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New Chiral Auxiliaries for Enolate Alkylations.

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New Chiral Auxiliaries for Enolate Alkylations **
By Kyu-Sung Jeong, Kevin Parris, Pablo Ballester,
and Julius Rebek, Jr.*
Asymmetric transformations are the concern of modern
synthetic chemistry, and chiral auxiliaries are one means by
which high stereoselection can be achieved."] We recently
introduced a system which shows exceptional selectivity in
cycloaddition reactions;[*] here we demonstrate its applicability in alkylation reactions.
The molecular skeleton of the new auxiliaries derives from
the commercially available Kemp triacid l.[31
Its imide acid
chloride 2 ar4]readily acylates amines or alcohols. For example, the amide 2b (m.p. 113-115°C) was obtained from 2a
and (9-I-phenylethylamine, and the ester 2d (m.p. 160162 "C) from 2a and (9-I-naphthylethanol, each in high
yield (87 and 70 %, re~pectively).[~]
The esters 2c and 2e have
been described in detail elsewhere141(Scheme 1).
with Me1 gave only the other diastereomer (6). With 500MHz NMR and HPLC as assays, the diastereoselectivity
was judged to be at least 200: 1. Regeneration of the alkylation products as optically active carboxylic acidsr7]with
simultaneous recovery of the auxiliaries can be easily
achieved using Evans' procedure['] (LiOH/H,O,).
Scheme 2. Ar
= phenyl;
LDA
lithium diisopropylamide.
+ 3b (CH,=R)
6 + (R)-C,H,-CH,-CH(CH,)-COOH + 3b (CH,-C,H,= R)
=
5 + (9-C,H,-CH,-CH(CH,)-COOH
CH
Ar, j'H3
+
H3C'
H3C'
3c-3f
3a
3b
Scheme I . Za, X=CI; Zb. X=(S)-NH-CH(CH,)C6HS; 2c, X=OMe; Zd,
X=(S)-O-CH(CH3)-2-naphthyi; Ze, X =O-CH2CH,-2-naphthyl; 3c, R = H ;
3d, R = M e; 3e. R=2-naphthyl; 3f, R=CH,-CH2-2-naphthyl. Ar = phenyl.
Reduction of 2 b (NaBH,/EtOH, 0 "C) followed by acid
treatment (p-TsOH/CH,CI,) gave the tricyclics 3a and 3 b as
an easily separable mixture of diastereomers [flash chromatography; 3 a (55%, m.p. 107-109"C), 3b (34%, m.p.
187- 189 "C)]. The structure of 3 b, established by X-ray
crystallography,161features the N-H bond near the asymmetric microenvironment. The methyl ester 2c was reduced,
firstly with NaBH,/EtOH and then with Et,SiH/CF,CO,H,
to give the bicyclic lactam 3d (m.p. 141- 143 "C). Saponification, activation (SOCI,), then coupling with j3-naphthol gave
3f (m.p. 82-84 "C).A parallel sequence of reductions afforded 3f from 2e, and the optically active 3c was obtained from
2d.
The tricyclic compound 3b proved to be a most effective
auxiliary for asymmetric alkylation reactions. Acylation of
3b (NaH/RCH,COCI/THF) furnished the propionyl and
the 3-phenylpropionyl derivatives 4 a and 4 b, respectively.
Deprotonation (LDA/THF, -78 "C) and alkylation of 4a
with benzyl bromide (- 78 "C, 10 min 0 "C, 3 - 5 h) gave a
single diastereomer (5) (Scheme 2). Parallel alkylation of 4 b
The alkylation results are summarized in Table 1. A comparison of the reactions of the diastereomers 3a and 3b,
clearly reveals that both the asymmetry of the cyclohexyl
moiety as well as that of the a-phenylethyl moiety contributes to the selectivity. An X-ray crystallographic study[61
of the alkylation product of 4 b (No. 5 ) established its structure as shown in 6. The product of entry No. 3 was also
obtained in suitable form for crystallographic analysis and
the structure was established as 7.
Table 1. Alkylation ofenolatederivatives (cf. 8 ) from which theacyl derivatives
were obtained by lithiation. E = electrophile. The products still contain the
auxiliary compound.
R-CH,-COCI + R-CHE-COOH, R = Me, E = PhCH, or R = PhCH,, R = Me
No.
R
Auxil. Acyl
cpd.
deriv.
EX
1
Me
Me
Me
PhCH,
PhCH,
PhCH,
3a
3b
3e
PhCH,Br
PhCH,Br
PhCH,Br
Me1
Me1
Me1
2
3
4
5
6
4a
3a
3b
3e
4b
Product
5
7
6
Diast.
ratio
63~37
>99:1
>99:1
>99:1
>99:1
98:2
Yield
I"/.]
