J. Org. Chem. 1993,58, 1305-1308
1306
Articles Practical Synthesis of a Highly Enantioselective Receptor for Peptides Shawn D.Erickson, Julian A. Simon, and W. Clark Still' D e p a r t m e n t of Chemistry, Columbia University, New York, New York 10027 Received September 21, 1992
A practical synthesisof a highly enantioselective,Cs-symmetrichost molecule (2)has been developed. The basic strategy is a significant improvement over the relatively lengthy previous synthesis and involves direct addition of a Boc-tyrosine amide anion derivative 4 to methyl 3,bbisfbromomethyl)benzoate to give an advanced intermediate (5). The final step, a triple macrolactamization, closes three 19-membered rings simultaneouslyto produce the bridged macrotricyclic receptor in 70-80 %I yield. We recently described the preparation and properties of a novel, C3-symmetric receptor (11.l This molecule is one of the most enantioselective synthetic receptors yet reported and binds N-Boc-N'-methylamide derivativesof simple amino acids with enantioselectivity ranging from 2 to 3 kcal/mol (90-99% Because such highly enantioselective receptors could have practical applications as resolving agents, we have worked to develop derivatives of 1 which could be covalently bound to a solid support. We report here the practical synthesisof one such material, the 0-allyl tyrosyl receptor 2.
R
1R 2R
While our original synthesis provided 1 in hundredmilligram quantities, it had several problems which made it unsuitable for preparation of 1or 2 on large scale. First, the unsymmetrical trisubstituted aromatic spacers were prepared by the desymmetrization reaction shown below. Although the reaction proceeded in reasonable yield (6070%), it required use of the relatively expensive di-tertbutyl iminodicarboxylate amine anion equivalent and a tedious chromatography of products having similar mobilities on silica gel: (1) Hong, J.-I.; Namgoong, S. K.; Bernardi, A.; Still, W. C. J. Am. 1991,113,5111. Chem. SOC. (2) Other enantioeelective hosta for neutral molecules: Canceill, J.; Lacombe, L.; Collet, A. J. Am. Chem. SOC.1981,107, 6993. Pirkle, W. H.;Pochapsky, T. C. J. Am. Chem. SOC.1987,109,5975. Sanderson, P. E.J.; Kilburn, J. D.; Still, W. C. J. Am. Chem. SOC.1989, I l l , 8314. Caetro, P. P.; Geor iadis, T. M.; Diederich, F. J . Org. Chem. 1989, 54, 5834. Liu, R.; Sanjerson, P. E. J.; Still, W. C. J. Org. Chem. 1990,55, 5184. Jeong, K . 4 . ; Muehldorf, A. V.; Rebek, J. J . Am. Chem. Soc. 1980, 112,6144. Webb, T.H.;Suh, H.; Wilcox, C. S. J . Am. Chem. SOC.1991, 113,8554.
A NaH, MF Br
-
Br
Second, the 8-step procedure starting from methyl 3,5bis(bromomethy1)benzoateprovided 1in only 9 7% overall yield. For a derivative of 1 which could be bound to a solid support, we chose the 0-allyl derivative2. Such otherwise stable ethers can be deprotected3 with transition metals to free phenols or attached4 directly to a support using free radical chemistry. In our new synthesis, we decided to avoid the problematicdi-tert-butyl iminodicarboxylate anion coupling and not to add nitrogen and amino acid in separate steps. Instead, we planned a more convergent route in which an N-anionic amino acid fragment would be added to bis(bromomethy1)benzoatein a single step. As summarized in the following diagram, our plan was to use a Boc-stabilized amide ion made from N-Boc-0allyltyrosine amide using methodology developed by Griecoand ~o-workers.~ In the event, however, the desired N-Boc amide turned out to be more reactive to acylation than was the primary amide. Thus, the major product with 1 equiv of BoczO and catalytic 4-(dimethylamino)pyridine (DMAP)was a tri-Boc amino acid amide. With excessBoc20/DMAP,the tri-Bocmaterialcouldbe isolated in 95% yield. As shown in Scheme I, the desired Boc-stabilizedamide anion could nevertheless be obtained and the planned (3) Kunz, H.; Unverzagt, C. Angew. Chem., Int. Ed. Engl. 1984,23, 436. (4) Tambute, A.;Begw, A.; Lienne, M.; Macaudiere, P.; Caude, M.; Rosset, R. New J. Chem. 1989, 13, 625. (5) Flynn, D.A.; Zelle, R. E.;Grieco, P. A. J. Org. Chem. 1985,48,2424.
0022-3263/93/1958-1305$04.00/0Q 1993 American Chemical Society
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2306 J. Org. Chem., Vol. 58, No.6,1993
a,b
BocHN
3
0
Erickson et al. Scheme I8
BocHN
4
PoN-BOC
e,f
-
0
5
2
BocHN
I
s,
6
Br
7
s,
(a) MethanoUammonia 41, rt, 2 days, 97%; (b) BoczO, i-PrzNEt, 4-DMAP (10 mol % ), CHzClz, 1h, 90%;(c) NaN(TMS12, THF, -78 "C, 3 min; add tetra-n-butylammonium iodide and methyl 3,5-bis(bromomethyl)benzoate;warm to 10 "C, 2 h, 82%; (d) benzene-1,3,6-trithiol, i-PrzNEt, KzC03, CHzC12, rt, 24 h, 86%;(g) THF, EtOH, H20, i-PrzNEt, THF, 8 h, 78%;(e) TFA, anisole, CHzClz, rt, 16 h, quant; (f)BOCZO, LiOH, 6 h, quant; (h) Fb-phenol, EDC, THF, rt, 4 h, 68%; (i) TFA, anisole, CHZC12, rt, 4 h, quant; Cj) T F A salt in DMA dropwise to i-PrzNEt, THF, rt, 40 h, 78%.
"'\
Boc20,DMAP
"'\
coupling achieved. Thus starting with commercially available 0-allyl-N-Boc-tyrosinemethyl ester (3),we used NH3to prepare the correspondingprimary amide and then formed the triBoc derivative 4 as described above. On treatment of 4 with sodium hexamethyldisilylazide in THF at -78 OC, a rapid deprotonationand Boc-migration occurred,leadingto the Boc-stabilizedamide anion shown below. While this anion was stable enough to be alkylated with benzylic bromides at low temperature, warming it to 15 OC caused elimination of tert-butoxide leading to 8. For preparation of 2, we used 1.2 equiv of 3,5-bis(bromomethy1)benzoatewith BQNI catalysisand obtained 5 in 82% yield.
Although the alkylation proceeded smoothly, we were concernedthat 5 might be acidic enough to have racemized under the basic conditions of the alkylation. To test for such racemization, we treated a sample of 8 with K&O3 in methanol and then with HC1 in methanol. The first treatment converted6the C-terminalBoc-amideto methyl ester while the second removed the two N-terminal Boc groups, yielding 0-allyltyrosine methyl ester. This material was then coupled using DCC to (8)-a-methoxy-a(trifluoromethy1)phenylacetic acid (Mosher's acid) to provide the corresponding amide. 'H and I3C NMR comparison of this material with corresponding amides from authentic D- and L-0-allyltyrosine methyl ester showed that very little (
