N-H Insertion reactions of rhodium carbenoids. Part 4. 1 New chiral dirhodium(II) carboxylate catalysts

The reaction of methyl 2-diazophenylacetate 1 and dimethyl α -diazobenzylphosphonate 2 with various N-H components in the presence of chiral dirhodium(II) catalysts results in N-H insertion in good yield but with little or no stereoselectivity.


Introduction
The synthesis of α-amino acids and peptides remains a topic of considerable importance and current interest.In previous papers, 2,3 we have reported that diazoesters react with a range of R 3 NH 2 compounds in the presence of dirhodium(II) catalysts to give α-amino acid derivatives, the products of N-H insertion of the intermediate rhodium carbene, in high yield (Scheme 1).
In an extension to this work, 4 we showed that N-protected amino acid amides also underwent N-H insertion reaction, in a new approach to dipeptides (Scheme 2).

Scheme 4
Dirhodium (II) catalysts.A wide range of chiral catalysts was selected for study.These encompassed the known catalysts 6-8 derived from mandelic acid, 14 2-methoxy-2-(trifluoromethyl)phenylacetic acid, 15 and N-benzenesulfonylproline, 16 as well as the novel catalysts 9 and 10 reported earlier. 10We also examined dirhodium(II) camphenate 11, 17 its related camphenate derivative 12, 11 Doyle's MEPY catalyst 13, 18 and our recently developed difluoro-MEPY 14. 13 Finally, we investigated four catalysts 15-18 identified using our parallel synthesis catalyst screen for new Si-H insertion catalysts, 12 and three new catalysts 19-21, also based on N-arenesulfonylamino acids (Figure 1).These new catalysts were prepared by reaction of the appropriate N-arenesulfonyl amino acid with dirhodium(II) carbonate. 19ith a range of chiral dirhodium(II) catalysts available, the N-H insertion reactions of both methyl 2-diazophenylacetate 1 and dimethyl α-diazobenzylphosphonate 2 were investigated.Benzyl carbamate was selected as the N-H component since it is known to give high yields of N-H insertion products with achiral dirhodium(II) catalysts. 2In the event, decomposition of methyl 2-diazophenylacetate, 1, in the presence of the 16 chiral dirhodium(II) catalysts gave the expected N-benzyloxycarbonylphenylglycine methyl ester 22 in good yield (62-92%).However, the enantiomeric excess (ee), as determined by HPLC on a chiral stationary phase, was less than 5% in all cases (Table 1).Likewise, the diazophosphonate 2 gave the aminophosphonate derivative 23 in 63-96% yield but with less than 10% ee (Table 1).Therefore, as with the corresponding O-H insertion reactions, 10 there is negligible enantioselectivity in the N-H insertion process when using chiral dirhodium(II) catalysts.a HPLC analysis was carried out on a Chiralcel OD column using 5% 2-propanol in hexane at 1.0 mL/min.b HPLC analysis was carried out on a Chiralcel OD column using 10% 2-propanol in hexane at 1.0 mL/min.

O
Despite the poor ee in the above reactions, we also investigated N-H insertion reactions involving the N-H bond in chiral amides.Earlier studies had shown that both Boc-Ala-NH 2 and Boc-Val-NH 2 underwent N-H insertion with methyl 2-diazophenylacetate 1 in modest diastereomeric excess (de) (20-25%) when using achiral dirhodium(II) acetate. 4This raises the question of whether the de could be raised (or lowered) by the use of an appropriate catalyst whose chirality was matched (or mis-matched) to that of the amino acid amide derivative.To investigate this possibility, methyl 2-diazophenylacetate, 1, was reacted with both (S)-and (R)-N-tert-butoxycarbonylalaninamide in the presence of a range of chiral dirhodium(II) catalysts (Table 2).In all cases the de of the product dipeptide 24 was less than that observed with dirhodium(II) acetate itself (25%), and there was no significant difference between the (R)-and (S)-enantiomers of the alaninamide derivative, i.e., no evidence of a match/mismatch situation.Similar results were obtained with the corresponding valinamides (Table 3), although in one case (Entry 1) there was some evidence that the chiral catalyst did influence the reaction to a small degree (ca.20% de when dirhodium(II) acetate used as catalyst).Finally, the diazophenylacetyl-phenylalanine derivative 5 was investigated.Insertion into both tert-butyland benzyl carbamate proceeded smoothly and gave the corresponding Nprotected phenylglycine-phenylalanine dipeptide methyl esters 26 and 27 in 69 and 91% yield, respectively, but with zero-or poor diastereoselectivity (Scheme 5).Attempts to extend the reaction to a stereoselective synthesis of the protected valine-phenylglycine-phenylalanine tripeptides 28 and 29 resulted in modest yields and zero diastereoselectivity. © ARKAT USA, Inc

Scheme 5
Hence, despite the fact that chiral dirhodium(II) catalysts have been used successfully to effect other enantioselective carbene reactions (cyclopropanation, C-H and Si-H insertion), we have found-as have others 20 -that simple chiral catalysts for stereoselective intermolecular carbene N-H insertion reactions remain elusive.

