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Efficient Recognition of Chiral Carbamoyl--Hydroxyacids with a Cleft-Type Receptor.

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a) G. Ege, H. Fischer, Tetrahedron 1967,23, 149-157; b) G. Ege, H. Vogler,
Theor. Chim Acra 1972,26,55-65; c) J. Aihara, Bull. Chem. Soc. Jpn. 1976,49,
1429-1430.
a) M. Randic, Pure Appl. Chem. 1983, 55, 347; b) H. Vogler, J. Mol. Strucr.
(Theorhem) 1985, 122, 333-341; c)Int. J. Quantum Chem. 1986, 30. 97;
d) P. M. Lahti, J. Org. Chem. 1988, 53, 4590-4593; e) N. L. Alhnger, F. Li,
L. Yan, J. C. Tai, J. Compur. Chem. 1990, f f , 868-895.
a) J. Cioslowski, P. B. O'Connor, E. D. Fleischmann, J. Am. Chem. Soc. 1991,
113, 1086-1089; b) Z. Zhou, J. Phys. Org. Chem. 1995,8, 103-107.
a) J. Aihara. 1 Am. Chem. SOC.1992, Ill, 865-868; b) J. Chem. Soc. Farodq
Trans. 1995, 91, 237-239.
Gaussian 94, Revision B.2: M. J. Frisch. G. W. Trucks, H. B. Schlegel,P. M. W.
Gill, B. G. Johnson, M. A. Robb, J. R. Cheeseman, T.Keith, G. A. Peterson,
J. A. Montgomery, K. Raghavachari, M. A. Al-Laham, V. G. Zakrzewski. J. V.
Ortiz, J. B. Foresman. J. Cioslowski. B. B. Stefanov, A. Nanayakkara. M.
Challacombe, C . Y Peng, P. Y. Ayah, W. Chen, M. W. Wong. J. L. Andres,
E. S. Replogle. R. Gomperts, R. L. Martin, D. J. Fox, J. S. Binkley. D. J. Defrees, J. Baker. J. P. Stewart, M. Head-Gordon, C. Gonzalez. J. A. Pople. Gaussian Inc., Pittsburgh, PA, 1995.
a)T. A. Keith. R. F. Bader, Chem. Pl?ys. Lerr. 1992. 194, 1-8; b) R. F. Bader.
T.A. Keith, J Chem. Phys. 1993, 99, 3683-3693.
P. von R. Schleyer, C. Maerker, A. Dransfeld, H. Jiao. N. J. R. van Eikema
Hommes, J. Am. Chem. Sor. 1996, ff8,6137-6138.
P. von R. Schleyer, H. Jiao, Pure Appl. Chem. 1996,68. 209-218.
a) P. von R. Schleyer, P. K. Freeman, H. Jiao. B. GoldfuO, Angew. Chem. 1995,
f07,332-335; Angen.. Chem. Int. Ed. Engl. 1995, 34, 337-340; b) H. Jiao, P.
von R. Schleyer in AIP Conference Proceedings 330, E.C.C.C. 1. Computarionul
Chemistry (Eds.: F. Bernardi, JLL. Rivail), American Institut of Physics,
Woodbury. NY. 1995, pp. 107-131.
a) V. I. Minkin, M. N. Glukhovtsev, B. Y. Simkin, Aromaticity and Antiaromaticity, Wiley, New York, 1994; b) P. J. Garrat. Aromaticiry, Wiley, New
York, 1986.
For a discussion of homodesmic equations, see: P. George, M. Trachtman.
C. W. Bock, A. M. Bret, J. Chem. Soc. Perkin Trans. 2.1976,1222-1227; For
a more restricted subclass of homodesmic reactions. see: B. A. Hess. Jr., L. J.
Schaad, L Am. Chem. Sor. 1983, 105, 7500-7505.
H. J. Dauben, Jr., J. D. Wilson, J. L. Laity, Nonbenzenoid Aromaticiry. Vol. I1
(Ed.: J. P. Snyder), Academic Press, New York, 1971, pp. 167-206, and references therein.
