 Hz, 1H, H-15), 3.55 (ddd,
JZ10.2, 7.8, 5.4 Hz, 1H, H-15), 2.67 (sextet, JZ6.9 Hz,
1H, H-13), 2.04 (t, JZ6.0 Hz, 2H, CH2-4), 1.98 (s, 3H,
Me-19), 1.73 (d, JZ0.9 Hz, 3H, Me-18), 1.66 (m, 4H,
CH2-14 and CH2-3), 1.48 (m, 2H, CH2-2), 1.19 (d, JZ
6.9 Hz, Me-20), 1.04 (s, 6H, Me-16, 17), 0.90 (s, 9H, t-Bu),
0.05 (s, 6H, SiMe2). 13C NMR d 142.5 (C-9), 139.3 (C-11),
137.3 (C-6), 136.6 (C-8), 130.84 (C-5), 130.8 (C-7), 125.5
(C-10), 117.3 (CN), 116.9 (C-12), 60.2 (C-15), 39.6 (C-2),
38.2 (C-14), 35.6 (C-13), 34.2 (C-1), 33.1 (C-4), 28.9 (C-16,
C-17), 25.9 (t-Bu), 21.7 (C-18), 20.0 (C-20), 19.1 (C-3),
18.2 (C-t-Bu), 12.9 (C-19), K5.4 (C–Si). UV lmax 332 nm.
HRMS m/z calcd for C27H46NOSi (MHC) 428.3349, found
428.3350. 11-cis. 1H NMR d 7.11 (d, JZ12.0 Hz, 1H,
H-11), 6.41 (d, JZ15.6 Hz, 1H, H-7), 6.32 (d, JZ12.3 Hz,
1H, H-10), 6.15 (d, JZ15.9 Hz, 1H, H-8), 3.65 (dt, JZ10.5,
5.4 Hz, 1H, H-15), 3.53 (m, 1H, H-15), 3.11 (dq, JZ14.1,
6.9 Hz, 1H, H-13), 2.04 (t, JZ6.0 Hz, 2H, CH2-4), 1.99 (d,
JZ0.9 Hz, 3H, Me-19), 1.71 (s, 3H, Me-18), 1.68 (m, 2H,
CH2-14), 1.62 (m, 2H, CH2-3), 1.48 (m, 2H, CH2-2), 1.16
(d, JZ6.9 Hz, Me-20), 1.03 (s, 6H, Me-16, 17), 0.88 (s, 9H,
t-Bu), 0.04 (s, 6H, SiMe2). 13C NMR d 143.6 (C-9), 138.9
(C-11), 137.4 (C-6), 138.7 (C-8), 131.2 (C-7), 129.1 (C-5),
122.9 (C-10), 120.1 (CN), 117.1 (C-12), 61.1 (C-15), 39.5
(C-2), 38.3 (C-14), 34.2 (C-1), 33.1 (C-4), 28.9 (C-16,
C-17), 28.5 (C-13), 25.9 (t-Bu), 21.7 (C-18), 19.5 (C-20),
19.1 (C-3), 18.2 (C-t-Bu), 12.8 (C-19), K5.8 (C–Si). UV
lmax 334 nm. HRMS m/z calcd for C27H46NOSi (MHC)
4.2.8. O-TBS-12-cyano-13-demethyl-13,14-dihydro-
retinol (16). Compound 16 was prepared according to
general procedure A with phosphonate 7 (0.42 g, 1.2 mmol),
NaH (60% in mineral oil, 0.04 g) and aldehyde 15 (0.54 g,
2.5 mmol) in dry THF (35 mL) at rt for 18 h. Chromato-
graphy (n-hexane/ether 25:1) afforded the two separated
clean isomers (all-trans: 11-cis 3:1) as yellow oils in 78%
yield. All -trans. 1H NMR d 6.98 (d, JZ12.0 Hz, 1H, H-11),
6.43 (d, JZ12.0 Hz, 1H, H-10), 6.38 (d, JZ16.2 Hz,
1H, H-7), 6.19 (d, JZ16.2 Hz, 1H, H-8), 3.64 (t, JZ6.0 Hz,
2H, CH2-15), 2.39 (t, JZ7.5 Hz, 2H, CH2-13), 2.03 (t, JZ
6.0 Hz, 2H, CH2-4), 1.97 (s, 3H, Me-19), 1.75 (m, 2H,
CH2-14), 1.72 (s, 3H, Me-18), 1.62 (m, 2H, CH2-3), 1.46
(m, 2H, CH2-2), 1.03 (s, 6H, Me-16, 17), 0.89 (s, 9H, t-Bu),
0.05 (s, 6H, SiMe2). 13C NMR d 142.5 (C-9), 140.4 (C-11),
137.3, (C-6), 136.6 (C-8), 130.9 (C-7 and C-5), 125.5
(C-10), 118.5 (CN), 111.1 (C-12), 61.3 (C-15), 39.6 (C-2),
34.2 (C-1), 33.1 (C-4), 31.2 (C-13), 30.9 (C-14), 28.9 (C-16,
C-17), 25.9 (t-Bu), 21.7 (C-18), 19.1 (C-3), 18.2 (C-t-Bu),
12.9 (C-19), K5.4 (C–Si). UV lmax 334 nm. HRMS m/z
calcd for C26H44NOSi (MHC) 414.3192, found 414.3202.
11-cis. 1H NMR d 7.13 (d, JZ12.3 Hz, 1H, H-11), 6.41 (d,
JZ15.9 Hz, 1H, H-7), 6.26 (d, JZ12.3 Hz, 1H, H-10), 6.14
(d, JZ16.2 Hz, 1H, H-8), 3.63 (t, JZ6.0 Hz, 2H, CH2-15),
2.43 (t, JZ7.5 Hz, 2H, CH2-13), 2.03 (t, JZ6.0 Hz, 2H,
CH2-4), 1.99 (d, JZ0.9 Hz, 3H, Me-19), 1.77 (m, 2H,
CH2-14), 1.70 (d, JZ0.9 Hz, 3H, Me-18), 1.60 (m, 2H,
CH2-3), 1.47 (m, 2H, CH2-2), 1.02 (s, 6H, Me-16, 17), 0.89
(s, 9H, t-Bu), 0.04 (s, 6H, SiMe2). 13C NMR d 143.6 (C-9),
139.6 (C-11), 137.4, (C-6), 136.6 (C-8), 131.4 (C-7), 130.9
(C-5), 122.9 (C-10), 121.5 (CN), 111.1 (C-12), 61.3 (C-15),
39.5 (C-2), 34.2 (C-1), 33.1 (C-4), 31.2 (C-14), 28.8 (C-16,
C-17), 25.9 (t-Bu), 24.9 (C-13), 21.7 (C-18), 19.1 (C-3),
18.2 (C-t-Bu), 12.8 (C-19), K5.4 (C–Si). HRMS m/z calcd
for C26H44NOSi (MHC) 414.3192, found 414.3203.
