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Enantioselective Synthesis of 3-Substituted 2-Ketoesters.

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University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW
(UK) on quoting the full journal citation.
[7] H. Wadle, E. Conradi, U. Miiller, K. Dehnicke, Z . Naturforsch. B 1986,41,
[S] H. W. Roesky, J. Schimkowiak, M. Noltemeyer, G. M. Sheldrick, 2.
Natirrforsch. B 1986, 41, 175-178.
[91 H. W. Roesky, J. Anhaus, H. G. Schmidt, G. M. Sheldrick, M. Noltemeyer, J. Chem. Sac. Dalton Trans. 1983, 1270-1279.
[lo] T. A. Kahanos, A . M . 2. Slawin, D. J. Williams, J. D. Woollins, J. Chem.
Chem. Comniun. 1990, 193- 194.
1111 N. Burford, T. Chivers, R. T. Oakley, A. W Cordes, P. N. Swepston, J.
Chem. SOC.Chem. Commun. 1980, 1204-1205.
I121 It is noteworthy that the out-of-plane twist of the PdCI, plane with respect
to the PdS,N, plane is such as to reduce the intermolecular CI...S
(131 E. Conradi, H. Wadle, U. Miiller, K. Dehnicke, 2.Naturfbrsch. B 1986,41,
48 - 52.
rect manipulation of the corresponding azaenolates possible.
The two-step synthesis of 2-ketoester 1 succeeded in a simple
fashion and in excellent yields by the esterification of ethyl
oxalyl chloride with the lithium salt of 2,6-di-tert-butyl-4methoxyphenol followed by the chemoselective nucleophilic
addition of methyl or ethyl Grignard reagents to the unsymmetrical ethyl aryl oxalate (Scheme 1).
1. n BuLi, THF, 0°C
92 - 98%
t Bu
Enantioselective Synthesis of 3-Substituted
Ar= *ti,
R J p r
t Bu
By Dieter Enders,* Hubert Dyker, and Gerhard Raabe
Dedicated to Professor Giinther Maier
on the occasion of his 60th birthday
Scheme 1. Synthesis of 2-ketoester 1.
As phosphoenolpyruvate (PEP) A, pyruvic acid plays a
central role in the biosynthesis of sialic acids and ulosonic
acids,"' whereby phosphoenolpyruvate undergoes C-C linkage to aldehydes by means of aldol reactions catalyzed by
aldolases. Important natural products such as N-acetylneuacid (KDO),
raminic acid, 3-deoxy-~-manno-octu~osonic
and 3-deoxy-~-arabino-2-heptulosonic
acid 7-phosphate
(DAHP), the precursor of shikimic acid, are formed in this
way. Chemical equivalents of phosphoenolpyruvate-metalated derivatives of pyruvic acid, for example chiral hydrazones B (R = H), or more generally derivatives of 2-ketocarboxylic acidsr'kan be considered d2 synthons C.r31In
recent years several such systems have been examined,[41but
to our knowledge no efficient general reagent for the transfer
of the synthon C to electrophiles in diastereo- and enantioselective reactions is available.
The reaction of 2-ketoester 1 with (Q-l-amino-2methoxymethylpyrrolidine (SAMP)[6,'1 provided the (E)configured hydrazone (a-2
as a pale yellow solid in almost
quantitative yield. The subsequent metalation with 2.2
equivalents of Lochmann-Schlosser base in tetrahydrofuran
at - 90 to - 78 "C yielded highly reactive azaenolates, which
were alkylated by a number of alkyl halides at - 100 "C in
good yields (51 - 72 %) and with high diastereomeric excesses
(de = 85 to > 95 %) to furnish hydrazones (S,S)-3. If less
base was used, the alkylation did not go to completion. By
the oxidative cleavage with ozone the alkylated hydrazones
were converted in good yields and without racemization to
the final products (S)-4, which were purified by flash chromatography (Scheme 2). This last step is not suitable for
compounds like (S,S)-3d which are easily oxidized by ozone.
