Hydroxylactams

Optically active (2R,3R)-dimethoxysuccinimide derivatives 4, prepared from (.R,./ -tartaric acid, arc reduced in excellent yield with high stereoselectivity by sodium borohydride in ethanol at 0- 5 °C to furnish a 20 1 mixture of diastereomeric hydroxylactams 543, which, on treatment with acid, give rise to the formation of the enantiomerically pure chiral /V-acylimini-um ions 6,... 

Acid-catalyzed solvolysis of hydroxylactams to (m)ethoxylactams has already been discussed. Secondary or tertiary alcohols can also be used, though in the latter case yields are lower. The reverse reaction, viz. hydrolysis of the alkoxy compounds, is generally performed in aqueous acid. 

Chloroalkenes are used as 7i-nucleophiIes in the acid-catalyzcd reaction of phthalimide-derived hydroxylactams. These cyclizations lead to sole formation of the thermodynamically less stable e/ r/(t-l-acetylpyrrolo[2,1-(v isoindole derivatives92. 

Formation of a vinyl-substituted pyrrolizidine derivative is also observed in case of an allylstan-nane cyclization94. Since the allylstannane moiety is acid sensitive, the iV-acyliminium ion is generated by exposure of the hydroxylactam to methanesulfonyl chloride and triethylamine in dichloromethane. The very rapid cyclization produces the endo-vinyl compound with very high stereoselectivity. 

Optically active 2-allylpiperidines and -pyrrolidines arc obtained by treating hydroxylactams containing the l-[(S)-l-arylethyl]substituent as an auxiliary (see Appendix) with tin(IV) chloride and trimethyl(2-propenyl)silane46. Interestingly, the moderate diastereoselection when the aryl group is phenyl decreases when 2-chlorophenyl is used, whereas the sense of the stereoselectivity reverses for 2,6-dichlorophenyl or pentachlorophcnyl. These results are rationalized by application of molecular orbital theory and substrate conformational preferences46. 

Thus the hydroxylactam 6 affords pyrrolizidine derivative 7 in high yield in a completely stereoselective fashion36. 

M-Acyliminium cyclizations of optically active mono- and di-oxygenated hydroxylactam derivatives have been used in the synthesis of a number of natural products. In case of a five-membered lactam the oxygen function adjacent to the iminium carbon directs attack of the internal nucleophile from the least hindered side, opposite to the substituent. In the examples given the size of the newly formed ring is determined by the electronic bias of the alkene substituent. 

Azabicycloalkanecarboxylatcs by Cyclization of Hydroxylactams in Formic Acid General Procedure16 ... 

Nickel-catalyzed carbonylation of a-ketoalkynes has also been reported by Arzoumanian et al. under phase-transfer conditions.94 The carbonylation gave either furanone or unsaturated carboxylic acids depending on the substituents of substrates (Eq. 4.53). A similar reaction, nickel-catalyzed cyanation of a-ketoalkynes with KCN in water, was also reported to afford unsaturated hydroxylactams (Eq. 4.54).95... 

In the same manner, compound 154, treated by hydrogen in the presence of Pd(OH)2/C in methanol, was transformed to the a-hydroxylactam 155 (Equation 23) <20010L1367>. 

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). 

Hydride reduction of 345, followed by hydrogenolytic deoxygenation of the resulting hydroxylactam afforded staurosporinone (293) (766) (Scheme 5.225). The same sequence was applied to the synthesis of the 12-methyl analog of staurosporinone (766). 

In 2007, Jacobsen and co-workers reported the enantioselective Pictet-Spengler-type cyclization of P-indolyl ethyl hydroxylactams affording highly enantioenriched indolizidinones and quinolizidinones with fully substituted stereogenic centers [205]. The hydroxylactam substrates prepared either by imide reduction using... 

Scheme 6.52 Products of the asymmetric Pictet-Spengler-type cyclization of p-indolyl ethyl hydroxylactams catalyzed by 53.

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.

Intramolecular cyclization of ally lie stannanes.1 The pyrrolizidine alkaloid isoretronecanol (3) can be synthesized efficiently by cyclization of the mesylate of the hydroxylactam 1 to give 2 stereoselectively. Oxidative cleavage followed by reduction of the keto group gives 3. 

Chiral benzo[t/ thiepine fused to pyrrole ring 163 was obtained via a tandem dehydrogenation/intramolecular arylation <2001TL573>. Treatment of ct-hydroxylactam 160 with trifluoroacetic acid (TFA) at 25 °C gave a separable mixture of 163 and 165 in 64% and 22% yields, respectively (Scheme 18). Formation of the minor product 165 was a consequence of deprotonation of /V-acyliminium ion 161, followed by isomerization of unstable enamide 164. Formation of benzo[t/ thiepine 163 can be explained by a 71-aromatic intramolecular arylation of... 

Oxidation of 172 with chromium trioxide in pyridine gave the monoketone 176, whereas oxidation of spiradine F under the same conditions afforded the hydroxylactam 177. Catalytic hydrogenation of compound 176 afforded the a-ketol 178. The latter was treated with sodium methoxide in benzene to give an enolated a-diketone (179), which definitely fixed the position of the hydroxyl group at C-6 in spiradine G. Comparison of an ORD curve of compound 178 with that of 5a-cholestane-6-one established the indicated absolute configuration for these alkaloids. It is worth noting that these alkaloids bear many structural similarities to the earlier mentioned alkaloid ajaconine. 

The authors described the preparation of 25 g of the chiral ds-hydroxylactam using these two microwave-assisted reactions in one day. Purification of the product was achieved using chromatography on silica gel. 

Isomerizations such as that of 23 into 24 and 25 into 26 need catalysis, since tautomeric forms of this type are stable and do not equilibrate in solution. The transformation of 25 to 26 reflects a general rule stating that five-membered hydroxylactams are more stable than six-membered isomers (85MI1). 

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). 

Irradiation of JV-oxides 152 yielded benz[d]-1,3-oxepines (153). Compounds 153 were unstale to moisture, hydrolyzing to 154 during chromatography (Scheme 12). Hydroxylactams 154, formed in 45-70% yield, were transformed nearly quantitatively into 155 (69CPB1290). Attempts to obtain 4-azaazulenones 157 from acridine /V-oxides 156 by this route have met with only limited success the main products were dibenzooxaazepines (79TL1273). 

Other fused azepines, with aromatic (e.g. 94a,b) or heteroaromatic fused rings (e.g. 94c,d) have been prepared via the Af-acyliminium ion intermediate 93 in high yields lactam reduction then yielded the respective amines 95a,b and 95c,d [01H1519]. An intramolecular Friedel-Crafts reaction has been used to synthesise the fused azepinone 99 (S,S configuration) from 98, the latter being prepared from the diastereopure a-hydroxylactam 96, via the acid 97 [02H449],... 

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],... 

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