Tetramic acids and derivatives by telluride-triggered Dieckmann cyclizations 1

Treatment of α-bromoacyl amides of esters of N -protected α-amino acids with lithium telluride yields an amide enolate which cyclizes to unstable tetramic acids (2, 4-pyrrolidinediones) which can be converted to stable derivatives (e.g. enol esters, silyl enol ethers, enol tosylates). Reaction conditions are modified to reduce unwanted side reactions: protonation of the enolate, self-catalyzed intermolecular aldol rections of the tetramic acids, and potential racemization at the α-carbon atom of the amino acid.


Introduction
Tetramic acids (2, 4-pyrrolidinediones) are structural components of a number of natural products that show antibiotic, anticancer (cytotoxicity), fungicidal, and antiviral activity. 2N-Acylhomoserine lactones are used by some bacteria to exchange information ("quorum sensing"); one lactone degrades to a tetramic acid derivative that is a potent poison for certain encroaching microorganisms. 3arious methods have been used to prepare tetramic acids. 2 The Dieckmann cyclization 4a of N-acyl-α-amino esters and related methods (e.g. the Reformatsky reaction) 4b are among the most useful.Enzyme-catalyzed formation of tetramic acids found in certain fungi proceeds by a Dieckmann cyclization.4c,4d Racemization at the chiral α-carbon atom of the starting amino acid ester caused by the base used in the Dieckmann reaction is an undesirable side reaction. 5Shorter reaction times (5-90 min), lower temperatures (i.e. to room temperature), and the use of elemental tellurium heralds the irreversible formation of the amide enolate confirmed by deuteration of enolate 3 to give 4b (Scheme 2), confirmed by NMR of the crude reaction mixture.Cyclization of the enolate via the usual tetrahedral intermediate 5 yields tetramic acids 6 (Scheme 2) (Table 2).
with addition of CD 3 OD 4b (R 1 = i -Bu, R 2 = Bn, R 3 = R 4 = H)  a Proline derivative 1 (racemic) was converted to its N-Boc derivative and Weinreb amide followed by removal of the Boc group by treatment with trifluoroacetic acid before conversion to 2h. a Yield was 92% for 7a and 100% for 7b when 3.5 equivalents of t-butyldiphenylsilyl chloride (TBDPSCl) were used, but the product was racemized.
Because of the instability of tetramic acids only three 6e, 6h, and 6k were isolated.The rest except 6c were converted to stable t-butyldiphenylsilyl ethers (TBDPS), enol esters, or enol tosylates 7a-b, 7e-g, 7i-j (Scheme 2) (Table 3).Once the lithium or sodium enolate is formed, it is susceptible to protonation to give the amide, 4a, which halts tetramic acid formation.To control this undesired protonation, potential proton donors such as the amino-acid-derived NH proton and acidic products (tetramic acid, methanol) must be nullified.This can be accomplished by the use of an N-protected amino acid and by neutralization of acids with an equivalent of base.The protection of the NH group of the amino acid starting materials by benzyl (Bn), pmethoxybenzyl (PMB), or 3, 4-dimethoxybenzyl (DMB) groups is accomplished by treatment with the aryl aldehyde to give the imine which is reduced with sodium borohydride. 23While an added base can reduce protonation, it may also cause racemization at the α-carbon of the former amino acid.For the telluride process shown in Scheme 2 to be most useful it must proceed between the Scylla of "protonation" to 4a and the Charybdis of racemization to racemic 6. 24 Reduction of the 4-carbonyl group of tetramic acid 6c is accomplished readily with sodium borohydride.5b, 25 The resulting diastereomer 8 derived from 6c is obtained with a dr 20:1, 25 which indicates little racemization at C-5 (Scheme 3).The diastereomeric ratio was determined using 1  Weinreb amides 26 were investigated (Scheme 2, 2h) because they are less acidifying for the α-amino acid proton, and the tetrahedral intermediate 5 is more stable than that derived from the methyl ester.25c This latter effect delays the formation of the acidifying C-4 carbonyl group which is expected to reduce both "back-protonation" and racemization as well as potentially limiting self-catalyzed reactions of the tetramic acids.While the bromoacetylation of the proline Weinreb amide was successful, that of N-benzyl leucine Weinreb amide was not, starting material being recovered.An interaction of bromoacetyl bromide with the Weinreb amide may provide an unstable intermediate that transfers the acyl group to the nitrogen atom of the amino acid derivative.This is reminiscent of the intermediate derived from DMF in its catalysis of acid chloride and formate ester formation in which there is acyl transfer. 