76
63
56
84
64
73
The efficacy of the new systems is demonstrated by their
control of electrophile approach to the enolate system. The
extended aromatic nucleus in these structures, shown in the
[*] Prof. Dr. J. Rebek, Jr., K:S. Jeong, K. Parris, P. Ballester
Department of Chemistry, University of Pittsburgh,
Pittsburgh, PA 15260 (USA)
and
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, MA 02139 (USA)
[**I
Research supported by the Hoechst Celanese Co.. Inc.
Angew. Chwm fnt. Ed. Engl. 29
(f990) No. 5
7
8
enolate 8, provides an effective barrier to external reagents,
while Li@-chelationfixes the configuration of the enolate.
;L"J VCH VerlagsgesellschQfi mhH, 0.6940 Weinheim. 1990
OS70-0833j90jOS05-055Sd 02.5010
555
are surprisingly stable in aqueous media. In screening experiments using the animal models Litomosoides carinii/cotton
rat and Onchocerca gibsoni/cattle, these salts show a high
activity against filaria.l31The latter model is best suited for
the evaluation of potential drugs against the human parasite
Onchocerca volvulus, which causes river blindness (onchocerciasis). Here we report on the synthesis of N-aminated imidazolium salts.
The amination of imidazole (1 a) with sodium hydroxylamine 0-sulfonate in water leads to a mixture of the l-amino- and 1,3-diaminoiniidazolium salts 2 a . HX and 3a, respectively, which can be separated as their benzylidenamino
derivatives 4 a and 7a, R = R" = H (Scheme 1). This amina-
The configuration of the alkylation products (e.g., 6 and 7)
are fully in accord with this analysis.
In summary, chiral auxiliary compounds (3) of a new
shape have been described, and their action can be related to
the stereoelectronics of enolate alkylations. The asymmetric
environment of the auxiliary compounds is so well defined in
structures such as 3 b that such materials show efficiency as
asymmetric protonation agents.
Received: December 13, 1989;
revised: February 16, 1990 [Z 3686 IE]
German version: Angew. Chem. 102 (1990)550
CAS Registry numbers:
Za, 109216-50-4;2b, 126295-07-6;2c, 126451-72-7;2d, 126295-08-7;2e,
126451-73-8;3a, 124223-11-6;3b, 124154-23-0;3c, 126295-09-8;3d, 12629510-1;3e, 126451-74-9;3f, 126295-11-2;4a, 126295-12-3;4b, 126295-13-4;5,
126295-14-5; 6, 126451-75-0; 7, 126295-15-6; MeCH,COCI, 79-03-8;
PhCH,CH,COCL 645-45-4;(9-1-phenylethylamine, 2627-86-3, (9-1-(2naphthyl)ethanol, 275441 8-9;B-naphthol, 135-19-3.
[l] a) J. K. Whitesell, Acc. Chem. Res. 18 (1985)280; b) W. Oppolzer, Telruhedron 43 (1987) 1969: c) K. A. Lutomski, A. I. Meyers, in J. E. Morrison
(Ed.): A.rymmerric Synthesis, Academic Press, New York 1984, Vol. 3,
Chap. 1; d) S. G.Davies, Chem. Brit. 25 (1989) 268; e) H. Kuntz, D.
Schanzenbach, Angen,. Chem. 101 (1989)1042;Angew Chem. lnt. Ed. Engl.
28 (1989) 1068; 0 D.A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem.
Sor. 109 (1982) 1737; g)M. Ihara, M. Takahashi, H. Niitsuma. N.
Taniguchi, K. Yasui, K. Fukumoto, J. Org. Chem. 59 (1989) 5413: h) R.
Schmierer, G. Grotemeier, G. Helmchen, A. Selim, Angew. Chem. 93 (1981)
209; Angew. Chem. Int. Ed. Engi. 20 (1981)207.
[2] D.P. Curran, K . 2 . Jeong, T. A. Heffner, J. Rebek, Jr., J Am. Chem. SOC.
111 (1989)9238.
[3] D.S.Kemp, K. S. Petrakis, J. Org. Chem. 46 (1981)5140.1 is avdikibk from
the Aldrich Chemical Company. For a convenient synthesis, see J. Rebek,
Jr., B. Askew, M. Killoran, D. Nemeth, F.-T. Lin, J Am. Chem. SOC.109
(1987)2426.
[4] B. Askew, P. Ballester, C. Buhr, K.-S. Jeong, S. Jones, K. Parris, K.