H. Jiao, N. J R. van Eikema Hommes, P. von R. Schleyer, A. de Meijere.
J. Org. Chem. 19!36,61,2826-2828.
F. Sondheimer, Arc. Chem. Res. 1972, 5, 81-91.
J. B. Pedley, R. D. Naylor, S. P. Kirby, ThermochemrcalDura ofOrgunic Compounds, 2nd ed.. Chapman and Hall, London, 1986.
R. L. Disch, J. M. Schulman, Chem. P h w Lett. 1988. 152.402-404.
which provides functional groups for forming additional hydrogen bonds with an a-functionalized carboxylic acid as the guest
(Scheme '1.
/
6 , = 5.21
6,, = 0.69
(9-5
(4-1
0
K,,,= 5.7 x 105 M-l
6,,
/,
= 1.46
6, =4.40
K,,, = 6.3 x 103 ~
-
1
Scheme 1. Complexes formed by receptors (R)-1 and (S)-1 and the guest (S)-5.
Compound 1 was obtained as a racemic mixture from the
known xanthone 213](Scheme 2). Carbamoyllactic acids should
be good guests for this receptor (Scheme I), and molecular models indicate that complexes of 1 and 5 should display
chiral discrimination. When host and guest have different
Efficient Recognition of Chiral Carbamoyla-Hydroxyacids with a Cleft-Type Receptor**
Mercedes Martin, Cesar Raposo, Marta Almaraz,
Mercedes Crego, Cruz Caballero, Manuel Grande,
and Joaquin R. Moran*
0
Efficient recognition of small, chiral organic molecules is still
a challenge for organic chemists.''] Recognition of a-substituted
chiral carboxylic acids is difficult because the chiral centers of
the guest and those of the host are usually far apart. This drawback, already pointed out by Rebek, Jr., et al.,fzlcan be overcome
in receptor 1 by making use of a suitable xanthone spacer,'31
[*] Prof. J. R. Morin, M. Martin, Dr. C. Raposo, M. Almaraz, Dr. M. Crego,
Prof. C. Caballero, Prof. M. Grande
[**I
Departamento de Quimica Organica, Universidad de Salamanca
Plaza de la Merced 1-5, E-37008 Salamanca (Spain)
Fax: Int. code +(23)294574
e-mail: mgrande(~gugu.usal.es
We thank the Junta de Castilla y Leon for financial support (grant SA 73/94),
Anna Lithgow for conducting the 400 MHz NMR titration experiments, and
the MEC for a fellowship (C. R.).
2386
0 VCH
Verlagsgesellschafi mbH, 0-69451 Weinheim. 1996
0
3,R= f3r
4, R= CloH2,NH
Scheme 2. Synthesis of rac-I. a) BrJCHCI,, -20°C (75%): b) CH,(CH,),NH,,
170°C (65%); c) PhPOClJPhBr, 130°C (90%).
057O-0833/96/3520-2386$ 15.0Of .25i0
Anaew. Chem. I n [ . Ed. End. 1996. 3.5 Nn 20
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configurations ((R,S)and (S,R) complexes), four linear hydrogen bonds can form without steric hindrance. In contrast, in the
(R,R) and (S,S) complexes the methyl group of the lactic acid
unit collides with the carbamate carbonyl group, thus weakening the fourth hydrogen bond between the carbamate NH group
and the phosphoryl oxygen atom (Scheme 1 , bottom).
Experimental data confirmed these predictions. When increasing amounts of (S)-5were added to a solution of rac-1 in
CDCI,, 'H NMR signals of receptor 1 were split as expected for
the formation of two diastereomeric c0mplexes.[~1Initial attempts to assess the relative stability of the two complexes by
plotting the 'H NMR shifts of the receptors against each otherIS1indicated an association constant ratio greater than twenty.
This result suggested that formation of the complex can be used
to separate the enantiomers of the receptor.[61Neither the host
nor the guest are eluted separately by TLC on silica gel plates
with CH,CI,/Et,O (9911) as eluent. However, under these conditions using TLC plates impregnated with (S)-5(1 % in Et,O),
the bright yellow enantiomeric receptors were easily separated
( R f ( ( R ) - l=
) 0.8, R,((S)-1) = 0.1). This large difference in R,
values can be explained because the complex is a closed structure in which all hydrogen bond donors are saturated, and it
thus has a low affinity for silica gel. Host-guest association
therefore offers a way in which the receptor can be eluted with
solvents of low polarity. However, this mechanism is only very
efficient in the case of the ( R ) host due to its large association
constant with (S)-5;the less stable complex with the ( S )host has
only a slightly increased R,.
