PR inhibitors,8,9 and several synthetic approaches have been
developed for these structures.9,10 These, however, have been
generally limited to the synthesis of isosteres with benzylic
or alkyl side chains R, R′. Recently, we have developed a
general strategy for the synthesis of isosteres 1 and 2 starting
from amino acids.11 We now report on the extension of this
approach to the synthesis of proline-containing dihydroxy-
ethylene isosteres 3.
introduce an ω-amino alkene chain via Horner-Emmons
olefination14 of 4 with Boc-protected amino aldehyde 5a
(Scheme 2) were frustrated by the propensity of the latter to
Scheme 2
The synthesis is based on the analysis shown in Scheme
1. It was anticipated that formation of a five-membered ring
Scheme 1
by exo ring opening of the oxirane would be preferred over
the competing 6-endo cyclization, leading thus to the required
pyrrolidine.12 The general approach is illustrated by the
synthesis of the Val-Pro dipeptide isostere 13. The synthesis
starts from the known phosphonate 4,13 readily obtained from
N-Boc valine methyl ester. Our initial attempts to directly
cyclize giving N-Boc-2-hydroxypyrrolidine, which did not
react with 4 under a variety of Horner-Emmons conditions.
Aldehyde 5b15 also failed to give the expected product 6b,
as elimination of azide took place under the basic conditions
required for the olefination. We thus resorted to introducing
the amino group at a later stage via the Curtius reaction of
the corresponding acid; to this end phosphonate 4 was
subjected to the Horner-Emmons olefination with aldehyde
5c,16 which proceeded smoothly giving the E-enone 6 as a
single isomer characterized by a 15.6 Hz coupling constant
between the vinyl protons.
Stereoselective reduction of the carbonyl group of 6 with
NaBH4 in methanol (Scheme 2) follows the Cram-chelate
rule,17 resulting in a 8:1 mixture of S,R (7) and S,S
diastereoisomers.10a,18 The major isomer 7 could be easily
isolated in pure form by column chromatography and was
converted into the corresponding oxazolidinone 8 in order
to confirm the stereochemical assignment (Scheme 2). The
value of 7.7 Hz for the coupling constant between the vicinal
ring protons of 8 and 10% NOE measured for the same
protons are both consistent with a cis disposition of the
substituents and therefore with the S,R configuration of 7.19
The second amino group was introduced at this stage of
the synthesis (Scheme 3); to this end the alcohol 7 was
(4) (a) Dugave, C.; Demange, L. Chem. ReV. 2003, 103, 2475. (b) Fischer,
G. Angew. Chem., Int. Ed. Engl. 1994, 33, 1415.
(5) (a) Pearl, L.; Taylor, W. Nature 1987, 328, 482. (b) DeClercq, E.
Nature ReV. Drug DiscoVery 2002, 1, 13.
(6) Recent examples: (a) Hanessian, S.; Sailes, H.; Therrien, E.
Tetrahedron 2003, 59, 7047. (b) Wang, X. D. J.; Hart, S. A.; Xu, B. L.;
Mason, M. D.; Goodell, J. R.; Etzkorn, F. A. J. Org. Chem. 2003, 68, 2343.
(c) Otaka, A.; Katagiri, F.; Kinoshita, T.; Odagaki, Y.; Oishi, S.; Tamamura,
H.; Hamanaka, N.; Fujii, N. J. Org. Chem. 2002, 67, 6152. (d) Vasbinder,
M. M.; Miller, S. J. J. Org. Chem. 2002, 67, 6240. (e) Saha, B.; Nandy P.
J.; Shukla, S.; Siddiqui, I.; Iqbal, J. J. Org. Chem. 2002, 67, 7858. (f)
Courcambeck, J.; Bihel, F.; De Michelis, C.; Que´le´ver, G.; Kraus, J. L. J.
Chem. Soc., Perkin Trans. 1 2001, 1421. (g) Edmonds, M. K.; Abell, A.
