Reliable chiral transfer through thermodynamic equilibrium of the intramolecular Meerwein-Ponndorf-Verley reduction and Oppenauer oxidation

Article abstract of DOI:10.1039/a704341d

Forward and reverse hydride transfer with rigorous diastereodifferentiation is attained using intramolecular Meerwein-Ponndorf-Verley reduction and Oppenauer oxidation of a 2-acetylphenyl ether containing an optically active 3-hydroxy-1-methylbutyl group.

Full text of DOI:10.1039/a704341d

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Reliable chiral transfer through thermodynamic equilibrium of the
intramolecular Meerwein–Ponndorf–Verley reduction and Oppenauer
oxidation
Morifumi Fujita,*† Yoshihiro Takarada, Takashi Sugimura and Akira Tai*
Faculty of Science, Himeji Institute of Technology, Kanaji, Kamigori, Ako-gun, Hyogo 678-12, Japan
Forward and reverse hydride transfer with rigorous
diastereodifferentiation is attained using intramolecular
Meerwein–Ponndorf–Verley reduction and Oppenauer oxi-
dation of a 2-acetylphenyl ether containing an optically
active 3-hydroxy-1-methylbutyl group.
produced by intermolecular hydride transfer from isopropoxide
or 1, was obtained. The remaining 32% was recovered as the
reactant 1, with no epimer 6.‡ The product 2 was readily
hydrolysed under alkaline conditions to give 1-(2-hydroxy-
phenyl)ethanol 4, which was isolated after conversion to
1-(2-methoxyphenyl)ethanol 5 [eqn. (2)]. From the negative
Meerwein–Ponndorf–Verley (MPV) reductions and Oppenauer
oxidations have been revealed to proceed via reversible hydride
transfer between carbonyl groups and alcohols.1 Recently,
intramolecular MPV reductions have been reported to proceed
with high stereodifferentiation.2–5 Reversible stereodifferentiat-
ing reactions, however, have the risk of lowering the ster-
eochemical purity as well as chemical yield of products due to
the reverse step, which does not always restore the formed
product to the same stereoisomer as the initial reactant. Previous
intramolecular stereocontrolled MPV reductions have suc-
ceeded as a result of the reaction being driven to completion
under kinetic control.2–5 In contrast, under thermodynamic
equilibrium, both the forward and reverse steps must proceed
with complete stereodifferentiation in order to prevent any
decrease in optical purity of the reactant from the reverse
step. Such stereodifferentiation reactions under thermodynamic
equilibrium, however, have not yet been described for the
intramolecular MPV–Oppenauer reaction.
O
O
OH
OH
O
OH
OH
O
O
(1)
Al(OPri)3
CH2Cl2
1
3
2
OH
O
O
OH OH
OH OMe
Me2SO4
NaOH
H2O
(2)
NaOH
2
4
5
We now report that the intramolecular hydride transfer of
2-acetylphenyl ether containing an optically active 3-hydroxy-
1-methylbutyl group (1) proceeds with rigorous stereodifferen-
tiation under thermodynamic equilibrium. The optically active
3-hydroxy-1-methylbutyl moiety acts as both the chiral auxil-
iary and hydride donor, and can easily be removed from the
product 2 by alkaline hydrolysis as a result of the oxidation of
the alcohol moiety to a ketone. Thus the multi-functional nature
and simple structure of the optically active 3-hydroxy-1-
methylbutyl moiety4,6 provide an opportunity to construct a
simple and reliable system for intramolecular chiral transfer via
thermodynamic equilibration of the MPV–Oppenauer reac-
tion.
optical rotation of 5, the absolute configuration of the a-position
of 2 was determined to be S.9§
When 6 was treated with Al(OPri)3 (2.0 equiv.) in CH2Cl2 at
reflux for 20 h, the other diastereoisomer 7 was obtained at 67%
yield [eqn. (3)] with the recovery of the reactant 6 in 33% yield.
Al(OPri)3
O
O
OH
OH
O
O
(3)
CH2Cl2
Evaluation of hydrogenation enthalpy data1,7 for the conver-
sion of ketones to the corresponding alcohols revealed that
acetophenone is favorable to some extent as a hydride acceptor
of intramolecular hydride transfer from the alcohol moiety, on
the basis of the estimation that the enthalpy change (DH) for
reduction of acetophenone by propan-2-ol is 23 kJ mol21, from
which the quilibrium constant (Kcalc) is calculated to be 3.0 at
313 K. The reactant, (1AS,3AR)-2-(3A-hydroxy-1A-methyl-
butoxy)acetophenone 1, was prepared in 66% yield via the
Mitsunobu reaction8 of (2R,4R)-pentane-2,4-diol with
2A-hydroxyacetophenone. The epimer of 1, (1AS,3AS-)-
2-(3A-hydroxy-1A-methylbutoxy)acetophenone 6, was also ob-
tained by inversion of the alcohol moiety of 1 in 78% yield via
the Mitsunobu reaction of 1 with benzoic acid followed by
hydrolysis.
6
7
These results indicate that the stereogenic centre at the hydroxy
group, but at the ether, is responsible for that of the newly
formed chiral centre.
The ratio of 1:2 remained constant at 1:2 and the
epimerisation of 1 to 6 was also not observed even after
extending the reaction period to 4 days. Increasing the quantity
of Al(OPri)3 to 4 equiv. also resulted in the same product
distribution of 1:2. The constant product ratio of 1:2 (1:2)
which is independent of the reaction time and the amount of
Al(OPri)3 indicates that the intramolecular hydride transfer
between 1 and 2 reaches an equilibrium with the equilibrium
constant K = 2.0 The recovery of the initial reactant without
empimerisation under the thermodynamic equilibrium implies
the complete stereodifferentiation of the reverse step. Such
rigorous stereodifferentiation in the reverse step as well as in the
forward step may be a consequence of the restricted orientation
of the carbonyl group and the alcohol in the transition state of
Treatment of 1 with Al(OPri)3 (2.0 equiv.) in CH2Cl2 at
reflux for 20 h caused the intramolecular hydride transfer from
the alcohol to the aromatic ketone to yield 2 as a single isomer
in 68% yield [eqn. (1)]. It should be noted that no diol 3,
Chem. Commun., 1997
1631

