Regioselective oxidative cleavage of benzylidene acetals: Synthesis of α- and β-benzoyloxy carboxylic acids

Article abstract of DOI:10.1002/anie.200905952

(Chemical Equation Presented) Ruthenium has twice the fun: The synthetic potential of the highly regio- and stereoselective title reaction, which relies on two oxidative cleavage steps promoted by RuCI3 in combination with NaIO ₄ (see example; Bz = benzoyl), was demonstrated with the synthesis of biologically active cis-(2R,3S)-3-hydroxypipecolic acid from D-glucose.

Full text of DOI:10.1002/anie.200905952

Communications
DOI: 10.1002/anie.200905952
Synthetic Methods
Regioselective Oxidative Cleavage of Benzylidene Acetals: Synthesis
of a- and b-Benzoyloxy Carboxylic Acids**
Ponminor Senthil Kumar, Amit Banerjee, and Sundarababu Baskaran*
Dedicated to Professor Srinivasan Chandrasekaran
In nature, a- and b-hydroxy carboxylic acids occur in a wide
variety of microorganisms and are recurrent intermediates in
the a- and b-oxidation pathways of fatty-acid degradation.[1]
Moreover, a-hydroxy acids have found extensive application
in synthetic organic chemistry as chiral intermediates,[2] chiral
Scheme 1. Direct oxidation of the benzylidene acetal 1 to the
b-benzoyloxy carboxylic acid 2. Bz=benzoyl.
ligands,[3] and resolving agents for alcohols and amines;[4] they
have also found application as antiaging factors in the
cosmetics industry.[5] As a consequence of the wide-ranging
Table 1: Direct oxidation of benzylidene acetals to a- and b-benzoyloxy
carboxylic acids.
biological and synthetic applications of this class of molecules,
the development of new methods for their synthesis has
attracted considerable interest.[6]
Entry
Substrate
Product
t [h] Yield[a] [%]
Benzylidene acetals are widely used for the protection of
1,2- and 1,3-diols;[7] deprotection occurs readily under cata-
lytic hydrogenation conditions or by hydrolysis.[8] Further-
more, benzylidene acetals can be cleaved regioselectively
under reductive conditions to give the corresponding syn-
thetically useful monoprotected diols.[9] Moreover, the oxida-
tive cleavage of benzylidene acetals to the corresponding
hydroxy benzoates has been achieved with several reagent
systems with varying degrees of regioselectivity.[10] Herein we
report a novel method for the direct conversion of benzyli-
dene acetals into the corresponding synthetically useful a-
and b-benzoyloxy carboxylic acids.
Intriguingly, the benzylidene acetal 1 underwent smooth
oxidative cleavage on treatment with RuCl3–NaIO4[11] to give
the corresponding benzoate-protected b-hydroxy carboxylic
acid 2 in good yield (Scheme 1). Encouraged by the facile
reaction of 1 with the RuCl3–NaIO4 reagent system, we tested
the generality of this methodology further with both five- and
six-membered benzylidene acetals, including substrates con-
taining sensitive functional groups (Table 1). Remarkably,
unsymmetrical benzylidene acetals underwent smooth oxida-
tive cleavage in a highly regioselective manner to give the
1
1.5
2
78
68
2
3
2
68
4
5
2
66
65
2.5
6
2.5
61
[a] Yield of the pure isolated product. Ms=methanesulfonyl.
corresponding a- and b-benzoyloxy carboxylic acids in good
yields (Table 1, entries 2–6).[12] The structure of oxidation
product 8 was confirmed unambiguously by single-crystal X-
ray analysis (Figure 1).[13]
[*] P. S. Kumar, A. Banerjee, Prof. Dr. S. Baskaran
Department of Chemistry
Indian Institute of Technology Madras
Chennai—600036 (India)
Fax: (+91)44-2257-0545
E-mail: sbhaskar@iitm.ac.in
Homepage: http://chem.iitm.ac.in/professordetails/
profsundarbabubaskaran/index.htm
[**] We thank DST and CSIR, India for financial support and DST-FIST
for providing NMR facilities. P.S.K. and A.B. thank DST (Unit on
Nano Science and Technology) and CSIR, New Delhi, for research
fellowships. We thank V. Ram Kumar for single-crystal X-ray
analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905952.
Figure 1. ORTEP diagram of compound 8.
804
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Reactive functional groups, such as tert-butyldiphenylsilyl
(TBDPS) ether, azide, ester, and N-Ts groups, were found to
be stable under the reaction conditions. Notably, optically
active benzylidene acetals underwent smooth oxidation to the
corresponding benzoyloxy carboxylic acids without any
epimerization (Table 1, entries 5 and 6).
Interestingly, benzylidene acetals with a free hydroxy