D. J. Org. Chem. 2001, 66, 3747. (h) Kraus, J. L.; Bouygues, M.;
Courcambeck, J.; Chermann, J. C. Bioorg. Med Chem. Lett. 2000, 10, 2023.
(i) No¨teberg, D.; Brånalt, J.; Kvarnstro¨m, I.; Linschoten, M.; Musil, D.;
Nystro¨m, J.-E.; Zuccarello, G.; Samuelsson, B. J. Med. Chem. 2000, 43,
1705.
(7) (a) HIV Medicine 2003; Hoffmann, C., Kamps, B. S., Eds.; Flying
Nature 2001, 410, 995. (c) Tomasselli, A. G.; Heinrikson, R. L. Biochim.
Biophys. Acta 2000, 1477, 189. (d) Moyle, G.; Gazzard, D. Drugs 1996,
51, 701.
(8) (a) Brik, A.; Wong, C.-H. Org. Biomol. Chem. 2003, 1, 5. (b) Leung,
D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000, 43, 305. (c) Babine,
R. E.; Bender, S. L. Chem. ReV. 1997, 97, 1359.
(9) (a) Tossi, A.; Bonin, I.; Antcheva, N.; Norbedo, S.; Benedetti, F.;
Miertus, S.; Nair, A. C.; Maliar, T.; Dal Bello, F.; Palu`, G.; Romeo, D.
Eur. J. Biochem. 2000, 267, 1715. (b) Tossi, A.; Benedetti, F.; Norbedo,
S.; Skrbec, D.; Berti, F.; Romeo, D. Bioorg. Med. Chem. 2003, 11,
4719.
(10) (a) Ghosh, A. K.; Bilcer, G.; Schiltz, G. Synthesis 2001, 2203. (b)
Kempf, D. J.; Sowin, T. J.; Doherty, E. M.; Hannick, S. M.; Codavoci, L.
M.; Henry, R. F.; Green, B. E.; Spanton, S. G.; Norbeck, D. W. J. Org.
Chem. 1992, 57, 5692.
(11) (a) Benedetti, F.; Miertus, S.; Norbedo, S.; Tossi, A.; Zlatoidzky,
P. J. Org. Chem. 1997, 62, 9348. (b) Benedetti, F. Berti, F.; Norbedo S. J.
Org. Chem. 2002, 67, 8635.
(14) Mikolajczyk, M.; Balczewski, P. Synthesis 1987, 659.
(15) Carrington, S.; Renault, J.; Tomasi, S.; Corbel, J.-C.; Uriac, P.;
Blagbrough, I. S. Chem. Commun. 1999, 1341.
(16) Huckstep, M.; Taylor, R. J. K.; Caton, M. P. L. Synthesis 1982,
881.
(17) (a) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191. (b) Reetz,
M. T. Acc. Chem. Res. 1993, 26, 462.
(12) Recent examples: (a) Ayad, T.; Genisson, Y.; Baltas, M.; Gorrichon,
L. Chem. Commun. 2003, 582. (b) Lee, J.; Hoang, T.; Lewis, S.; Weissman,
S. A.; Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 2001, 42,
6223. (c) Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 5546.
(13) Deziel, R.; Plante, R.; Caron, V.; Grenier, L.; Llinas-Brunet, M.;
Duceppe, J.-S.; Malenfant, E.; Moss, N. J. Org. Chem. 1996, 61, 2901.
(18) (a) Albeck, A.; Persky, R. Tetrahedron 1994, 21, 6333. (b) Maugras,
I.; Poncet, J.; Jouin, P. Tetrahedron 1990, 46, 2807. (c) Dufour, M.-N.;
Jouin, P.; Poncet, J.; Pantaloni, A.; Castro, B. J. Chem. Soc., Perkin Trans.
1 1986, 1895. (d) Tramontini, M. Synthesis 1982, 605.
(19) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P. J. Org. Chem.
1990, 55, 1439.
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