In such cases the SAMP hydrazone can be converted to
ketoesters ( 9 - 4 with boron trifluoride-ether in acetone/
water with the addition of paraformaldehyde. This method
was previously employed in a similar way for the cleavage of
dim ethyl hydra zone^.[^^ In comparison to the oxidative cleavage this method gave somewhat better yields; however, reacn
We now report on the synthesis of a chiral, homologous
PEP equivalent B (R = CH,) by the application of our
SAMP-/RAMP- hydrazone methodrs~61
and the use of B in
the synthesis of highly enantio-enriched 3-substituted 2-ketoesters. Our initial attempts at metalating hydrazones of
methyl and tert-butyl pyruvate and trapping them with electrophiles were unsuccessful and led primarily to self-acylated
products. Only after we sterically blocked the ester reactivity
esterr7]was the dias the 2,6-di-tert-butyl-4-methoxyphenyl
Prof. Dr. D. Enders, Dip1.-Chem. H. Dyker, Dr. G. Raahe
lnstitut fiir Organische Chemie der Technischen Hochschule
Professor-Pirlet-Strasse 1, D-W-5100 Aachen (FRG)
This research was supported by the Fonds der Chemischen Industrie and
the companies Degussa, BASF, Bayer. and Hoechst (donation of chemicals). H.D. thanks the Fonds der Chemischen lndustrie for a Kekule fellowship.
0 VCH Verlagsgesellschaft mbH, W-6940 Weinheim, 1992
R o
39 - 67%
I ,
0 3 ,CHzCIz, -78°C
1. t BuOWn BuLi (2.25equiv.)
THF, 4 +-78°C
2. RX, -1 00°C +RT
51 - 72%
80 - 90Oro
R o
Scheme 2. Enantioselective synthesis of the 3-substituted 2-ketoester 4
$3.80+ .2S/O
Angew. Chem. Int. Ed. Engl. 3f (1992) No. 5
tion times of one to two days were required (monitored by
thin-layer chromatography).
The enantiomeric excess of the 3-substituted ketoester (S)4 a was determined by a 'H NMR shift experiment with
Eu(hfc), , and proved that the cleavage with ozone and
boron trifluonde-ether proceeded without racemization. In
the other cases the enantiomeric excesses are based on the
diastereomeric excesses of hydrazones 3 as determined by
13CNMR spectroscopy. The enantiomers (R)-4 are accessible simply by changing the chiral auxilliary (RAMP instead
of SAMP), as was demonstrated for (R)-4e and (R)-4h.
Table 1. The highly enantio-enriched 3-substituted 2-ketoesters 4 prepared by
the enantioselective alkylation of 2-ketoesters 1 via the SAMP hydrazones
e[e] PhCH,Br
h [el PhCH,O(CH,),I
Yield 3
Yield 4 [a]
ee [b]
61 -65
87 (97) [c]
90 (96)
54-62 [d] 80-88 (85)
65 [d]
82 (-1
85 (-)
81 (92)
80 (-)
[a] Yield of the pure ketoester 4 after cleavage of hydrazone 3 with ozone or
BF,.Et,O (in parentheses). [b] Determined by 'H NMR shift experiments with
Eu(hfc), and/or by 13C NMR spectroscopy of the hydrazone intermediate,
whose absolute configuration is given in parentheses. [c] m.p. 56- 57 "C. [d]m.p.
78-79 "C. [el RAMP was used as the chiral auxiliary.
The absolute configuration of hydrazones 3, and thus also
of ketoesters 4, was determined by X-ray structure analysis
of (S,9-3e (Fig. l).['ol
The (S)configuration found at the
newly formed stereogenic center is in agreement with that
predicted by the postulated mechanism for electrophilic substitutions via SAMPIRAMP hydra zone^.^'^]
$ 9 2
Fig. 1. Structure of (S,9-3e in the crystal (Schakal plot[l5])
This method permits for the first time the highly enantioselective transfer of a homologous pyruvate unit to electrophiles.[16] Preliminary enzyme-mimetic applications of
Angen. Chem. Int. Ed. Engl. 31 (1992) No. 5
this new procedure to asymmetric aldol reactions are
promising and should allow a simple and stereoselective approach to important natural products and drugs." 'I
Experimental Procedure
A solution of 6.6 mmol Lochmann-Schlosser base was prepared by the addition of a solution of nBuLi in n-hexane (4.4 mL, 1.5 M) to a solution of potassium tert-butoxide (0.74 g) in TH F (20 mL) at - 78 "C under argon. This solution
was cooled to -90 "C, and hydrazone ( 9 - 2 (1.3 g, 3 mmol) dissolved in THF
(4 mL) was added. The reaction mixture was stirred for 2 h and allowed to warm
to - 78 "C. The reaction mixture was then cooled to - 100 "C, and a solution
of 6.6 mmol of the alkyl halide in 3 mL of THF was added dropwise. The
reaction temperature was held at -100°C for 2h before the solution was
allowed to warm to 0-10°C over 12h. The solution was neutralized by the
addition of glacial acetic acid (0.4 g, 6.6 mmol) in water (2 mL) and then extracted with ether (200 mL). After the phases were separated, the ethereal phase
was washed with a buffer solution (10 mL, pH 7) and saturated NaCl solution
(10 mL) and dried over MgSO,. The solvent was removed in vacuum, and the
crude hydrazone was purifed by flash chromatography (silica gel, petroleum
ether/ethyl acetate 9: 1).