Both preparative TLC and Pirkle-type column chromatography"] on S O , impregnated with (S)-5provide an edSy way to
isolate the complexes of the enantiomeric receptors 1. Decomplexation was accomplished either by washing an ethereal solution of the complex with aqueous sodium carbonate, by conventional chromatography on SiO, with petroleum ether/EtOAc
( l / l ) as eluent, or by crystallization from methanol, in which the
(S)-5 remains in the solution. The receptors isolated are enantiomerically pure (m.p. 102-105 "C; (R)-1: [a], = - 180
(c = 0.55 in CHCI,); (S)-1:[a], = +176 (c = 0.60 in CHCI,).
Owing to the presence of two independent aromatic chromophores in the receptor I, the absolute configurations could be
confirmed by CD spectroscopy by applying the exciton chirality
method.['] The xanthone moiety (complex absorption bands at
i, ( E ) = 347 nm (ca. 10000; 'L&; 236, 252, 271 (ca. 21000,
'La)) interacts with the phenylphosphonic group (absorption
band at As,,= 235 nm) to give rise to bisignate bands with a split
Cotton effect (Davidov splitting) around 280 and 240nm
(Fig. 1). The second is stronger because the absorption bands
are more intense and closer to each other. In fact, the C D spectrum of the dextro host shows two bisignate bands at 296/
265 nm ( A t = + 13/ - 5 ) and 246/228 nm (AE = + 221 - 20;
Fig. l ) , which is in accord with a positive dihedral angle between
the xanthone and the phenyl axis and corresponds to an ( S )
configuration at the chiral phosphorus atom (see insert in
Fig. 1 ) .
A strong anisotropic effect in the (R,S)complex also supports
these assignments. The 'H NMR signal of the methyl group in
complexed (S)-5 (6 = 0.69) is shifted upfield by A6 = 0.88 relative to the analogous signal of the free guest (6 = 1S7); this
implies that the methyl group is fixed in the shielding cone of the
phosphorus phenyl ring (Scheme 1). A similar shielding effect
for the signal of the z-H of the lactic unit in the ( S , S ) complex
(A6 = 0.78; shift from 6 = 5.18 to 6 = 4.40) suggests that the
main difference in the geometry of the diastereomeric associates
is the position of the hydrogen atom and the methyl group of the
guest (Scheme 1).
A n e m ChrTm Inr fid Enpl
1994. 35. No 20
Fig. 1. CD spectrum of the receptor (S)-l.
Conventional NMR titration of these receptors with (Sf-5 is
not an accurate method for quantifying the chiral discrimination. Only the association constant of the weak (S,S) complex
(K,,, = 6.3 x lo3 M-') lies in the range that can be measured
with the NMR method,['l whereas the strong (R,S) associate
shows a value above lo5 M - ' . Competitive titration, however,
can be used to estimate this large association constant; a scale
can be constructed (Table 1) which is similar to the reactivity
scales developed by Huisgen.['ol
To apply this method, complexes with stabilities lying between those of the previously discussed diastereomeric associates are necessary. Competitive NMR titrations" were carried
out with lo-' M CDCI, solutions of both guests. Increasing
M stock solution of optically pure host 1
amounts of a 5 x
were added until saturation was achieved. The proton shifts of
the enantiomeric guests were plotted against each other, and the
ratios of the association constants were calculated by making
use of a Monte Carlo nonlinear curve-fitting method.
