Stereoselective α-amidoalkylation reactions of phenylglycinol- derived bicyclic lactams

The sterochemical outcome of α-amidoalkyltaion reactions from chiral non-racemic bicyclic lactams trans-1 and cis-1 using indole, allyltrimethylsilane, higher order organocuprates, TMSCN, and Grignard reagents is discussed. © 2003 Elsevier Science. All rights reserved ——— * Corresponding author. Tel.:+34 93 4024538; fax:+34 93 4024539; e-mail: amat@farmacia.far.ub.es; jbosch@farmacia.far.ub.es


Introduction
Chiral bicyclic lactams derived from R-or Sphenylglycinol have emerged as powerful tools for the enantioselective synthesis of piperidine derivatives. 1 In this context, in previous work we have reported the preparation of the phenylglycinol-derived lactams cis-1 and trans-1. 2 Pure lactam cis-1 is easily accessible by cyclocondensation of (R)-phenylglycinol with methyl 5oxopentanoate under neutral conditions, followed by column chromatography of the resulting 85:15 diasteromeric mixture of lactams, while lactam trans-1 is obtained by equilibration of the above mixture under acidic conditions followed by chromatographic purification (Scheme 1). Both lactams cis-1 and trans-1 have proven to be versatile chiral building blocks for the synthesis of diversely substituted enantiopure piperidines as they allow the stereocontrolled formation of C-C bonds at the different carbon positions of the piperidine ring. 4 In particular, the enantioselective synthesis of 2-alkyl-and 2-arylpiperidines from these lactams requires the stereocontrolled introduction of the substituent at the piperidine α-position by asymmetric αamidoalkylation, 5,6 a process that has been reported to occur with moderate to high stereoselectivity from trans-1. 7 Thus, reaction of trans-1 with indole in the presence of TiCl 4 leads to a 3:1 mixture of 6-indolyl-2-piperidones 2a and 2b, 8 whereas reaction of trans-1 with allyltrimethylsilane in the presence of TiCl 4 gives a 9:1 mixture of the allylated products 3a and 3b 4b (Table 1,  entries 1 and 2).
Similarly, the addition of higher order alkyl and phenyl cyanocuprates in the presence of BF 3 .Et 2 O takes place in good yields and high stereoselectivities to give the corresponding 6-alkyl-and 6-aryl-2-piperidones (4-6; Table 1, entries [3][4][5]. 4b In all the above cases the major stereoisomer results from an inversion of the configuration at the C-8a stereocenter. This stereoselectivity can be accounted for by considering that the iminium ion generated by interaction of trans-1 with the Lewis acid undergoes nucleophilic attack upon the less hindered face as depicted in A (Figure 1).

