2206
D. P. Hruszkewycz et al.
PRACTICAL SYNTHETIC PROCEDURES
a Beckman Instruments unit (model 127 pump, model 166 detector)
using 1 mL/min of 90% MeOH–H2O through a Polaris C18,
4.6 × 250 mm column with monitoring at 360 nm. 1H and 13C NMR
spectra were recorded in acetone-d6 on a Bruker DRX400 instru-
ment (400 MHz for 1H). Electrospray mass spectra were measured
on a Micromass QTOF mass spectrometer in the Ohio State Univer-
sity Campus Chemical Instrument Center.
In our experience, alkaline hydrolysis of 8 on larger scales
leads to significant decomposition of the base labile 2.
This is a sufficiently general problem that Sigma-Aldrich
has introduced a flow process microreactor useful for this
situation and has applied the device (costing ca. $25000)
to the industrial-scale saponification of 8 to 2 in 70%
yield.8 Alternatively, reductive cleavage of 8 to 2 has been
used with little detail provided.9 In our hands, this ap-
proach also results in significant decomposition of 2.
Once 2 is obtained, oxidation to 1 is most frequently ac-
complished using activated MnO2.10 We and others find
that reacting 2 with activated MnO2 does produce 1, but
typically requires many days of stirring. Also, variable
Retinal (1)
To a stirred solution of 8 (1.08 g, 3.28 mmol) in anhyd MeOH was
added Na pieces (0.078 g, 3.38 mmol) and the mixture was allowed
to stir for 45–60 min at which time TLC indicated the complete con-
sumption of 8. The solution was concentrated by one half and
passed through a column containing Amberlite IRA-400 (chloride
form, 0.8 g, 1.4 meq/mL exchange capacity) and the eluent was con-
and sometimes poor recoveries with overoxidation prod- centrated. The residue containing 2 was suspended in CH2Cl2 (5
mL) and the soluble portion eluted into a column composed of a
slurry of oven-dried MnO2 (5.4 g, 61.87 mmol) and of diatoma-
ceous earth (53.8 g) in CH2Cl2 (200 mL). Once the crude 2 was elut-
ed well into the column bed, flow was stopped for 12 h and the
uct contaminants are observed. Many years ago, Wald
passed 2 over a MnO2 column to produce 1 smoothly, al-
though the extent of side-product formation increased
with column length.11 Thus, an improved, low-cost pro-
column was protected from light and air. The column was then elut-
cess for generating 1 would be useful.
ed with CH2Cl2, the solvent was evaporated, and the residue was
column chromatographed (silica gel; 19:1 hexanes–EtOAc, then 9:1
hexanes–EtOAc) to give 0.85 g (90%) of solid 1 and 0.08 g (8%) of
liquid 13-cis isomer15 of retinal.
We hypothesized that transesterification of 8 in anhydrous
methanol with catalytic sodium would generate 2 with
minimal exposure to base. We were disappointed to learn
that this process has been tried and requires many hours
for completion (20–24 h) and gives only modest yields of
2 (40–50%).12 However, when one equivalent of sodium
metal and a dilute methanolic solution of 8 (Scheme 1)
were employed, the transesterification was complete in
30–60 minutes and the resulting 2 could be separated from
the basic medium quickly by volume reduction and pas-
sage through an ion-exchange resin (Amberlite IRA-400,
chloride form). After extensive experimentation on the ra-
tio of MnO2 to 2 and the ratio of inert matrix to MnO2, it
was determined that a column packed with a 5–10:1 (w/w)
mixture of diatomaceous earth to MnO2 containing 20
equivalents of MnO2 relative to 8, and eluted with CH2Cl2,
readily oxidizes 2 to 1. Depending on reaction scale, the
retinoid-containing column needs to sit for 2–12 hours
prior to elution with CH2Cl2 to effect complete oxidation,
although 3.5 hours is usually a sufficient delay before elu-
tion. Careful column chromatography can then separate
the resulting isomers of 1. Yields of the retinal (1) over the
two steps on a one-gram scale have been as good as 98%
with a 92:8 ratio of the separated all-trans/13-cis isomers
being formed. If it proves desirable to avoid the final
lengthy column chromatography, formation of the revers-
ible crystalline retinal complex with hydroquinone13 al-
lows for easy isolation of at least 55% of the all-trans
retinal. The remaining sample enriched in the 13-cis iso-
mer can then be subjected to iodine-catalyzed photoi-
somerization.14 In our hands, this produced a 3:1
equilibrium mixture of all-trans/13-cis isomer in 1.5
hours from which more all-trans isomer could be isolated.