27The more rigid proline framework lacks the N-benzyl group and may allow more favorable conformations, 10 vs 9, for acyl transfer.Best yields of the tetramic acid 6h derived from racemic proline were obtained when an equivalent of LHMDS or LDA was added.The bases LDA and NaH (heterogeneous in THF) are reported to cause racemization of tetramic acids 25c,28 and were not investigated further.Other conditions involving methyl esters of N-bromoacetyl derivatives of N-benzylamino acids produced significant amounts of the protonated enolate 4a: higher temperature (65-70 o C); longer reaction time (5 days); different solvents (9:1 ether-THF, DME); additives [TiCl4, LiOTf, In(OTf)3, Sc (OTf)3, Yb(OTf)3, ZnBr2, MgBr2, 4A molecular sieves; DBU]; 0.5 equiv.excess of LiEt3BH.Only with DME at 65-70 o C and with DBU (base effect) were the amounts of tetramic acid 6 greater than 4a (ratios 6/4a = 54/46, 56/44, respectively).Application of the telluride procedure to the synthesis of 3,3-disubstituted-tetramic acids is not complicated by "back protonation" or a self-catalyzed aldol condensation because the acidic protons are not present.No extra base is required.The 3,3-dimethyltetramic acid 6k derived from (L)-leucine is the sole product although its formation is slower (Scheme 4).The addition of one equivalent of crown ether (15-crown-5) to the sodium telluride-triggered reaction avoids the need for added base in the conversion of the α-bromoacetamides of Lphenylalanine, L-leucine, and L-isoleucine methyl esters (Scheme 5) and reduces the reaction time from 40-50 min.to 20-30 min.Presumably, the crown ether facilitates the sodium enolate's attack on the carbonyl group of the ester in the Dieckmann reaction by formation of a more favorable conformation while shielding the enolate from protonation and/or by increasing the rate of deprotonation of the tetramic acid by the crown-complexed sodium methoxide and perhaps by hydrogen bonding of the product methanol with the oxygen atoms of the crown ether to slow its diffusion to the enolate anion.Figure 1 shows how 15-crown-5 might affect an halophilic attack by sodium telluride.Crown ethers do not seem to have been used in aldol reactions involving oxazolidinone chiral auxiliaries, but catalysis by chiral crown ethers complexed with a Lewis acid (e.g.Pb 2+ , Ce 3+ ) is observed in reactions of silyl enol ethers with aldehydes.29a,b In reactions of other silyl enol ethers with aldehydes catalyzed by gallium (III) triflate in water-ethanol, hydrolysis of the enol ether was complete and no aldol product was observed.In the presence of chiral semi-crown ethers, only traces of hydrolysis product were observed; the aldol product was obtained in yields of 49-90% with mainly syn selectivity.29c The chiral gallium-semi-crown ether catalysts are said to accelerate the aldol reaction relative to the hydrolysis reaction.Application of the telluride procedure (Li2Te, 1 equiv.LHMDS, THF, rt) for the synthesis of tetramic acids indicates that little racemization occurred at the C-5 position as determined by NMR studies on tetramic acid derivatives obtained from L-isoleucine [(2S,3S)-2-amino-3methylpentanoic acid].Tetramic acids derived from isoleucine have been used previously to determine the amount of racemization.5b,7 Because the formation of 3,3-dimethyltetramic acids (Scheme 4) does not require added base to suppress "back protonation", the danger of racemization by the base is avoided.
Conversion of tetramic acids to enol ethers, enol esters or enol tosylates (Scheme 2, Table 3) could circumvent the self acid-catalyzed aldol condensation and acid-catalyzed racemization and provide stable intermediates that could readily be converted back to the parent tetramic acid if that is desired.While the t-butyldiphenylsilyl (TBDPS) enol ethers are stable, their preparation resulted in some racemization, most likely caused by silylation of the amide carbonyl oxygen 30 to give an intermediate (Scheme 6) in which the CH proton derived from the α-amino acid is expected to have greater acidity.Workup removes the silyl group from the amide leaving racemized 4-silyl enol ether derivatives.Yields of the silyl enol ether were best (7a, 92%, and 7b, 100%) when 3.5 equivalents of TBDPSCl were used, but racemization of 7a was nearly complete, er = 53:47.It is likely that all the silyl enol ethers were racemized to some extent (small rotations for 7a and 7b) when only 1.15 equivalents of TBDPSCl were used but this was not investigated further.
The preparation of the enol benzoate 7g and tosylate 7e (Scheme 2, Table 3) derived from Lisoleucine did not involve racemization at the C-5 of the tetramate derivative because the proton NMR spectra did not show the presence of the other diastereomer (which would be derived from (2R, 3S)-2-amino-3-methylpentanoic acid).The N-protective groups may need to be removed from the tetramic acid derivatives for further synthesis operations.The N-benzyl group could not be cleaved under frequently used conditions: H2, Pd/C, EtOAc or EtOH; H2, Pd(OH)2/C; ceric ammonium nitrate (CAN); DDQ.Removal of an N-3,4-dimethoxybenzyl (

