Palladium-catalyzed coupling reaction of an enol nonaflate with (vinyl)tributylstannanes and acetylenes: A highly stereoselective synthesis of 8,18-13C2-labeled retinal

Article abstract of DOI:10.1055/s-2005-865294

Here we report that enol nonaflates exhibit higher reactivity than the corresponding enol triflates in palladium-catalyzed cross-coupling reactions with various (vinyl)tributylstannanes and acetylenes. We also highlight the reaction of a vinyl nonaflate,

Full text of DOI:10.1055/s-2005-865294

PAPER
1581
Palladium-Catalyzed Coupling Reaction of an Enol Nonaflate with
(Vinyl)tributylstannanes and Acetylenes: A Highly Stereoselective Synthesis
of 8,18-13C2-Labeled Retinal1
1
3
A
H
ighly Stereose
k
lective Synth
i
esis of
m
8,18-
C
Labeled R
o
etinal ri Wada,* Yasuhiro Ieki, Saeko Nakamura, Masayoshi Ito
2
Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada, Kobe 658-8558, Japan
Fax +81(78)4417562; E-mail: a-wada@kobepharma-u.ac.jp
Received 4 January 2005; revised 25 January 2005
*
18
Abstract: Here we report that enol nonaflates exhibit higher reac-
tivity than the corresponding enol triflates in palladium-catalyzed
11
11
12
8
8
6
CHO
CHO
1
6
12
14
14
1
10
10
cross-coupling reactions with various (vinyl)tributylstannanes and
acetylenes. We also highlight the reaction of a vinyl nonaflate, con-
taining two 13C-labeled carbon atoms with an alkenyl stannane,
which afforded the trisubstituted E-olefin stereoselectively in high
yield. The E-olefin was then transformed into the corresponding all-
E-retinal.
*
*
*
18
1:6s-cis
1:6s-trans
Figure 1 Conformations of retinal
Key words: alkenyl stannane, coupling reaction, labeled retinal,
solid-state NMR, vinyl nonaflate
We recently reported an efficient method for the prepara-
tion of 9Z-retinoic acid analogs using a palladium-cata-
lyzed coupling reaction of vinyl triflate, which was
derived from 2,6,6-trimethyl-1-cyclohexen-1-acetalde-
hyde, with (Z)-3-tributylstannyl-2-propenol derivatives.9
However, when we applied this method to the preparation
of 8,18-13C2 retinal 1, through the reaction of labeled vinyl
triflate with (E)-3-tributylstannyl-2-butenol, we were un-
able to synthesize the labeled triflate (Scheme 1).
It is well known that retinal is the chromophore in protein
pigments, such as rhodopsin, bacteriorhodopsin and
phoborhodopsin.2 These proteins perform significant
functions in their respective vital cells and the conforma-
tion of the retinal chromophore plays an important role.
Over the past two decades, a number of reports on the syn-
thesis of retinal analogs have been published. Retinal an-
alogs are required to examine the retinal structure and
protein environment around the retinal chromophore in
the pigments.3 Recently, it has been shown that a new sol-
id-state NMR method for the measurement of internuclear
distances in retinal proteins using double 13C-labeled reti-
nal, or 13C-labeled retinal4 and 13C-enriched apo-protein5,
is a powerful tool that can be used to determine the chro-
mophore structure in a protein. In order to investigate the
conformation around the cyclohexene ring of the chro-
mophore (6s-cis or 6s-trans) in phoborhodopsin, which
was obtained from Halobacterium halobium, we have
synthesized (all-E)-8,16-ethanoretinal (fixed with 6s-
trans) and (all-E)-8,18-ethanoretinal (fixed with 6s-cis).
Binding experiments using these molecules suggested
that retinal has a 6s-trans conformation in the protein.6 In
order to verify this conformation using solid-state NMR
we required the double 13C-labeled retinal at the 8 and 18
positions (8,18-13C2 retinal 1; Figure 1).
R
R
9
OTf
Bu3Sn
Bu3Sn
OH
CO2H
OTf
1
*
OH
*
Scheme 1
Until now, it has been widely accepted that enol nona-
fluorobutanesulfonates (nonaflates, Nf) exhibit compara-
ble reactivity to enol triflates in coupling reactions and
afford the products in good yield. However, the published
reports on the subject are limited in number and are main-
ly restricted to the Heck reaction.10,11 Here we describe the
results of the Stille and Sonogashira coupling reactions
using the enol nonaflate derived from (2,6,6-trimethyl-1-
cyclohexen-1-yl)acetaldehyde. We also highlight the dif-
ference in its reactivity compared to that of the corre-
sponding enol triflate, which was included in our previous
communication.12 In addition, we report the highly stereo-
Enol trifluoromethanesulfonates (triflates, Tf) are useful
for the preparation of olefinic compounds via coupling re-
actions, such as the Heck, Stille, Suzuki and Sonogashira
reactions,7 and have been widely used in the synthesis of
natural products and related compounds.8
SYNTHESIS 2005, No. 10, pp 1581–1588
x
x.
x
x
.
2
0
0
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Advanced online publication: 07.04.2005
DOI: 10.1055/s-2005-865294; Art ID: F00105SS
© Georg Thieme Verlag Stuttgart · New York

1582
A. Wada et al.
PAPER
selective synthesis of 8,18-13C2-labeled all-E-retinal, Subsequently, we focused on the synthesis of labeled ret-
which was achieved by the application of the coupling re- inal. Our synthetic route started with the preparation of
action using enol nonaflate.
double 13C-labeled 2,6,6-trimethyl-1-cyclohexen-1-ace-
taldehyde (11). 13C-Labeled 2,6,6-trimethylcyclohex-
anone (9) was obtained by the reaction of 2,2-
dimethylcyclohexanone (8) and 13C-methyl iodide using
lithium diisopropylamide (LDA) as a base in 78% yield.
