Intermolecular reactions Mitsunobu reaction

Intermolecular reactions of hydroxylamines with secondary alkyl halides and mesylates proceed slower than with alkyl triflates and may not provide sufficiently good yield and/or stereoselectivity. A nseful alternative for these reactions is application of more reactive anions of 0-alkylhydroxamic acids or 0-alkoxysulfonamides ° like 12 (equation 8) as nucleophiles. The resulting Af,0-disubstituted hydroxamic acids or their sulfamide analogs of type 13 can be readily hydrolyzed to the corresponding hydroxylamines. The same strategy is also helpful for synthesis of hydroxylamines from sterically hindered triflates and from chiral alcohols (e.g. 14) through a Mitsunobu reaction (equation 9). 

Intermolecular and intramolecular nucleophilic substitution of an alcoholic hydroxy group by the triphenylphosphine/dialkyl azodicarboxylate redox system is widely used in the synthesis and transformation of natural products and is known in organic chemistry as the Mitsunobu reaction.1951 This reaction starts with formation of the zwitterionic phosphonium adduct 19 (Scheme 9) from triphenylphosphine and diethyl (or diisopropyl) azodicarbox-... 

Eight-membered A,iV -protected cyclic sulfonylamide 89, bearing two different protecting groups, was demonstrated as useful intermediate for preparation of pseudopeptides. Synthesis of 89 was carried out in two steps by an intermolecular Mitsunobu reaction followed by intramolecular N-alkylation (Scheme 20 <2003T6051>). 

Mitsunobu reaction. Intermolecular dehydration reaction occurring between alcohols and acidic components on treatment with diethyl azodicarbox-ylate and triphenyl phosphine under mild neutral conditions. The reaction exhibits streospecificity and regional and functional selectivity. 

The inversion of secondary alcohols into the corresponding esters, followed by hydrolysis of the ester intermediate into the inverted alcohol, has been one of the most commonly used applications of the Mitsunobu reaction during the last forty years. After the initial discovery by Mitsunobu, this method has been used hundreds of times to invert alcohols in all kinds of organic molecules. Intermolecular and intramolecular inversion reactions are possible, although the latter reaction to make lactones is used much less... 

The intermolecular Mitsunobu alkylation can be followed by a number of other reactions to make larger cyclic structures. The example below shows a phenol alkylation to make a chiral precursor for the synthesis of repintonan (BAY-3702), a high affinity 5-HTia receptor agonist in clinical trials as an ischemic stroke treatment.After the initial Mitsunobu reaction, the alkylated intermediate 99 is converted into the chromene 100 according to a protocol initially developed by Grubbs and Chang. 

Intermolecular Mitsunobu reaction was used in the synthesis of a 1,4-oxazepine (eq 15). ... 

Alkylation. Alkylation of the title compound is also a key transformation to gain access to more elaborated triazoles. It has been shown that alkylation of the N-2 position using methyl iodide is possible by a Sn2 process (eq 3). Both N-1 and N-2 positions can be alkylated with no selectivity for either regioisomer. Various alkylating aromatic or aliphatic agents can be used and yields higher than 80% can be obtained. It is also possible to alkylate via a Mitsunobu reaction to afford a similar alkylation at the N-2 position (eq A)P It has also been shown that it is possible to alkylate both the N-1 and N-3 posihons to form nitrenium ions using an intermolecular hydroamination method (eq 5). ... 

Reaction with Di- and Polyols. Although intermolecular dehydration between two molecules of alcohols to afford acyclic ethers usually does not occur with the DEAD-TPP system, intramolecular cyclization of diols to produce three to seven-membered ethers is a common and high yielding reaction. Contrary to an early report, 1,3-propanediol does not form oxetane. Oxetanes can be formed, however, using the trimethyl phosphite modification of the Mitsunobu reaction. The reaction of (5)-1,2-propanediol and ( )-l,4-pentanediol with DEAD and TPP affords the corresponding cyclic ethers with 80-87% retention of stereochemistry at the chiral carbon, while (5)-phenyl-1,2-ethanediol affords racemic styrene oxide. In contrast to the reaction of the same 1,2-diols with benzoic acid (eq 4), oxyphos-phonium salts (25a) and (25b) have been postulated as key intermediates in the present reaction (eq 20). ... 

A Mitsunobu process simultaneously coupled the enyne acid fragment 4 to /J-lactam 10 and inverted the CIO stereochemistry to the required (S)-configured ester 11 in 93% yield. A deprotection provided alcohol 12, the key /J-lactam-based macrolactonization substrate, which, under conditions similar to those reported by Palomo for intermolecular alcoholysis of /J-lactams (Ojima et al, 1992, 1993 Palomo et al, 1995), provided the desired core macrocycle 13 of PatA 13 (Hesse, 1991 Manhas et al, 1988 Wasserman, 1987). Subsequent Lindlar hydrogenation gave the required E, Z-dienoate. A Stille reaction and final deprotection cleanly provided (-)-PatA that was identical in all respects to the natural product (Romo etal, 1998 Rzasaef al, 1998). This first total synthesis confirmed the relative and absolute configuration of the natural product and paved the way for synthesis of derivatives for probing the mode of action of this natural product. 

The disadvantage of the intermolecular dipolar cycloaddition strategy is nonstereoselectivity. A recent stereoselective synthesis of lasubine 1 (2) utilizes the intramolecular tt cyclization of an /V-acyliminium ion as a key step (Scheme 4) (16). The reaction of carbinol 38, prepared from 3,4-dimethoxybenzaldehyde (33) and allylmagnesium bromide, with glutarimide under Mitsunobu conditions... 

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