Asymmetric formation of α-amino acid esters through dynamic kinetic resolution: A cyclic carbonate as an optically active CO2 synthon

Full text of DOI:10.1021/ja984061x

4520
J. Am. Chem. Soc. 1999, 121, 4520-4521
Scheme 1
Asymmetric Formation of r-Amino Acid Esters
through Dynamic Kinetic Resolution: A Cyclic
Carbonate as an Optically Active CO2 Synthon
Jon A. Tunge,† Daniel A. Gately,‡ and Jack R. Norton*,†
Department of Chemistry, Columbia UniVersity
New York, New York, 10027
Department of Chemistry, Colorado State UniVersity
Fort Collins, Colorado, 80523
ReceiVed NoVember 25, 1998
We have reported the conversion of N-aryl benzyl and
phenethylamines into R-amino acid esters utilizing ethylene
carbonate as a CO2 equivalent.1,2 Use of the optically active
ethylenebis(tetrahydroindenyl) (EBTHI) zirconium complex 1
resulted in product formation in >98% ee (Scheme 1). These
experiments revealed that the ring carbons of zirconaaziridines3
such as 2 are configurationally labile; thus, the optical purity of
the products depended on the concentration of ethylene carbonate.1b,c
The utility of the transformation in Scheme 1 is limited by the
stoichiometric use of the optically active EBTHI complex. We
now report that asymmetric induction is achieved when an
enantiopure carbonate is allowed to react with a racemic zircon-
aaziridine derived from the inexpensive Cp2ZrCl2. Cyclic carbon-
ates with C2 symmetry4 are attractive as optically active CO2
synthons because the required vicinal diols are available in high
yield and optical purity from the Sharpless dihydroxylation.5 For
our initial investigation we have used 1,2-diphenylethylene
carbonate (5), because both enantiomers of the corresponding diol
are easily prepared on a kilogram scale5b and are commercially
available.
The stereochemical outcome of Scheme 2 will be determined
by Curtin-Hammett kinetic considerations similar to those
previously applied1b to Scheme 1. The kinetic system in Scheme
2 displays two well-defined boundaries. If (a) the two enantiomers
(R)-6 and (S)-6 are not converting on the time scale of the insertion
(i.e., kS[5], kR[5] . kinv), the reaction can be run as a kinetic
resolution. However, the yield of optically pure product is limited
to 50%, and the enantiomeric purity of the product is greatly
affected by the extent of conversion. If (b) the enantiomers are
rapidly interconverting relative to insertion (i.e., kS[5], kR[5] ,
kinv), the reaction can be run to 100% conversion, and the product
Scheme 2
ratio will equal the relative rates of insertion. The latter extreme
(condition b) is termed a dynamic kinetic resolution (DKR)6 and
avoids limitations on yield and conversion.
We have determined the configurational lability, necessary for
DKR, of the ring carbons in zirconaaziridines derived from Cp2-
ZrCl2. To obtain a diastereoexcess from treatment of a racemic
mixture with a stoichiometric amount of an optically active
reagent, the enantiomers of the racemate must not only intercon-
vert but also react at different rates.7 The insertion of 5 into the
racemic zirconaaziridines 6 is such a case. Addition of 1.2 equiv
of 5 to 6a in C6D6 at room temperature resulted in a 24% de.
Repeating this experiment with 6b gave 7b in 25% de, indicating
that epimerization was competitive with insertion.
A Curtin-Hammett kinetic analysis8 shows that, at low
conversion, the product ratio R-7/S-7 will be equal to kR/kS. This
ratio, termed the selectivity factor s, can be more accurately
determined with the use of a test developed by Hoffmann.7 When
a racemic zirconaaziridine is treated with a racemic C2 symmetric
carbonate, the ratio of diastereomeric products is equal to kR/kS
(Scheme 3). Thus, when 6a is allowed to react with racemic 5,
the de is 76%, indicating an s of 7.3. When 6b is treated in the
same manner, the de is 90%, indicating a rate constant ratio s of
19. The data in Table 1 show that the diastereodifferentiation is
good for zirconaaziridines with aromatic substituents. Importantly,
this test is independent of the rate of epimerization of the
zirconaaziridine.
In order for DKR to be possible, inversion at the ring carbon
must be much faster than insertion. Unfortunately, when 5 is
added all at once to 6 at room temperature the maximum
selectivity is not realized. For example, rapid addition of 5 to 6b
provides the product metallacycle in only 22% de.
However, insertion can be kept much slower than epimerization
if 5 is added to 6 slowly via syringe pump. Thus, syringe pump
addition of a solution of 5 to 6b over the period of 4 h forms the
product metallacycle 7b in 90% de at 100% conversion. The same
experiment repeated with 6a results in a 76% de. As Table 2
†Columbia University.
‡ Colorado State University.
(1) (a) Gately, D. A.; Norton, J. R.; Goodson, P. A. J. Am. Chem. Soc.