1
428.3349, found 428.3320. 9-cis. H NMR d 7.06 (d, JZ
11.7 Hz, 1H, H-11), 6.55 (d, JZ15.6 Hz, 1H, H-8), 6.35 (d,
JZ12 Hz, 1H, H-10), 3.62 (dt, JZ10.2, 5.4 Hz, H-15), 3.57
(m, H-15), 2.67 (sextet, JZ6.6 Hz, 1H, H-13), 2.04 (d, JZ
1.2 Hz, 3H, Me-19), 2.03 (t, JZ6.0 Hz, 2H, CH2-4), 1.73 (d,
JZ0.9 Hz, 3H, Me-18), 1.66 (m, 4H, CH2-14, CH2-3), 1.48
(m, 2H, CH2-2), 1.17 (d, JZ6.9 Hz, Me-20), 1.03 (s, 6H,
Me-16, 17), 0.90 (s, 9H, t-Bu), 0.05 (s, 6H, SiMe2).
4.2.10. All-trans-O-TBS-12-formyl-13-demethyl-13,14-
dihydroretinol (18). General procedure C. All-trans 16
(0.29 g, 0.7 mmol) was dissolved in n-hexane (10 mL)
under Ar atmosphere. The solution was cooled to K78 8C
and DIBAL-H (1 M in hexane, 1.2 mL) was added. The
reaction was stirred at K78 8C for 35 min. Wet silica gel
and ether were added and the reaction mixture was stirred at
0 8C overnight. The mixture was filtered through Celite. The
Celite was then washed with ethyl acetate. The organic
phase was dried (MgSO4), filtered and evaporated. The
obtained isomeric mixture (11-cis and all-trans in 1:3.5
ratio) was separated by chromatography (n-hexane/ether/
ethyl acetate 4:2:1) (yellow oils, 82% yield). 1H NMR
(acetone-d6) d 10.40 (s, 1H, CHO), 7.46 (d, JZ12.6 Hz, 1H,
H-11), 7.25 (d, JZ12.9 Hz, 1H, H-10), 6.48 (d, JZ16.2 Hz,
1H, H-7), 6.32 (d, JZ16.2 Hz, 1H, H-8), 3.64 (t, JZ6.3 Hz,

R. Yefidoff, A. Albeck / Tetrahedron 60 (2004) 8093–8102
8099
2H, CH2-15), 2.35 (dd, JZ8.1, 7.2 Hz, 2H, CH2-13), 2.07
(d, JZ1.2 Hz, 3H, Me-19), 2.03 (m, CH2-4), 1.73 (d,
JZ0.6 Hz, 3H, Me-18), 1.64 (m, 4H, CH2-14 and CH2-3),
1.49 (m, 2H, CH2-2), 1.06 (s, 6H, Me-16, 17), 0.92 (s, 9H,
t-Bu), 0.07 (s, 6H, SiMe2). 13C NMR d 189.8 (CHO), 142.5
(C-9), 140.1 (C-11), 137.5 (C), 137.4 (C-8), 137.36 (C),
130.0 (C-7), 129.9 (C), 122.3 (C-10), 62.0 (C-15), 39.4
(C-2), 33.9 (C-1), 32.7 (C-4), 32.1 (C-14), 28.4 (C-16,
C-17), 26.9 (C-13), 25.4 (t-Bu), 21.1 (C-18), 18.9 (C-3),
17.9 (C-t-Bu), 11.4 (C-19), K6.1 (C–Si). UV lmax 352 nm.
HRMS m/z calcd for C26H45O2Si (MHC) 417.3189, found
417.3243.
JZ12.0 Hz, 1H, H-10), 6.46 (d, JZ15.9 Hz, 1H, H-7), 6.22
(d, JZ16.2 Hz, 1H, H-8), 3.55 (dt, JZ10.8, 5.7 Hz, 1H,
H-15), 3.43 (ddd, JZ10.4, 7.8, 5.4 Hz, 1H, H-15), 3.09 (m,
1H, H-13), 2.08 (d, JZ1.2 Hz, 3H, Me-19), 2.03 (CH2-4),
1.77 (m, 1H, H-14), 1.71 (d, JZ0.9 Hz, 3H, Me-18), 1.64
(m, 3H, H-14, CH2-3), 1.48 (m, 2H, CH2-2), 1.19 (d, JZ
7.2 Hz, Me-20), 1.03 (s, 6H, Me-16, 17), 0.87 (s, 9H, t-Bu),
0.00 and K0.02 (s, 3H, SiMe). 13C NMR d 195.1 (CHO),
145.8 (C-11), 145.3 (C-48), 144.0 (C-48), 137.4 (C-48),
137.1 (C-8), 131.6 (C-7), 131.1 (C-48), 124.5 (C-10), 61.2
(C-15), 39.2 (C-2), 36.7 (C-14), 34.2 (C-1), 32.8 (C-4), 28.9
(C-16, C-17), 27.9 (C-13), 25.9 (t-Bu), 21.7 (C-18), 19.1
(C-3), 18.7 (C-20), 18.2 (C-t-Bu), 12.9 (C-19), K5.3 (C–Si).
UV lmax 356 nm.
