Highly diastereoselective α-hydroxylation of fox chiral auxiliary-based amide enolates with molecular oxygen

Article abstract of DOI:10.1021/ol100211s

"Figure Presented" Using a trifluoromethylated oxazolidine (Fox) chiral auxiliary, the hydroxylation reaction of enolates was very efficiently performed under smooth and friendly conditions with molecular oxygen as oxidizer. This reaction occurred with an extremely high diastereoselectivlty. After cleavage, the chlral auxiliary Is efficiently recovered and highly valuable enantlopure oxygenated carboxylic acids and alcohols are released.

Full text of DOI:10.1021/ol100211s

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1496-1499
Highly Diastereoselective
r-Hydroxylation of Fox Chiral
Auxiliary-Based Amide Enolates with
Molecular Oxygen
Hodney Lubin, Arnaud Tessier, Gre´gory Chaume, Julien Pytkowicz, and
Thierry Brigaud*
Laboratoire “ Synthe`se Organique Se´lectiVe et Chimie bioOrganique ” (SOSCO),
UniVersite´ de Cergy-Pontoise, 5 Mail Gay-Lussac 95000 Cergy-Pontoise Cedex, France
thierry.brigaud@u-cergy.fr
Received January 27, 2010
ABSTRACT
Using a trifluoromethylated oxazolidine (Fox) chiral auxiliary, the hydroxylation reaction of enolates was very efficiently performed under
smooth and friendly conditions with molecular oxygen as oxidizer. This reaction occurred with an extremely high diastereoselectivity. After
cleavage, the chiral auxiliary is efficiently recovered and highly valuable enantiopure oxygenated carboxylic acids and alcohols are released.
Enantiopure R-hydroxy carbonyl compounds play an im-
portant role in asymmetric synthesis as well as building
blocks for total syntheses.1 The oxidation of an enolizable
carbonyl group is the most direct method to synthesize such
compounds and has received a great deal of attention.2 One
of the first examples reported in the literature was the
oxidation of steroidal ketone enolates by molecular oxygen
followed by the reduction of the intermediate R-hydroper-
oxide by zinc dust.3 This low-yielding procedure was
improved in the 1960s by using trialkyl phosphite as
reductant4 and was extensively applied to different substrates
mainly during the 1980s but very occasionally later for the
R-hydroxylation of amide enolates.2,5 However, the molec-
ular oxygen oxidation of enolates suffers from several
limitations such as low yields and frequent complications
due to decomposition or rearrangement of the intermediate
hydroperoxide.6 Moreover, the overoxidation often limits
these reactions to tertiary carbons in the R position of the
carbonyl group. For these reasons, the oxidation of enolates
has been more recently performed using Davis’
sulfonyloxaziridine,1a,7
Vedejs’
MoOPH
complex
(MoO5·HMPA·pyridine)8 or various classical oxidizing re-
agents.2 The stereoselectivity of these oxidations was mainly
controlled by the chirality of the substrates. Chiral induction
(1) (a) Davis, F. A.; Chen, B.-C. Chem. ReV. 1992, 92, 919–934. (b)
Coppola, G. M.; Schuster, H. F. R-Hydroxy acids in enantioselectiVe
synthesis; Wiley-VCH: Weinheim, 1997.
(5) (a) Wasserman, H. H.; Lipshutz, B. H. Tetrahedron Lett. 1975, 21,
1731–1734. (b) Kim, M. Y.; Starrett, J. E., Jr.; Weinreb, S. M. J. Org.
Chem. 1981, 46, 5383–5389. (c) Williams, R. M.; Armstrong, R. W.; Dung,
J.-S. J. Am. Chem. Soc. 1985, 107, 3253–3266. (d) Hartwig, W.; Born, L.
J. Org. Chem. 1987, 52, 4352–4358. (e) Adam, W.; Metz, M.; Prechtl, F.;
(2) For general reviews, see: (a) Jones, A. B. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Ley, S. V., Ed.; Pergamon Press Ltd.:
Oxford, 1991; Vol. 7, pp 151-191. (b) Chen, B.-C.; Zhou, P.; Davis, F. A.;
Ciganek, E. In Organic Reactions; Overman L. E., Ed.; John Wiley & Sons
Inc.: New York, 2003; Vol. 62, pp 1-356.