For the cleavage, 1 mmol of the hydrazone was dissolved in CH,CI, (50 mL)
and cooled to - 78 "C under argon. Ozone was passed through the solution at
that temperature until the reaction was complete (reaction progress monitored
by TLC). After the excess ozone was dispelled with argon, the reaction mixture
was allowed to warm to room temperature. The solvent was removed in vacuum, and the product was purified by flash chromatography (silica gel,
petroleum ether/ethyl acetate/isopropanol 95 : 5 : 1). Alternatively, the hydrazone was dissolved in 10 mL acetone and 1 mL water, and BF,.Et,O (0.38 mL,
3 mmol) was added dropwise. Paraformaldehyde (0.15 g, 5 mmol) was then
added, and the reaction mixture was stirred 15h at room temperature. To
ensure complete reaction another portion of BF,.Et,O (0.38 mL, 3 mmol) was
added, and the reaction mixture was stirred another 12- 24 h (reaction progress
again monitored by TLC). Solvent was removed in vacuum, and the residue was
taken up in ether, washed with saturated NH,CI solution (5 mL) and saturated
NaCl solution ( 5 mL), and dried over MgSO,. After evaporation of the solvent
the crude product was purifed by flash chromatography as described above.
Received: December 3, 1991 [ZSOSl IE]
German version: Angew. Chrm. 1992, 104,649
[I] F. M. Unger, Adv. Curbohydr. Chem. Biochem. 1980,38,323; R. Schauer,
ibid. 1982, 40, 132.
[2] a) J. M. Brown in Compr. Org. Chem. (Eds.: D. H. R. Barton, W. D.
Ollis). Pergamon Press, Oxford, 1979, V01.2, p. 779; b) A. J. L. Cooper,
J. Z. Ginos, A. Meister, Chem. Rev. 1983, 83, 321.
[3] D. Seebach, Angew. Chem. 1979, 91, 259; Angew. Chem. Int. Ed. Engl.
1979, 18, 239.
Chim. Fr. 1966, 1435; b) R. R. Schmidt, R.
[4] a) C. G. Wermuth, BUN.SOC.
Betz, Angew. Chem. 1984, 96,420; Angew. Chem. In[. Ed. Engl. 1984, 23,
430; c) R. Metternich, W. Liidi, Tetrahedron Lett. 1988, 29, 3923; d) A.
Esswein, R. Betz, R. R. Schmidt, Helv. Chim. Actu 1989, 213; e) E. R.
Org. Chem. 1989,54, 2936; f) A. Dondoni,
Koft, P. Dorff, R. Kullnig, .
G. Fantin, M. Fogagnolo, Tetrahedron Lett. 1989, 30, 6063; g) A. Dondoni, G. Fantin, M. Fogagnolo, P. Merino, Tetrahedron Lett. 1990, 31,
4513; h) A. Dondoni, P. Merino, J. Org. Chem. 1991,56,5294; i) I. Tapia,
V. Alcazar J. R. Moran, C. Caballero, M. Grande, Chem. Lett. 1990, 697;
j) D. R. Williams, J. W. Benbow, ibid. 1990,31, 5881 ;k) A. G. M. Barrett,
Org. Chem. 1991, 56, 1894.
D. Dhanak, S. A. Lebold, M. A. Russel, .
151 D. Enders in Asymmetric Synthesis (Ed.: J. D. Morrison), Academic Press,
Orlando, 1984, Vol. 3, p. 275.
[6] D. Enders, P. Fey, H. Kipphardt, Org. Synth. 1987, 65, 173, 183.
[7] a) C. H. Heathcock, M. C. Pirrung, S. H. Montgomery, J. Lampe, Tetrahedron 1981, 37, 4087; b) R. Haner, D. Seebach, Chimiu 1985, 39, 356;
c) M. P. Cooke, Jr., J. Org. Chem. 1986,51, 1638; T. Vettiger, D. Seebach,
Liebigs Ann. Chem. 1990, 189.
