An improved synthesis of retinal (Vitamin A Aldehyde)

Full text of DOI:10.1080/00304948.2013.798572

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Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
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An Improved Synthesis of Retinal
(
Vitamin A Aldehyde)
a
a
Davidson A. Sacolick & Robert W. Curley Jr.
a
Division of Medicinal Chemistry and Pharmacognosy, College of
Pharmacy , The Ohio State University , Columbus , OH , 43210 , USA
Published online: 24 Jun 2013.
To cite this article: Davidson A. Sacolick & Robert W. Curley Jr. (2013) An Improved Synthesis of
Retinal (Vitamin A Aldehyde), Organic Preparations and Procedures International: The New Journal for
Organic Synthesis, 45:4, 325-327, DOI: 10.1080/00304948.2013.798572
To link to this article: http://dx.doi.org/10.1080/00304948.2013.798572
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Organic Preparations and Procedures International, 45:325–327, 2013
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.798572
OPPI BRIEF
An Improved Synthesis of Retinal
Vitamin A Aldehyde)
(
Davidson A. Sacolick and Robert W. Curley, Jr.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy,
The Ohio State University, Columbus, OH 43210, USA
In recent years, we have been engaged in the synthesis and study of vitamin A analogs
1
,2
(
retinoids) as breast cancer chemotherapeutic and chemopreventive agents. For these
syntheses, a substantial amount of retinal (2, vitamin A aldehyde) is needed. This relatively
unstable polyene is expensive, costing about $200/g. Recently, we published an efficient
3
synthesis of 1 starting from retinyl acetate (1) which is available at low cost (<$5/g)
because of its production as a vitamin supplement. This synthesis proceeded with transes-
terification of 1 with methanol followed by oxidation of the obtained retinol upon passage
through a column of MnO2/diatomaceous earth. Although the yields of 2 were good, about
8% of the retinal obtained was the 13-cis isomer which required careful chromatographic
removal to give a solid product. We now find, however, that scaling of this oxidation column
to handle greater than about one gram g of 1 results in a column of unwieldy proportions
and slows elution of 1 sufficiently to result in a significant increase in the formation of
side-products and in a reduction in yields. We now report a modification of this synthesis
which is much faster, is easily scaled to use at least 5 g of 2 as starting material, and
3
produces no more than 2–4% of the 13-cis isomer of 1. As we previously reported, stirring
2
in a dilute anhydrous methanolic solution with one equivalent of sodium metal completes
transesterification to retinol in forty minutes. We now recommend no volume reduction
of the resulting solution before passage through an ion-exchange resin (Amberlite IRA-
400, chloride form) to give a quantitative yield of the base labile retinol, which is used as
obtained. Removal of methanol gives a red oil which is dissolved in a minimum amount
of dry dichloromethane followed by addition of activated MnO2 (25 equiv.) and dry ethyl
4
acetate. The thick suspension was stirred for 4.5–5.0 h to complete the oxidation to 2.
After filtration of the suspension through a pad of diatomaceous earth to remove insoluble
inorganic materials, the filtrate was evaporated in vacuo to provide product 2 as a yellow-
orange solid in 85% yield. If desired, further purification may be accomplished using flash
Received January 12, 2013.
Address correspondence to Robert W. Curley, Jr., Division of Medicinal Chemistry and Phar-
macognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. E-mail:
curley.1@osu.edu
325

326
Sacolick and Curley
5
column chromatography on silica gel (5% ethyl acetate/hexane, followed by 10% ethyl
acetate/hexane) .
Scheme 1
Experimental Section
All solvents and reagents were purchased as reagent grade from Sigma-Aldrich (Milwau-
kee, WI) and were used as obtained. Reactions were performed in oven-dried glassware
under an argon atmosphere and gold fluorescent lights. Analytical TLC was acquired on sil-
ica gel 60 F254 aluminum-backed plates from Merck (Darmstadt, Germany). Flash column
chromatography was carried out on silica gel 60 (230–400 mesh) from Merck. Analysis
by HPLC was performed on a Beckman Instruments unit (model 127 pump, model 166
detector) using 1 mL/min of 90% MeOH-H2O through a Polaris C18 column with monitor-
1
13
ing at 360 nm. H and C NMR spectra were recorded in CDCl3 on a Bruker Instruments
1
DRX400 spectrometer (Billerica, MA) operating at 400 MHz for H measurements. Elec-
trospray mass spectra were measured on a Micromass QTOF mass spectrometer in the Ohio
State University Campus Chemical Instrument Center.
Procedure
To a stirred solution of 1 (5.10 g; 15.5 mmol) in 500 mL of anhydrous methanol was added
sodium pieces (0.39 g; 1.1 equiv.) and the mixture stirred for 40 minutes at which time TLC
(20% ethyl acetate/hexane) indicated complete consumption of 2. The solution was passed
through Amberlite IRA-400 ion-exchange resin (6.5 g; chloride form) and the column was
rinsed with methanol. The eluent was concentrated under reduced pressure to a red oil
which was dissolved in the minimum amount of dry dichloromethane (2–3 mL). After
addition of activated MnO2 (33.0 g; 24.4 equiv.) and dry ethyl acetate (40 ml dried over 4
˚
A molecular sieves), the thick suspension was stirred for 5 hrs at which time TLC indicated
complete oxidation to 1. After filtration of the solution through a pad of diatomaceous earth
and rinsing with dichloromethane, the filtrate was evaporated in vacuo to give 2 (3.75 g,
◦
6
◦
8
(
1
5%) as a yellow-orange solid, mp. 57.5–60 C (lit. mp. 57 C); HPLC: tR = 10.3 min
1
∼96%). H NMR (CDCl3): δ 0.93 (s, 6H, CMe2), 1.36 (m, 2H, CH2), 1.51 (m, 2H, CH2),
.61 (s, 3H, CH3), 1.90 (m, 2H, CH2), 1.91 (s, 3H, CH3), 2.20 (s, 3H, CH3), 5.83 (d, 1H, J
=
8 Hz, 14-CH), 6.03–6.25 (m, 4H, vinyls), 7.03 (dd, 1H, J = 11.6 and 14.9 Hz, 12-CH),
13
9
.97 (d, 1H, J = 8 Hz, CHO). C NMR (CDCl3): δ 13.6, 13.7, 19.9, 22.4, 29.7, 33.8,
34.9, 40.3, 129.7, 130.19, 130.21, 130.96, 133.1, 135.3, 137.8, 138.3, 141.7, 155.1, 191.3.
+
HRMS (ESI): m/z [M + Na] : Calcd for C20H28O + Na: 307.2038. Found: 307.2040.

Improved Synthesis of Retinal (Vitamin A Aldehyde)
Acknowledgment
327
We gratefully acknowledge support of this research in the form of a grant from the National
Cancer Institute (CA49837).
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