The addition of 1-13C-labeled lithium salt of ethyl acetate
to 9, followed by dehydration with thionyl chloride in py-
ridine, afforded the double 13C-labeled ester 10 in 73%
yield as the sole product. Reduction of the ester function
with LiAlH4 and subsequent oxidation using Mukaiya-
ma’s method16 gave the desired aldehyde 11 in 58% yield.
The aldehyde 11 was converted to the nonaflate 12 by
treatment with nonafluorobutanesulfonyl fluoride in the
presence of potassium tert-butoxide in THF at reflux for
one hour (modification of the reported conditions)17 in
63% yield as a single stereoisomer. The palladium-cata-
lyzed coupling of 12 with (E)-3-tributylstannyl-2-butenol
(4d) in the presence of a catalytic amount (2.5 mol%) of
Pd2(dba)3·CHCl3 with triphenylarsine (AsPh3) provided
the 9E-alcohol 13 in 67% yield. The structure of 13 was
determined by conversion to the aldehyde 14 using man-
ganese (IV) oxide (MnO2) oxidation (75%) and subse-
quent comparison of its spectral data with those
previously reported.18
Enol nonaflate 3a was prepared in 52% yield by treatment
of (2,6,6-trimethyl-1-cyclohexen-1-yl)acetaldehyde 213
with nonafluorobutanesulfonyl fluoride (NfF) using po-
tassium tert-butoxide as a base in THF and heating under
reflux14 for one hour. An alternative approach to access 3a
by reaction of the silyl enol ether derived from 2 with NfF
in the presence of a catalytic quantity of tetrabutylammo-
nium fluoride10a was unsuccessful. Enol nonaflate 3a is a
rather stable compound. If kept in the refrigerator at –30
°C, it can be stored for several months without decompo-
sition. Enol triflate 3b was obtained using our reported
method.9
Initially, in order to compare the reactivity in the coupling
reactions of enol nonaflate 3a or enol triflate 3b with
various (vinyl)tributylstannanes 4 and acetylenes 6, the
reactions were carried out using tris(dibenzylideneace-
tone)dipalladium–chloroform adduct (Pd2dba3·CHCl3) or
tetrakistriphenylphosphine palladium [Pd(PPh3)4] as a
catalyst (Scheme 2). The results are summarized in
Tables 1 and 2. In all cases, only one product (5 or 7) was
obtained and the coupling reaction proceeded stereospe-
cifically with retention of the double bond configuration.
The stereochemistry of the coupling product was deter-
The Horner–Emmons reaction of aldehyde 14 with tri-
ethyl phosphonocrotonate using n-BuLi as a base in the
presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyri-
midinone (DMPU)18 gave the ester 15 as a mixture of the
double-bond isomers [13E:13Z = ca. 83:17] in 87% yield.
The final transformation of the ester into the aldehyde was
achieved by a LiAlH4 reduction and subsequent MnO2 ox-
idation in 43% yield, and pure all-E-isomer 1 was ob-
tained after preparative high-performance liquid
chromatography (HPLC) (Scheme 3).
1
mined using H NMR.15 When (vinyl)tributylstannanes
that contained an electron-withdrawing group were used,
high temperatures and extended reaction times were re-
quired in order to ensure completion of the coupling reac-
tion with enol nonaflate.
It is notable that the enol nonaflate 3a displayed a slightly
higher reactivity than that of the corresponding enol tri-
flate 3b except in cases of the olefin containing an elec-
tron-withdrawing group. This finding is in accordance
with that previously reported for the coupling of an aryl
nonaflate or an aryl triflate with an arylzinc bromide.11a
R1
R2
R1
Bu3Sn
4
R2
Pd2dba3·CHCl3,
AsPh3/DMF
5
t-BuOK,
OX
(47-quant.)
NfF/THF
CHO
R3
(52%)
R3
3a: X = Nf
b: X = Tf
2
6
Pd(PPh3)4, Et3N,
CuI/C6H6
7
(33-quant.)
Scheme 2
Synthesis 2005, No. 10, 1581–1588 © Thieme Stuttgart · New York

PAPER
A Highly Stereoselective Synthesis of 8,18-13C2-Labeled Retinal
1583
Table 1 Cross-Coupling of Enol Perfluorosulfonate 3 with Various (Vinyl)tributylstannanes 4
Entry
1
Stannane 4
Reaction time (h) Temp
Product 5
Yield (%)a
from 3a
from 3b
3
3
3
r.t.
r.t.
r.t.
quant.
quant.
quant.
63
Bu3Sn
OH
OH
4a
5a
5b
2
3
62
75
Bu3Sn
OH
4b
OH
Bu3Sn
4c
5c
4
5
2
r.t.
r.t.
quant.
92
69
87
OH
Bu3Sn
OH
4d
5d
2
Bu3Sn
OH
OH
4e
5e
6
7
8
0.5
r.t.
91
47
57
73
45
61
Ph
Ph
Bu3Sn
4f
5f
14
r.t.
SiMe3
SiMe3
Bu3Sn
4g
5g
5
3
80 °C
CO2Et
CO2Et
Bu3Sn
4h
5h
5i
9
80 °C
62
63
Bu3Sn
CO2Et
CO2Et
4i
a Isolated yield.