[XI a) D. Enders, P. Fey, H. Kippbardt, Org. Prep. Proc. Int. 1985,17,1; b) D.
Enders, H. Eichenauer, Chem. Ber. 1979, 112, 2933.
[9] R. E. Gawley, E. J. Termine, Synth. Commun.1982, 12, 15.
[lo] Suitable single crystals were obtained by crystallization from n-hexane.
Orthorhombic, space group P2,2,2, (19), a = 9.600(2), 6 = 13.109(1),
c = 24.331(6) A. V = 3062.0 A3, M,,,, = 522.73, and Z = 4 provide a calculated densityp = 1.134 gcm-3. Total number ofelectrons perelemental
cell F(O00) = 1136, Cu,. radiation ( A = 1.54179 A, graphite monochromator), p = 5.93 cm- ' (no absorption correction). Enraf-Nonius four-circle
diffractometer, Qj26 scans, 20 "C. Of 3581 independent reflections
(+ h + k + 0 2625 were observed ( I ) > 2a(I), R. = O.Ol), sin O/
= 0.628 for solution and refinement. The structure was solved with
direct methods (GENSIN[I I] and GENTAN1121 of the XTAL3.0 program
package[l3]). Positions of the hydrogen atoms were calculated. 344
parameters were refined, R = 0.090 (R, = 0.097). residual electron density
0 VCH Verlag,~gesellschaftmbH, W-6940 Weinheim, 1992
0.3 e k 3 . Further details of the crystal structure investigation may be
obtained from the Fachinformationsrentrum Karlsruhe, Gesellschaft fur
wissenschaftlich-technische Information mbH, D-W-7514 EggensteinLeopoldshafen 2 (FRG) on quoting the depository number CSD-56193,
the names of the authors, and the journal citation.
1111 ,,GENS",
V. Subramanian, S. R. Hall, XTAL 3.0 Reference Manual
(Eds.: S . R. Hall, J. M. Stewart), Universities of Western Australia and
Maryland 1990.
1121 ,,GENTAN', S. R. Hall XTAL 3.0 Reference Manual (Eds.: S. R. Hall,
J. M. Stewart), Universities of Western Australia and Maryland 1990.
1131 XTAL 3.0 Reference Marzua/(Eds.: S . R. Hall, J. M. Stewart), Universities
of Western Australia and Maryland 1990.
1141 a) D. Enders, Chem. Scr. 1985, 25, 139; b) D. Enders, G. Bachstiidter,
K. A. M. Kremer, M. Marsch, K. Harms, G. Boche, Angew. Chem. 1988,
100, 1580; Angew. Chem. I n f . Ed. Engl. 1988,27, 1522.
1151 E. Keller, Chem. Unserer Z . 1986, 20, 178.
[16] All new compounds provided correct elemental analyses and spectra
(NMR, IR, MS).
1171 D. Enders, H. Dyker, unpublished results.
Biochemical Degradation of Cyanamide and
Dicyandiamide **
By Lydia M . Estermaier,* A . Heidemarie Sieber,
Friedrich Lottspeich, Dagmar H . M . Matern,
and Guido R. Hartmann
Dedicated to Professor Heinz Harnisch
on the occasion of his 65th birthday
Nitrate is the predominant form of nitrogen in the soil
available to most plants grown under normal field conditions and is taken up as such as a source of nitrogen. It is
produced from ammonium ions by oxidation catalyzed by
soil microorganisms (nitrification)."] Due to the cation exchange properties of soil, NHZ is more easily accumulated
than NO; which is rapidly lost by leaching.r2'Most artificial
fertilizers contain nitrogen in the form of nitrate or ammonium ions. However, the first synthetic compound used as
nitrogen fertilizer was cyanamide, which is synthesized from
calcium carbide and atmospheric nitrogen in an exothermic
reaction. Despite its relatively high cost, cyanamide is still
used in agriculture and horticulture as a nitrogen fertilizer,
particularly in the form of its calcium salt, because of its
other useful properties. In addition to its ability to provide
nitrogen it acts also as a herbicide (defoliating weeds),I3]
pesticide, fungicide, and bactericide.[41In this last function it
is also utilized for the deodorization of liquid manure.
Cyanamide is also active in halting the dormancy of grape
and other fruits. This discovery opened a new field of
application as plant growth regulator.