Results and discussion
In this article we report i) new α-amidoalkylation reactions from trans-1, which provide access to 2piperidones bearing a functionalized substituent at C-6; ii) the dramatic change of stereoselectivity when Grignard reagents are used instead of higher order cyanocuprates, and iii) a comparative study of the behavior of cis-1 and trans-1 in α-amidoalkylation reactions.
As could be expected from previous results, treatment of lactam trans-1 with lithium 2-methyl-1-propenylcyanocuprate in the presence of BF 3 .Et 2 O gave the 6substituted 2-piperidone 7a in 52% yield as the only isolable product (entry 6). Very minor amounts (<5%) of the C-6 diastereomer were detected from the crude reaction mixture. The interest of the above vinylation lies in the fact that lactam 7a could be converted to alcohol 8 in excellent yield by ozonolysis followed by NaBH 4 reduction (Scheme 3), thus opening a simple route for the stereoselective introduction of a hydroxymethyl substituent at the piperidine 2-position, an appendage present in many natural and synthetic azasugars. 9 A similar stereoselectivity was observed in the addition of trimethylsilyl cyanide in the presence of TiCl 4 : a 95:5 mixture of nitriles 9a and 9b, respectively, was obtained in 74% yield ( The absolute configuration of the new stereogenic center of 6-substituted lactams 7 and 9 was assigned from the NMR data following the correlation observed in a series of related diastereomeric phenylglycinol-derived lactams. 10 Thus, in the major isomers a the benzylic proton appears more shielded than in the minor isomers b, whereas the benzylic and C-6 carbons are more deshielded. In sharp contrast with the uniform stereoselectivity of the above reactions, Grignard reagents reacted with lactam trans-1 with retention of the configuration at C-8a to give diastereomers b as the major products. Thus, reaction of trans-1 with methylmagnesium bromide gave a 15:85 mixture of piperidones 4a and 4b in 73% yield ( Table 1, entry 8). n-Propylmagnesium bromide (entry 9) also reacted with excellent yield (72%) and stereoselectivity (5a:5b; 5:95 ratio). 11 As expected reaction of trans-1 with phenylmagnesium bromide (entry 10) and 2-methyl-1propenylmagnesium bromide (entry 11) took also place with high stereoseelectivity to give piperidones 6b and 7b, respectively, in 72% and 56% yield. The remarkable change of stereoselectivity in the above reactions with Grignard reagents can be explained by considering that, in the absence of an additional Lewis acid, the magnesium may coordinate with the oxygen of the oxazolidine ring. Subsequent delivery of the alkyl or aryl group from the same face of the C-O bond would account for the observed retention of configuration.
We then decided to study the stereochemical outcome of α-amidoalkylation reactions from the C-8a epimeric lactam cis-1. In fact, α, β-unsaturated lactams derived from cis-1 and trans-1 undergo conjugate addition reactions with opposite facial selectivity. 12 Somewhat surprisingly, lactam cis-1 was recovered unchanged after treatment with indole (25 ºC, 30 min) or allyltrimethylsilane (25 ºC, 4 h) in the presence of TiCl 4 , under the conditions previously employed in the reactions from trans-1. These α-amidoalkylations required longer reaction times (25 h) and took place in lower yields (2a + 2b: 10%; 3a + 3b: 45%) than the similar reactions from trans-1 (Scheme 4). In both cases, bicyclic lactam trans-1, formed by equilibration of the unreacted starting lactam cis-1, was also isolated to a considerable extent. The observed stereoselectivity in the reaction with indole is a consequence of an equilibration process after prolonged exposure of the resulting indolylpiperidones to TiCl 4 . 8 On the other hand, under the reaction conditions successfully used in the reaction with trans-1, cis-1 reacted with npropylmagnesium bromide with very low yield and stereoselectivity to give a 4:3 diastereomeric mixture of the corresponding lactams 5a and 5b, most of the starting material cis-1 being recovered unchanged. Finally, only complex mixtures were formed from phenylmagnesium bromide. As a consequence of these discouraging results, no further α-amidoalkylation reactions using cis-1 were studied. In conclusion, starting from a single enantiomer of phenylglycinol, via a common lactam trans-1, either piperidones 4a-7a or their epimers 4b-7b are easily accessible by choosing the appropriate organometal derivative, which gives access to the two enantiomeric series of 2-alkyl substituted piperidines.

General
Melting points were determined in a capillary tube and are uncorrected.   2.3. (6S)-6-Hydroxymethyl-1-[(1R)-1-phenyl-2hydroxyethyl]-2-piperidone, 8. A stream of ozone gas was bubbled through a cooled (−78 ºC) solution of 5a (100 mg, 0.36 mmol) in CH 2 Cl 2 (1 mL) and methanol (4 mL) until it turned pale blue. The solution was purged with O 2 , and the temperature was raised to room temperature. Then, NaBH 4 (14 mg, 0.36 mmol) was added to the mixture, and the resulting suspension was cooled at −78 ºC and stirred for 1 h. Additional NaBH 4 (14 mg, 0.37 mmol) was added, and the temperature was raised to room temperature. After 1 h of stirring, the mixture was concentrated, and the residue was dissolved in CHCl 3 . The organic solution was washed with 5% aqueous HCl, dried, and concentrated.