Abstract
Straightforward syntheses of cyclopropyl analogues of β-homoornithine and β-homoglutamic acid are reported. The key step is the titanium-mediated cyclopropanation of 3-benzyloxypropionic acid N,N-dibenzylamide (6), affording N,N-dibenzyl-N-[1-(2-benzyloxyethyl)-2-ethenylcyclopropyl]amine (7) in 56% yield as a 2.5:1 mixture of E- and Z-diastereomers. Further transformations of 7 in 9 and 6 simple steps, respectively, furnished 3,6-bis(N-tert-butoxycarbonylamino)-3,4-methanohexanoic acid (13) and 3-(N-tert-butoxycarbonylamino)-3,4-methanohexane-1,6-diacid dimethylester (16) as interesting protected β-(aminocyclopropyl)carboxylic acid building blocks for potentially active small peptide analogues. The structure of the crystalline intermediate tert-butyl (E)-N-{2-[2-(N-tert-butoxycarbonylamino)ethyl-1-(2-hydroxyethyl)]cyclopropyl}carbamate (12) was proved by X-ray diffraction.
Key words
amino acids - low valent titanium - medicinal chemistry - cyclopropanes - structure elucidation
References
2 (a) Part 112 in the series: Cyclopropyl Building Blocks for Organic Synthesis.
1b For Part 111 see: Brackmann F.
Es-Sayed M.
de Meijere A.
Eur. J. Org. Chem.
2005,
in press
1c Part 110: Knoke M.
de Meijere A.
Eur. J. Org. Chem.
2005,
in press
3a
Salaün J.
Top. Curr. Chem.
2000,
207:
1
3b
Cativiela C.
Díaz-de-Villegas MD.
Tetrahedron: Asymmetry
2000,
11:
645
3c
Salaün J.
Baird MS.
Curr. Med. Chem.
1995,
2:
511
3d
Burgess K.
Ho KK.
Moyesherman D.
Synlett
1994,
575
4 Review: Gnad F.
Reiser O.
Chem. Rev.
2003,
103:
1603
5a
Funabashi Y.
Tsubotani S.
Koyama K.
Katayama N.
Harada S.
Tetrahedron
1993,
49:
13
Total syntheses see:
5b
Yuan C.
Williams RM.
J. Am. Chem. Soc.
1997,
119:
11777
5c
Sokolov VV.
Kozhushkov SI.
Nikolskaya S.
Belov VN.
Es-Sayed M.
de Meijere A.
Eur. J. Org. Chem.
1998,
777
5d
Belov VN.
Brands M.
Raddatz S.
Krüger J.
Nikolskaya S.
Sokolov VV.
de Meijere A.
Tetrahedron
2004,
60:
7579
6a inventors; German Offen., No. DE 19838998A1.
; Chem. Abstr. 2000, 132, 180819z
6b inventors; German Offen., No. DE 10141271A1.
; Chem. Abstr. 2003, 138, 205087
6c Kordes, M.; Brands, M.; Es-Sayed, M.; de Meijere, A. Eur. J. Org. Chem. 2005, in press.
7
Kordes M.
Dissertation
Universität Göttingen;
Germany:
1999.
8
Kordes M.
Winsel H.
de Meijere A.
Eur. J. Org. Chem.
2000,
3235
9a
Chaplinski V.
de Meijere A.
Angew. Chem., Int. Ed. Engl.
1996,
35:
413 ; Angew. Chem. 1996, 108, 491
Reviews:
9b
Kulinkovich OG.
de Meijere A.
Chem. Rev.
2000,
100:
2789
9c
Breit B.
J. Prakt. Chem.
2000,
342:
211
9d
Sato F.
Urabe H.
Okamoto S.
Chem. Rev.
2000,
100:
2835
9e
Sato F.
Urabe H.
Okamoto S.
Synlett
2000,
753
9f
de Meijere A.
Kozhushkov SI.
Savchenko AI. In
Titanium and Zirconium in Organic Synthesis
Marek I.
Wiley-VCH;
Weinheim:
2002.
p.390
9g
de Meijere A.
Kozhushkov SI.
Savchenko AI.
J. Organomet. Chem.
2004,
689:
2033
Reviews:
10a
Mitsunobu O.
Synthesis
1981,
1
10b
Hughes DL.
Org. React. (N.Y.)
1992,
42:
335
10c
Hughes DL.
Org. Prep. Proced. Int.
1996,
28:
127
11a
Staudinger H.
Meyer J.
Helv. Chim. Acta
1919,
2:
635
11b Review: Gololobov YG.
Kasukhin LF.
Tetrahedron
1992,
48:
1353
12 Crystallographic data (excluding structure factors) for the structures reported in this paper have been deposited as supplementary publication no. CCDC-260818 with the Cambridge Crystallographic Data Centre. Copies of the data can be obtained free of charge on application to The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK Fax: (+44)1223-336-033; E-mail: deposit@ccdc.cam.ac.uk.
13a
Rall M.
Harmony MD.
Cassada DA.
Staley SW.
J. Am. Chem. Soc.
1986,
108:
6184
13b
de Meijere A.
Chaplinski V.
Winsel H.
Kusnetsov MA.
Rademacher P.
Boese R.
Haumann T.
Traetteberg M.
von R. Schleyer P.
Zywietz T.
Jiao H.
Merstetter P.
Gerson F.
Angew. Chem. Int. Ed.
1999,
38:
2430 ; Angew. Chem. 1999, 111, 2582
14
Wolff H.
Org. React. (N.Y.)
1947,
3:
307