O
*
CO2Et
*
O
CHO
a
b, c
d, e
f
*
8
9
10
11
*
*
13
9
ONf
X
X
g
i
*
*
*
*
12
*
*
13 X = CH2OH
14 X = CHO
15 X = CO2Et
h
d, h
16 X = CHO
Bu3Sn
OH
4d
Scheme 3 Reagents and conditions: a) LDA, 13C-MeI–THF, r.t., 78%; b) LDA, 1-13C-EtOAc–THF, –78 °C, 79%; c) SOCl2–pyridine, 0 °C,
93%; d) LiAlH4–Et2O, 0 °C; e) i-PrMgBr, azodicarbonyldipiperidine–Et2O, r.t., 58% from 10; f) t-BuOK, C4F9SO2F–THF, reflux, 63%; g)
Pd2(dba)3·CHCl3, Ph3As, 7–DMF, r.t., 67%; h) MnO2–CH2Cl2, r.t., 75% from 13, 43% from 15; i) (EtO)2P(O)CH2C(Me)=CHCO2Et, n-BuLi–
THF, –78 °C, 87%.
Synthesis 2005, No. 10, 1581–1588 © Thieme Stuttgart · New York

1584
A. Wada et al.
PAPER
Table 2 Cross-Coupling of Enol Perfluorofulfonate 3 with Various Acetylenes 6
Entry
Acetylene 6
Reaction time (h) Temp
Product 7
Yield (%)a
from 3a
from 3b
b
1
2
14
2
r.t.
r.t.
33
–
OH
6a
OH
82c
70c
58
OTBS
7a
6b
3
4
5
2
2
3
r.t.
70
Ph
Ph
6c
7c
r.t.
quant.
64
78
21
SiMe3
SiMe3
CO2Et
6d
7d
80 °C
CO2Et
6e
7e
a Isolated yield.
b Not performed.
c After treatment with TBAF (2 steps).
Table 3 Spectroscopic Data for 5 and 7
Product
EI–HRMS: m/z
IR (CDCl3):
1H NMR (300 MHz, CDCl3):
d, J (Hz)
13C NMR (75 MHz, CDCl3): d
n (cm–1)
5a
Calcd for
C14H22O:
3610, 3446,
1.00 (s, 6 H), 1.44 (m, 2 H), 1.59 (m, 3 H), 1.69 19.2, 21.6, 28.8, 32.9, 34.0, 39.5,
2969, 1647, 1457 (s, 3 H), 2.02 (t, J = 7.0 Hz, 2 H), 4.19 (t, J = 7.0 63.6, 129.7, 129.9, 130.0, 132.1,
206.1669; found:
206.1667
Hz, 2 H), 5.78 (dt, J = 6.0, 15.0 Hz, 1 H), 6.03
(dd, J = 10.0, 16.0 Hz, 1 H), 6.14 (d, J = 16.0 Hz,
1 H), 6.31 (ddt, J = 1.0, 10.0, 15.0 Hz, 1 H)
132.3, 132.8
5b
5c
5d
5e
Calcd for
C14H22O:
206.1669; found:
206.1686
3610, 3450,
1.01 (s, 6 H), 1.45 (m, 2 H), 1.61 (m, 3 H), 1.71 19.1, 21.6, 28.8, 33.0, 34.0, 39.5,
2930, 1636, 1457 (s, 3 H), 2.01 (t, J = 6.0 Hz, 2 H), 4.32 (t, J = 7.0 58.9, 127.5, 127.7, 130.2, 131.8,
Hz, 2 H), 5.55 (dt, J = 7.0, 10.0 Hz, 1 H), 6.15 (t, 133.6, 137.3
J = 10.0 Hz, 1 H), 6.23 (d, J = 16.0 Hz, 1 H), 6.32
(dd, J = 10.0, 16.0 Hz, 1 H)
Calcd for C13H20: 2931, 1633,
176.1564; found: 1596, 1458
176.1576
1.00 (s, 6 H), 1.45 (m, 2 H), 1.60 (m, 2 H), 1.69 19.2, 21.6, 28.9, 32.9, 34.0, 39.6,
(s, 3 H), 2.00 (t, J = 6.0 Hz, 2 H), 5.03 (d, J = 10.0 114.9, 129.7, 131.9, 133.8, 137.2,
Hz, 1 H), 5.14 (d, J = 17.0 Hz, 1 H), 6.04 (dd, J = 137.9
16.0, 10.0 Hz, 1 H), 6.14 (d, J = 16.0 Hz, 1 H),
6.40 (dt, J = 17.0, 10.0 Hz, 1 H)
Calcd for
C15H24O:
220.1826; found:
220.1843
3610, 3449,
1.00 (s, 6 H), 1.45 (m, 2 H), 1.60 (m, 3 H), 1.69 12.4, 19.2, 21.5, 28.8, 32.8, 34.1,
39.4, 59.4, 127.1, 128.3, 128.9,
4.26 (t, J = 7.2 Hz, 2 H), 5.62 (t, J = 7.2 Hz, 1 H), 136.9, 137.5
6.03 (d, J = 16.0 Hz, 1 H), 6.14 (d, J = 16.0 Hz,
1 H)
2960, 1615, 1458 (s, 3 H), 1.85 (s, 3 H), 2.00 (t, J = 6.0 Hz, 2 H),
Calcd for
C15H24O:
220.1826; found:
220.1821
3599, 3450,
2936, 1617, 1455 (s, 3 H), 1.91 (s, 3 H), 2.00 (t, J = 6.0 Hz, 2 H),
4.29 (t, J = 7.0 Hz, 2 H), 5.54 (t, J = 7.0 Hz, 1 H), 129.4, 136.0, 137.7
1.01 (s, 6 H), 1.45 (m, 2 H), 1.62 (m, 3 H), 1.70 19.2, 20.4, 21.6, 28.9, 32.9, 34.0,
39.4, 58.5, 126.8, 129.2, 129.3,
6.19 (d, J = 16.0 Hz, 1 H), 6.39 (d, J = 16.0 Hz,
1 H)
Synthesis 2005, No. 10, 1581–1588 © Thieme Stuttgart · New York

PAPER
A Highly Stereoselective Synthesis of 8,18-13C2-Labeled Retinal
1585
Table 3 Spectroscopic Data for 5 and 7 (continued)
Product
EI–HRMS: m/z
