Mild, racemization free cleavage of ketone SAMP-hydrazones with oxalic acid - Recycling of the chiral auxiliary

Article abstract of DOI:10.1055/s-1998-1765

Cleavage of ketone SAMP-hydrazones 1a-f with a saturated aqueous oxalic acid solution gives the corresponding ketones 2a-f in excellent yields and with high enantiomeric purity (ee = 90 - 99%). The chiral auxiliary SAMP is recovered from the aqueous phase in good yield (85%) and with unchanged enantiomeric purity. This racemisation free cleavage procedure is compatible with functionalities sensitive to oxidative cleavage conditions, such as ozonolysis, or to strong acids.

Full text of DOI:10.1055/s-1998-1765

July 1998
SYNLETT
721
Mild, Racemization Free Cleavage of Ketone SAMP-Hydrazones with Oxalic Acid - Recycling
of the Chiral Auxiliary
Dieter Enders,* Thomas Hundertmark, Ryszard Lazny
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, D-52074 Aachen, Germany
Fax: Int. +241/8888-127; E-mail: Enders@RWTH-Aachen.de
Received 23 April 1998
1a
Abstract: Cleavage of ketone SAMP-hydrazones 1a-f with a saturated
aqueous oxalic acid solution gives the corresponding ketones 2a-f in
excellent yields and with high enantiomeric purity (ee = 90 - 99%). The
chiral auxiliary SAMP is recovered from the aqueous phase in good
yield (85%) and with unchanged enantiomeric purity. This racemisation
free cleavage procedure is compatible with functionalities sensitive to
oxidative cleavage conditions, such as ozonolysis, or to strong acids.
as it is the case in ozonolysis and no toxic methylating reagents are
1a
needed as in the salt method. Usually, the rate of hydrolysis of α-
branched hydrazones is faster than non-branched ones, nevertheless, full
conversion giving the unbranched ketones was also achieved in
relatively short time with the new method (Table 1, entries 1f-h).
The constant strive for achieving high efficiency in modern asymmetric
synthesis results in a need for the development of non-stoichiometric
methods or procedures allowing for the recycling of chiral reagents.
Asymmetric electrophilic substitutions alpha to the carbonyl group of
aldehydes and ketones via lithiated SAMP/RAMP-hydrazones are
1,2
among the well established methods in asymmetric synthesis.
Although many methods for the cleavage of achiral hydrazones have
3-5
been described in the literature,
and several methods have been
developed in our group specifically for the cleavage of SAMP-
6
hydrazones, there is still a need for a better direct recovery of the chiral
7
hydrazine SAMP. We describe here the use of a simple organic acid,
8
i.e. oxalic acid, for racemization free cleavage of SAMP-hydrazones
Scheme 1
and recovery of the chiral auxiliary.
Hydrolytic cleavage of N,N-dialkylhydrazones by strong organic and
inorganic acids is well known, however, such conditions are usually not
suitable for the preparation of optically active carbonyl compounds via
the SAMP-hydrazone method because of the configurational lability of
the stereocenter alpha to the carbonyl group under such harsh
conditions. Furthermore, the extraction of the oxidation sensitive
hydrazine from the basified aqueous solution is not trivial. The most
commonly used methods for the cleavage of SAMP- hydrazones to
carbonyl compounds are ozonolysis and methiodide formation with
1
iodomethane followed by acid hydrolysis in a two phase system. There
are however many functional groups which are sensitive to ozone and/or
methylating reagents and as such are not always compatible with these
methods. Therefore we were interested in developing
a mild,
racemization free cleavage procedure which would also allow the
recovery and recycling of the chiral auxiliary.
During the investigation of various methods our attention was drawn to
oxalic acid by the fact that SAMP can be easily recovered from the
corresponding oxalate salt. Representative examples of ketones
prepared via the new method are given in Table 1. The alkylated
1
hydrazones were prepared by the standard SAMP alkylation with
13
diastereoselectivities of de = 90-99% as indicated by C NMR
spectroscopy. We have found that SAMP-hydrazones of ketones are
hydrolyzed by aqueous oxalic acid in a short time. Fortunately, the acid
sensitive acetonide group (Table 1, entries 1d-f) was not hydrolyzed and
the α-alkylated ketones were protected from racemization when the
reaction was run in a two phase system (aqueous and ethereal). This was
readily proven by comparing the enantiomeric excesses of ketones
cleaved from the same batch of hydrazone both by ozonolysis and by the
new procedure. However, the oxalic acid method was more amenable to
larger scale reactions (40 mmol) since it usually gave pure ketones
which did not require chromatographic purification. Moreover, during
oxalic acid cleavage no carcinogenic nitrosoamine by-product is formed
Recovery of the chiral auxiliary was achieved by extraction of the
basified aqueous phase with a mixture of THF and diethyl ether. In order
to increase the recovery yield the volume of water must be kept at a
minimum (the hydrazine is water soluble). The spectroscopic data of the
recovered SAMP are identical with the original sample. The ee-value
remained unchanged as shown by NMR analysis of Mosher's
derivatives. The crude auxiliary was recovered in 80-90% yield and had