4.2.11. 11-cis-O-TBS-12-formyl-13-demethyl-13,14-
dihydroretinol (18). The 11-cis isomer was similarly
prepared according to general procedure C with 11-cis 16
(0.09 g, 0.22 mmol) and DIBAL-H (1 M in hexane,
0.35 mL) in n-hexane (5 mL). Chromatography (n-hexane/
ether/ethyl acetate 4:2:1) provided pure 11-cis 18 (yellow
oil, 85% yield). 1H NMR d 9.47 (s, 1H, CHO), 7.24 (d, JZ
12.3 Hz, 1H, H-11), 6.52 (d, JZ11.7 Hz, 1H, H-10), 6.49 (d,
JZ16.2 Hz, 1H, H-7), 6.27 (d, JZ15.9 Hz, 1H, H-8), 3.61
(t, JZ6.3 Hz, 2H, CH2-15), 2.45 (dd, JZ8.1, 7.5 Hz, 2H,
CH2-13), 2.10 (d, JZ1.2 Hz, 3H, Me-19), 2.05 (t, JZ
6.3 Hz, 2H, CH2-4), 1.74 (d, JZ0.9 Hz, 3H, Me-18), 1.61
(m, 4H, CH2-14 and CH2-3), 1.48 (m, 2H, CH2-2), 1.06 (s,
4.2.14. O-THP-12-carbethoxy-13-demethyl-13,14-di-
hydroretinol (20). Compound 20 was prepared according
to general procedure A with phosphonate 11 (0.84 g,
2.3 mmol), NaH (60% in mineral oil, 0.085 g) and aldehyde
15 (1.0 g, 4.6 mmol) in dry THF at rt for 2 days. The
obtained isomeric mixture (11-cis as a major product, along
with some all-trans and 9-cis) was purified and partially
separated by chromatography (n-hexane/ether, 20:1) (yellow
oil, 46% yield). 11-cis. 1H NMR d 7.63 (d, JZ12.3 Hz, 1H,
H-11), 6.35 (d, JZ16.2 Hz, 1H, H-7), 6.33 (d, JZ12.0 Hz,
1H, H-10), 6.18 (d, JZ16.2 Hz, 1H, H-8), 4.55 (dd, JZ4.5,
3.0 Hz, H, H-20), 4.22 (q, JZ7.2 Hz, 2H, CH2OCO), 3.86
(ddd, JZ11.1, 7.5, 3.3 Hz, 1H, H-60), 3.74 (dt, JZ9.9,
6.3 Hz, 1H, H-15), 3.47 (m, 1H, H-60), 3.37 (dt, JZ9.9,
6.3 Hz, 1H, H-15), 2.58 (dt, JZ13.5, 7.5 Hz, 1H, H-13),
2.50 (dt, JZ13.5, 6.9 Hz, 1H, H-13), 2.03 (d, JZ1.2 Hz,
3H, Me-19), 2.02 (t, JZ6.3 Hz, 2H, CH2-4), 1.80–1.48 (m,
CH2-3, CH2-14, CH2-30, CH2-40, CH2-50), 1.70 (d, JZ
0.9 Hz, 3H, Me-18), 1.46 (m, 2H, CH2-2), 1.31 (t, JZ
7.2 Hz, 3H, ester-Me), 1.03 (s, 6H, Me-16, 17). 13C NMR d
168.3 (CO2), 142.9 (C-9), 137.5 (C-6), 137.3 (C-8), 134.5
(C-11), 130.3 (C-12), 130.2 (C-5), 129.8 (C-7), 124.6
(C-10), 98.8 (C-60), 66.6 (C-15), 62.1 (C-200), 60.3 (C-21),
39.5 (C-2), 34.1 (C-1), 33.0 (C-4), 30.7 (C-5 ), 29.4 (C-14),
28.80(C-16, 17), 25.4 (C-30), 23.4 (C-13), 21.6 (C-18), 19.5
(C-4 ), 19.1 (C-3), 14.2 (C-22), 12.8 (C-19). UV lmax
334 nm. HRMS m/z calcd for C27H42O4 (M.C) 430.3083,
found 430.3073. All-trans. 1H NMR d 7.03 (d, JZ12.0 Hz,
1H, H-10), 6.79 (d, JZ12.0 Hz, 1H, H-11), 6.34 (d, JZ
15.6 Hz, 1H, H-7), 6.01 (d, JZ15.6 Hz, 1H, H-8), 4.57 (dd,
JZ3.9, 2.7 Hz, 1H, H-20),0 4.22 (q, JZ7.2 Hz, 2H,
CH2OCO), 3.86 (m, 1H, H-6 ), 3.75 (m, 1H, H-15), 3.49
(m, 1H, H-60), 3.36 (dt, 1H, H-15), 2.46 (m, 2H, CH2-13),
1.94 (s, 3H, Me-19). 9-cis. 1H NMR d 7.69 (d, JZ12.3 Hz,
1H, H-11), 6.88 (d, JZ15.3 Hz, 1H, H-8), 6.28 (d, JZ
12.0 Hz, 1H, H-10), 6.09 (d, JZ15.9 Hz, 1H, H-7). HRMS
m/z calcd for C27H42O4 (M.C) 430.3083, found 430.3054.
6H, Me-16, 17), 0.91 (s, 9H, t-Bu), 0.06 (s, 6H, SiMe2). 13
C
NMR d 194.6 (CHO), 145.4 (C-9), 144.9 (C-11), 141.0,
(C-6), 137.4 (C-5 or C-12), 137.0 (C-8), 131.7 (C-7), 131.2
(C-12 or C-5), 124.5 (C-10), 62.6 (C-15), 39.6 (C-2), 34.3
(C-1), 33.2 (C-4), 32.1 (C-14), 28.9 (C-16, C-17), 25.9
(t-Bu), 21.8 (C-18), 20.5 (C-13), 19.1 (C-3), 18.3 (C-t-Bu),
12.9 (C-19), K5.3 (C–Si). UV lmax 354 nm. HRMS m/z
calcd for C26H45O2Si (MHC) 417.3189, found 417.3184.
4.2.12. All-trans-O-TBS-12-formyl-13,14-dihydroretinol
(19). All-trans 19 was prepared according to general
procedure C with all-trans 17 (0.33 g, 0.77 mmol) and
DIBAL-H (1 M in Hexane, 1.4 mL) in n-hexane (10 mL).
1
The product was obtained as yellow oil (88% yield). H
NMR d 10.32 (s, 1H, CHO), 7.26 (d, JZ12.6 Hz, 1H, H-11),
7.00 (d, JZ12.9 Hz, 1H, H-10), 6.42 (d, JZ16.2 Hz, 1H,
H-7), 6.20 (d, JZ15.9 Hz, 1H, H-8), 3.56 (t, JZ6.6 Hz, 1H,
CH2-15), 2.88 (sextet, JZ6.9 Hz, 1H, H-13), 2.03 (d, JZ
1.2 Hz, and t, JZ6 Hz, 5H, Me-19 and CH2-4), 1.76 (m, 1H,
H-14), 1.72 (d, JZ0.9 Hz, 3H, Me-18), 1.62 (m, 3H, H-14,
CH2-3), 1.47 (m, 2H, CH2-2), 1.10 (d, JZ6.9 Hz, Me-20),
1.03 (s, 6H, Me-16, 17), 0.88 (s, 9H, t-Bu), 0.02 (s, 6H,
SiMe2). 13C NMR d190.2 (CHO), 143.3 (C-48), 141.6
(C-48), 138.9 (C-11), 137.5 (C-48), 137.2 (C-8), 130.9 (C-7),
130.7 (C-48), 122.0 (C-10), 61.5 (C-15), 39.5 (C-2), 39.1
(C-14), 34.2 (C-1), 33.1 (C-4), 30.4 (C-13), 28.9 (C-16,
C-17), 25.9 (t-Bu), 21.7 (C-18), 20.6 (C-20), 19.1 (C-3),
18.3 (C-t-Bu), 12.3 (C-19), K5.3 (C–Si). UV lmax 354 nm.
HRMS m/z calcd for C27H46O2Si (M.C) 430.3267, found
430.3223.
