Mitsunobu reaction with phthalimide

Theil et al. developed a method for chemoenzymatic synthesis of both enantiomers of cispentacin [89]. frans-2-Hydroxymethylcyclopentanol, obtained by the sodium borohydride reduction of ethyl 2-oxocyclopentanecarboxylate, was monosilylated with tert-butyldimethylsilyl (TBDMS) chloride to afford 55. Lipase PS-catalysed transesterification with vinyl acetate in /erf-butyl methyl ether furnished the ester 56 and the alcohol 57. The deacetylated 58 was obtained by the Mitsunobu reaction with phthalimide, triphenylphosphine and diethyl azodicarboxylate (DEAD) to furnish the cis oriented 59 with inversion of configuration (not retention as mentioned in the original article) (Scheme 9). Desilylation, Jones oxidation and subsequent deprotection with aqueous methylamine gave the ( R,2S) enantiomer 5 [89]. The (15, 2/f) enantiomer was prepared by the same route from the silyl alcohol 57. 

Isomannide (80) was the core for a hexahydrofurofuran library." Primary amines were loaded onto solid-support by reductive amination and acylated with bromoacetic acid to give bromides 79 (Scheme 7.16). Alkylation of bromides 79 on solid-support with isomannide (80) gave the solid-supported alcohols 81. A Mitsunobu reaction with phthalimide (82) proceeded to furnish amines 83 in excellent yield and purity after removal of the protecting group." " Support-bound primary amines 83 were converted to secondary amines by stepwise imine formation with aldehydes 84 and reduction with sodium borohydride." The hindered secondary amines 85 were acylated with acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates to yield 87 after cleavage from solid-support. 

A new route to bromopyrroles was developed. It depends on addition of HBr to A-protected y-aminoynones. When applied to alkynyl ketones, 2-aryl or 2-alkyl 4-bromopyrroles are formed. 2-Alkyl or 2-aryl 3-bromopyrroles can be obtained from acetals of V-aminoynals. The ketones are made from A -protected propargylamines by ( -acylation. The acetals are made from 3,3-diethoxypropyne by addition to an aldehyde followed by introduction of the amino group by reaction with phthalimide under Mitsunobu conditions. <95S276>... 

For the preparation of Gly- j/-[CF=CH]-Pro in relation to the study of cyclophilin A inhibitors, Welch and co-workers employed the Peterson reaction of a-fluoro-a-trimethylsilyl acetate (15a,b) with ketone 10. E/Z selectivity was found to be influenced by the ester part of the acetate (see Scheme 10.4) [15]. The reaction of tert-butyl ester 15a gave almost an equal amount of the isomers (lib, E Z= 1 1.1), while moderate E selectivity was observed when trimethylphenyl ester 15b was used (11c, E Z= 6 1). Conversion of ester Z-llb to amino derivative 16 was achieved via the Mitsunobu reaction of phthalimide with the alcohol formed by the DIBAL-H reduction of Z-llb. 

It was converted to the phthalimide via a Mitsunobu reaction, reduced to the amine, and the amine was coupled with />-nitrophenylacetic acid to give the precursor to the macrocycle. Macrocylization was done via Troger s base formation using Johnson s method, which resulted in two isomers of the amide macrocycle. These were separated and reduced to give the cyclophane host. This was the first time two diastereomers were observed in these syntheses and the separation of these diastereomers was very difficult. 

Treatment of 75 with lithium acetylide ethylenediamine complex afforded the acetylene derivative 78 (85%), which was transformed into the vinyl alcohol 79 by partial hydrogenation using Lindlar catalyst. Employing the Mitsunobu reaction, compound 79 was transformed into the phthalimide 80, which was converted into the benzamide 82 (64%) via the primary amine 81 by sequential deacylation and benzoylation. When the... 

Another application of 50 is the synthesis of /3,y-unsaturated amino acids such as 102 (Scheme 17). To this end, 50 was debenzylated with sodium in ammonia and then submitted to a Mitsunobu reaction. Clean SN2 -reaction with crnf/ -stereochemistry occurred to furnish phthalimide 100 which was converted into the acid 102 by standard modifications (13). 