Experimental Section
For general experimental details, see ref.
After stirring overnight the solvent was removed under reduced pressure and the remaining colourless solid was partitioned between water (100 mL) and ethyl acetate (100 mL).The aqueous phase was then extracted with further ethyl acetate (2 x 100 mL).The organic extracts were combined, dried (Na 2 SO 4 ) and the solvent removed under reduced pressure to yield yellow oil.This crude product was then subjected to flash silica gel chromatography using light petroleum and ethyl acetate (9:1) as eluent to yield N-( 4

Insertion Reactions Methyl 2-(benzyloxycarbonylamino)phenylethanoate (22).
To a stirred solution of methyl 2diazophenylethanoate 1 (100 mg, 0.57 mmol) in dry dichloromethane (2 mL) under a nitrogen atmosphere was added benzyl carbamate (94.4 mg, 0.63 mmol) followed by a chiral dirhodium(II) carboxylate catalyst (2 mol %).After stirring for 30 min the solvent was removed under reduced pressure to yield a green oil.This crude product was then subjected to flash silica gel chromatography using light petroleum and ethyl acetate (4:1) as eluent to yield the title compound as a colourless solid, m.p. 74-75 °C, data as before. 2Dimethyl α-N-(benzyloxycarbonylamino)benzylphosphonate (23).To a stirred solution of dimethyl α-diazobenzylphosphonate 2 (100 mg, 0.44 mmol) in dry toluene (2 mL) was added benzyl carbamate (334 mg, 2.20 mmol) followed by a chiral dirhodium(II) carboxylate catalyst (2 mol %).After heating under reflux for 2 h, the solvent was removed under reduced pressure to yield a pale yellow solid.This crude product was then subjected to flash silica gel chromatography using light petroleum and ethyl acetate (1:2) as eluent to yield a colourless solid, m.p. 117-118 °C, data as before.

(R-or S-)-N-(tert-Butoxycarbonyl)alanyl-(R,S)-phenylglycine methyl ester (24).
To a stirred solution of methyl 2-diazophenylethanoate 1 (50 mg, 0.28 mmol) in dry dichloromethane (4 mL) under a nitrogen atmosphere was added (R-or S-)-N-(tert-butoxycarbonyl)alaninamide (58.8 mg, 0.31 mmol) followed by a chiral dirhodium(II) carboxylate catalyst (2 mol %).After stirring for 1 h the solvent was removed under reduced pressure to yield a green oil.This crude product was then subjected to flash silica gel chromatography using light petroleum and ethyl acetate (7:3) as eluent to yield an inseparable diastereomeric mixture of the title compound as a colourless oil; data as before. 4

(R-or S-)-N-(tert-Butoxycarbonyl)valinyl-(R,S)-phenylglycine methyl ester (25).
To a stirred solution of methyl 2-diazophenylethanoate 1 (50 mg, 0.28 mmol) in dry chloroform (4 mL) under a nitrogen atmosphere was added (R or S)-N-(tert-butoxycarbonyl)valinamide (67.5 mg, 0.31 mmol) followed by a chiral dirhodium(II) catalyst (2 mol.%).After stirring for 1 h the solvent was removed under reduced pressure to yield a green oil.This crude product was then subjected to flash silica gel chromatography using light petroleum and ethyl acetate (4:1) as eluent to yield an inseparable diastereomeric mixture of the title compound as a colourless oil; data as before.

Figure 1 .
Figure 1.Chiral dirhodium(II) catalysts (only one of the four bridging ligands is shown in each case). 2.
(S)-phenylalanine methyl ester 5 (82 mg, 0.25 mmol) in dry dichloromethane (3 mL) over 1 h.The reaction mixture was then stirred at reflux for a further 17 h before being allowed to cool to room temperature and concentrated in vacuo to give the crude product.Flash chromatography (Boc-(R)-Val-(R,S-)-Phg-(S)-Phe-OMe (29).