Stereospecific synthesis of a-substituted syn-α,β-diamino acids by the diaza-cope rearrangement

Article abstract of DOI:10.1021/ol9021904

Diaza-Cope rearrangement is used to make a variety of a-substituted syn-α,β-diamino acids. The rearrangement takes place with complete transfer of stereochemical integrity (>97% de and >98% ee) giving only one of four possible stereoisomers as determined

Full text of DOI:10.1021/ol9021904

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5258-5260
Stereospecific Synthesis of
r-Substituted syn-r,ꢀ-Diamino Acids by
the Diaza-Cope Rearrangement
Hyunwoo Kim and Jik Chin*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, ON, M5S 3H6 Canada
jchin@chem.utoronto.ca
Received September 22, 2009
ABSTRACT
Diaza-Cope rearrangement is used to make a variety of r-substituted syn-r,ꢀ-diamino acids. The rearrangement takes place with complete
transfer of stereochemical integrity (>97% de and >98% ee) giving only one of four possible stereoisomers as determined by X-ray crystallography,
1H NMR, and chiral HPLC. The observed stereospecificity can be explained in terms of DFT computation. This represents the first 1,4-diaza-
Cope rearrangement with a ketone.
It has been known for over 30 years that diimines derived
from meso-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (hpen)
Scheme 1. Stereospecific Diaza-Cope Rearrangement
and a wide variety of aryl aldehydes undergo diaza-Cope
rearrangement (DCR) to give interesting meso vicinal di-
amines.1 More recently, we developed a stereospecific
synthesis of chiral vicinal diamines by the rearrangement of
diimines prepared from (R,R)/(S,S) hpen and aryl or alkyl
aldehydes.2 However, it has been a challenge to use ketones
for the rearrangement. The reaction did not work when the
aldehydes were replaced with acetone.3 Despite inherent
difficulties with ketones, DFT computation indicated to us
that electron-deficient ketones may work by lowering the
kinetic and thermodynamic barriers to the rearrangement
reaction. We examined the reactivity of R-ketoesters in the
(1) Vo¨gtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1.
(2) (a) Kim, H.; So, S. M.; Kim, B. M.; Chin, J. Aldrichimica Acta
2008, 41, 77. (b) Kim, H.; Nguyen, Y.; Yen, C. P.-H.; Chagal, L.; Lough,
A. J.; Kim, B. M.; Chin, J. J. Am. Chem. Soc. 2008, 130, 12184. (c) Kim,
H.-J.; Kim, H.; Alhakimi, G.; Jeong, E. J.; Thavarajah, N.; Studnicki, L.;
Koprianiuk, A.; Lough, A. J.; Suh, J.; Chin, J. J. Am. Chem. Soc. 2005,
127, 16370. (d) Kim, H.; Staikova, M.; Lough, A. J.; Chin, J. Org. Lett.
2009, 11, 157.
rearrangement reaction (Scheme 1). There has been much
interest in developing synthetic methods for making unnatural
amino acids4 including diamino acids.5 The diaza-Cope
rearrangement provides a highly stereospecific “one pot”
route to R-substituted syn-R,ꢀ-diamino ester diimines (4a
to 4f).
(3) Vo¨gtle, F.; Goldschmitt, E. Angew. Chem., Int. Ed. Engl. 1973, 12,
767.
10.1021/ol9021904 CCC: $40.75
Published on Web 10/20/2009
 2009 American Chemical Society