IR (CDCl3):
1H NMR (300 MHz, CDCl3):
d, J (Hz)
13C NMR (75 MHz, CDCl3): d
n (cm–1)
5f
Calcd for C19H24: 2932, 1593, 1490 0.98 (s, 6 H), 1.45 (m, 2 H), 1.62 (m, 2 H), 1.75 19.2, 21.7, 28.9, 33.2, 34.2, 39.7,
252.1877; found:
252.1869
(s, 3 H), 2.00 (t, J = 6.0 Hz, 2 H), 6.18–6.26 (dd, 111.9, 126.1, 128.5, 130.3, 131.4,
J = 10.0, 16.0 Hz, 1 H), 6.30 (d, J = 16.0 Hz, 1
H), 6.49 (d, J = 16.0 Hz, 1 H), 6.89 (dd, J = 10.0,
16.0 Hz, 1 H), 7.16–7.42 (m, 5 H)
132.2, 133.4, 134.9, 137.5, 141.0
5g
5h
Calcd for
C16H28Si:
248.1959; found:
248.1957
2961, 1627,
1598, 1457
0.09 (s, 9 H), 1.02 (s, 6 H), 1.45 (m, 2 H), 1.60
–1.2, 19.2, 21.7, 28.8, 33.1, 34.1,
(m, 2 H), 1.71 (s, 3 H), 2.00 (t, J = 6.0 Hz, 2 H), 39.6, 130.0, 131.5, 132.1, 136.01,
5.76 (d, J = 16.0 Hz, 1 H), 6.05 (dd, J = 10.0, 16.0 137.2, 145.1
Hz, 1 H), 6.17 (d, J = 16.0 Hz, 1 H), 6.58 (dd, J =
10.0, 16.0 Hz, 1 H)
Calcd for
C16H24O2:
248.1775; found:
248.1788
2933, 1699,
1619, 1458
1.03 (s, 6 H), 1.30 (t, J = 7.2 Hz, 3 H), 1.45 (m, 2 14.3, 19.0, 21.6, 28.8, 33.3, 34.0,
H), 1.61 (m, 2 H), 1.72 (s, 3 H), 2.03 (t, J = 6.0
Hz, 2 H), 4.21 (q, J = 7.2 Hz, 2 H), 5.82 (d, J =
16.0 Hz, 1 H), 6.20 (dd, J = 11.0, 16.0 Hz, 1 H),
6.57 (d, J = 16.0 Hz, 1 H), 7.34 (dd, J = 11.0, 16.0
Hz, 1 H)
39.6, 60.1, 119.2, 130.5, 132.9,
136.9, 140.4, 145.7, 167.3
5i
Calcd for
C16H24O2:
248.1775; found:
248.1779
2933, 1703,
1608, 1458
1.07 (s, 6 H), 1.29 (t, J = 7.2 Hz, 3 H), 1.45 (m, 2 14.2, 19.0, 21.8, 28.8, 33.6, 34.0,
H), 1.61 (m, 2 H), 1.79 (s, 3 H), 2.05 (t, J = 6.0
Hz, 2 H), 4.18 (q, J = 7.2 Hz, 2 H), 5.59 (d, J =
11.0 Hz, 1 H), 6.51 (d, J = 16.0 Hz, 1 H), 6.61 (t,
J = 11.0 Hz, 1 H), 7.47 (dd, J = 11.0, 16.0 Hz, 1
H)
39.9, 59.7, 115.5, 128.9, 133.9,
136.9, 140.7, 125.9, 166.7
7a
Calcd for
3608, 3450,
1.00 (s, 6 H), 1.44 (m, 2 H), 1.59 (m, 3 H), 1.70 19.0, 21.5, 28.7, 33.0, 33.9, 39.4,
C14H20O:
204.1513; found:
204.1520
2932, 2209, 1604 (s, 3 H), 1.99 (t, J = 6.0 Hz, 2 H), 4.41 (d, J = 4.0 51.7, 85.3, 87.0, 111.2, 131.6,
Hz, 2 H), 5.47 (dt, J = 2.0, 16.5 Hz, 1 H), 6.59 (d, 136.8, 141.7
J = 16.0 Hz, 1 H)
7c
7d
7e
Calcd for C19H22: 2932, 2360,
250.1721; found: 1593, 1489
250.1712
1.05 (s, 6 H), 1.45 (m, 2 H), 1.61 (m, 2 H), 1.76 19.0, 21.6, 28.8, 33.1, 34.0, 39.6,
(s, 3 H), 2.00 (t, J = 6.0 Hz, 2 H), 5.68 (d, J = 16.0 89.2, 89.4, 118.9, 123.7, 127.8,
Hz, 1 H), 6.68 (d, J = 16.0 Hz, 1 H), 7.25–7.35
128.2, 131.4, 131.7, 137.1, 141.0
(m, 5 H)
Calcd for
C16H26Si:
2961, 2123,
1598, 1457
0.21 (s, 9 H), 0.98 (s, 6 H), 1.45 (m, 2 H), 1.58
–0.1, 19.0, 21.5, 28.7, 33.1, 34.0,
(m, 2 H), 1.71 (s, 3 H), 2.00 (t, J = 6.0 Hz, 2 H), 39.6, 93.9, 104.9, 111.8, 131.9,
2461803; found:
246.1802
5.50 (d, J = 16.5 Hz, 1 H), 6.63 (d, J = 16.5 Hz,
136.9, 141.9
1 H)
Calcd for
2933, 2207,
1.00 (s, 6 H), 1.35 (t, J = 7.2 Hz, 3 H), 1.45 (m, 2 14.0, 18.9, 21.5, 28.7, 33.4, 34.0,
C16H22O2:
246.1618; found:
246.1627
1699, 1619, 1458 H), 1.60 (m, 2 H), 1.73 (s, 3 H), 2.03 (t, J = 6.0
Hz, 2 H), 4.25 (q, J = 7.2 Hz, 2 H), 5.56 (d, J =
6.0 Hz, 1 H), 6.95 (d, J = 16.0 Hz, 1 H)
40.0, 61.8, 80.9, 86.7, 134.7,
136.7, 147.8, 154.2, 111.9
LC-6A instrument with a Shimadzu UV-VIS detector (SPD-6AV)
and a LiChrosorb Si-60 column (5 mm, 1.0 × 30 cm). All reactions
were carried out under a N2 atmosphere. THF and Et2O were puri-
fied by distillation from benzophenone-sodium ketyl under N2.