4.2.15. O-THP-12-carbethoxy-13,14-dihydroretinol
(21). Compound 21 was prepared according to general
procedure A with phosphonate 14 (1.2 g, 3.2 mmol), NaH
(60% in mineral oil, 0.12 g) and aldehyde 15 (0.65 g,
3.0 mmol) in dry THF at rt for 3 days. Chromatography
(n-hexane/ether 25:1) afforded a complex diastereoisomeric
mixture of the all-trans and 11-cis isomers, as well as minor
amounts of a product derived from the phosphonate of the
4.2.13. 11-cis-O-TBS-12-formyl-13,14-dihydroretinol
(19). 11-cis 19 was prepared according to general procedure
C with 11-cis 17 (0.69 g, 1.6 mmol) and DIBAL-H (1 M in
Hexane, 2.9 mL) in n-hexane (21 mL). The product was
obtained as yellow oil in 85% yield. 1H NMR d 9.43 (d, JZ
2 Hz, 1H, CHO), 7.19 (d, JZ12.0 Hz, 1H, H-11), 6.53 (d,
1
3-protected butanediol (yellow oil, 52% yield). H NMR d
7.60, 7.58 and 7.57 (d, JZ12.3 Hz, 1H, H-11), 6.79 (JZ

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R. Yefidoff, A. Albeck / Tetrahedron 60 (2004) 8093–8102
1
12.0 Hz, 2H-10), 6.73 (dd, JZ12.0, 0.9 Hz, 1H, H-11), 6.71
(dd, JZ12.0, 0.9 Hz, 1H, H-11), 6.42 (d, JZ12.3 Hz, 1H,
H-10), 6.41–6.30 (m, 2H-10, 4H-7), 6.27 (d, 12 Hz, 1H,
H-10), 6.25 (d, JZ16.2 Hz, 1H, H-7), 6.19 (d, JZ16.2 Hz,
1H, H-8), 6.17 (d, JZ15.9 Hz, 1H, H-8), 6.16 (d, JZ16.2,
1H, H-8), 6.15 (d, JZ15.9 Hz, 1H, H-8), 6.13 (d, JZ
15.6 Hz, 1H, H-8), 4.71 (dd, JZ4.2, 3 Hz, 1H, H-20), 4.63
(dd,0 JZ4.8, 3.0 Hz, 1H, H-20), 4.54 (t, JZ3.3 Hz, 1H,
H-2 ), 4.52 (dd, JZ4.7, 2.7 Hz, 1H, H-20), 4.40 (dd, JZ4.5,
2.7 Hz, 1H, H-20), 4.23, 4.20, 4.19, 4.18, (q, JZ6.9 Hz, 2H,
ester-CH2), 3.95–3.10 (m, H-13, CH2-15 and CH2-60), 2.78
(m, 1H, H-13), 2.63 (ddd, JZ13.8, 10.8, 6 Hz, 1H, H-13),
2.45 (m, 1H, H-13), 2.02, 2.01, 2.00, 1.95 and 1.94 (d, JZ
1.2 Hz, 3H, Me-19), 1.98 (m, 2H, CH2-4), 1.9–1.4 (m, 12H,
CH2-2, CH2-3, CH2-14, CH2-30, CH2-40, CH2-50), 1.70 (d,
JZ0.9 Hz, 3H, Me-18), 1.70, 1.69 and 1.68 (s, 3H, Me-18),
1.317, 1.29 (t, JZ6.9 Hz, 3H, ester-Me), 1.25 (d, JZ6.3 Hz,
3H, Me-20), 1.21 (d, JZ7.2 Hz, 3H, Me-20), 1.18 (t, JZ
6.9 Hz, 3H, ester-Me), 1.15 (d, JZ6.9 Hz, 3H, Me-20), 1.13
(d, JZ6.0 Hz, 3H, Me-20), 1.02, 1.02, 1.01, 1.00 and 0.99
(s, 6H, Me-16, 17). UV lmax 334 nm. HRMS m/z calcd for
C28H44O4 444.3240, found 444.3214.
trans. H NMR d 7.04 (d, JZ11.7 Hz, 1H, H-11), 6.44 (d,
JZ11.7 Hz, 1H, H-10), 6.38 (d, JZ15.9 Hz, 1H, H-7), 6.20
(d, JZ15.9, 1H, H-8), 3.67 (m, 1H, H-15), 3.62 (m, 1H,
H-15), 2.66 (dquintet, JZ8.1, 6.6 Hz, 1H, H-13), 2.49 (t,
JZ7.8 Hz, 1H, OH), 2.03 (t, JZ6.3 Hz, 2H, CH2-4), 1.99
(d, JZ1.2 Hz, 3H, Me-19), 1.75 (m, 2H, CH2-14), 1.72 (s,
3H, Me-18), 1.62 (m, 2H, CH2-3), 1.47 (m, 2H, CH2-2),
1.23 (d, JZ6.6 Hz, 3H, Me-20), 1.03 (s, 6H, Me-16, 17).
13C NMR d 142.9 (C), 139.4 (C-11), 137.3 (C), 136.5 (C-8),
131.0 (C-7), 130.8 (C), 125.3 (C-10), 117.2 (CN), 116.6 (C),
59.9 (C-15), 39.5 (C-2), 38.1 (C-14), 35.5 (C-13), 34.1
(C-1), 33.0 (C-4), 28.8 (C-16, 17), 21.6 (C-20), 20.0 (C-18),
19.1 (C-3), 13.0 (C-19). UV lmax 334 nm. HRMS m/z calcd
for C21H31NO (MC) 313.2406, found 313.2410. 11-cis. 1H
NMR d 7.13 (d, JZ12.3 Hz, 1H, H-11), 6.42 (d, JZ
15.9 Hz, 1H, H-7), 6.33 (d, JZ12.1 Hz, 1H, H-10), 6.16 (d,
JZ15.9, 1H, H-8), 3.71 (dt, JZ10.7, 5.4 Hz, 1H, H-15),
3.60 (dt, JZ10.7, 6.6 Hz, 1H, H-15), 3.08 (sextet, JZ
6.9 Hz, 1H, H-13), 2.04 (d, JZ5.4 Hz, 2H, CH2-4), 2.00 (d,
JZ1 Hz, 3H, Me-19), 1.76 (td, JZ6.9, 5.7 Hz, 2H, CH2-14),
1.71 (d, JZ1 Hz, 3H, Me-18), 1.62 (m, 2H, CH2-3), 1.48
(m, 2H, CH2-2), 1.19 (d, JZ6.9 Hz, 3H, Me-20), 1.033 (s,
3H, Me-16), 1.026 (s, 3H, Me-17). 13C NMR d 144.2 (C-9),
139.0 (C-11), 137.4 (C-6), 136.6 (C-8), 131.6 (C-7), 131.1
(C-5), 125.6 (CN), 116.9 (C-12), 60.2 (C-15), 39.6 (C-2),
37.9 (C-14), 34.3 (C-1), 33.1 (C-4), 29.0 (C-16), 28.9
(C-17), 28.8 (C-13), 21.8 (C-18), 19.6 (C-20), 19.1 (C-3),
12.9 (C-19). HRMS m/z calcd for C21H31NO (MC)
4.2.16. 12-Cyano-13-demethyl-13,14-dihydroretinol
(1). General procedure D. A mixture of all-trans and 11-
cis (2.6:1) 16 (0.34 g, 0.8 mmol) was dissolved in dry THF
(10 mL). A solution of Bu4NCFK (1 M in THF, 0.88 ml)
was added and the reaction mixture was stirred at rt for 1 h.
