N-Hydroxylactams

Alkylation of hydroxamic acids as a method of co-N-hydroxyamino acids (2) synthesis was introduced by Maurer and Miller 196), When N- r -butoxycarbonyl-6-hydroxynorleucine benzylhydroxamate (248) or a homologue was treated with triphenylphosphine and diethylazodi-carboxylate (DEAD) under Mitsunobu conditions 197), intramolecular alkylation took place leading to N-hydroxylactams (249) or (250) as well as lesser amounts of hydroximates Z-(251) and -(252) (Scheme 50). The products were separated and distinguished by NMR spectrometry 196,198,199). Derivatives of the seven-membered N-hydroxylactam (253) were applied for the total synthesis of mycobactin S2 (254) 199) (Scheme 51). 

P-hydroxy-P-(o-hydroxyaryl)-a-methylenesulfoxides 43, 553 N-Hydroxylactams s. Hydroxamic acids, cyclic a-Hydroxy-y-lactolides... 

Tetracyclic benzo[/]-4-oxopyrrolo[l,2-fl]thieno[3,2-c]azepine 103a, as well as its piperidone homolog 103b, can be prepared through intramolecular N-acyliminium ion cyclization of hydroxylactams 102 (Scheme 20 (2001 HI 519)). 

Tetracyclic lactam 134 was similarly obtained from the hydroxylactam by N-acyliminium ion cyclization (01H(55)1519, 02BKC1623). 

Scheme 6.53 Proposed mechanism for the 53-catalyzed asymmetric Pictet-Spengler-type cyclization of P-indolyl ethyl hydroxylactams Hydroxylactam (1) forms chlorolactam (2) followed by chiral N-acyliminium chloride-thiourea complex (3) and the observed product generated by intramolecular cyclization catalysis and enantioinduction result from chloride abstraction and anion binding.

Cyclization reactions of a-acyliminium ions with allyl- and propargyl-silanes constitute a useful method for the preparation of various N-bridgehead bicyclic systems. Thus, from a reaction of hydroxylactams 107 and 108, the azaazulenes 109 and 110 were obtained in excellent yields (83TL1407). Similarly, the keto amide 112 was obtained from the imide 111 by reduction to the corresponding hydroxylactam and acid-catalyzed cyclization (84JCS(P1)2477). 

A study of the 4,4 -di-fert-butylbiphenyl(DTBB)-catalysed lithiation of dihydrodibenzothiepine 165 has been reported lithiation results in 166, which can then be converted into t he alcohol d erivatives 168 or 170 via t he 1 ithiated d erivatives 167 or 169 respectively [01TL2469]. The preparation of the chiral pyrrolobenzo[c/]thiepine 174 via intramolecular attack on the electrophile 173 (derived in turn from the hydroxylactam 171 via 172) has been reported the yield was 64% for 174, n = 2 [01TL573],... 

Treatment of 92 with sodium in liquid ammonia brought about the reductive desulfurization and cleavage of the benzylic G-N bond to give an intermediate 6-hydroxylactam, which was cyclized with TiCU to give the diazocine 93 as minor product (6%) and the azocine derived from the cyclization on the 3-position of the indole, as major product (35%) (Equation 9) <2004JOC8681>. 

In the synthesis of the antidepressant (-)-Rolipram, Meyers et al. [26] tried to convert bicyclic lactam 39 to hydroxylactam 40 by use of dissolved metals. The increased yield of 40 on going from Li -> K -> Na parallels fhe reduction potential of the metals Li (3.0), K (2.9), and Na (2.7). The reduction potential of calcium is known to be even lower. When 39 is treated with calcium metal (10 equiv.) in liquid ammonia, fhe desired 40 is produced in 84% yield (Scheme 4.11). The same type of reduction is applicable to the conversion of 41 to 42 [27]. Furthermore, treatment of tricyclic lactam 43 wifh EtsSiH and I ifTi gives poor isolated yield (22%) of the polar diamino alcohol 44. In contrast, calcium-ammonia reduction of 43 produces N-unsubstituted hydroxylactam 45 in an excellent yield. 

In 2010, Jacobsen and coworkers reported a new thiourea catalyst for the enantioselective cationic polycyclisation of hydroxylactams. The expansive and polarisable moiety of 1,9-dihydropyrene in catalyst 13 proved optimal for this transformation, evidently due to cation-n interactions stabilising transition state. The tetracyclic adducts were afforded in moderate yields, high enantioselectivities and as a single diastereomer (Scheme 19.16). 

The formation of N-acyUminium ions by a thiourea-mediated catalytic reaction was investigated with P-indolyl ethyl hydroxylactams. The generation of the N-acyltmrriinium in the presence of an indole can be successfully used in a Pictet-Spengler-type cycUzation of such compounds, affording highly enantioenriched indoUzidinones and quinoUzidinones (Scheme 26.14) [88]. 

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