Dicyandiamide, the product of dimerization of cyanamide,
is applied in agriculture as an inhibitor of nitrification. It
prevents the oxidation of NH,' by Nitrosomonas europea16]
Dr. L. M. Estermaier, A. H. Sieber, Dip].-Chem. D. H. M. Matern,
Prof. Dr. G. R. Hartmann (deceased)
Institut fur Biochemie der Universitat
Karlstrasse 23
D-W-8000 Munich 2 (FRG)
Dr. F. Lottspeich
Laboratorium fur Molekulare Biologie - Genzentrum
D-W-8033 Martinsried (FRG)
These investigations have been supported by SKW Trostberg AG and the
Fonds der Chemischen Industrie. We are very grateful to Prof. M. H. Zenk
and Dr. T. Kutchan, Munich, for generous help with plant cell cultures and
for discussions and to Dr. R. J. Youngman, Trostberg, for information. We
wish to thank Prof. K. Kobashi, Toyama, for N-isopentenoylphosphoric
trisamide and Prof. A. Bock and G. Miiller, Munich, for the supply of
bacterial strains.
0 VCH Vedagsgesellschafl mbH, W-6940 Wernheim, 1992
and thereby stabilizes the supply of nitrogen available in the
The mechanism of the biological degradation of these
compounds poses an interesting ecological problem. When
applied to fields, cyanamide usually disappears within a couple of days, depending on the soil and its moisture content.
It was clear from the beginning that some catalytic mechanism must be involved in the degradation. For a long time it
was thought that inorganic catalysts present in the soil are
involved in this process, until the experiments of Ernst1'I
clearly showed the preponderance of biological mechanisms,
although the biochemistry of this particular degradation was
not elucidated.
An inducible enzyme, cyanamide hydratase (EC,
highly specific for the hydration of cyanamide (but not dicyandiamide) to urea, was first detected in the soil fungus
Myrothecium verrucaria['] and purified to h~mogeneity.[~]
However, it is unlikely that this enzyme is generally responsible for the biological degradation of cyanamide in the soil,
since it is expressed by the fungus only in the complete absence of any other nitrogen source, and expression immediately stops if another nitrogen source becomes available.
Hofmann et a1.I' O1 described another enzymatic activity in
extracts of commercial soybean flour which catalyzes the
disappearance of cyanamide. We have purified this cyanamide-degrading enzyme from soybean flour (type I, not
roasted, Sigma, Munich) in six steps to apparent homogeneity. Its molecular mass is about 600000, and it consists of six
identical subunits. The first 23 amino acids at the N-terminus
of the subunit were sequenced using the methodology described by Eckerskorn et al.[''] The sequence was the same
as that at the N-terminus of urease from jack
findings suggested that the isolated enzyme may be identical
to urease from soybean.
We therefore tested the commercially available, highly
purified urease from jack bean (Canavalia ensiformis)
(type VII, Sigma, Munich) for its ability to degrade
cyanamide. Such a comparison disclosed that jack bean
urease indeed exhibited the same specific enzymatic
activity (310i 20 nmolmin-'mg-'), and the same K, value
(0.15~0.05M) with cyanamide as substrate as the enzyme
from soybean. Similarly the optimum of pH (7.0) and temperature (70 "C) was the same. In the reaction two moles of
ammonia were formed for each mole of cyanamide consumed. Obviously urease catalyzed a cyanamide hydrolase
reaction [Eq.(a)].
+ 2H,O
+ CO,
Additional evidence that urease is responsible for the
cyanamide hydrolase activity was provided by the effect of
specific inhibitors of urease;[13,14] all of them inhibited the
cyanamide hydrolase activity (Table 1).
To determine the substrate specificity we have tested not
only cyanamide but also cyanamide derivatives such as N formylcyanamide, acetylcyanamide, and benzoylcyanamide
for hydrolysis by urease. But even with a 100-fold greater
enzyme concentration than that used in the experiments with
unsubstituted cyanamide and with prolonged incubation
times up to 24 h, no hydrolysis was detectable.
Since cyanamide is hydrolyzed by urease we investigated
also cyanic acid as a substrate. In contrast to cyanamide,
cyanic acid is rather unstable at pH 7.0 and decomposes
rapidly without addition of a catalyst. Nevertheless, the
degradation of this compound is also distinctly enhanced by
OS70-0833192JOSOS-0620$3.50+ .25jO
Angew. Chem. Int. Ed. Engl. 31 (1992) No. 5
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synthesis, ketoesters, enantioselectivity, substituted
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