After evaporation of the solvent, the isomers were separated
by chromatography (ethyl acetate/hexane 1:2) (yellow oils,
100% yield). All-trans. 1H NMR d 7.02 (d, JZ11.9 Hz, 1H,
H-11), 6.43 (d, JZ11.9 Hz, 1H, H-10), 6.39 (d, JZ16.1 Hz,
1H, H-7), 6.20 (d, JZ16.1 Hz, 1H, H-8), 3.71 (t, JZ6.2 Hz,
2H, CH2-15), 2.43 (t, JZ7.5 Hz, 2H, CH2-13), 2.03 (t, JZ
6.2 Hz, 2H, CH2-4), 1.99 (s, 3H, Me-19), 1.84 (quintet, JZ
7.4 Hz, 2H, CH2-14), 1.72 (s, 3H, Me-18), 1.62 (m, 2H,
CH2-3), 1.47 (m, 2H, CH2-2), 1.03 (s, 6H, Me-16, Me-17).
13C NMR d 142.8 (C-9), 140.6 (C-11), 137.2 (C-6), 136.4
(C-8), 131.0 (C-7), 130.8 (C-5), 125.3 (C-10), 118.4 (CN),
110.6 (C-12), 61.0 (C-15), 39.5 (C-2), 34.1 (C-1), 33.0
(C-4), 31.1 (C-14), 30.8 (C-13), 28.8 (C-16, C-17), 21.6
(C-18), 19.0 (C-3), 12.9 (C-19). UV lmax 334 nm. HRMS
m/z calcd for C20H30NO (MHC) 300.2327, found 300.2310.
11-cis. 1H NMR d 7.15 (d, JZ12.1 Hz, 1H, H-11), 6.43 (d,
JZ16.1 Hz, 1H, H-7), 6.26 (d, JZ12.1 Hz, 1H, H-10), 6.16
(d, JZ16.1 Hz, 1H, H-8), 3.71 (t, JZ6.1 Hz, 2H, CH2-15),
2.47 (t, JZ7.4 Hz, 2H, CH2-13), 2.03 (t, JZ6.6 Hz, 2H,
CH2-4), 2.00 (s, 3H, Me-19), 1.85 (quintet, JZ7.6 Hz, 2H,
CH2-14), 1.72 (s, 3H, Me-18), 1.62 (m, 2H, CH2-3), 1.47
(m, 2H, CH2-2), 1.03 (s, 6H, Me-16, Me-17). 13C NMR d
144.1 (C-9), 139.8 (C-11), 137.4 (C-6), 136.5 (C-8), 131.7
(C-7), 131.0 (C-5), 122.6 (C-10), 121.5 (CN), 110.6 (C-12),
61.4 (C-15), 39.5 (C-2), 34.2 (C-1), 33.1 (C-4), 30.9 (C-14),
28.9 (C-16, C-17), 24.9 (C-13), 21.7 (C-18), 19.1 (C-3),
12.9 (C-19). UV lmax 336 nm. HRMS m/z calcd for
C20H30NO (MHC) 300.2327, found 300.2311.
1
313.2406, found 313.2395. 9-cis. H NMR d 7.10 (d, JZ
11.7 Hz, 1H, H-11), 6.56 (d, JZ15.9 Hz, 1H, H-8), 6.38 (d,
JZ15.9 Hz, 1H, H-7), 6.37 (d, JZ11.7, 1H, H-10), 3.71 (dt,
JZ10.8, 6.0 Hz, 1H, H-15), 3.62 (ddd, JZ10.8, 7.5, 1.8 Hz,
1H, H-15), 2.65 (dquintet, JZ8.1, 6.9 Hz, 1H, H-13), 2.06
(d, JZ0.9 Hz, 3H, Me-19), 2.05 (t, JZ6 Hz, 2H, CH2-4),
1.76 (m, 2H, CH2-14), 1.74 (d, JZ0.9 Hz, 3H, Me-18), 1.64
(m, 2H, CH2-3), 1.49 (m, 2H, CH2-2), 1.21 (d, JZ6.9 Hz,
3H, Me-20), 1.04 (s, 6H, Me-16, 17). 13C NMR d 142.0
(C-9), 138.1 (C-11), 137.7 (C-6), 132.2 (C-8), 130.6 (C-5),
128.8 (C-7), 123.8 (C-10), 117.1 (CN), 116.1 (C-12), 60.1
(C-15), 39.4 (C-2), 38.0 (C-14), 35.5 (C-13), 34.2 (C-1),
33.0 (C-4), 28.9 (C-16, 17), 21.8 (C-18), 20.9 (C-20), 19.9
(C-19), 19.1 (C-3).
4.2.18. All-trans-12-formyl-13-demethyl-13,14-dihydro-
retinol (3). All-trans 3 was prepared according to general
procedure D with all-trans 18 (0.11 g, 0.26 mmol) and
Bu4NCFK (1 M in THF, 0.26 mL) in dry THF (7 mL). It
was purified by chromatography (hexane/ethyl acetate 5:1),
providing a mixture of 1:1 all-trans and 11-cis 3, along with
small amounts of the 9-cis congener (yellow oil, 78% yield).
1H NMR d 10.34 (s, 1H, CHO), 7.38 (d, JZ12.6 Hz, 1H,
H-11), 6.99 (d, JZ12.6 Hz, 1H, H-10), 6.44 (d, JZ16.2 Hz,
1H, H-7), 6.20 (d, JZ16.2 Hz, 1H, H-8), 3.59 (t, JZ6 Hz,
2H, CH2-15), 2.38 (t, JZ7.2 Hz, 2H, CH2-13), 2.03 (m, 5H,
Me-19 and CH2-4), 1.73 (s, 3H, Me-18), 1.64 (m, 4H, CH2-14
and CH2-3), 1.48 (m, 2H, CH2-2), 1.04 (s, 6H, Me-16, 17).
13C NMR d 190.7 (CHO), 144.0 (C-9), 142.0 (C-11), 137.5
(C), 136.9 (C-8), 131.4 (C-7), 131.0 (C), 121.5 (C-10), 61.4
(C-15), 39.5 (C-2), 34.2 (C-1), 33.1 (C-4), 32.6 (C-14), 28.9
(C-16, C-17), 26.5 (C-13), 21.8 (C-18), 20.2 (C-13), 19.1
(C-3), 12.4 (C-19). UV lmax 354 nm. HRMS m/z calcd for
C20H30O2 (MC) 302.2246, found 302.2283.
