Asymmetric Synthesis of Vitamin D3 Analogues: Organocatalytic Desymmetrization Approach toward the A-Ring Precursor of Calcifediol

Article abstract of DOI:10.1021/acs.orglett.5b02813

A novel asymmetric synthesis has been developed for the construction of the A-ring of a chiral precursor to calcifediol. The highlights of this synthesis include (i) the introduction of the stereochemistry at the C5-position of the A-ring through the orga

Full text of DOI:10.1021/acs.orglett.5b02813

Letter
pubs.acs.org/OrgLett
Asymmetric Synthesis of Vitamin D Analogues: Organocatalytic
3
Desymmetrization Approach toward the A‑Ring Precursor of
Calcifediol
Haifeng Wang, Linjie Yan, Yan Wu, Yipei Lu, and Fener Chen*
Department of Chemistry, Fudan University, Shanghai 200433, P. R. China
*
S Supporting Information
ABSTRACT: A novel asymmetric synthesis has been developed for the construction of the A-ring of a chiral precursor to
calcifediol. The highlights of this synthesis include (i) the introduction of the stereochemistry at the C5-position of the A-ring
through the organocatalytic enantioselective desymmetrization of a prochiral cyclic anhydride using a bifunctional urea catalyst
and (ii) the introduction of the exo-cyclic (Z)-dienol side chain by a tandem Claisen rearrangement/sulfoxide thermolysis of an
allylic alcohol.
alcifediol (25-hydroxyvitamin D , 1) is a biologically
cyclic anhydride 3 using an organocatalytic anhydride
desymmetrization strategy.
Our retrosynthetic analysis of 2 is depicted in Scheme 2. It
was envisaged that the chiral dienol 2 could be assembled from
3
C
active metabolite of vitamin D and represents the major
3
1
circulating form of vitamin D present in human plasma. The
3
medicinal importance of 1 for the treatment of various
metabolic diseases as well as renal failure, rickets, and
osteoporosis has attracted considerable interest from research-
ers working in a variety of different fields, including synthetic
Scheme 2. Retrosynthetic Analysis
2
organic chemistry. The chiral dienol 2 is a precursor of the A-
ring building block required for the preparation of 1 (Scheme
1). Several studies have been reported to date describing the
Scheme 1. Structures of 25-Hydroxyvitamin D (1) and the
3
A-Ring Allyl Alcohol 2
the allylic alcohol 14 through a one-pot tandem Claisen [3,3]-
sigmatropic rearrangement/sulfoxide thermolysis reaction
followed by the reduction of the resulting ester. Compound
1
4 could be synthesized from 12 via the E elimination and the
2
reduction of the benzyl ester to give the required allylic alcohol
4. In turn, compound 12 could be prepared from hemiester 4
via a series of transformations. Finally, it was envisaged that the
chiral hemiester 4 could be synthesized by the organocatalytic
enantioselective alcoholysis of the meso-cyclic anhydride 3.
To allow for the introduction of the required stereochemical
information into the key intermediate 4, we directed our
1
development of elegant synthetic processes for the synthesis of
2
, including Lythgoe’s partial approach starting from vitamin D2
or vitamin D . Several stereoselective total syntheses have also
3
been reported on the basis of Lythgoe’s chiral pool approach
3
and William’s catalytic asymmetric strategy. Despite significant
progress in this area, the development of an efficient and
practical process for the preparation of 2 has not yet been
achieved and is still highly desired. Herein, we report a novel
catalytic asymmetric synthesis of 2 from commercially available
Received: September 29, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02813
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Organic Letters
Letter
research efforts toward the development of an efficient process
for the asymmetric alcoholysis of the prochiral cyclic anhydride
significant increase in the enantioselectivity for the formation of
the desired product 4 inform 69 to 88% ee (Table 1, entries
1,10−11). Increasing the loading of the catalyst to 10 mol % led
to a significant increase in the catalytic activity, as well as the
enantioselectivity (90% ee, entries 12). Pleasingly, the
enantioselectivity of 4 (90% ee) was further increased to 96%
ee in 87% yield by a single recrystallization from methyl tert-
butyl ether.
3
. In this way, we investigated the synthesis of (1S,6R)-
hemiester 4 from 3 using a series of chiral bifunctional urea4
catalysts I−V, which were developed by our group (Table 1).
Table 1. Conditions for the Optimization of the
Enantioselective Formation of the Benzyl Hemiester 4
The iodolactonization of 4 under the conditions established
by Van Tarnelen et al. (i.e., NaHCO , I /KI, rt) furnished the
3
2
corresponding iodolactone 5 in 86% yield, although a long
5
reaction time (3 days) was needed. Pleasingly, the treatment of
4
with NIS in dichloromethane at room temperature gave 5 in
9
1% yield following a much shorter reaction time (only 1 h)
(
Scheme 3). The absolute configuration of 5 was determined
Scheme 3. Synthesis of Lactone 7
c
d
e
entry
cat.
solvent
concn
time (h) yield (%) ee (%)
6
by X-ray crystallographic analysis. The subsequent reductive