Alternatively, to a solution of retinal isomer mixture in Et2O (ca.
500 mg/mL) was added 3 volumes of a warm ethereal solution of
hydroquinone (1.5 equiv). The Et2O was then evaporated with ar-
gon and the resulting pink solid triturated with petroleum ether (bp
35–60 °C) and allowed to stand on ice for 1 h. The solid was then
vacuum-filtered with cold petroleum ether rinsing, dissolved in
Et2O, washed 3 times with aq 5 N KOH (until all purple color was
extracted into the H2O), then with brine. Evaporation of the Et2O
provided the trans-1 in 55% yield. To a ~2 mg/mL methanolic so-
lution of the residue from the petroleum ether trituration (~5:1 13-
cis/trans retinal) was added 3 drops of a 3.2 mg/mL methanolic so-
lution of I2 and the solution was irradiated at 520 nm for 75 min. Af-
ter this time, HPLC analysis showed no further change to the then
3:1 mixture of trans/13-cis retinal from which more trans-1 could
be isolated by the hydroquinone complexation method.
Mp 58–59.5 °C; Rf = 0.37 (hexanes–EtOAc, 4:1); HPLC: tR = 9.8
min (>98%).1H NMR: d = 1.04 [s, 6 H, C(CH3)2], 1.48 (m, 2 H,
CH2), 1.62 (m, 2 H, CH2), 1.72 (s, 3 H, CH3) 2.04 (m, 2 H, CH2),
2.06 (s, 3 H, CH3), 2.37 (s, 3 H, CH3), 5.91 (d, J = 8 Hz, 1 H, 14-
CH), 6.2–6.5 (m, 4 H, vinyls), 7.29 (dd, J = 11.5, 14.1 Hz, 1 H, 12-
CH), 10.13 (d, J = 8 Hz, 1 H, CHO).
13C NMR (100 MHz): d = 12.95, 19.8, 21.9, 29.2, 33.6, 34.8, 40.2,
129.7, 129.8, 130.5, 130.7, 133.1, 135.8, 138.2, 138.4, 141.3, 155.1,
191.1.
HRMS (ESI): m/z [M + Na]+ calcd for C20H28O + Na: 307.2038;
found: 307.2025.
Acknowledgment
We gratefully acknowledge support in the form of a grant from the
National Cancer Institute (CA49837) as well as helpful discussions
with Prof. R. W. Doskotch.
References
All reagents were purchased as reagent grade from Sigma-Aldrich
and were used as obtained. Reactions were performed in oven-dried
glassware under an argon atmosphere and gold fluorescent lights.
Column chromatography was performed on silica gel 60 (70–230
mesh) from Merck. Analytical TLC was performed on silica gel 60
F245 aluminum plates from Merck. Analytical HPLC was done on
(1) Wald, G. Nature 1934, 134, 65.
(2) Ziouzenkova, O.; Orasanu, G.; Sharlach, M.; Akiyama, T.
E.; Berger, J. B.; Viereck, J.; Hamilton, J. A.; Tang, G.;
Dolnikowski, G. G.; Vogel, S.; Duester, G.; Plutzky, J. Nat.
Med. 2007, 13, 695.
Synthesis 2011, No. 14, 2205–2207 © Thieme Stuttgart · New York
Hruszkewycz, Damian P.