Renz, M. Synthesis 1994, 563–566
.
(6) (a) Gardner, J. N.; Carlon, F. E.; Gnoj, O. J. Org. Chem. 1968, 33,
1566–1570. (b) Avramoff, M.; Sprinzak, Y. J. Am. Chem. Soc. 1963, 85,
1655–1657. (c) Doering, W.; Von, E.; Haines, R. M. J. Am. Chem. Soc.
1954, 76, 482–486.
(3) Bailey, E. J.; Barton, D. H. R.; Elks, J.; Templeton, J. F. J. J. Chem.
Soc. 1962, 1578–1591.
(4) Gardner, J. N.; Carlon, F. E.; Gnoj, O. J. Org. Chem. 1968, 33,
3294–3297.
(7) (a) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703–5742.
(b) Davis, F. A. J. Org. Chem. 2006, 71, 8993–9003
.
10.1021/ol100211s  2010 American Chemical Society
Published on Web 03/10/2010

by auxiliaries,9 chiral oxidizing reagents,10 chiral catalysts,11
chiral phase transfer catalysts, and enzymes12 has also been
reported. Furthermore, it appears in the literature that the
most standard method extensively used in recent years is
the oxidation of oxazolidinone-based chiral amide enolates
with Davis’ oxaziridine.13 Intriguingly, the very attractive
oxidation with molecular oxygen has not yet been developed
for the synthesis of enantiopure compounds by mean of chiral
auxiliaries-based methods. This is probably due to the poor
stability of the intermediate hydroperoxides. To the best of
our knowledge, the only example of a diastereoselective
hydroxylation of a chiral amide enolate in the presence of
molecular oxygen was reported by Adam et al.14 In this
pioneering work, the authors reported the autoxidation of
an amide titanium enolate using (S)-prolinol as chiral
auxiliary. The resulting chiral R-hydroxy amide was obtained
in a rather good yield but with a low diastereoselectivity
(34% de). Provided that the diastereoselectivity of this kind
of reaction could be improved, we believe that the cheap
and environmentally friendly molecular oxygen oxidation
could be a very attractive alternative to onerous or toxic
oxidizing agents. We report herein that fluorinated oxazo-
lidine (Fox) chiral auxiliary presents outstanding perfor-
mances to meet these requirements.
alkylation compound. For example, the benzylation of the
potassium enolate of 1a gave the diastereomerically pure
benzylated amide 2a in 63% isolated yield, the R-hydroxy
amide 3a in 11% yield, and the hydroperoxide 4 in 15%
yield (Scheme 1). Similar oxygenated compounds were also
obtained as very minor products from sodium enolates. We
assumed that these oxygenated compounds were probably
resulting from the enolate oxidation by residual molecular
oxygen dissolved in the solvent. As these compounds were
obtained as single diastereomers, we anticipated that the Fox
chiral auxiliary would be an excellent chiral auxiliary for
the oxygen-mediated oxidation of enolates.
Scheme 1
.
Unexpected Diastereoselective R-Oxidation of
N-Acyloxazolidine 1a
In order to characterize the R-hydroxy amide 3a and to
compare with the diastereoselectivity achieved by a standard
oxidation method, the sodium enolate of 1a was treated with
Vedejs’ reagent (Scheme 2).8b,e Under these conditions, the
R-hydroxy amide 3a was obtained in 49% yield and with
only 62% de. This result shows the superiority of the
molecular oxygen oxidation in term of diastereoselectivity
of the reaction.
We recently reported the highly diastereoselective alky-
lation of fluorinated oxazolidine (Fox) derived amide eno-
lates.15-17 In the course of our studies, while using KHMDS
as base, we were surprised to isolate two oxygenated side
products in addition to the expected diastereomerically pure
(8) (a) Vedejs, E. J. Am. Chem. Soc. 1974, 94, 5944–5946. (b) Mimoun,
H.; Seree de Roche, I.; Sajus, L. Bull. Soc. Chim. Fr. 1969, 1481–1492. (c)
Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43, 188–
196. (d) Vedejs, E.; Martinez, G. R. J. Am. Chem. Soc. 1980, 102, 7994–
7996. (e) Vedejs, E.; Larsen, S. Org. Synth. 1986, 64, 127–137. (f) Marin,
J.; Didierjean, C.; Aubry, A.; Briand, J.-P.; Guichard, G. J. Org. Chem.