deiodination of 5 was performed with 10% Pd/C in methanol
1
2
3
4
5
6
7
8
9
I
MTBE
MTBE
MTBE
MTBE
MTBE
CH Cl
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
40
40
36
40
40
40
40
42
40
45
45
50
92
89
93
91
90
90
93
90
89
92
93
93
69
62
49
56
57
47
50
55
67
77
88
90
II
III
IV
V
I
under an atmosphere of H in the presence of sodium acetate
2
to give the corresponding lactone 7. Bromolactone 6 was
prepared in 88% yield from 4 using NBS instead of NIS under
conditions similar to those used for the formation of 5.
However, the reductive debromination of 6 failed to provide 7
under the same hydrogenation conditions as those used for 5.
The subsequent treatment of 7 with MeOH in the presence
of Na CO at room temperature gave diester 8, which was
2
2
I
CH CN
3
I
toluene
THF
I
2
3
10
11
12
I
MTBE
MTBE
MTBE
immediately protected with TBSCl in the presence of imidazole
in DMF to give tert-butyldimethylsilyl ether 9 in 80% yield over
the two steps (Scheme 4). The hydrolysis of 9 with lithium
hydroxide (1.8 equiv) in a 2 mL/2 mL/2 mL mixture of THF/
I
0.025
0.025
b
I
a
Unless otherwise noted, all of the reactions were carried out with
anhydride (0.5 mmol), catalyst I−V (0.025 mmol), and benzyl alcohol
b
c
MeOH/H O at 40 °C led to the formation of a 7:1 (m/m)
2
(
2.5 mmol). The catalyst loading was 10 mol %. The concentration
d e
mixture of hemiester 10 and the corresponding dicarboxylic
acid, which was purified by silica gel chromatography to afford
pure 10 in 71% yield.
of 3 (mol/L). Yield of the isolated product. Enantiomeric excess was
determined by chiral HPLC analysis using a chiral stationary phase.
The result of our initial experiment showed that the exposure of
Scheme 4. Synthesis of Hemiester 10
3
to benzyl alcohol in the presence of catalyst I (5 mol %) in
MTBE (0.1 M) at room temperature gave the desired
hemiester 4 in 92% yield with 69% ee (Table 1, entries 1).
The subsequent screening of a wide range of catalysts (i.e.,
catalysts II−V) and solvents, including dichloromethane,
toluene, acetonitrile, and tetrahydrofuran, failed to afford any
improvement in the enantioselectivity of the desymmetrization
process (Table 1, entries 2−9). It is noteworthy that the
reaction showed a very strong dilution effect. For example,
decreasing the concentration of the anhydride from 0.1 to 0.025
mol/L in the presence of catalyst I (5 mol %) led to a
B
DOI: 10.1021/acs.orglett.5b02813
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Letter
Acid 10 was then converted to the N-hydroxy-2-thiopyridone
ester 11 (Barton ester), which was taken forward into the next
step without isolation. Thus, the irradiation of 11 with a xenon
(catalyst) in methylene chloride at 100 °C in a sealed tube for
12 h afforded the conjugated dienoate esters 16a/16b. Notably,
the dienoate esters 16a/16b were isolated after chromatog-
raphy in 83% yield as a 1:9 mixture of E/Z geometrical isomers.
The irradiation of the mixture with UV light in the presence of
9-fluorenone as the photosensitizer gave the pure Z-isomer 16b
lamp as irradiation source in the presence of BrCCl at room
3
temperature for 30 min resulted in the replacement of the
carboxyl group with a bromo substituent via a Hunsdiecke7r
radical-chain process to give 12 in 65% yield (Scheme 5).
9
in 85% yield. The subsequent reduction of 16b with DIBAL-H
in THF at −78 °C gave the A-ring precursor of calcifediol 2.
In conclusion, we have developed an efficient new method
for the enantioselective synthesis of the A-ring allylic alcohol 2
starting from the readily available prochiral cyclic anhydride 3.
The key features of this synthetic route include (i) the facile
construction of the stereochemistry at the C5-position of the A-
ring through an organocatalytic enantioselective desymmetriza-
tion reaction and (ii) the introduction of an exo-cyclic (Z)-
dienol side chain through a tandem Claisen rearrangement/
sulfoxide thermolysis reaction. Further work toward the
synthesis of calcifediol is underway in our laboratory.
Scheme 5. Synthesis of Allylic alcohol 14
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02813.
Experimental procedures, spectroscopic and analytical
data, and NMR spectra of new compounds(PDF)
X-ray data for compound 5 (CIF)
Compound 12 was then treated with DBU in CHCl under
reflux conditions to give the dehydrobromination product 13 in
3
9
7% yield. The α,β-unsaturated ester 13 was then reduced with
AUTHOR INFORMATION
Corresponding Author
■
DIBAL-H in THF at −78 °C to afford the allylic alcohol 14 in
91% yield.
Previously, Posner and co-workers achieved the synthesis of
*E-mail: rfchen@fudan.edu.cn.
the A-ring phosphine of calciferol (1α, 25-hydroxyvitamin D3)
by taking advantage of a sulfinyl orthoester to allow for the
Notes
The authors declare no competing financial interest.
direct conversion of the allylic alcohol into the corresponding
8
2
-carbon-extended, conjugated dienoate ester. The synthesis
REFERENCES
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(
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DOI: 10.1021/acs.orglett.5b02813
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