4.2.17. 12-Cyano-13,14-dihydroretinol (2). Retinol analog
2 was prepared according to general procedure D with 17
(0.3 g, 0.7 mmol, a mixture of isomers) and Bu4NCFK (1 M
in THF, 0.8 ml) in dry THF (10 mL). The product isomeric
mixture was purified and separated by chromatography
(ethyl acetate/hexane 1:2) (yellow oils, 90% yield). All-

R. Yefidoff, A. Albeck / Tetrahedron 60 (2004) 8093–8102
8101
4.2.19. 11-cis-12-Formyl-13-demethyl-13,14-dihydro-
retinol (3). 11-cis 3 was prepared from 11-cis 18 according
to general procedure D as yellow oil in 77% yield. It was
further purified by HPLC on a 5m PVA-Sil (250!4.6 mm,
(MgSO4) filtered and evaporated, providing a mixture of
11-cis, 9-cis and all-trans isomers in a ratio of 30:2:1,
respectively. Chromatography (hexane/ether 2:1) afforded
clean 11-cis 5 as yellow oil and a fraction containing the
1
˚
1.20 A, YMC) column, using a mixture of 7% dioxane in
three isomers (79% overall yield). 11-cis. H NMR d 7.62
hexane at a flow rate of 1.5 mL/min. Retention time:
26.3 min. 98% purity. lmax (hexane)Z342 nm, 3Z18600.
1H NMR d 9.48 (s, 1H, CHO), 7.30 (d, JZ12.3 Hz, 1H,
H-11), 6.51 (d, JZ15.9 Hz, 1H, H-7), 6.49 (d, JZ12.3 Hz,
1H, H-10), 6.27 (d, JZ16.2 Hz, 1H, H-8), 3.53 (t, JZ
6.0 Hz, 2H, CH2-15), 2.52 (t, JZ7.2 Hz, 2H, CH2-13), 2.12
(s, 3H, Me-19), 2.05 (t, JZ6.0 Hz, 2H, CH2-4), 1.75 (s, 3H,
Me-18), 1.66 (m, 4H, CH2-14 and CH2-3), 1.49 (m, 2H,
CH2-2), 1.06 (s, 6H, Me-16, 17). 13C NMR d 195.5 (CHO),
146.5 (C-9), 146.0 (C-11), 140.2 (C), 137.4 (C), 136.8
(C-8), 132.4 (C-7), 131.5 (C), 124.0 (C-10), 60.9 (C-15),
39.5 (C-2), 34.2 (C-1), 33.2 (C-4), 31.7 (C-14), 28.9 (C-16,
C-17), 21.8 (C-18), 19.5 (C-13), 19.1 (C-3), 13.0 (C-19).
UV lmax 354 nm. MS m/z 303 (MHC).
(d, JZ12.3 Hz, 1H, H-11), 6.34 (d, JZ15.9 Hz, 1H, H-7),
6.28 (d, JZ12.3 Hz, 1H, H-10), 6.17 (d, JZ15.9 Hz, 1H,
H-8), 4.20 (q, JZ7.2 Hz, 2H, ester-CH2), 3.55 (t, JZ6.3 Hz,
2H, CH2-15), 2.52 (t, JZ7.2 Hz, 2H, CH2-13), 2.01 (d, JZ
0.9 Hz, 3H, Me-19), 1.98 (t, JZ6.3 Hz, 2H, CH2-4), 1.68
(m, 5H, CH2-14 and Me-18), 1.58 (m, 2H, CH2-3), 1.42 (m,
2H, CH2-2), 1.29 (t, JZ6.9 Hz, 3H, ester-Me), 1.00 (s, 6H,
Me-16, 17). 13C NMR d 168.9 (CO2), 143.5 (C-9), 137.4
(C-6), 137.2, (C-8), 134.9 (C-11), 130.3 (C-12), 130.2 (C-7),
129.7 (C-5), 124.3 (C-10), 61.3 (C-15), 60.6 (ester-CH2),
39.5 (C-2), 34.1 (C-1), 33.0 (C-4), 32.3 (C-14), 28.8 (C-16,
17), 22.5 (C-13), 21.6 (C-18), 19.1 (C-3), 14.2 (ester-CH3),
12.8 (C-19). UV lmax 340 nm. HRMS m/z calcd for
1
C22H34O3 (M.C) 346.2508, found 346.2490. All-trans. H
NMR d 6.99 (d, JZ12.0 Hz, 1H, H-10), 6.82 (d, JZ
12.0 Hz, 1H, H-11), 6.33 (d, JZ16 Hz, H-7), 6.13 (d, JZ
16.2 Hz, 1H, H-8), 4.21 (q, JZ7.2 Hz, 2H, ester-CH2), 3.62
(t, JZ6.3 Hz, 2H, CH2-15), 2.42 (t, JZ7.2 Hz, 2H, CH2-13),
2.01 (CH2-4), 1.94 (d, JZ1.2 Hz, 3H, Me-19), 1.70 (s, 3H,
Me-18), 1.58 (m, 2H, CH2-3), 1.42 (m, 2H, CH2-2), 1.29 (t,
JZ7.2 Hz, 3H, ester-Me), 0.98 (s, 6H, Me-16, 17). 13C
NMR d 169.1 (CO2), 141.7 (C-9), 137.8 (C-8), 135.7 (C-11),
129.4 (C-7), 126.3 (C-10), 61.9 (C-15), 60.3 (ester-CH2),
39.6 (C-2), 34.2 (C-1), 33.1 (C-4), 32.4 (C-14), 28.9 (C-16,
17), 22.3 (C-13), 21.8 (C-1O-8), 19.2 (C-3), 14.3 (ester-CH3),
12.9 (C-19). UV lmax 338 nm. HRMS m/z calcd for
C22H34O3 (M.C) 346.2508, found 346.2547. 9-cis. 1H
NMR d 7.72 (d, JZ12.3 Hz, 1H, H-11), 6.70 (d, JZ
15.9 Hz, 1H, H-8), 6.33 (d, JZ15.9 Hz, 1H, H-7), 6.19 (d,
JZ12.3 Hz, 1H, H-10), 4.19 (q, JZ6.9 Hz, 2H, ester-CH2),
3.56 (t, JZ6.3 Hz, 2H, CH2-15), 2.51 (t, JZ7.2 Hz, 2H,
CH2-13), 2.02 (CH2-4), 2.02 (d, JZ1.2 Hz, 3H, Me-19),
1.71 (d, JZ0.9 Hz, 3H, Me-18), 1.58 (m, 2H, CH2-3), 1.42
(m, 2H, CH2-2), 1.28 (t, JZ7.2 Hz, 3H, ester-Me), 1.01 (s,
6H, Me-16, 17).