group underwent facile cleavage to give the corresponding a-
benzoyloxy carboxylic acids with the loss of one carbon atom
(Table 2). The reaction sequence involved in the direct
Scheme 3. Synthesis of chiral a-benzoyloxy carboxylic acids from
terminal olefins. (DHQD)2PHAL=hydroquinidine 1,4-phthalazinediyl
diether; PTSA=p-toluenesulfonic acid.
Table 2: Direct oxidation of hydroxy benzylidene acetals to a-benzoyloxy
carboxylic acids.
Entry
1
Substrate
Product
t [h]
Yield[a] [%]
68
Table 3: Synthesis of optically active a-benzoyloxy carboxylic acids.
Entry
1
Substrate
(ee [%])
Product
(ee [%])
t
[h]
Yield[a]
[%]
2.5
2
1.5
71
2
2
61
62
[a] Yield of the pure isolated product.
2
conversion of the hydroxy benzylidene acetal 15 into the
corresponding a-benzoyloxy carboxylic acid 16 is shown in
Scheme 2. The oxidation of 15 with RuCl3–NaIO4 results in
the vicinal-diol intermediate 15a, which undergoes further
oxidative cleavage to give compound 16.
3
4
5
2.5
2
66
64
63
2.5
Scheme 2. Regioselective oxidative cleavage of the hydroxy benzylidene
acetal 15 to the a-benzoyloxy carboxylic acid 16.
6
2.5
66
Since the stereochemical integrity of the benzoyloxy
carboxylic acid product is maintained under the reaction
conditions, a reliable three-step protocol was developed for
the synthesis of optically active a-benzoyloxy carboxylic acids
from terminal olefins. Optically active benzylidene acetals
were prepared readily from terminal olefins through Sharp-
less asymmetric dihydroxylation (SAD) of a 1-alkene, fol-
lowed by treatment with benzaldehyde dimethyl acetal under
acidic conditions (Scheme 3). The exposure of the resulting
chiral benzylidene acetal to the RuCl3–NaIO4 reagent system
led to smooth regioselective oxidative cleavage to the
corresponding optically active (R)-a-benzoyloxy carboxylic
acid in good yield without any racemization (Table 3).[12]
Similarly, (S)-a-benzoyloxy carboxylic acids can be synthe-
sized from terminal olefins by using hydroquinine 1,4-
phthalazinediyl diether ((DHQ)2PHAL) as a catalyst in the
SAD step. The optical purity of the synthesized compounds
was determined by HPLC analysis on chiral columns (see the
Supporting Information).
7
8
2
63
64
2.5
[a] Yield of the pure isolated product.
cis-(2R,3S)-3-hydroxypipecolic acid 37 from d-glucose. The
piperidine–benzylidene acetal derivative 35, prepared from
d-glucose by a previously reported procedure,[14] was trans-
formed into the corresponding N-Ts-protected piperidine
derivative 36 in 88% yield upon treatment with tosyl chloride.
Direct oxidation of the benzylidene acetal derivative 36 with
the RuCl3–NaIO4 reagent system furnished the corresponding
cis-(2R,3S)-3-hydroxypipecolic acid derivative 37 as the only
product in 69% yield (Scheme 4).
A plausible mechanism for the direct oxidation of
benzylidene acetals to a- and b-benzoyloxy carboxylic acids
is shown in Scheme 5. It is likely that coordination of RuO4 to
The synthetic potential of this methodology was further
tested in the stereoselective synthesis of the protected
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Communications
(1:1:0.5; 6 mL), and the resulting mixture was stirred at room
temperature for 2 h. 2-Propanol (1 mL) was then added to the
reaction mixture, and the mixture was filtered through a pad of Celite.
The solid mass collected was washed with EtOAc. The filtrate was
then washed with an aqueous NaHCO3 solution (0.5m; 10 mL), and
the aqueous layer was acidified with 1n HCl (pH 2) and then
extracted with EtOAc (2 ꢀ 20 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. Purification of the crude compound by column chromatog-
raphy on silica gel (gradient elution with 25–30% EtOAc in hexane)
yielded pure 2 (92 mg, 78%) as a foamy solid. IR (neat): v = 2931,
1
2857, 1724, 1452, 1272, 1111, 710 cmÀ1; H NMR (400 MHz, CDCl3):
Scheme 4. Stereoselective synthesis of protected cis-(2R,3S)-3-hydroxy-
pipecolic acid 37. Ts=p-toluenesulfonyl.
d = 7.96–7.94 (m, 2H), 7.48–7.47 (m, 1H), 7.37–7.34 (m, 2H), 4.53 (t,
J = 6.2 Hz, 2H), 2.78 ppm (t, J = 6.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d = 176.2, 166.3, 133.2, 129.8, 129.7, 128.4, 59.9, 33.7 ppm;
HRMS (ESI): m/z calcd for C10H10O4Na: 217.0473 [M+Na]+; found:
217.0477.
Received: October 22, 2009
Published online: December 28, 2009
Keywords: benzylidene acetals · hydroxy carboxylic acids ·
.
oxidation · regioselectivity · terminal alkenes
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