2002, 67, 8440–8449.
Scheme 2. Diastereoselective Hydroxylation of
N-Acyloxazolidine 1a with Vedejs’ Reagent
(9) (a) Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem.
Soc. 1985, 107, 4346–4348. (b) Davis, F. A.; Vishawakarma, L. C.
Tetrahedron Lett. 1985, 26, 3539–3542. (c) Gamboni, R.; Tamm, C. HelV.
Chim. Acta 1986, 69, 615–620. (d) Enders, D.; Bhushan, V. Tetrahedron
Lett. 1988, 29, 2437–2440.
(10) (a) Davis, F. A.; Haque, M. S.; Ulatowski, T. G.; Towson, J. J.
Org. Chem. 1986, 51, 2402–2404. (b) Davis, F. A.; Haque, M. S. J. Org.
Chem. 1986, 51, 4083–4085. (c) Davis, F. A.; Ulatowski, T. G.; Haque,
M. S. J. Org. Chem. 1987, 52, 5288–5290. (d) Davis, F. A.; Weismiller,
M. C.; Sankar Lal, G.; Chen, B.-C.; Prezslawski, R. M. Tetrahedron Lett.
1989, 30, 1613–1616. (e) Davis, F. A.; Weismiller, M. C.; Murphy, C. K.;
Reddy, R. T.; Chen, B.-C. J. Org. Chem. 1992, 57, 7274–7285.
(11) (a) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.;
Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488–16489. (b) Brown, S. P.;
Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003,
125, 10808–10809.
As we suspected that residual molecular oxygen should
be the only possible reactant able to oxidize the enolate, we
decided to submit the sodium enolate of 1a to a bubbling
stream of oxygen at -78 °C. To our great delight, the
hydroperoxide 4 was isolated in 85% yield and 97:3 dr after
an aqueous workup (Scheme 3).18 This result clearly
indicates that the hydroperoxide is the product of the reaction
whereas the R-hydroxy compound 3a should result from its
reduction. To this end, the reductions of 4 with a 2 M
aqueous sodium bisulfite solution or a saturated sodium
sulfite aqueous solution were attempted. Unfortunately, under
these conditions, the R-hydroxy amide 3a was only obtained
in low yield and the hydroperoxide 4 mostly decomposed.
(12) Adam, W.; Lazarus, M.; Saha-Moller, C. R.; Schreier, P. Acc. Chem.
Res. 1999, 32, 837–845.
(13) For recent examples, see: (a) Raghavan, S.; Subramanian, S. G.;
Tony, K. A. Tetrahedron Lett. 2008, 49, 1601–1604. (b) Kaliappan, K. P.;
Gowrisankar, P. Synlett 2007, 1537–1540. (c) Monma, S.; Sunazuka, T.;
Nagai, K.; Arai, T.; Shiomi, K.; Matsui, R.; Ohmura, S. Org. Lett. 2006, 8,
5601–5604. (d) Pichlmair, S.; de Lera Ruiz, M.; Vilotijevic, I.; Paquette,
L. A. Tetrahedron 2006, 62, 5791–5802. (e) Gaich, T.; Karig, G.; Martin,
H. J.; Mulzer, J. Eur. J. Org. Chem. 2006, 3372–3394.
(14) Adam, W.; Metz, M.; Prechtl, F.; Renz, M. Synthesis 1994, 563–
566.
(15) Tessier, A.; Pytkowicz, J.; Brigaud, T. Angew. Chem., Int. Ed. 2006,
45, 3677–3681
.
(16) Sini, G.; Tessier, A.; Pytkowicz, J.; Brigaud, T. Chem.sEur. J.
2008, 14, 3363–3370
(17) Tessier, A.; Lahmar, N.; Pytkowicz, J.; Brigaud, T. J. Org. Chem.
2008, 73, 3970–3973
.
(18) The hydroperoxide 4 was conveniently isolated after aqueous
workup, but it decomposed over silica gel.
.