4.2.20. All-trans-12-formyl-13,14-dihydroretinol (4). All-
trans 4 was prepared according to general procedure D with
all-trans 19 and (0.52, 1.2 mmol) Bu4NCFK (1 M in THF,
1.2 mL) in dry THF (14 mL). The product, all-trans isomer,
was obtained as a yellow oil (83%). 1H NMR (acetone-d6) d
10.33 (s, 1H, CHO), 7.38 (d, JZ12.6 Hz, 1H, H-11), 7.15
(d, JZ12.9 Hz, 1H, H-10), 6.48 (d, JZ16.2 Hz, 1H, H-7),
6.28 (d, JZ16.2 Hz, 1H, H-8), 3.45 (td, JZ6.5, 2.4 Hz, 1H,
H-15), 3.43 (td, JZ6.5, 2.4 Hz, 1H, H-15), 2.89 (sextet, JZ
7.2 Hz, 1H, H-13), 2.06 (d, JZ1.2 Hz, 3H, Me-19), 2.03 (t,
JZ6.6 Hz, 2H, CH2-4), 1.73 (d, JZ0.9 Hz, 3H, Me-18),
1.63 (m, 4H, CH2-14 and CH2-3), 1.48 (m, 2H, CH2-2), 1.12
(d, JZ6.3 Hz, Me-20), 1.03 (s, 6H, Me-16, 17). 13C NMR d
192.1 (CHO), 144.8 (C), 143.4 (C), 140.5 (C-11), 139.0 (C),
138.6 (C-8), 131.7 (C-7), 130.4 (C), 123.8 (C-10), 61.3
(C-15), 40.8 (C-2), 38.3 (C-14), 35.4 (C-1), 34.2 (C-4), 30.8
(C-13), 29.7 (C-16, C-17), 22.5 (C-18), 21.1 (C-20), 20.4
(C-3), 12.9 (C-19). UV lmax 354 nm. HRMS m/z calcd for
C21H32O2 (MC) 316.2402, found 316.2425.
4.2.21. 11-cis-12-Formyl-13,14-dihydroretinol (4). 11-cis
4 was similarly prepared. The product, 11-cis isomer
exclusively, was obtained as a yellow oil (76%). It was
4.2.23. 12-Carbethoxy-13,14-dihydroretinol (6). Com-
pound 6 was prepared according to general procedure E
with 21 (0.23 g, 0.5 mmol) and PPTS (0.014 g, 0.06 mmol)
in ethanol (10 mL). The product isomeric mixture was
separated by chromatography (n-hexane/ether 3:1 to 1:1),
affording two fractions, of the all-trans and the 11-cis
isomers of 6 (yellow oils, 63% yield). 11-cis 6 was further
purified by HPLC (inertSil prep-sil, 20!250 mm column,
7% ethyl acetate in n-hexane, flow rate 35 mL/min,
detection at 324 nm, retention time 37.3 min). All-trans.
1H NMR d 6.81 (d, JZ12.1 Hz, 1H, H-10), 6.78 (d, JZ
11.9 Hz, 1H, H-11), 6.29 (d, JZ15.9 Hz, 1H, H-7), 6.15 (d,
JZ16.1 Hz, 1H, H-8), 4.28 (q, JZ7.1 Hz, 2H, ester-CH2),
3.64 (m, 2H, CH2-15), 2.85 (sextet, JZ7.0 Hz, 1H, H-13),
2.02 (t, JZ6.3 Hz, 2H, CH2-4), 1.98 (s, 3H, Me-19), 1.74
(m, 1H, H-14), 1.70 (s, 3H, Me-18), 1.62 (m, 3H, H-14 and
CH2-3), 1.46 (m, 2H, CH2-2), 1.35 (t, JZ7.2 Hz, 3H, ester-
Me), 1.18 (JZ7.0 Hz, 3H, Me-20), 1.02 (s, 6H, Me-16, 17).
13C NMR d 169.0 (CO2), 141.0 (C-9), 137.8 (C-8), 137.7
(C-6), 135.2, (C-12), 132.0 (C-11), 129.9 (C-5), 129.2 (C-7),
126.0 (C-10), 60.8 (C-15), 60.6 (ester-CH2), 40.2 (C-14),
39.5 (C-2), 34.2 (C-1), 34.0 (C-13), 33.0 (C-4), 28.9 (C-16,
˚
purified by HPLC on a 5m PVA-Sil (250!4.6 mm, 1.20 A,
YMC) column, using a mixture of 7% dioxane in hexane at a
flow rate of 1.5 mL/min. Retention time: 23.1 min. 93%
purity. lmax (hexane)Z336 nm, 3Z22400. 1H NMR
(acetone-d6) d 9.48 (d, JZ1.8 Hz, 1H, CHO), 7.39 (d, JZ
12.3 Hz, 1H, H-11), 6.72 (d, JZ12.0 Hz, 1H, H-10), 6.55 (d,
JZ16.2 Hz, 1H, H-7), 6.35 (d, JZ16.2 Hz, 1H, H-8), 3.42
(m, CH2-15), 3.15 (dqd, JZ6.9, 6.6, 1.8 Hz, 1H, H-13), 2.14
(d, JZ1.2 Hz, 3H, Me-19), 2.05 (m, CH2-4), 1.94 (m, H-14),
1.74 (d and m, JZ0.9 Hz, Me-18 and H-14), 1.64 (m, CH2-3),
1.48 (m, CH2-2), 1.20 (d, JZ7.2 Hz, 3H, Me-20), 1.064 and
1.056 (s, 3H, Me-16 and Me-17). HRMS m/z calcd for
C21H32O2 (MC) 316.2402, found 316.2415.
4.2.22. 12-Carbethoxy-13-demethyl-13,14-dihydroretinol
(5). General procedure E. PPTS (0.017 g, 0.07 mmol) was
added to a solution of 11-cis 20 (0.3 g, 0.7 mmol) in ethanol
(10 mL). The mixture was stirred at 55 8C for 1.5 h, cooled
to rt and the solvent was evaporated to half its volume. The
mixture was diluted with ether, washed with water, dried

8102
R. Yefidoff, A. Albeck / Tetrahedron 60 (2004) 8093–8102
Chem. 1985, 4, 199–213. (f) Gawinowicz, M. A.;
Goodman, D. S. Biochemistry 1982, 21, 1899–1905.
7. (a) Souto, M. L.; Borhan, B.; Nakanishi, K. Methods Enz.
2000, 316, 425–435. (b) Souto, M. L.; Um, J.; Borhan, B.;
Nakanishi, K. Helv. Chim. Acta 2000, 83, 2617–2628.
(c) Ding, W.-D.; Tsipouras, A.; Ok, H.; Yamamoto, T.;
Gawinowicz, M. A.; Nakanishi, K. Biochemistry 1990, 29,
4898–4904. (d) Boehm, M. F.; Gawinowicz, M. A.; Foucault,
A.; Derguini, F.; Nakanishi, K. J. Am. Chem. Soc. 1990, 112,
7779–7782.
