Azide displacement-reduction

Methyltryptophan derivatives have been synthesized stereoselectively using chiral auxiliaries. Conjugate addition of magnesium methylcuprate to the indole acrylic add (392) gives an enolate which can be trapped by bromination to give the product (393), which can then be transformed into the tryptophan (394) by azide displacement, reduction and hydrolysis (Scheme 131) <92TL7491>. 

The diastereomerically related keto esters 53 and 55, activated for removal of the chiral auxiliary, were obtained from 5 and 9. The requisite nitrogen atom was introduced by an azide displacement of chloride and at an opportune stage of the synthesis an intramolecular aminolysis of the carboxylic ester provided the enantiomerically related keto lactams 54 and 56. Although shorter routes to these popular synthetic targets have been reported in recent years, the conversion of 9 to (—)-iso-nitramine (ten steps, 50% overall yield) clearly illustrates the efficiency of the asymmetric Birch reduction-alkylation strategy for construction of the azaspiroundecane ring system. 

A concise synthesis of tetra-O-ethyl aldonolactam 83 starting from 1 has been reported [102]. After protection of its primary alcoholic moiety as a trityl ether, saponification and treatment with EtBr generated 80. Acidic hydrolysis liberated 81 that was esterified (tosylate). The latter was displaced with NaNs to give azide 82. Reduction of 82 resulted in lactam 83 (Scheme 24). 

With oxjizolin-2-one 43 in hand, simple functional group transformations ensued. Thus, mesylation of 43 using methylsufonyl chloride gave mesylate 44, which was followed by an Sn2 displacement with NaNa to produce azide 45. Reduction of the... 

Having the 2-alkylated 5-bromolactones in hand, the conversion to isoiminosugars were performed by transforming the bromine to an amino group via an azide displacement followed by reduction. This gave directly the optically pure lactams by ciystallisation. Reduction of the lactam function gave... 

The installation of the amine functionality at C5 is accomplished by mesylation of 41 followed by azide displacement to give 44 (71% yield over four steps). The P-aminopropanamide 13 is then introduced directly to the lactone under 2-hydroxypyridine catalysis to give the penultimate intermediate 45. Reduction of the azide and isolation as the hemifumarate salt provides aliskiren hemifiimarate (l).37 Based on the information disclosed to date, the synthesis of aliskiren is accomplished with an overall yield of 14% from iso vanillin 14 with a longest linear sequence of 15 steps. Given the complexity of aliskiren, this is a remarkably efficient process, and it should be noted that this analysis likely only establishes a lower limit of efficiency, as further optimization of the route on a manufacturing scale is expected. 

It is essential that the ketene is formed reaction of the acid chlorides 115 with (/ )-(+)-pantolactone 112 also gives the esters 117 but as a 1 1 mixture of diastereoisomers. A useful application is the preparation of unusual amino acids such as 120 by SN2 displacement of halide with azide and reduction of the azido group. It is best to hydrolyse the ester at the azide stage 118 to reduce racemisation but even so some does occur both in the azide displacement and in the hydrolysis. 

Cleavage of 5a,6a- and 6a,7a- epoxides with azide ion and subsequent reduction with hydrazine has led to the preparation of 6 -amino-steroids, although similar treatment of 16a,17a-epoxypregnenolone acetate was accompanied by D-homoannulation to give, after reduction, the 16j3-amino-Ha-ketone. Azide displacement (lithium azide in DMF) of 3a,20j8-diacetoxy-... 

Introducing azide with retention of configuration via double inversion at C-7 of the triflate 245 led to the synthesis of 7-cp/-casuarine (253). Thus, treatment of 245 with cesium triflu-oroacetate in butanone followed by potassium carbonate in methanol afforded the inverted alcohol 250. Triflation of the free hydroxyl group of 250 followed by Sn2 displacement using azide ion furnished the azide 251. Reduction of the lactone 251 followed by mesylation afforded 252. This was converted into 253 in 17% overall yield from 245 by a series of steps analogous to that used in the synthesis of 249. 

The lactone 145, obtained from lactone 144 in two steps, gave upon reduction, followed by mesylation and selective displacement of the primary O-mesyl group with azide ion, the azide 146. Reductive cyclization and benzylation of 146 furnished 147, whose primary hydroxyl group was oxidized to produce the aldehyde 148. On the other hand, protection of... 

The known 7-e carboxylic acid 506, obtained by the condensation of acrylic acid with furan, was used as a substrate for synthesis of validamine, (510) a component of validamycin antibiotics. The treatment of 506 with hydrogen peroxide in formic acid gave the tricyclic compound 507, which after reduction and hydrolysis afforded cyclitol. Treatment of 508 with 2,2-dimethoxy-propane in the presence of an acid gave a mixture of diisopropylidene derivatives in which compound 509 was predominant. Introduction of an amino group, by way of a tosyl ester and azide displacement, followed by hydrogenation and hydrolysis, completed the synthesis of DL-val-... 

A sequence of bromination of a 3-indolyl acyl group followed by azide displacement and reduction, provides an effective route to 3-(a-aminoacyl)indoles <88JHC469>. Indoles react readily with oxalyl chloride at C-3 and the products have been used in combination with aryl acetic acid derivatives to generate indolyl-substituted maleic anhydrides and imides, as precursors for indolocarbazole antibiotics <90TL2353,93TL5623>. 

The aminotetritol compound 20 has been synthesized from ethyl 3,4-0-isopropylidene-D-erythronate (available from o-isoascorbic acid according to Vol. 26, p. 190, ref 22) by azide displacement of the 2-0-triflate followed by a reduction-de-O-isopropylidenation-reprotection sequence, as an intermediate for the preparation of D-r/ireo-C-18-sphingosine. ... 

A short synthesis of 3,4,6-tri-0-benzyl-l,5-dideoxy-l,5-imino-D-mannitol has been achieved by acid-catalysed hydrolysis, followed by controlled reductive amination of a per-benzylated l,6 -diazido-l,6 -dideoxy-sucrose derivative. Further transformation by way of an azide displacement of a 2-0-triflyl derivative afforded ultimately 2-acetamido-l,2,5-trideoxy-l,5-imino-D-glucitol (2-acet-amido-1,2-dideoxynojirimycin). ... 

Benzyl 2,3,4-triacetamido-2,3,4,6-tetradeoxy-a-D-galacto-pyranoside has been synthesized from the corresponding 3,4,6-tri-O-mesyl-allopyranoside by selective reduction at C-6 (NaBH j-DMSO), followed by azide-displacement of the sulphonates at 3 and 4 with Inversion mass spectral fragmentation of its derived alditol acetate was also recorded. 

Suami s group has synthesized the isomeric 3,4-, 2,5-, 4,5-, and 4,6-dideoxy-streptamines using standard reactions of either azide ion or hydrazine on dideoxy-inositol sulphonates or oxirans. The reduction of l,2 3,4-dianhydroinositoIs and 1,2-anhydroinositol sulphonates with lithium aluminium hydride has furnished a series of dideoxy- or 1,4-anhydrodeoxy-inositols e.g., see Scheme 117), 1-Amino-1-deoxy-wyo-inositol has been synthesized by way of an azide displacement on 1l-1, 2 3,4-di-0-cyclohexylidene-5-0-methyl-6-0-toluene-/7-sul-phonyl-cA/ra-inositol. ... 

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