Williams, J. Rebek. Jr., J Am. Chem. SOC.lli (1989) 1082.
[S] All new compounds were characterized by a full complement of high-resolution spectra ('H-NMR, FT-IR, MS).
[6] Complete details of the crystallographic studies of 3b, 6 and 7 will be
published elsewhere.
[7] The (9-and (R)-2-methyl-3-phenylpropionicacids released from 5 and 6 ,
respectively, were coupled to optically active 1-phenylethylamine: NMR
analysis showed >99:1 enantiomeric purity.
[S] D. A. Evans, J. A. Ellman, T. C. Britton, Tetrahedron Letr. 28 (1987)6141.
1-Amino- and 1,3-Diaminoimidazolium Salts**
By Helmut Link,* Wilhelm Klotzer,
Eva Maria Karpitschka, Marc Montavon,
Renate Miissner, and Nicolas Singewald
Stepwise amination of imidazoles to give the previously
unknown 1,3-diaminoimidazolium salts 3 may be accom0-(diphenylphosphinoy1)hydroxylamine
plished
with
(DPH).
Some derivatives of these quaternary salts have
interesting chemical and biological properties. For example,
the 1,3-bis[(p-aminobenzylidene)amino]imidazoliumsalts 7
[*] Dr. H. Link, Dr. M. Montavon
[**I
556
Phannazeutische Forschungsabteilung, F. Hoffmann-LaRoche AG
CH-4002 Basel (Switzerland)
Prof. Dr. W. Klotzert, Dr. E. M. Karpitschka, Dr. R. Mussner, Dr. N.
Singewald
Institut fur Organische und Pharmazeutische Chemie der Universitat
A-6020Innsbruck (Austnd)
We thank Dr. W Arnold (NMR), Dr. W Vetter and W Meisrer (MS), Dr.
M . Grosjean (IR), and Dr. A. Dirscherl (microanalysis) for spectroscopic
and analytical investigations as well as B. Schaffner, U. Brombacher,
R. Villard, D . Wechsler, and R. Schlagbauer for synthetic work.
0 VCH
Verlagsgesellschuft mbH. 0-6940 Weinheim, 1990
m
N
7R
1=7
N
NH
YR
l x .
R
2
1
r==l
N
N-NH2
YI
N-N=CH-
3
C6H4R'
m
E-NZ.@.:N-N=CH-
R
R
4
5
A
H2N-N'.9.:N-N=CH-
YR x .
C6H4R'
6
C6H4R'
A
R"CeH4 -CH=N-N'..Q.:N-N=CH-
yR x .
C6H4R'
7
a:R=H. b.R=C,H,. c:R=CH,
Scheme 1
tion method is also suitable for water-soluble 2-, 4-,and
5-substituted imidazoles such as 2-methyl-, 2-ethyl-, and
2-methyl-4-hydroxymethylimidazole.2-Isopropylimidazole,
2-phenylimidazole, and 2-methylbenzimidazole can only be
diaminated in very small yield by this method. We have now
found that DPH is a suitable reagent for the amination of
water-insoluble imidazoles. For example, the sodium salt of
2-phenylimidazole (1 b) reacts in N-methylpyrrolidone with
1 molar equivalent of DPH to give 1-amino-2-phenylimidazole (2 b; 50-70% yield after chromatography). Further amination with DPH in dichloromethane to give 1,3-diamino-2phenylimidazolium salt 3b proceeds in high yield (88 % after
conversion to the chloride with Amberlite). We also obtained
product 3b, X = CI, in 40-50% yield by treatment of 1 b
with 0-(mesitylenesulfonyI)hydroxylamine (MSH) in tetrahydrofuran in the presence of sodium hydrogen carbonate followed by anion exchange (Amberlite).
1-Amino- and 1,3-diaminoimidazolium salts may be
stored at room temperature without noticeable decomposition. I-Aminoimidazole (2, R = H, alkyl, phenyl) undergoes
condensation with aldehydes such as p-dimethylaminobenzaldehyde in glacial acetic acid to give 4, which reacts, in turn,
with electrophilic reagents such as a-halo esters or benzyl
halides to give 5. Treatment of 4 with DPH results in amination to give 6, which can be converted into 7 by reaction with
aldehydes. The 1,3-bis(benzylidenamino)imidazoliumsalts
with identical substituents R',R" may also be obtained directly from 3. The stepwise condensation of 3 with two different aldehydes to give 7 ( R =+ R ' ) is also possible, but
requires careful purification of the first condensation product 6.
0570-0%33190iOS05-0S56SC 02.50j0
Angew. Chrm. lnr. Ed. Engi. 29 (19901 No. 5
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