Commercially available chemicals were used without further puri-
fication, except when otherwise stated. Diisopropylamine was puri-
fied by distillation from CaH2. 13C-methyl iodide and ethyl 1-13C-
acetate were purchased from Aldrich. Standard workup means that
the organic layers were washed with brine, dried over anhyd
Na2SO4, filtered and concentrated in vacuo below 30 °C using a ro-
tary evaporator.
In summary, we have demonstrated that the enol nonaflate
displays higher reactivity than that of the enol triflate in
the palladium-catalyzed coupling reactions, and have also
accomplished the stereoselective synthesis of 8,18-13C2
all-E-retinal 1. Binding experiments with the apo-protein
are currently in progress.
UV spectra were recorded using a JASCO Ubest-55 instrument and
IR spectra were recorded using a Perkin-Elmer FT-IR Paragon 1000
1
spectrometer. H NMR spectra were obtained using a Varian Ge-
mini-200 or Gemini-300 NMR spectrometer in CDCl3, unless oth-
(E)-2-(2,6,6-Trimethylcyclohexen-1-yl)ethenyl Nonafluorobu-
tanesulfonate (3a)
A solution of the aldehyde (2, 498 mg, 3.0 mmol), t-BuOK (505 mg,
1.9 mmol) and nonafluorobutanesulfonyl fluoride (586 mg, 4.5
mmol) in THF (20 mL) was heated under reflux for 1 h. After cool-
ing, the reaction was quenched with sat. aq NH4Cl (50 mL) and ex-
1
erwise stated. Coupling constants between 13C and H nuclei are
shown as 1J, 2J and 3J for one-, two- and three-bond couplings, re-
spectively. Mass spectra were determined using a Hitachi M-4100
instrument. Column chromatography was performed using Merck
silica gel 60. Preparative HPLC was conducted using a Shimadzu
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1586
A. Wada et al.
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tracted using Et2O (3 × 70 mL), followed by the standard workup.
The residue was purified using column chromatography (eluting
with hexane) to give the enol nonaflate 3a (713 mg, 52%) as a col-
orless oil.
evaporation of the solvent, the organics were extracted with Et2O
(3 × 70 mL), followed by the standard workup. The residue was pu-
rified using column chromatography (Et2O–hexane, 1:5) to give the
hydroxy ester (2.75 g, 79%) as a pale yellow oil.
IR (CHCl3): 2962, 2935, 1645, 1423 cm–1.
Thionyl chloride (1.3 ml, 18 mmol) was added to a solution of the
hydroxy ester (2.75 g, 12 mmol) in pyridine (20 mL) at 0 °C, and
the resulting mixture was stirred for 10 min. The reaction was
quenched with 5% HCl (200 mL) with cooling in an ice bath, and
the organics were extracted using Et2O (3 × 80 mL) followed by the
standard workup. The residue was purified using column chroma-
tography (Et2O–hexane, 1:6) to give the ester (10, 2.31 g, 93%) as a
colorless oil.
1H NMR (300 MHz): d = 0.98 (s, 6 H, 2 × Me), 1.40–1.70 (m, 4 H,
2 × CH2), 1.68 (s, 3 H, Me), 1.90–2.70 (m, 2 H, CH2), 6.22 (br d, J =
12.0 Hz, 1 H, CH), 6.45 (d, J = 12.0 Hz, 1 H, CH).
HRMS: m/z calcd for C15H17F9O3S: 448.0753; found: 448.0754.
UV (EtOH): lmax = 235.5 nm.
IR (CHCl3): 2958, 2932, 1728, 1593 cm–1.
Coupling with Vinyl Stannanes; Typical Procedure
Pd2dba3·CHCl3 adduct (2.5 mol%, 26 mg) was added to a stirred so-
lution of enol nonaflate (3a, 1 mmol), (vinyl)tributylstannane (4, 1.5
mmol) and AsPh3 (20 mol%, 60 mg) in DMF (2 mL) in one portion
under a N2 atmosphere. After stirring for the period indicated in
Table 1, the reaction was quenched with sat. aq NH4Cl solution (3
mL) and extracted with Et2O (3 × 10 mL). The extracts were washed
with sat. aq NaCl solution (10 mL) and then dried over Na2SO4. The
solvent was removed under reduced pressure and the residue was
purified using column chromatography on silica to afford the cou-
pled product 5. The yield of each reaction is shown in Table 1 and
the spectral data for each product are summarized in Table 3.