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1 H), 2.58 (s, 3 H), 2.56 (s, 1 H), 2.06–1.98 (m, 1 H), 1.74–1.68 (m, 1 H),
1.35 (d, J 5.9, 3 H), 1.23 (d, J 6.4, 3 H). For 2: d 7.33 (d, J 7.8, 1 H), 7.20
(t, J 7.8, 1 H), 6.93 (t, J 7.8, 1 H), 6.89 (d, J 7.8, 1 H), 5.07–5.01 (m, 1 H),
4.98–4.91 (m, 1 H), 2.96 (dd, J 5.9, 16.6, 1 H), 2.67 (dd, J 6.3, 16.6, 1 H),
2.50 (d, J 4.9, 1 H), 2.17 (s, 3 H), 1.45 (d, J 6.3, 3 H), 1.36 (d, J 5.9, 3 H).
For 6: d 7.68 (d, J 7.8, 1 H), 7.41 (t, J 7.8, 1 H), 7.01 (d, J 7.8, 1 H), 6.95
(t, J 7.8, 1 H), 4.86–4.79 (m, 1 H), 4.12–4.04 (m, 1 H), 2.58 (s, 3 H), 2.04
(d, J 4.4, 1 H), 1.91–1.85 (m, 1 H), 1.79–1.72 (m, 1 H), 1.34 (d, J 6.4, 3 H),
1.23 (d, J 5.9, 3 H). For 7: d 7.32 (d, J 7.8, 1 H), 7.20 (t, J 7.8, 1 H) 6.93 (t,
J 7.8, 1 H), 6.89 (d, J 7.8, 1 H), 5.07–5.02 (m, 1 H), 4.95–4.90 (m, 1 H), 2.96
(dd, J 6.3, 16.6, 1 H), 2.68 (dd, J 5.9, 16.6, 1 H), 2.17 (s, 3 H), 1.46 (d, J 6.3,
3 H), 1.35 (d, J 5.9, 3 H).
§ The enantiomeric purity of 5 was determined to be over 99% ee by GC
analysis using a CHROMPACK-Chirasil-DEX CB (i.d. 0.25 mm 3 25 m)
column. The column temperature was maintained at 120 °C. The retention
time of the S isomer 5 was 16.9 min and that of the R isomer was 19.0
min.
Al(OPri)2
Me
O
O
OH
OH
O
O
O
O
O
Me
H
Me
1
2
Me
Me
O
O
OH
O
OH
O
O
H
Me
O
O
Al(OPri)2
6
7
Scheme 1
1 For recent review, see C. E. de Graauw, J. A. Peters, H. van Bekkum and
J. Huskens, Synthesis, 1994, 1007.
the intramolecular MPV–Oppenauer reaction (Scheme 1).
Preferential intramolecular coordination to aluminium also
ensures from no formation of 3 generated by intermolecular
MPV reduction is observed. Thus, the intramolecular hydride
transfer proceeds without mixing the equilibrium between 1 and
2 with that between 6 and 7.
In conclusion, a rigorous diastereodifferentiating hydride
transfer has been achieved under a thermodynamic equilibrium,
resulting from both the forward and reverse steps of the
equilibrium proceeding diastereospecifically.
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This work was partially supported by a Grant-in-Aid for
Encouragement of Young Scientists No. 08750961 from the
Ministry of Education, Science, Sports and Culture, Japan.
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Footnotes and References
† E-mail: fuji@sci.himeji-tech.ac.jp
‡ The epimers are distinguishable by use of H NMR (400 MHz, CDCl3)
1
spectroscopy. Selected data for 1: d 7.68 (d, J 7.8, 1 H), 7.41 (t, J 7.8, 1 H),
7.00 (d, J 7.8, 1 H), 6.95 (t, J 7.8, 1 H), 4.77–4.69 (m, 1 H), 4.03–3.98 (m,
Received in Cambridge, UK, 20th June 1997; 7/04341D
1632
Chem. Commun., 1997