N-Deprotection and Cyclization

8 2-1 midazolines, lmidazolidin-2-ones and Benzimidazoles by Ugi-4CR with N-Deprotection and Cyclization 

An extension of the above method for the preparation of cyclic ureas (imidazolidin-2-ones) was developed by the same group [63], by employing carbon dioxide/methanol in place of a carboxylic acid, and the UDC strategy. Additionally, treatment of the Ugi-5CR products with base afforded hydantoins in good yield. 

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Intramolecular cyclization DKP formation through intramolecular cyclization of the Nj—C2 bond is an efficient route to ring closure and the construction of these head-to-tail dipeptides involves the coupling of an N-protected a-amino acid to an a-amino ester, followed by N-deprotection and cyclization. " ... 

The Hulme group reported an efficient three-step, one-pot solution-phase synthesis of 2-imidazolines employing the UDC strategy [62], The reaction between N-Boc-protected a-aminoaldehydes, amines, acids, and isocyanides afforded the N-Boc-protected a-acylamino amides 94 which, upon heating in addic medium, underwent N-deprotection and cyclization to 2-imidazolines 95 (Scheme 2.34). This procedure was adapted to combinatorial synthesis in a rack of 96 reaction vials. 

The Hulme group has reported two three-step, one-pot solution-phase procedures for the preparation of 2,5-diketopiperazines, based on the UDC strategy. The first method [74a] used ethyl glyoxylate as a bifunctional carbonyl input in an Ugi-4CR with amines, isocyanides, and N-Boc a-amino acids that afforded adducts 121, which were N-deprotected and cyclized to the desired products 122 (Scheme 2.44). The second method [8c] used Armstrong s convertible isocyanide 1 in a reaction with N-Boc a-amino acids, aldehydes, and amines that afforded products 123, which were deprotected and cyclized to diketopiperazines 124 (Scheme 2.44). 

Similarity, compound 207 was thermally cyclized to give 216 and 217. The latter, 217, was converted into 218 and 219 in 72 and 11% yield, respectively (Scheme 21). ° The major one was sequentially debenzylated and diacylated to give 220, which was converted to the iodo derivative 221, followed by exposure to zinc in boiling ethanol to allow concurrent reductive ring cleavage, N-deprotection and cyclization to afford the vinyl lactam 222 in a diastereoisomerically pure state. Ozonolysis of 222 followed by reduction with sodium borohydride and then further reduction with LiAlH4 afforded (-l-)-31. On the other hand, the minor isomer 219 afforded the (-l-)-platynecine [(- -)-30] by following similar steps. 

For example, reaction of the chiral N- and C-protected amino acid derivatives 62 and 63, respectively, with tert-butyl isocyanide 64 and benzaldehyde 65 yields the Ugi product 66. N-deprotection and cyclization under basic conditions yields the two stereoisomers 67 (R,R,R) and 68 (R,R,S), differing in the benzaldehyde-derived stereocenter. The two diastereomers can be conveniently separated using silica chromatography (Scheme 15.21). 

Gronowitz and associates coupled 2-(2-trimethylstannyl-3-thienyl)-l,3-dioxolane (75) with tert-butyl N- (o/t/io-bromo tbienyl)carbamate (127) to give the Stille adduct, which underwent acid-catalyzed deprotection and cyclization to deliver dithienopyridine 128 [112]. The... 

A novel route to the ring-fused lactam (159) has been described by Thomas, the key step of which involves regiospecific attack of the bifunctional nucleophiles (156) at the 6-position of 2-methoxypyridine to give the lactims (157).1( Subsequent deprotection and cyclization of (158) can be accomplished in one step to afford the products (159) in moderate to good yields. In another N-alkylative procedure, the halogenoalkylimines (160), readily available by alkylation of the corresponding a-amino-ester... 

Clavepictines A and B (210 and 211, respectively) were obtained from the allenic ester 227. The reduction of its ester group to aldehyde, followed of addition to the latter of hexylmagnesium bromide, OH protection, and N-deprotection gave compound 228. A silver(i)-mediated cyclization of this compound afforded quinolizidine 229 and its C-6 epimer in a 7 1 ratio (Scheme 44). The former compound was readily converted into the target alkaloids <1997JOC4550>. 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

Alder/retrograde Diels-Alder reaction sequence of a diaryl alkyne with a 3,6-dicarbomethoxy tetrazine. The resulting diazine (14) is then reduced, cleaved and cyclized with Zn/acetic acid to the 2,3,4,5-tetrasubstituted pyrrole (15), which is then N-alkylated with a-bromo-4-methoxyacetophenone to give a pentasubstituted pyrrole (16). The synthesis of lukianol A is completed by ester hydrolysis, decarboxylation, ring closure and deprotection. 

In this route a dihydroisoquinoline (58) is N alkylated with a highly functionalized o -bromoacetophenone (59) to give a quaternary salt (60), which is treated with base and cyclizes to a pyrroloisoquinoline (60). The pyrrole nucleus is then formylated under Vilsmeier-Haack conditions at position 5 and a proximate mesylated phenolic group is deprotected with base to yield a pen-tasubstituted pyrrole (61). Subsequent oxidative cyclization of this formylpyr-role produces the 5-lactone portion of lamellarin G trimethyl ether (36). This sequence allows for rapid and efficient analog synthesis as well as the synthesis of the natural product. 