Org. Lett., Vol. 12, No. 7, 2010
1497

ogy. Starting from diastereomerically pure compounds 3a
and 3b as representative substrates, we focused our attention
on the removal of the Fox chiral auxiliary in order to obtain
the corresponding enantiomerically pure R-hydroxy acids and
diols. The removal of the Fox chiral auxiliary of 3a was
performed by LiAlH4 reduction according to our previously
reported procedure.15 Unfortunately, the expected R-hydroxy
aldehyde could not be properly isolated because of its high
solubility in water. Thus, we considered the protection of
the hydroxyl group as a prerequisite for the reductive
cleavage. The benzylation of 3a and 3b into 5a and 5b was
achieved in 98% and 96% yield, respectively, using standard
conditions without epimerization of the newly formed
stereocenter. The benzylated hydroxy compounds 5a,b were
then submitted to LiAlH4 reduction to give the aldehydes
7a,b and the Fox chiral auxiliary 8 through the hydrolysis
of the intermediate hemiaminals 6a,b (Scheme 4).22
Scheme 3
.
Diastereoselective Oxidation of N-Acyloxazolidine
1a with Molecular Oxygen
In order to obtain the target R-hydroxy amide in good
yield, we decided to perform the reduction of the intermediate
peroxide in situ with triethyl phosphite. Under these condi-
tions, the expected R-hydroxy amide 3a was obtained in
excellent yield (91%) and with high diastereoselectivity (94%
de) (Table 1, entry 1). Moreover, the reaction turned out to
be completely diastereoselective (>98% de) with more
sterically hindered enolates (Table 1, entries 2 and 3). In
these experiments, no trace of the minor diastereomer could
be detected by 19F and H NMR in the crude reaction
1
mixture.19 The oxidation of the highly hindered tert-butyl
substrate 1d was achieved in reasonable yield without loss
of stereoselectivity provided that the temperature was raised
to -50 °C (Table 1, entry 4). This methodology was
extended to the ꢀ-amino substrate 1e allowing the preparation
of the highly valuable ꢀ-amino-R-hydroxyl compound 3e in
a good yield and with a complete diastereoselectivity (Table
1, entry 5). In order to investigate the possible extension of
this reaction to other nonfluorinated chiral auxiliaries, the
oxidation of the enolate with an Evans’-type chiral auxiliary20
was attempted. However, under our standard conditions no
traces amount of the expected R-hydroxy imide21 were
detected, and a complex mixture, probably resulting from
the degradation of the intermediate peroxide, was obtained.
In our opinion, it seems that the Fox chiral auxiliary plays
a crucial role in the stabilization of the intermediate peroxide
species allowing highly selective reactions.
Scheme 4. Removal of the Fox Chiral Auxiliary 8
At this stage, the aldehydes 7a,b and the Fox chiral
auxiliary 8 were not easily separated by silica gel chroma-
tography. As we anticipated that the chiral auxiliary 8 would
be stable under aldehyde oxidation and NaBH4 reduction
conditions, we decided to submit the amides 5a,b to a two-
step procedure without separation of the intermediate alde-
hyde/oxazolidine mixtures. According to this procedure
involving the sequence LiAlH4 reduction/hydrolysis/oxida-
tion or NaBH4 reduction, the enantiopure carboxylic acids
9a,b and the alcohols 10a,b were conveniently obtained from
5a,b (Scheme 5). In each case, the chromatographic separa-
tion of the carboxylic acids or the alcohols and the oxazo-
lidine was easily achieved and the Fox chiral auxiliary 8
was efficiently recovered (Scheme 5).
Table 1. R-Hydroxylation of trans-Fox Amide Enolates with
Molecular Oxygen
The (R) configurations of 9a,b and 10a,b were assigned
by comparison of their optical rotation value with literature
data.19b,23 The enantiopurity of the carboxylic acid 9a and
the alcohol 10b were confirmed by formation of their
diastereomerically pure (R)-Mosher’s ester and (S)-phenyl-
entry
R
yielda (%)
deb (%)
product
1
2
3
4
5
Me
Bn
90
81
70
42
75
94 (R)c
>98 (R)
>98 (R)
>98 (R)
>98 (R)
3a
3b
3c
3d
3e
iPr
tBud
(19) These diastereoselectivities are comparable or better to those
generally achieved by the alternative approach involving the chiral auxiliary-
based alkylations of benzyloxyacetyl amides. (a) Crimmins, M. T.; Emmitte,
K. A.; Katz, J. D. Org. Lett. 2000, 2, 2165–2167, and references cited
therein. (b) Chun, C. C.; Lee, G.-J.; Kim, J. N.; Kim, T H. Tetrahedron:
Asymmetry 2005, 2989–2992.
