Daucus carota mediated-reduction of cyclic 3-oxo-amines

Article abstract of DOI:10.1021/ol8029214

Carrots (Daucus carota) were used to reduce cyclic amino-ketones in high yields and enantiomeric excesses. This cheap, eco-compatible, and efficient reducing reagent allows the easy access to precursors of biologically active products.

Full text of DOI:10.1021/ol8029214

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1245-1248
Daucus carota Mediated-Reduction of
Cyclic 3-Oxo-amines
Romain Lacheretz, Domingo Gomez Pardo, and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS,
10 rue Vauquelin, 75231-Paris Cedex 05, France
janine.cossy@espci.fr
Received December 19, 2008
ABSTRACT
Carrots (Daucus carota) were used to reduce cyclic amino-ketones in high yields and enantiomeric excesses. This cheap, eco-compatible, and
efficient reducing reagent allows the easy access to precursors of biologically active products.
Numerous natural and non-natural products with interesting
biological activities contain in their structure a piperidine
core of type A, possessing a quaternary stereogenic center
at C3 with the (R)- or (S)-configuration. These piperidines
of type A are present in non-natural products such as
capromorelin,1 or in natural products such as isonitramine2
and sibirine2a,3 (Figure 1). Piperidines of type B can be the
precursors of piperidines of type A and can be obtained from
4-hydroxypiperidino esters C, using a diastereoselective
alkylation developed by Frater4 where the control of the
quaternary stereogenic center is directed by the hydroxy
group at C4 (Scheme 1).
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Nickerson, D. F.; Ng, O.; Pirie, C. M.; Ragan, J. A.; Rose, C. R.; Tess,
Figure 1. Piperidine derivatives containing a quaternary center.
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Numerous chemical and biochemical methods have been
developed for reducing ꢀ-keto-esters of type D to the
corresponding optically pure ꢀ-hydroxyesters.5 However,
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10.1021/ol8029214 CCC: $40.75
Published on Web 02/12/2009
2009 American Chemical Society

On the basis of these results, and as reductases are present
in a great variety of plants and vegetables,9 carrots (Daucus
carota) were selected to reduce piperidinones 1 and 2 because
this plant usually gives good results10 (Scheme 3).
Scheme 1
.
Retrosynthesis Analysis of Optically Active
Piperidines of Type A
Scheme 3. Reduction of ꢀ-Keto-ester by Daucus carota
agents as well as the isolation of pure ꢀ-hydroxyesters in
high yields from the reaction or fermentation media.6
Recently, plant cell culture and plant roots have been used
in reductions. These biocatalysts are active in aqueous media
under mild, economically viable conditions, and they are
more eco-compatible than organometallics.7 The most com-
mon biocatalyst used to selectively reduce the ketone in
ketoesters is baker’s yeast.8 Appropriately, the reduction of
N-benzyl-ꢀ-piperidinone ester 1 using baker’s yeast was
initially examined. When compound 1 (2 mmol) was treated
with baker’s yeast (4 g) in the presence of sucrose (5 g) in
water (60 mL) at 37 °C for 24 h, the corresponding
ꢀ-hydroxyester 3 was not detected. On the contrary, when
N-Boc-ꢀ-ketoester 2 was treated under the same conditions
used for 1, the expected cis-4-hydroxypiperidine ester 4 was
isolated in 80% yield but, very disappointgly, in its racemic
form (Scheme 2). We have to point out that the reduction of
Compound 1 (2 mmol) was treated with carrots (140 g)
in water (600 mL) at rt, and after 48 h, K2CO3 was added
(pH ) 10) before extraction [the reaction media was acidic
(pH ) 5)] and two hydroxyesters 3′ (cis-isomer) and 3′′
(trans-isomer) were isolated in 80% yield in a ratio of
70/30 in favor of the trans-isomer. Both isomers 3′ and 3′′
were obtained with an identical enantiomeric excess (ee )
94%). N-Boc-piperidone ester 2 was also reduced by carrots
and 4′ (cis-isomer) as well as 4′′ (trans-isomer) were isolated
in 91% yield in a diastereomeric ratio of 60/40 in favor of
the cis-isomer. Compounds 4′ and 4′′ were obtained with a
similar enantiomeric excess of 91%. The absolute configu-
ration of the stereogenic centers were determined by
comparison of the [R]D of compounds 4′ and 4′′ descibed in
the literature.11
Scheme 2. Reduction of ꢀ-Keto-ester by Baker’s Yeast
We have to point out that the ratio 4′/4′′ depends on the pH
of the solution. When the reduction was achieved in the presence
(7) (a) Wong, C. H.; Whitesides, G. M. In Enzymes in Synthetic Organic
Chemistry; Pergamon Press: Oxford, 1994. (b) Drauz, K.; Waldmann, H.
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N-Boc-ꢀ-ketoester 2 by baker’s yeast was already described
in the literature to provide cis-4-hydroxyester 4 with a good
enantiomeric excess,5a but these results have been contra-
dicted by Bols and Willert5b who have reported the formation
of 4 as a racemate which confirmed our results.
(6) (a) Kitamura, M.; Ohkuma, T.; Tokunaga, M.; Noyori, R. Tetrahe-
dron Asymmetry 1990, 1, 1–4. (b) Ratovelomanana-Vidal, V.; Genêt, J. P.
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1246
Org. Lett., Vol. 11, No. 6, 2009