In a typical reaction, aryl aldehyde (2.0 mmol) is reacted
with hpen (1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane) (2.0
mmol) in DMSO (2.0 mL) to form an imidazolidine
intermediate. In solution, the five-membered ring intermedi-
ates (2a to 2f) are in equilibrium with the corresponding ring-
opened monoimines. Although ring-opened monoimines
become more significant (∼10%) with electron-rich alde-
hydes, the equilibrium favors the five-membered rings in
DMSO solution. The imidazolidine ring formation is sluggish
for indole-3-carboxaldehyde due to its electron-rich character.
However, tosylation of the aldehyde (1f) results in facile
formation of the imidazolidine (2f). A large excess (20 mmol)
of ethyl pyruvate is added to the intermediate mixture and
stirred for 3 h at ambient temperature to give the rearranged
diimines (4a to 4f). Remarkably, only a single diastereomer
The absolute configuration of one of the product diimines
4b was determined by X-ray crystallographic analysis. Figure
1 shows the crystal structure of a square-planar Ni(II)
1
of the mixed diimine was detected by H NMR spectra for
all cases. Although some degree of disproportionation leading
to symmetric diaryl diimines (5) is unavoidable, the desirable
diimines (4a to 4f) can be readily separated by column
chromatography in isolated yields of 52-67% (Table 1). It
Figure 1. Crystal structure of the nickel(II) complex of 4b (ORTEP
diagram with thermal ellipsoids at 30% probability).
complex formed from 4b.6 The crystal structure shows that
the configuration at the quaternary center is R, while that at
the other stereocenter is S when the R,R form of hpen is
used for the synthesis. In the crystal structure, the aryl and
ester groups occupy the axial positions.
Table 1. Stereospecific Synthesis of R-Substituted
syn-R,ꢀ-Diamino Ester Diimines
Hydrolysis of the diimine (4a) gave the corresponding
R-substituted syn-R,ꢀ-diamino ester in 81% yield (Supporting
Information). R,ꢀ-Diamino acids are a special class of vicinal
diamines present in many natural products and biologically
active compounds.5 R-Substituted amino acids are attractive
building blocks for their use as robust analogues of natural
amino acids and as powerful enzyme inhibitors.7 Although
a variety of synthetic methods for making R,ꢀ-diamino acids
or R-substituted amino acids have been reported, it has been
a challenge to synthesize R-substituted R,ꢀ-diamino acids.
Only recently their efficient stereoselective synthesis was
reported through the aza-Henry (nitro-Mannich) reaction.8
Interestingly, the syn/anti selectivity for the aza-Henry
reaction can be controlled by complementary catalysts: a
Ni2-Schiff base catalyst9 provides the anti products, while
a bifunctional organocatalyst10 provides the syn products.
In addition to catalytic C-C bond forming reactions, we
propose that the sigmatropic rearrangements can provide a
highly stereospecific and convergent route to R-substituted
(R,S)-4
entry
Ar
(R,S)-4/(S,S)-5a yield (%)b de (%)a ee (%)c
1
2
3
4
5
6
Ph (a)
12/1
15/1
8/1
5/1
10/1
10/1
60
65
65
58
67
52
>97
>97
>97
>97
>97
>97
>98
>98
>98
>98
>98
>97
4-FC6H4 (b)
C6F5 (c)
4-HOC6H4 (d)
2-furanyl (e)
N-tosyl-3-indolyl (f)
a Determined by 1H NMR analysis of the crude mixture. b Isolated yield
after column chromatography. c Determined by chiral-phase HPLC.
can be seen from Table 1 that the diaza-Cope rearrangement
is highly stereospecific even with pyruvate as with aldehydes
(within the detection limits of NMR for de and HPLC for
ee). Thus, this one-pot reaction allows us to prepare
interesting analogues of natural amino acids such as pheny-
lalanine (4a), tyrosine (4d), and tryptophan (4f) as well as a
variety of unnatural amino acids in enantiomerically pure
form.
(6) Crystal data: C27H24.26Cl2.74FN2NiO4, T ) 150(2) K, orthorhombic,
0.26 × 0.06 × 0.05 mm3, P212121, Z ) 4, n˜calcd ) 1.496 Mg/m3, a )
10.9019(9) Å, b ) 13.4448(11) Å, c ) 18.6462(16) Å, a ) 90°, b ) 90°,
g ) 90°, V ) 2733.0(4) Å3, R1 ) 0.0718, wR2 ) 0.1655 (I > 2s(I)); R1 )
0.1221, wR2 ) 0. 1961 (all data), GOF on F2 ) 1.047.
(4) (a) Na´jera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584. (b)
Perdih, A.; Dolenc, M. S. Curr. Org. Chem. 2007, 11, 801. (c) Park, H.;
Kim, K. M.; Lee, A.; Ham, S.; Nam, W.; Chin, J. J. Am. Chem. Soc. 2007,
129, 1518.
(7) For reviews, see: (a) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetra-
hedron: Asymmetry 2007, 18, 569. (b) Ohfune, Y.; Shinada, T. Eur. J. Org.
Chem. 2005, 5127. (c) Vogt, H.; Bra¨se, S. Org. Biomol.Chem. 2007, 5,
406. For selected examples, see: (d) Dickstein, J. S.; Fennie, M. W.; Norman,
A. L.; Paulouse, B. J.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130,
15794. (e) Branca, M.; Gori, D.; Guillot, R.; Alezra, V.; Kouklovsky, C.
J. Am. Chem. Soc. 2008, 130, 5864.
(5) For a review, see: (a) Viso, A.; Ferna´ndez de la Pradilla, R.; Garc´ıa,
A.; Flores, A. Chem. ReV. 2005, 105, 3167. For selected examples, see: (b)
Trost, B. M.; Malhotra, S.; Olson, D. E.; Maruniak, A.; Du Bois, J. J. Am.
Chem. Soc. 2009, 131, 4190. (c) Herna´ndez-Toribio, J.; Arraya´s, R. G.;
Carretero, J. C. J. Am. Chem. Soc. 2008, 130, 16150. (d) Yan, X.-X.; Peng,
Q.; Li, Q.; Zhang, K.; Yao, J.; Hou, X.-L.; Wu, Y.-D. J. Am. Chem. Soc.
2008, 130, 14362. (e) Cutting, G. A.; Stainforth, N. E.; John, M. P.; Kociok-
Kohn, G.; Willis, M. C. J. Am. Chem. Soc. 2007, 129, 10362.
(8) (a) Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151. (b)
Uraguchi, D.; Koshimoto, K.; Ooi, T. J. Am. Chem. Soc. 2008, 130, 10878.
(9) Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2008, 130, 2170.
(10) Singh, A.; Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 5866.
Org. Lett., Vol. 11, No. 22, 2009
5259