1H NMR (300 MHz): d = 0.96 (s, 6 H, 2 × Me), 1.24 (t, J = 7.0 Hz,
3 H, CO2CH2CH3), 1.59 (d, 1J = 125 Hz, 3 H, Me) 1.30–1.70 (m, 4
H, 2 × CH2) 1.90–2.10 (t, 2 H, CH2), 3.04 (d, 2J = 8.0 Hz, 2 H, CH2),
4.12 (qd, J = 7.0 Hz, 3J = 3.0 Hz, 2 H, CO2CH2CH3).
HRMS: m/z calcd for C1113C2H22O2: 212.1686; found: 212.1687.
(8,18-13C2)-(2,6,6-Trimethylcyclohexen-1-yl)acetaldehyde (11)
A solution of the ester (10, 1.9 g, 9.4 mmol) in anhyd Et2O (10 mL)
was added dropwise to a suspension of LiAlH4 (410 mg, 11 mmol)
in anhyd Et2O (30 mL) at 0 °C. After stirring for an additional 30
min at the same temperature, the excess LiAlH4 was destroyed by
the addition of sat. potassium sodium tartrate solution (10 mL). Af-
ter removal of the resulting solid by suction filtration, the filtrate
was extracted using Et2O (3 × 40 mL) followed by the standard
workup to give the crude alcohol (1.5 g, 8.8 mmol).
Coupling with Acetylenes; Typical Procedure
Pd(PPh3)4 (10 mol%, 58 mg) was added to a stirred solution of enol
nonaflate (3a, 0.5 mmol), acetylene (6, 1 mmol), diisopropylamine
(2 mmol, 200 mg) and CuI (15 mol%, 35 mg) in benzene (3 mL) in
one portion under a N2 atmosphere. After stirring for the indicated
period in Table 2, the reaction was quenched with sat. aq NH4Cl so-
lution (3 mL) and extracted with Et2O (3 × 10 mL). The extracts
were washed with sat. aq NaCl solution (10 mL) and then dried over
Na2SO4. The solvent was removed under reduced pressure and the
residue was purified using column chromatography on silica to pro-
vide the coupled product 7. The yield of each reaction is cited in
Tables 1 and 2, and the spectral data for each product are summa-
rized in Table 3.
Diisopropylmagnesium bromide (0.71 M Et2O solution, 16 mL,
11.4 mmol) was added to a dissolved solution of the alcohol in an-
hyd THF (10 mL) at 0 °C. After stirring for 10 min, a solution of
azodicarbonyldipiperidine (2.7 g, 10 mmol) in anhyd THF (5 mL)
was added at 0 °C, and the resulting mixture was stirred for an ad-
ditional 2 h. The reaction was quenched with brine (20 mL) and the
organics were extracted using Et2O (3 × 30 mL) followed by the
standard workup. The residue was purified using column chroma-
tography (Et2O–hexane, 1:4) to afford the aldehyde (11, 870 mg,
58%) as a pale yellow oil.
(18-13C)-2,2,6-Trimethylcyclohexanone (9)19
IR (CHCl3): 2959, 2933, 1678, 1468 cm–1.
A solution of 2,2-dimethylcyclohexanone (8, 3.5 g, 28 mmol) in
THF (7 mL) was added to a stirred solution of LDA prepared from
n-BuLi (1.56 M hexane solution, 20 mL, 31 mmol) and diisopropy-
lamine (3.12 g, 31 mmol) in THF (30 mL), at –70 °C. The resulting
mixture was allowed to warm to r.t. and then stirred for an addition-
al 2 h. A solution of 13C-methyl iodide (2.0 g, 14 mmol) in THF (4
mL) was added at –70 °C and the mixture was stirred for a further 2
h. After the addition of sat. aq NH4Cl (80 mL) and evaporation of
the solvent, the organics were extracted with Et2O (3 × 70 mL), fol-
lowed by the standard workup. The residue was purified using col-
umn chromatography (Et2O–hexane, 1:5) to give the ketone (9, 1.54
g, 78% based on 13C-MeI) as a pale-yellow oil.
1H NMR (300 MHz): d = 0.97 (s, 6 H, 2 × Me), 1.40–1.50 (m, 2 H,
CH2), 1.57 (d, 1J = 125.5 Hz, 3 H), 1.50–1.70 (m, 2 H, CH2), 1.90–
2.10 (m, 2 H, CH2), 3.09 (br d, 2J = 7.5 Hz, 2 H, CH2), 9.51 (td, J =
2.5 Hz, 1J = 173 Hz, 1 H, CHO).
HRMS: m/z calcd for C913C2H18O: 168.1424; found: 168.1421.
(8,18-13C2)-(E)-2-(2,6,6-Trimethylcyclohexen-1-yl)ethenyl
Nonafluorobutanesulfonate (12)
A solution of the aldehyde (11, 216 mg, 1.3 mmol), t-BuOK (218
mg, 1.9 mmol) and nonafluorobutanesulfonyl fluoride (586 mg, 1.9
mmol) in THF (12 mL) was heated under reflux for 1 h. After cool-
ing, the reaction was quenched with sat. aq NH4Cl (30 mL) and ex-
tracted using Et2O (3 × 50 mL), followed by the standard workup.