of a phosphate buffer (pH ) 7), the ratio 4′/4′′ was determined
to be 85/15. Furthermore, when 4′ was treated with carrots for
48 h at rt, the pH of the solution was determined to be five and
epimerization of 4′ to 4′′ was observed. However, this epimeri-
zation was not observed when compound 4′ was treated in acidic
conditions (pH ) 5) without carrot plants. These results
suggested that the epimerization is due to the enzymatic
machinery present in carrots.
yield (66-78%) and good enantiomeric excess (75-95%).
The best enantiomeric excesses were obtained for the
N-tosyl- and N-Boc-piperidin-3-ones 8 and 11. The (S)-
configuration of the newly created stereogenic center in 18
and 21 was established by comparison with the [R]D reported
in the literature.12
In order to determine the scope and limitation of the
reduction of cyclic amino ketones by carrots, pyrrolidinones
12-14 were examined (Table 2). When 12-14 were treated
As Daucus carota seems suitable for the enantioselective
reduction of piperidones, piperidin-3-ones 5-11 were examined
(Table 1). When piperidin-3-one ammonium chloride 5 and
Table 2. Reduction of Five-Membered Ring Amino-Ketones by
Daucus carota
Table 1. Reduction of Six-Membered Ring Amino-Ketones by
Daucus carota
with carrots, the corresponding 3-hydroxypyrrolidines were
isolated in good yield (67-83%) and good enantiomeric
excess(82-96%).Inthecaseofcompound13,thecis-hydroxy-
proline ester 23 was isolated with a diastereoselectivity of
98%. It is worth noting that for all the obtained 3-hydroxy-
piperidines and 3-hydroxypyrrolidines, the configuration of
the stereogenic center at C3 was (S) except for compound
23, in which the configuration of the stereogenic center
bearing the hydroxy group is (R).13 These results are in
perfect agreement with the Prelog’s rules as the Pro-R
“hydride” of the NADH is transferred to the Re face of the
ketone.14 A model can be proposed in order to rationalize
the hydride transfer (Scheme 4).
Scheme 4. Prelog Model
N-benzyl-piperidin-3-one 6 were treated with carrots, the
recovery of the corresponding piperidin-3-ols was very low (0%
to 11%) due probably to the high solubility of the hydroxy-
lamines in water. To avoid extraction problems, the amino group
of the piperidin-3-one was protected with electron-withdrawing
groups such benzoyl (compound 7), tosyl (compound 8),
trifluoroacetyl (compound 9), acetyl (compound 10) and tert-
butoxycarbonyl (compound 11) groups.
When submitted to reduction with carrots, 7-11 were
transformed to the corresponding piperidin-3-ols in good
In the case of the reduction of L-proline derivative 13, it
can be suggested that the configuration of the methyl ester
Org. Lett., Vol. 11, No. 6, 2009
1247

plays a role in the control of the (R)-configuration of the
corresponding hydroxy group in 23. We suppose that the
conventional Pro-R “hydride” transfer on the Re face of
the ketone is related to a steric effect due to the configuration
of the methyl ester. The “hydride” transfer should certainly
be faster on the Si face of the ketone thus generating the
formation of cis-diastereomer 23 (Scheme 5).
(Scheme 6). After transformation of 2 to 4′/4′′ by Daucus
carota (yield ) 91%, ee ) 91%), the mixture of 4′ and 4′′
were diastereoselectively alkylated by benzylbromide [LDA
(2.5 equiv), BnBr (1.3 equiv), THF, -78 to 0 °C] to produce
25 in 60% yield. After the oxidation of 25, using Dess-Martin
periodinane, 26 was isolated in 68% yied. This later
compound constitutes a formal synthesis of capromorelin.1
Scheme 6. Formal Synthesis of Capromorelin
Scheme 5. Reduction of 13
In summary, we have developed an alternative, cheap,
convenient, and eco-compatible procedure for the preparation
of optically active cyclic 3-hydroxyamines and we have
applied this methodology for the enantioselective synthesis
of an advanced precursor of capromorelin.
The enantioselective reduction of cyclic ꢀ-amino ketones
by Daucus carota can be applied to the synthesis of an
advanced precursor of capromorelin, an antiaging drug
Acknowledgment. Sanofi-aventis is thanked for financial
support and for a grant to R.L.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
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