Figure 2. Energy profile for the diaza-Cope rearrangement of (R,R)-3a (enthalpy values in kcal/mol).
syn-R,ꢀ-diamino acids. The Claisen rearrangement has been
used for the diastereoselective synthesis of R-substituted
amino acids.7
the rearrangement, the difference in the transition state
energies (2.4 kcal/mol) translates to a product ratio ((R,S)-
4a/(S,S)-4a) of about 57 at 25 °C. On the basis of the A
values12 of the methyl and ester groups (1.8 and 1.1 kcal/
mol, respectively), the methyl group would be expected to
be on the equatorial position and the ester on the axial
position of cyclohexane. Interestingly, computation shows
that the transition state with the ester in the equatorial position
(TS1) is more stable than the transition state with the methyl
group in the equatorial position (TS2) consistent with the
observed product stereochemistry ((R,S)-4b, Figure 1).
In conclusion, a ketone has been used for the first time in
1,4-diaza-Cope rearrangements to give diamino acids with
quaternary chiral centers. The excellent stereospecificity of
the reaction can be rationalized by DFT computation and
We anticipated the stereospecific rearrangement based on
DFT computation (B3LYP at the 6-31G(d) level). Figure 2
shows the energy profile for diaza-Cope rearrangement of
the starting diimine (R,R)-3a11 to give the diaminoester
diimine (R,S)-4a. The starting ketoimine can exist in the E
((R,R)-3a) or Z ((R,R)-3a′) forms. Computation shows that
the E isomer is slightly more stable than the Z isomer (0.39
kcal/mol). The rearrangement of the E isomer through the
most stable, chairlike, six-membered ring transition state
(TS1 with four equatorial and one axial substituents) leads
to diaminoester diimine (R,S)-4a. The rearrangement of the
Z isomer through the most stable, chairlike, six-membered
ring transistion state (TS2 with four equatorial and one axial
substituents) leads to diaminoester diimine (S,S)-4a. Com-
putation shows that the enthalpy change for rearrangement
of (R,R)-3a to (R,S)-4a (-9.0 kcal/mol) is comparable to
the enthalpy change for rearrangement of (R,R)-3a′ to (S,S)-
4a (-8.9 kcal/mol). However, the kinetic barrier for conver-
sion of (R,R)-3a to (R,S)-4a (12.5 kcal/mol) is about 2.0 kcal/
mol lower than the kinetic barrier for conversion of (R,R)-
3a′ and (S,S)-4a (14.5 kcal/mol). We suggest that the reaction
is under kinetic control as the selectivity is expected to be
low under thermodynamic control. Assuming that the starting
diimines (E and Z isomers) are in rapid equilibrium prior to
1
confirmed by HPLC, H NMR, and X-ray crystallography.
Acknowledgment. We gratefully acknowledge the finan-
cial support of the Natural Sciences and Engineering
Research Council (NSERC) of Canada. We thank Dr. Alan
J. Lough (University of Toronto) for X-ray analysis.
Supporting Information Available: Experimental, spec-
troscopic, computational, and crystallographic details. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9021904
(12) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry, Part
A: Structure and Mechanisms, 4th ed.; Springer: New York, 2000; p 135.
(11) Methyl ester of (R,R)-3a was used for the computation.
5260
Org. Lett., Vol. 11, No. 22, 2009