17), 21.7 (C-18), 20.8 (C-20), 19.2 (C-3), 14.3 (ester-Me),
12.4 (C-19). UV lmax 330 nm. HRMS m/z calcd for
C23H36O3 (M.C) 360.2664, found 360.2671. 11-cis. 1H
NMR d 7.61 (d, JZ12.3 Hz, 1H, H-11), 6.42 (d, JZ
12.0 Hz, 1H, H-10), 6.38 (d, JZ15.3 Hz, 1H, H-7), 6.19 (d,
JZ16.2 Hz, 1H, H-8), 4.23 (q, JZ7.2 Hz, 2H, ester-CH2),
3.62 (sextet, JZ6.3 Hz, 1H, H-15), 3.55 (ddd, JZ10.8, 8.1,
5.7 Hz, 1H, H-15), 3.18 (m, 1H, H-13), 2.04 (m, 5H, CH2-4
and Me-19), 1.99 (m, 1H, H-14), 1.86 (m, 1H, H-14), 1.73
(d, JZ0.9 Hz, 3H, Me-18), 1.61 (m, 2H, CH2-3), 1.49 (m,
2H, CH2-2), 1.33 (t, JZ7.2 Hz, 3H, ester-Me), 1.25 (d, JZ
6.9 Hz, 3H, Me-20), 1.05 (s, 3H, Me-16), 1.04 (s, 3H,
Me-17). 13C NMR d 168.5 (CO2), 143.5 (C-9), 137.5 (C-6),
137.4 (C-8), 134.8 (C-11), 133.8 (C-12), 130.5 (C-5), 130.1
(C-7), 124.0 (C-10), 61.4 (C-15), 60.3 (ester-CH2), 39.6
(C-2), 38.1 (C-14), 34.3 (C-1), 33.1 (C-4), 29.3 (C-13),
28.99 and 28.96 (C-16 and C-17), 21.8 (C-18), 19.7 (C-20),
19.2 (C-3), 14.3 (ester-Me), 12.9 (C-19). UV lmax 338 nm.
8. Yefidoff, R.; Weiss, L.; Avisar, D.; Albeck, A. Bioorg. Chem.
2004, 32, 38–50.
9. (a) Gollapalli, D. R.; Rando, R. R. Biochemistry 2003, 42,
5809–5818. (b) Rando, R. R. Angew. Chem., Int. Ed. Engl.
1990, 29, 461–480.
10. (a) Corson, D. W.; Kefalov, V. J.; Cornwall, M. C.; Crouch,
R. K. J. Gen. Physiol. 2000, 116, 283–297. (b) Stecher, H.;
Prezhdo, O.; Das, J.; Crouch, R. K.; Palczewski, K.
Biochemistry 1999, 38, 13542–13550. (c) Tan, Q.; Nakanishi,
K.; Crouch, R. K. J. Am. Chem. Soc. 1998, 120, 12357–
12358. (d) Buczylko, J.; Saari, J. C.; Crouch, R. K.;
Palczewski, K. J. Biol. Chem. 1996, 271, 20621–20630. (e)
Wang, Q.; Kochendoerfer, G. G.; Schoenlein, R. W.;
Verdegem, J. E.; Lugtenburg, J.; Mathies, R. A.; Shank, C. V.
J. Phys. Chem. 1996, 100, 17388–17394. (f) Can˜ada, F. J.;
Law, W. C.; Rando, R. R. Biochemistry 1990, 29, 9690–9697.
11. (a) Yan, B.; Xie, A.; Nienhaus, G. U.; Katsuta, Y.; Spudich,
J. L. Biochemistry 1993, 32, 10224–10232. (b) Iwasa, T.
Biochemistry 1992, 31, 1190–1195.
Acknowledgements
This research was supported by a United States-Israel
Binational Science Foundation grant no. 2000390.
References and notes
12. Lange, G. L.; Gottardo, C. Synth. Commun. 1990, 20,
1473–1479.
1. (a) Rando, R. R. Chem. Rev. 2001, 101, 1881–1896. (b) Nau,
H., Blaner, W. S., Eds.; Handb. Exp. Pharma 1999, 139.
(c) Packer, L., Ed.; Methods Enz. 1990, 190.
13. (a) Wada, A.; Hiraishi, S.; Takamura, N.; Date, T.; Aoe, K.;
Ito, M. J. Org. Chem. 1997, 62, 4343–4348. (b) Steinberg, G.;
Sheves, M.; Bressler, S.; Ottolonghi, M. Biochemistry 1994,
33, 12439–12450.
2. Noy, N. Biochem. J. 2000, 348, 481–495. (b) Packer L.
Methods Enz. 1990, 189, 193–373.
3. (a) Nakanishi, K.; Crouch, R. Isr. J. Chem. 1995, 35, 253–272.
(b) Sani, B. P.; Wille, J. J.; Dawson, M. L.; Hobbs, P. D.; Bupp,
J.; Rhee, S.; Chao, W. R.; Dorsky, A.; Morimoto, H. Chem.
Biol. Interact. 1990, 75, 293–304.
14. (a) Rando, R. R. Chem. Biol. 1996, 3, 255–262. (b) Rando,
R. R.; Chang, A. J. Am. Chem. Soc. 1983, 105, 2879–2882.
15. Verdegem, P. J. E.; Monnee, C. F.; Mulder, P. P. J.;
Luchtenburg, J. Tetrahedron Lett 1997, 38, 5355–5358.
16. Stahl, E. Thin-Layer Chromatography. 2nd ed.; Springer:
Berlin, 1969, pp 217–218.
4. (a) Nakanishi, K. Chem. Pharm. Bull. 2000, 48, 1399–1409.
(b) Borhan, B.; Souto, M. L.; Imai, H.; Shichida, Y.;
Nakanishi, K. Science 2000, 288, 2209–2212.
17. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923–2925.
5. Feng, Y.; Menick, D. R.; Katz, B. M.; Beischel, C. J.; Hazard,
E. S.; Misra, S.; Ebrey, T. G.; Crouch, R. K. Biochemistry
1994, 33, 11624–11630.
18. Hobley, G.; Stuttle, K.; Wills, M. Tetrahedron 2003, 59,
4739–4748.
6. (a) Gollapalli, D. R.; Rando, R. R. Biochim. Biophys. Acta
2003, 1651, 93–101. (b) Nesnas, N.; Rando, R. R.; Nakanishi,
K. Tetrahedron 2002, 58, 6577–6584. (c) Ruiz, A.; Winston,
A.; Lim, Y.-H.; Gilbert, B. A.; Rando, R. R.; Bok, D. J. Biol.
Chem. 1999, 274, 3834–3841. (d) Shi, Y. Q.; Furuyoshi, S.;
Hubacek, I.; Rando, R. R. Biochemistry 1993, 32, 3077–
3080. (e) Gawinowicz, M. A.; Goodman, D. S. J. Protein
19. This compound was previously prepared by various methods:
(a) Davis, K. J.; Bhalerao, U. T.; Rao, B. V. Indian J. Chem.,
Sect B: Org. Chem. Incl. Med. Chem. 2001, 40B, 656–661.
(b) Ogawa, Y.; Mori, H.; Yamada, H.; Kon, K. J. Antibiot.
1984, 37, 44–56. (c) Nouguier, R. Tetrahedron Lett. 1982,
23, 2951–2952.