Allylic amines. With phthalimide as nucleophile in the modified Mitsunobu reaction, high yields of the A -allylated phthalimides are prepared. The phthaloyl group can be removed with methylamine in methanol. 

Lastly, phthaloyl-protected (R)-alanine 112 is formed in high yield by reaction of 2 with phthalimide [40]. Recently, polystyrene-supported methyl azodicarboxylate has been used as a replacement for the soluble dialkyl azodicarboxylates in the Mitsunobu reaction [41]. Yields generally are not as high as in the classical reaction (e.g., 2 112, 45% yield), but, purification can be expedited simply by filtration of the nonexplosive resin. 

A second non-selective addition of vinyl Grignard to 661 produces a mixture of alcohols 662 and 665. The hydroxyl center is inverted with phthalimide under Mitsunobu conditions, after which the phthaloyl group is cleaved with hydrazine and the resulting amine acylated to give 664 and 667 (separable by HPLC). Compound 667 is then debenzylated, the acetonide group is hydrolyzed, and the olefin is ozonolyzed to give 668 as a crystalline solid. Likewise, 664 is converted to 669. By a parallel sequence of reactions, 660 is transformed to 670 and 671. Ozonolysis as the last step is a critical feature of these syntheses, because the A-acetyl-hexosamines are generated very cleanly, and such compounds are notoriously difficult to purify. 

N 0 Me 0 From hydroxymethyl polystyrene by treatment with COClj, HjNNHCOjMe and NBS or Cl,.2i Mitsunobu reactions esters from carboxylic acids and alcohols lactones from hydroxy acids A/-aUcylation of phthalimides, a-alkylation of cyanoacetate carbodiimides from thioureas. ... 

Two different N-protected hydroxylamines have been used to accomplish the synthesis of these novel hydroxylamine-functionalized resins. fV-Hydroxy-phthalimide has been employed in two ways first, as a nucleophile to splace either a resin-bound chloride ion (30) or a resin-bound mesylate ion (31) Figure 8a) and second, to generate the active phosphonium species required to perform a Mitsunobu reaction on a hydroxyl-functionalized resin (32) (Figure 8b). In both cases, the resin-bound iV-hydroxyphthalimide ester that is generated is subsequently treated with hydrazine to afford resin-bound hydroxylamine. 

Yields are largely comparable with standard Mitsunobu reactions between alcohols and phthalimide, with enantiomeric excesses varying from 69 to 97%, depending on the alcohol substrate. For example, using 5-metbyl lactate (8), 6a was obtained in a 52% yield, the product 6a exhibiting an ee of 92% (eq8). 

In comparison, a standard Mitsunobu reaction between 5-ethyl lactate and phthalimide gave a 45% yield of the expected protected D-alanine derivative with an ee greater than 99%, while Barrett s modified method using potassium phthalimide and an imidate ester gave a 25% yield with racemization. (Note Less than complete inversion of configuration has been noted with the use of 7 as a Mitsunobu-type reagent. )... 

Scheme 10.23. Use of the Mitsunobu protocol (alcohol, triphenylphosphine, diethyl azodi-carboxylate, and phthalimide in THF) in reaction with (5)-(+)-2-octanol to produce (R)-(-)-2-octylamine. See Corelli, F. Summa, V. Brogi, A. Monteagudo, EBotta, M. J. Ore. Chem., 1995,60,2008.

The reaction of 2-C-hydroxymethyl glycals with phenols or phthalimide under Mitsunobu conditions to produce 2-C-methylene glycosides has been reported (See Vol. 27, p. 178, ref. 51 for the same reaction under Lewis acid conditions). The condensation of malononitrile and methyl 4,6-( -benzylidene-3-deoxy-a-D-crytAro-hexopyranoside-2-ulose under basic conditions affords the corresponding methyl 4,6-0-benzylidene-2-(dicyanomethylene)-2,3-dideoxy-a-D-eryt/iro-hexo-pyranoside. This latter compound on reaction with 3-benzyl-2-methylthio-2-thiazolinium iodide affords butadiene 58 whilst with 3-benzyl-4,5-dihydro-2-methylthio-l,3-thiazinium iodide, 59 is produced. ... 

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