(Bn)2NCH2
a Yield of pure isolated product. b Determined by 19F NMR on the crude
mixture. c Diastereomerically pure (R)-3a was obtained after recrystallization
in cyclohexane. d Conditions: T ) -50 °C, 12 h. 29% of starting material
was recovered.
(20) Sodium enolate of the (S)-4-isopropyl-3-propionyl-1,3-oxazolidin-
2-one.
(21) Kihara, N.; Ollivier, C.; Renaud, P. Org. Lett. 1999, 1, 1419–1422.
(22) For a previously reported similar reduction of SuperQuat amide
into hemiaminal, see: Davies, S. G.; Nicholson, R. L.; Smith, A. D. Org.
Biomol. Chem. 2005, 3, 348–359.
The removal and the recovery of the Fox chiral auxiliary
is a key step to justify the synthetic value of this methodol-
1498
Org. Lett., Vol. 12, No. 7, 2010

auxiliary,21 allow us to propose an ionic mechanism for the
molecular oxygen oxidation of the sodium enolate of 1a.
In accordance with our previous theoretical study on the
alkylation of Fox amide enolates,16 we propose an electro-
philic mechanism involving a chelated transition state
presenting F···Na and O···Na interactions leading to a very
highly diastereoselective Re face oxidation of the enolate
(Figure 1).
Scheme 5. Two-Step Procedure for the Synthesis of Enantiopure
Carboxylic Acids 9a,b and Alcohols 10a,b with Efficient
Recovery of the Chiral Auxiliary 8
ethylamide derivatives. In each case, one single diastereomer
was obtained.
Figure 1. Postulated transition state leading to the Re face oxidation
of the enolate.
We envisage two plausible mechanisms for this hydroxy-
lation reaction. The first one would consist of the electrophilic
addition of molecular oxygen to the enolate. The second one
would involve a single electron transfer from the enolate to
oxygen leading to a radical in the R position of the carbonyl
group followed by the trapping of this radical by molecular
oxygen. In order to discriminate these two potential mech-
anisms, the hydroxylation was performed according an
irrefutably radical pathway. The iodinated compound 1124
was treated with triethylborane under oxygen atmosphere
according to the procedure previously reported by Renaud
et al.21 (Scheme 6). Under these conditions, although the
In summary, we have reported that 2-(trifluoromethyl)ox-
azolidine (Fox) exhibits outstanding properties as a chiral
auxiliary for amide enolates hydroxylation. The R-hydroxy-
lation reaction of enolates using this chiral auxiliary was very
efficiently performed in smooth and friendly conditions using
molecular oxygen as oxidizer. The reaction is generally
completely diastereoselective, and the chiral auxiliary is
conveniently removed and recovered to give enantiopure
oxygenated carboxylic acids and alcohols.
Acknowledgment. We thank the French ministry of
research for awarding a research fellowship to H.L. and A.T.
and Central Glass Co. for financial support and the gift of
trifluoroacetaldehyde hemiacetal. We also thank the French
Fluorine Network.
Scheme 6
.
Radical Oxidation of the N-Iodoacylated Oxazolidine
11 with Molecular Oxygen
Supporting Information Available: Complete experi-
mental procedures and characterization data for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL100211S
conversion of 11 was not complete (41% conversion), the
R-hydroxyamide 3a was obtained with a low diastereose-
lectivity (46% de). This low diastereoselectivity can be
explained by the absence of chelation in the radical inter-
mediate. These results, which are consistent with those
reported by Renaud et al. with an Evans’-type chiral
(23) (a) Nakata, M.; Arai, M.; Tomooka, K.; Ohsawa, N.; Kinoshita,
M. Bull. Chem. Soc. Jpn. 1989, 62, 2618–2635. (b) Fuganti, C.; Grasselli,
P.; Spreafico, R.; Zirotti, C. J. Org. Chem. 1984, 49, 543–546. (c) Cardillo,
G. Tetrahedron 1989, 45, 1501–1508.
(24) Compound 11 was prepared by electrophilic iodination of the
sodium enolate of 1a with N-iodosuccinimide.
Org. Lett., Vol. 12, No. 7, 2010
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