1995, 117, 986-996. (b) Gately, D. A.; Norton, J. R. J. Am. Chem. Soc. 1996,
118, 3479-3489. (c) The configurational lability of zirconaaziridines was first
noted by the Buchwald group in their initial investigation of these reagents:
Grossman, R. B. Ph.D. Thesis, Massachusetts Institute of Technology,
Cambridge, MA, 1991.
(2) For other examples of R-carboxylation of amines, see: Faibish, N. C.;
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10.1021/ja984061x CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/27/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 18, 1999 4521
Scheme 3
indicate a maximum de of 82% for the reaction of 9e with (R,R)-
5. Syringe pump addition of carbonate (R,R)-5 to a solution of
9e results in a product having 77% de (Table 2), showing that
the DKR limit is nearly reached. Similarly, syringe pump addition
of (R,R)-5 to 9d produces the product 7d with a 71% de,
approaching the maximum value predicted by the Hoffmann test.
-
4
(1)
Table 1. Selectivity Factors s Determined from the Reaction of
Complexes 6 and 9 with (rac)-5 at Room Temperature (Scheme 3)
Protonolysis of the metallacycles formed in the above reactions
gives 2-hydroxyethyl esters 11 (eq 3). These compounds can be
obtained in >95% de by recrystallization or by chromatography.
The 2-hydroxy group facilitates hydrolysis,11 so that the esters
can be transesterified to the methyl esters under mild conditions.
Treatment with catalytic amounts of NaOH in MeOH provides
the methyl esters in quantitative yield after 15 min at room
temperature.12 Likewise, NaOH/H2O treatment gives the optically
active R-amino acids. The transesterification occurs without
significant racemization13 (Table 3), and the optically active diol
is recovered.
complex
dea (%)
s
complex
dea (%)
s
6a
6b
6cb
9d
76
90
>95
74
7.3
19
9e
9f
9g
82
21
45
10.1
1.5
2.6
>39
6.7
a Determined by integration of the 1H NMR Cp resonances.
b Determined by the generation of 6c in the presence of (rac)-5.
Table 2. Results of Syringe Pump Additiona of (R,R)-5 to 6 and 9
de
de
de
de
(obs)b (predicted)
(obs)b (predicted)
complex
(%)
(%)
complex
(%)
(%)
6a
6b
9d
76
90
71
76
90
74
9e
9f
77
18
82
21
a 0.6 M (R,R)-5 in C6H6 added to 0.3 M zirconium complex in C6H6
via syringe pump over the period of 4-4.5 h at room temperature.
The reactions we report here permit the direct asymmetric
carboalkoxylation of the R position of an amine with an optically
active CO2 equivalent. Future experiments will attempt to
1
b Determined by integration of the H NMR Cp resonances.
Table 3. Yields and ee’s of Amino Acid Methyl Esters Prepared
by Hydrolysis and Transesterification of Complexes 7 and 10 (eq 3)
determine the rates and mechanism of the interconversion (kinv)
of enantiomeric zirconaaziridines.
R-amino ester ee (%)a yieldb R-amino ester ee (%)a yieldb
Acknowledgment. We thank Boulder Scientific for generously
supplying us with Cp2ZrCl2. We are grateful to T. Takahashi (Tokyo
Institute of Technology) and R. Bittman (Queens College) for valuable
discussions. This work was supported by NSF grant CHE-98-96151.
12a
12b
98.6
96
57
69
12d
12e
99.1
>95
47
30
1
a Determined by H NMR analysis of the (+)-MTPA13a,14 amides
except for 12a and 12d which were determined by HPLC separation
on a Bakerbond OD chiralcel column. b Yields correspond to overall
yields based on (R,R)-5. Configurations of 12a,b,e were verified by
comparison of 1H NMR spectra of (+)-MTPA amides or HPLC
retention times with those of authentic samples.
Supporting Information Available: Spectroscopic and analytical data
for complexes 6-10 and amino acid esters 11 and 12 (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA984061X
(10) For other examples of 1-azaallylmetal complexes see: Hitchcock, P.
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Organometallics 1997, 16, 2263-2275. Dewith, J.; Horton, A. D.; Orpen, A.
G. Organometallics 1993, 12, 1493-1496.
shows, these values are in good agreement with those predicted
by the Hoffmann test, showing that dynamic kinetic resolution
conditions have been reached.
Attempting to generate zirconaaziridines containing â-hydro-
gens leads instead to η3-1-azaallyl zirconocene hydride complexes
of the type 9 (eq 1). A similar result has been observed by Whitby
and co-workers, who noted that the azaallyl complex reacted to
give products expected from a zirconaaziridine.9,10 Our complexes
9 also react like zirconaaziridines to give the expected metalla-
cycles, implicating an equilibrium between the azaallyl form and
the zirconaaziridine (eq 2). The Hoffmann test results for 9e
(11) Bruice, T. C.; Fife, T. H. J. Am. Chem. Soc. 1962, 84, 1973-1979.
(12) The esters 11 are transesterified without observable racemization by
treatment with 10 mol % (0.004 M) NaOH in MeOH for 15 min.
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1994, 13, 190-199.
(14) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543-
2549.