Guests 6-8 were tested (Table 1). The phenyl ring in (S)-carbamoylmandelic acid (S)-6 slightly hinders complex formation
5, R = Y e , X = O
HI R y C O O H
CI
D""
/
6,
R = Ph, X = O
7, R = M e , X = U H
o
0,
R=
P~I,
x=un
and a competitive titration provides an association constant
that is 2.3 times less than that measured for (S)-5.However, this
new complex is still too strong for a precise value to be obtained
Table 1. Association constants of the complexes between guests 5-8 and receptor
1 (in CDCI,, 20 'C)
Host/guest complex [a]
K,, [M- '1
KSs3ratio
[ ( ~ ) -wl 5 1
5.7 x
2.5 x
6.4 x
5.8 x
1
[(R)-l-(S)-61
[(R)-1-(071
r(RI-1 .(S)-8l
[(R)-l.(R1-51
I(R)-l-(R)-61
l(R)-1.(R)-71
10' [b]
10' [b]
lo4 [c. d]
lo4 [c, dl
4.7 x lo3 [d]
6.3
[dl
23
}13
}13
}21
3.1 x lo3 [b]
[a] Data for only one of the enantiomeric complexes is given. [b] From competition
experiments. [c] Average from direct measurement and competition experiments.
Id] Direct titration.
C VCH EdamPesellschafi mbH 0.69451 Wernherm 1996
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in direct NMR measurements. Steric interactions between the
receptor phosphorus atom and the NH of amino acid derivatives lead to further reduction in complex stability. Urea derivatives of (S)-alanine and (S)-phenylglycine, (7 and 8, respectively), have association constants of K,,, = 6.4 x lo4 M - ' and 5.8 x
lo4 M - ' , respectively. Due to its better association, the (S)-alanine derivative (S)-7 was selected for competitive titration
against ( S ) - 6 (Kass((S)-6)/Kass((S)-7)
= 3.9). The association
]
be readily measured by standard
constant of [ ( R ) - l - ( R ) - 6could
NMR titration (K,,, = 4.7 x lo3 M - ' ) . Competitive titration be= 13, a
tween (R)-6 and ( a - 7 afforded Kass((S)-7)/Kass((R)-6)
ratio that, within the experimental error, confirms the previously measured value for the association constant of compound 7.
From the above values the association constant for [ ( R ) - l .
(S)-5] was calculated to be K,,, = 5.7 x l o 5 M - ' (Table 1). This
indicates that the chiral recognition displayed by these complexes is the best in this series: Kays((R)-l)/Kass((S)-l)
= 90. With
(S)-6 this ratio is reduced to 53.
Received: May 2. 1996 [Z9092IE]
German version: Angew. Chem. 1996. 108. 2512-2514
Keywords: enantiomeric resolution
recognition receptors
-
- hydroxyacids
molecular
[I] a ) J. Rebek, Jr.. B. Askew. P. Ballester. A. Costero. J. Am. Cliem. Soc. 1988,
Iff), 923; b) A. Galin. D. Andreu. A.M. Echavarren. P. Prddos. J.
de Mendoza, rbid. 1992, 114, 3 51 1: c) A. Bochardt. W. C. Still. ihid. 1994, f f6.
7467, d) V. Alcazar, F. Diederich, Angew. Chem. 1992, 104, 1503; Angew
Chem. Int. Ed. Engl. 1992.31. 1521; e) K. Araki. K. Inada, S. Shinkai, Angeu..
Chem. 1996, 108, 92; Angew. Cheni. Inr. Ed. Engl. 1996, 35. 72; f ) M. Crego.
A. Partearroyo, C Raposo, M. L. Mussons. J. L. Lopez. V. Akdzdr. J. R.
Moran. Tetrahedron Lett. 1994, 35. 1435.
121 B. C. Hamann. N. R. Branda, J. Rebek. Jr.. Tefrahedron Lett. 1993,34.6837.
[3] M. Crego, C. Raposo, M. C. Caballero. E. Garcia, J. G. Saez, J. R. Morin,
Tetrahcvlron Lett. 1992, 33, 7431.
141 V. Alcazar, L. Tomlinson. K. N. Houk, F. Diederich. Tefruhedron Left 1991.
32, 5309.
[5] K. A. Connors. Binding Constants, The Measurement of Moleculur C0mple.Y
Stubilitj. Wiley. New York. 1987.
16) a) "Application of Biochemical Systems in Organic Chemistry": D. J. Cram in
7i.chnique.s qf Chemisrrv Series. Vo/. 111 (Eds.: J. B. Jones, C. S. Sih. D. Perlman.). Wiley, New York, 1976, p. 815; b) H. Dugas. Bioorgunic Chrmistq.. 2nd
ed., Springer-Verlag. New York. 1989; c) W. H. Pirkle. E. M. Doherty. J. A m .