Construction of the azepine ring by C-N bond formation. Aranapakam et al. synthesized 5,10-dihydro-4H-benzo[l7]thieno[2,3-e]azepine 111 and 4H-benzo[ 7]thieno[3,2-e]azepin-10(9H)-one 113 (X = CO) starting from the corresponding tributylstannyl derivatives 110 and 112, which react with 2-nitrobenzyl bromide and [(Ph)3P]4Pd. Sequential deprotection and reductive cyclization were carried out in one step with zinc and aqueous acetic acid (Scheme 22 (1999BMCL1733)). 

Piperazine-2,5-diones can be symmetric or asymmetric. Symmetric DKPs are readily obtained by heating amino acid esters,1179-181 whereas asymmetric DKPs are obtained directly from the related dipeptides under basic or, more properly, acid catalysis, or by cyclocondensation of dipeptide esters.1182-185 As an alternative procedure hexafluoroacetone can be used to protect/activate the amino acid for the synthesis of symmetric DKPs or of the second amino acid residue for synthesis of the dipeptide ester and subsequent direct cyclocondensation to DKPs.1186 The use of active esters for the cyclocondensation is less appropriate since it may lead to epimerization when a chiral amino acid is involved as the carboxy component in the cyclization reaction. Resin-bound DKPs as scaffolds for further on-resin transformations are readily prepared using the backbone amide linker (BAL) approach, where the amino acid ester is attached to the BAL resin by its a-amino group and then acylated with a Fmoc-protected amino acid by the HATU procedure, N -deprotection leads to on-resin DKP formation1172 (see Section 6.8.3.2.2.3). 

Among the electrophilic handles proposed for head-to-tail and side-chain-to-tail cyclization of peptides on solid support by intrachain aminolysis with concurrent detachment of the product from the resin in the protected form (see Section 6.8.3.1.3), generally the oxime resin (also called Kaiser resin)1364 365 and a thioester resin[363l are recommended (see Scheme 14). In addition to the classical head-to-tail cyclization,[3431 the oxime resin is used for side-chain cyclizations as well as for the synthesis of multicyclic peptides vide infra). Due to its dual functions, the oxime resin can be employed only with Boc/Bzl chemistry it is not compatible with Fmoc/tBu chemistry where the basic N -deprotection leads to free amino groups and thus to premature cyclization reactions. To avoid this premature cleavage of the... 

Two approaches to the 2-benzazepine system, in particular the 2-benzazepinone 142, have been reported by Le Diguarher et al. The first started from (acid-catalyzed cyclization to 141 N-alkylation and carbamate deprotection then afforded 142. The second route was based on A-HOC aminomalonate 144 and 2,2 -dibromo-o-xylene, and then steps via 145 and... 

Chen and co-workers at Procter and Gamble developed a traceless synthesis of 2,5-diketopiperazines [18b] by employing the universal Rink-isocyanide resin. The Ugi-4CR between the resin, aldehydes, amines, and N-Fmoc-protected a-amino acids afforded the resin-bound dipeptide derivatives 131 which were N-deprotected on treatment with piperidine in DMF. Cyclization by heating with 10% AcOH in DCE smoothly provided the desired diketopiperazines 132 in good yields (Scheme 2.47). 

An efficient asymmetric synthesis of the 3-substituted /3-sultams 163 has been reported. The key step of the synthesis is the Lewis acid-catalyzed aza-Michael addition of the enantiopure hydrazines (A)-l-amino-2-methoxy-methylpyrrolidine (SAMP) or CR,l ,l )-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]octane (RAMBO) to the alke-nylsulfonyl sulfonates 176. /3-Hydrazino sulfonates were obtained in good yield and excellent enantioselectivity. Cleavage of the sulfonates followed by chlorination resulted in the corresponding sulfonyl chlorides 177. The (A)-3-substituted /3-sultams 163 have been obtained in moderate to good yields and high enantioselectivity over two steps, an acidic N-deprotection followed by in situ cyclization promoted by triethylamine (Scheme 55) <2002TL5109, 2003S1856>. 

The conjugate addition of iV-sulfinyl metalloeneamines to enones gave 19, which is converted in a facile manner to the corresponding piperidine in good diastereoselectivity after sequential stereoselective reduction, N-deprotection, cyclization, and imine reduction (Equation 35) <2005JOC7342>. 

Enantiospecific syntheses have utilized the chirality available in D-alanine and L-alanine. For instance, coupling and cyclization (after the necessary deprotection) of N-allyl-N-BOC-D-alanine with L-alanine methyl ester, followed by lithium aluminum hydride reduction of the diketopiperazine provided (—)-(2R,5S)-l-allyl-2,5-dimethylpiperazine (Scheme 6) [27,39], Ra-cemization was not observed during the synthesis. 

The hexahydropyrazinones 179 were subjected to further peptide coupling with various N-protected amino acids, deprotection and repeated cyclization to give bicyclic dipeptides with a spirocyclopropaneoctahydropyrazinopyrazine skeleton of type 182 (Scheme 54). Compounds of the types 182 and 179 represent potentially useful classes of geometrically defined peptidomimetics. For example, the skeleton of 179 has been found in the hydrolysis products of the naturally occurring lysomarasmine [90]. 

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