Conclusions
Cyclization of N-protected α-bromoacyl amides of α-amino acid methyl esters or Weinreb amides to tetramic acids is initiated by telluride ion, which rapidly and irreversibly forms the amide enolate.Proton transfer from an unprotected NH group or from the tetramic acid or methanol products to the enolate anion inhibits the Dieckmann cyclization and reduces the yield.

Experimental Section
General.NMR spectra were recorded on a Bruker DPX300 or DPX 500 instrument with tetramethylsilane as internal standard.Chemical shifts are reported in ppm downfield from tetramethylsilane.Optical rotations were measured on a JASCO 1000 or Rudolph Autopol III polarimeter.All reactions were conducted in an atmosphere of dry argon or nitrogen according to standard vacuum line techniques.Unless otherwise noted, all commercially available reagents were used as received without further purification.Tetrahydrofuran was distilled or vacuumtransferred from sodium or potassium benzophenone ketyl immediately before use; ether, from sodium benzophenone ketyl; and dichloromethane, from calcium hydride.Pyridine and triethylamine were distilled from sodium hydroxide immediately before use.All other liquid reagents were distilled immediately before use.Thin layer chromatography was performed with the use of Merck Silica Gel 60 plates impregnated with a fluorescent indicator (254 nm).Thin layer chromatography plates were visualized by exposure to ultraviolet light, iodine, anisaldehyde, or phosphomolybdic acid.Flash column chromatography was performed with the use of Premium Grade Silica Gel.
General procedure for the preparation of lithium telluride 21 A solution of lithium triethylborohydride in THF (7.98 mL, 1 M, 7.98 mmol) was added to a suspension of tellurium pieces (509 mg, 3.99 mmol) in THF (7.95 mL) at room temperature.The mixture was stirred for 20 h.Hydrogen evolved, and the color of the mixture gradually becomes nearly white.This 0.25 M "stock suspension" of finely divided lithium telluride in THF is stable ARKAT USA, Inc.
for weeks at room temperature under an argon atmosphere and the slurry can be transferred easily with an airtight syringe equipped with a stainless steel needle.

Scheme 5 .
Scheme 5. Cyclization of α-bromoamides by sodium telluride in the presence of a crown ether.

Table 2 .
Tetramic acids 6 a Most of the other tetramic acids were unstable and were converted to derivatives. a