Chem. Soc. 1989, 111. 4113.
[7] W. H. Pirkle, J. Finn in A.s~fnrnefricSjnthesis. Vo/. f (Ed.: J. D. Morrison),
Academic Press, New York, 1985, p. 87.
181 K. Nakanishi. N. Berova, in Circular Dichruism. Principles and Applicutions
(Eds.: K . Nakanishi, N. Berova. R. W. Woody) VCH. New York, 1994. p. 361.
191 C. S Wilcox in Frontiers in Suprumolecrrlur Organic Chemi.stry and PhofochemistrJ (Eds.: H.-J. Schneider, H. Durr), VCH. Weinheim, 1990, p. 123.
[lo] R. Huisgen. L. Xingya, Terrahedron Lert. 1983, 24. 4185.
[ t l ] The ratio of the association constants for the complexes formed in the competitive NMR titration was CdlCUkdted according to Equation (a). where 6, is the
chemical shift of the free host. 6, that of the complexed host. and 6 that
observed
Enantioselective Synthesis of Vicinal
Amino Alcohols by Oxa-Michael Addition of
( - )-N-Formylnorephedrine to Nitroakenes**
Dieter Enders,* Andreas Haertwig, Gerhard Raabe, and
Jan Runsink
Enantiomerically pure 1,2-amino alcohols A are characteristic structural features of many natural products and drugs, and
play an important role as chiral building blocks, auxiliaries, and
ligands in transition metal catalyzed reactions.['] They can be
prepared from amino acids (for example, from the chiral pool),
by resolution, or by asymmetric synthesis. Numerous diastereoand enantioselective syntheses have been described that lead to
vicinal amino alcohols for example by C-C['I or C-N bond
formation,[31aminohydr~xylation,[~~
or indirectly by hydroboration of enamines.[']
An alternative retrosynthetic analysis leads to a hydroxide
synthon B and a /I-amino cation synthon C by disconnection of
the C - 0 bond. The oxa-Michael additionf6.'] of a chiral synthetic hydroxide equivalent with a removable auxiliary, like
(-)-( 1R,2S)-N-formylnorephedrine ((R,S)-2),to (E)-nitroalkenes ( 1 , as equivalents for C ) should open a new enantioselective
pathway to the title compounds A.
Interestingly, the oxa-analogous Michael addition was published in 1878 by F. Loydl in his work about the synthesis of
malic acid from fumaric acid,[*] five years earlier than the discovery of the actual Michael reaction by Komnenos, Claisen,
and Crismer. After further early work,['] some groups tried later
to find a diastereo- and enantioselective version of this reaction.["] Some intermolecular oxa-Michael additions in which
the chirality information is contained in the acceptor," 'I as well
as several enzymatic variants"
are already available.
Diastereoselective intramolecular oxa-Michael addition is widely used in natural product synthesis.['31 To the best of our
knowledge, the enantioselective intermolecular oxa-Michael addition with removable chirality information in the oxygen-containing nucleophile has not been reported. We have now succeeded in developing such an asymmetric oxa-Michael addition,
by which vicinal amino alcohols are prepared with high asymmetric induction and in good yields by using an enantiomerically pure alcoholate.
[*] Prof. Dr. D. Enders. DipLChem. A. Haertwig. Dr. G. Raabe. Dr. J. Runsink
[**I
2388
ic) VCH Verlagsgesellschaft mbH, 0-69451 Weinheim. 1996
Institut fur Organische Chemie der Technischen Hochschule
Professor-Pirlet-Strasse 1 , D-52074 Aachen (Germany)
Fax: Int. code +(241)8888127
e-mail' enders(o rwth-aachen.de
This work was supported by the Deutsche Forschungsgemeinschaft (Leibniz
Prize and Sonderforschungsbereich 380) and by the Fonds der Chemischen
Industrie. We thank the companies Degussa AG, BASF AG, Bayer AG, and
Hoechst AG for the donation of chemicals.
0570-0833~94~3S20-238X
$ 15.00-t 2510
AnQew. Chem. Inl. Ed. E n d . 1996.35. No. 20
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