The residue was purified using column chromatography (hexane) to
give the enol nonaflate 12 (366 mg, 63%) as a colorless oil.
IR (CHCl3): 2960, 2928, 1702 cm–1.
1H NMR (300 MHz): d = 0.98 (dd, J = 6.5 Hz, 1J = 126.5 Hz, 3 H,
Me), 1.04 (s, 3 H, Me), 1.18 (s, 3 H, Me), 1.20–1.70 (m, 4 H, 2 ×
CH2), 2.00–2.10 (m, 2 H, CH2), 2.50–2.70 (m, 1 H, CH).
IR (CHCl3): 2962, 2935, 1645, 1423 cm–1.
HRMS: m/z calcd for C813CH16O: 141.1234; found: 141.1228.
1H NMR (300 MHz): d = 0.98 (s, 6 H, 2 × Me), 1.40–1.70 (m, 4 H,
2 × CH2), 1.68 (d, 1J = 126.0 Hz, 3 H, Me), 1.90–2.70 (m, 2 H, CH2),
6.22 (dd, J = 12.0 Hz, 2J = 11.0 Hz, 1 H, CH), 6.45 (dd, J = 12.0 Hz,
1J = 206.5 Hz, 1 H, CH).
HRMS: m/z calcd for C1313C2H17F9O3S: 450.0821; found:
450.0802.
(8,18-13C2) Ethyl (2,6,6-Trimethylcylohexen-1-yl)acetate (10)
A solution of ethyl 1-13C-acetate (2.0 g, 22.5 mmol) in THF (3 mL)
was added to a stirred solution of LDA prepared from n-BuLi (1.56
M hexane solution, 15.8 mL, 24.7 mmol) and diisopropylamine (2.5
g, 24.7 mmol) in THF (20 mL) at –70 °C. The resulting mixture was
stirred for an additional 30 min. A solution of the ketone (9, 2.1 g,
15 mmol) in THF (10 mL) was added at –70 °C and the mixture was
further stirred for 2 h. After addition of sat. aq NH4Cl (80 mL) and
UV (EtOH): lmax = 235.5 nm.
Synthesis 2005, No. 10, 1581–1588 © Thieme Stuttgart · New York

PAPER
A Highly Stereoselective Synthesis of 8,18-13C2-Labeled Retinal
1587
(8,18-13C2)-(2E,4E)-3-Methyl-5-(2,6,6-trimethylcyclohexen-1-
yl)-2,4-pentadienol (13)
(8,18-13C2) (All-E)-Retinal (1)
A solution of the ester (15, 245 mg, 0.74 mmol) in anhyd Et2O (5
mL) was added to a stirred suspension of LiAlH4 (50 mg, 1.3 mmol)
in anhyd Et2O (20 mL) at 0 °C. The resulting mixture was stirred at
0 °C for 15 min and then the excess LiAlH4 was destroyed by the
addition of aq potassium sodium tartrate (10 mL). The precipitate
was removed by filtration through Celite® and washed with Et2O
(20 mL). The filtrate was dried over Na2SO4, and then concentrated
to give the hydroxy compound as a pale yellow oil. A mixture of the
resulting hydroxy compound and active MnO2 (2.1 g, 24 mmol) in
anhyd CH2Cl2 (20 mL) was shaken at r.t. for 3 h and then filtered
through Celite®. Evaporation of the filtrate gave an oil that was pu-
rified using column chromatography (Et2O–hexane, 1:9) to yield
the aldehyde (90 mg, 43%) as an orange oil. Pure all-E-isomer 1 was
obtained by preparative HPLC using 12% Et2O–hexane as an elu-
ent.
Pd2(dba)3·CHCl3 (128 mg, 0.125 mmol, 0.05 equiv) was added to a
stirred solution of triflate (12, 1.1 g, 2.5 mmol), triphenylarsin (152
mg, 0.5 mmol) and E-3-tributylstannyl-2-butenol (4d, 941 mg, 2.6
mmol, 2 equiv) in DMF (4 mL) at r.t. under N2. The resulting mix-
ture was stirred for 2 h and the reaction was quenched with sat. aq
NaCl (5 mL) and extracted with Et2O (3 × 10 mL) followed by the
standard workup. The residue was purified using column chroma-
tography (Et2O–hexane, 3:7) to afford the coupled alcohol 13 (371
mg, 67%) as a colorless oil.
IR (CHCl3): 3609, 3454, 2958, 2929, 1627, 1458 cm–1.
1H NMR (300 MHz): d = 1.00 (s, 6 H, 2 × Me), 1.40–1.70 (m, 5 H,
3
2 × CH2, OH), 1.68 (d, 1J = 122.5 Hz, 3 H, Me), 1.85 (d, J = 4.0
Hz, 3 H, Me), 2.00 (br t, J = 6.5 Hz, 2 H), 4.30 (br t, J = 6.0 Hz, 2
H, CH2), 5.62 (q, J = 3J = 6.0 Hz, 1 H, CH), 6.03 (dd, J = 17.0 Hz,
1J = 154.5 Hz, 1 H, CH), 6.13 (br d, J = 17.0 Hz, 1 H, CH).
IR (CHCl3): 2960, 2928, 1655, 1594, 1559 cm–1.