722
LETTERS
SYNLETT
sufficient purity (GC analysis) to be used again for preparation of
hydrazones.
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119, 7483. k) Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.;
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Am. Chem. Soc.
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In conclusion, the cleavage of SAMP hydrazones with an aqueous
saturated solution of oxalic acid allows the efficient recovery and
recycling of the valuable and sensitive chiral auxiliaries SAMP and its
enantiomer RAMP. In addition, this experimentally straightforward
method causes virtually no racemization of the chiral ketones and is
compatible with compounds sensitive to oxidative cleavage conditions,
such as ozonolysis, or to strong acids. It also paves the way for the
application of recyclable, polymer -supported SAMP-analogues.
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, 109, 539; Angew. Chem.
Int. Ed. Eng.
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110, 85; Angew. Chem. Int. Ed. Eng.
37
(3) Hydrolytic cleavage: a) Protic acid and salt method: Avaro, M.;
Levisalles, J.; Rudler, H. J. Chem. Soc. Chem. Commun. 1969, 446;
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1990, 429. c) Cation exchange resin: Ranu, B.
Soc. Perkin Trans. 1
C.; Sarkar, D. C. J. Org. Chem. 1988, 53, 878. d) Lewis acid:
Gawley, R. E.; Termine, E. J. Synth. Commun. 1982, 12, 15; Sacks,
C. E.; Fuchs, P. L. Synthesis 1976, 456. e) Exchange with carbonyl
compound: Hershberg, E. B. J. Org. Chem. 1948, 13, 542; Ried, W.;
Mühle, A. Liebigs Ann. 1962, 656, 119; Maynez, S. R.; Pelavin, L;
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Boruah, A.; Baruah, B.; Prajapati, D.; Sandhu, J. S. Synlett 1997,
1251.
General Procedure for the SAMP-Hydrazone Cleavage: A solution of
the hydrazones 1 (15 mmol) in ether or hexane (60 mL) was vigorously
stirred at r.t. with a sat. aqueous solution of oxalic acid (22 mL) for 0.5-
14 h (TLC control). The aqueous layer was separated, extracted with
ether or hexane and the organic extracts were combined, dried (MgSO )
4
and concentrated under vacuum. The residue was taken up again in
hexane (12 mL), filtered, and the solvent was removed under vacuum to
give ketone 2 which, if necessary, could be further purified by
chromatography.
(4) Oxidative cleavage: a) Peracid: Horner, L.; Fernekess, M. Chem.
1961, , 712; Duraisamy, M.; Walborsky, H. M.
94
Ber.
Soc.
J. Am. Chem.
, 3252. b) MnO : Maier, G.; Heep, U. Angew. Chem.
2
Procedure for the Recovery of SAMP: The aqueous layer was partially
concentrated, basified with conc. KOH solution, treated with a 2:1
mixture of ether/THF (ca. 3 times the volume of aq. phase) followed by
1983,
105
1965, , 967. c) Peroxide: Ho, T.-L.; Olah, G. A.
77
1976,
Synthesis
611; Enders, D.; Eichenauer, H.; Pieter, R. Chem. Ber. 1979, 112,
3703; Choi, H. C.; Kim, Y. H. Synth. Commun. 1995, 24, 2307.
d) Perborate: McKillop, A.; Tarbin, J. A. Tetrahedron 1987, 43,
1753. e) Periodate: Corey E. J.; Enders D. Tetrahedron Lett. 1976, 3.
f) Copper salts: Corey, E. J.; Knapp, S. Tetrahedron Lett. 1976,
3667; Ziegler, F. E.; Becker, M. R. J. Org. Chem. 1990, 55, 2800;
Mino, T.; Fukui, S.; Yamashita, M. J. Org. Chem. 1997, 62, 734.
g) Singlet oxygen: Friedrich, E.; Lutz, W.; Eichenauer, H.; Enders,
D. Synthesis 1977, 894. h) Nitrosation: Olah, G. A.; Ho, T.-L.
anhyd. MgSO and K CO until the aqueous phase solidified. Then the
4
2
3
mixture was vigorously stirred, and filtered hot. The solid was extracted
again with ether/THF and the combined extracts were concentrated. The
residue was taken up in CH Cl , dried (MgSO ), filtered and
2
2
4
concentrated under vacuum to give SAMP (1.66 g, 85%). The
analytically pure sample was prepared by distillation.
1976, 610; Caglioti, L.; Gasparrini, F.; Misiti, D.;
Synthesis
Palmieri, G. Synthesis 1979, 207; Laszlo, P.; Polla, E. Tetrahedron
1984,
, 3309. i) Transition metal halides: Olah, G. A.;
Acknowledgements: This work was supported by the Deutsche
Forschungsgemeinschaft (Leibniz prize) and the Fonds der Chemischen
Industrie. We thank Degussa AG, BASF AG, Bayer AG and Hoechst
AG for the donation of chemicals.
Lett.
25
Welch, J.; Ho, T.-L. J. Am. Chem. Soc. 1976, 98, 6717; Olah, G. A.;
Welch, J.; Suria Prakash, G. K.; Ho, T.-L. Synthesis 1976, 808.
Olah, G. A.; Welch, J.; Synthesis 1976, 809; Olah, G. A.; Welch, J.;
Henninger, M. Synthesis 1977, 308. j) Ozonolysis: Erickson, R.;
Andrulis Jr., P. J.; Collins, J. C.; Lunge, M. L.; Mercer, G. D. J. Org.
References and Notes
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34
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(5) Reductive cleavage: Mc Murry, J. E.; Silvestri, M. J. Org. Chem.
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40
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31
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4
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61