1H NMR (300 MHz, C6D6): d = 1.11 (s, 6 H, 2 × Me), 1.40–1.80 (m,
6 H, 3 × CH2), 1.76 (d, 1J = 125.5 Hz, 3 H, Me), 1.78 (d, 3J = 4.0 Hz,
3 H, Me), 1.94 (s, 3 H, Me), 5.95 (d, J = 8.0 Hz, 1 H, CH), 6.03 (d,
J = 15.0 Hz, 1 H, CH), 6.04 (dd, J = 11.0 Hz, 3J = 8.0 Hz, 1 H, CH),
6.31 (dd, J = 17.0 Hz, 1J = 137.5 Hz, 1 H, CH), 6.35 (br d, J = 17.0
Hz, 1 H, CH), 6.84 (dd, J = 11.5, 15.0 Hz, 1 H, CH), 10.01 (d, J =
8.0 Hz, 1 H, CHO).
HRMS: m/z calcd for C1313C2H24O: 222.1893; found: 222.1909.
UV (EtOH): lmax = 260, 237 nm.
(8,18-13C2)-(2E,4E)-3-Methyl-5-(2,6,6-trimethylcyclohexen-1-
yl)-2,4-pentadienal (14)
A mixture of the alcohol (13, 160 mg, 0.72 mmol) and MnO2 (2.0
g, 23 mmol) in anhyd CH2Cl2 (10 mL) was stirred at r.t. for 3 h. Af-
ter filtration through Celite®, the filtrate was concentrated under re-
duced pressure. The residue was purified using column
chromatography (Et2O–hexane, 1:4) to afford the aldehyde (14, 118
mg, 75%) as a pale yellow oil.
HRMS: m/z calcd for C1813C2H28O: 286.2206; found: 286.2186.
UV (EtOH): lmax = 377 nm.
Acknowledgment
IR (CHCl3): 2959, 2931, 1656, 1593 cm–1.
This work was supported, in part, by the Kobe Pharmaceutical Uni-
versity Collaboration Fund and The Science Research Promotion
Fund from the Japan Private School Promotion Foundation.
1H NMR (300 MHz): d = 1.04 (s, 6 H, 2 × Me), 1.40–1.70 (m, 4 H,
2 × CH2), 1.72 (d, 1J = 126.0 Hz, 3 H, Me), 2.21 (br t, J = 6.5 Hz, 2
H), 2.31 (d, 3J = 4.0 Hz, 3 H, Me), 5.93 (dd, J = 8.0 Hz, 3J = 9.0 Hz,
1 H, CH), 6.20 (dd, J = 16.5 Hz, 1J = 155.5 Hz, 1 H, CH), 6.74 (br
d, J = 16.5 Hz, 1 H, CH), 10.13 (d, J = 8.0 Hz, 1 H, CHO).
References
HRMS: m/z calcd for C1313C2H22O: 220.1736; found: 220.1753.
(1) Retinoids and related compounds: Part 28. See also Part 27:
Wada, A.; Fukunaga, K.; Ito, M.; Mizuguchi, Y.; Nakagawa,
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(2) The chromophore of rhodopsin is (11Z)-retinal, and those of
the others are (all-E)-retinal, respectively: (a) Yoshizawa,
T.; Wald, G. Nature (London) 1963, 197, 1279. (b) Hara,
T.; Hara, R. Nature (London) 1968, 219, 450.
UV (EtOH): lmax = 324, 283 nm.
(8,18-13C2)-Ethyl all-E-Retinoate (15)
n-BuLi (1.59 M hexane solution, 0.68 mL 1.1 mmol) was added to
a solution of triethyl 3-methyl-4-phosphonocrotonate (285 mg, 1.1
mmol) and DMPU (460 mg, 3.6 mmol) in THF (5.5 mL) at 0 °C.
After stirring for 30 min, the solution was cooled to –78 °C and a
solution of the aldehyde (14, 198 mg, 0.9 mmol) in THF (3 mL) was
added. The resulting mixture was stirred for an additional 2 h. The
reaction was quenched with sat. NH4Cl (5 mL) and extracted using
Et2O (3 × 20 mL), followed by the standard workup. The residue
was purified by column chromatography (Et2O–hexane, 1:9) to give
the pentaenyl ester (15, 258 mg, 87%) as a pale yellow oil. NMR
analysis indicated that the all-E- and 13Z-isomers of the double
bond were present in a ratio of 83:17.
(c) Stoeckenius, W.; Bogomolni, R. A. Annu. Rev. Biochem.
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IR (CHCl3): 2959, 2929, 1698, 1598, 1576 cm–1.
1H NMR (300 MHz): d = 1.03 (s, 6 H, 2 × Me), 1.29 (t, J = 7.0 Hz,
3 H, CO2CH2CH3), 1.40–1.70 (m, 4 H, 2 × CH2), 1.67 (d, 1J = 146.5
Hz, 3 H, Me), 2.00 (d, 3J = 3.0 Hz, 3 H, Me), 2.05 (br t, J = 6.5 Hz,
2 H, CH2), 2.35 (s, 3 H, Me), 4.17 (q, J = 7.0 Hz, 2 H, CO2CH2CH3),
5.77 (s, 1 H, CH), 6.14 (dd, J = 16.5 Hz, 1J = 154.5 Hz, 1 H, CH),
6.15 (dd, J = 11.5 Hz, 3J = 8.0 Hz, 1 H, CH), 6.26 (br d, J = 16.5 Hz,
1 H, CH), 6.28 (d, J = 15.0 Hz, 1 H, CH), 6.99 (dd, J = 11.5, 15.0
Hz, 1 H, CH).
HRMS: m/z calcd for C2013C2H32O2: 330.2468; found: 330.2483.
Derguiri, F.; Bigge, C. F.; Chen, A.-H.; Hu, S.; Wang, J.;
UV (EtOH): lmax = 352 nm.
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1588
A. Wada et al.
PAPER
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Synthesis 2005, No. 10, 1581–1588 © Thieme Stuttgart · New York