Natural products Mitsunobu reaction

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 glycosylation based on the Mitsunobu reaction has been most commonly directed to the synthesis of O-aryl glycosides, a structural motif found in a variety of natural products [80-82], Early work by Grynkiewicz [83,84], among others [85-87], established the viability of triphenylphosphine and diethylazodicarboxylate to promote the glycosylation of phenol acceptors at ambient temperature. More recently, Roush and coworkers have discovered that the glycosylation performed well in the... 

The second reaction uhhzed with this reagent was the Mitsunobu reaction ]97], a reachon known to require chromatographic purification to obtain pure product because side-products are formed. An insoluble polymer approach to this problem is known [98], however, the nature of the support means that the reachon is inherently heterogeneous (see above). The reaction between phenol and a series of alco-... 

A new method for the preparation of pyrrolo[2,l-c][l,4]benzothiazepine 292 starting from aldehyde 291 with an intramolecular Mitsunobu cyclization in the last step has been reported (Scheme 63 (1999T1479)). A disadvantage of this procedure is the redox nature of the Mitsunobu reaction, which is responsible for a side oxidation of the thiol group and poor isolated yields of the product. 

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-... 

For example, the fermentation of (2-bromoethyl)-benzene with recombinant E. coli furnished excellent yields of the corresponding c/.v-diol. enantiopure 3-(2-bromoethyl)-benzene-l,2-diol. The latter was used as a building block in the total synthesis of (+)-codeine (Fig. 29). Besides a Mitsunobu inversion of one of the stereogenic centers, two successive Heck cyclizations led to the enantiomer of the natural product [173]. Slight modifications of the reaction sequence, generating an epoxide intermediate, also furnished access to the naturally occurring enantiomer (—)-codeine [28]. 

The reaction proceeds with clean inversion, which makes the Mitsunobu Reaction with secondary alcohols a powerful method for the inversion of stereogenic centres in natural product synthesis. 

Allylic chlorides. The last steps in a synthesis of cis-maneonene-A (4), a natural product isolated from a Hawaiian alga, require conversion of the allylic alcohol 2 into the chloro compound 3. Ghosez s chloroenamine (1) proved more effective than the Mitsunobu reagent, PfQHjlj-NCS, or CHjSOjCl-LiCl. The reaction with 1 occurs with inversion. ... 

In the stereoselective total synthesis of ( )-14-deoxyisoamijiol by G. Majetich et al., the last step was the epimerization of the C2 secondary allylic alcohol functionality. The Mitsunobu reaction resulted only in a poor yield (30%) of the inverted product, so the well-established sulfoxide-sulfenate rearrangement was utilized. The allyic alcohol was first treated with benzenesulfenyl chloride, which afforded the thermodynamically more stable epimeric sulfenate ester via an allylic sulfoxide intermediate. The addition of trimethyl phosphite shifted the equilibrium to the right by consuming the desired epimeric sulfenate ester and produced the natural product. 

The enantioselective total synthesis of the complex bioactive indole alkaloid enf-WIN 64821 was accomplished by L.E. Overman and co-workers." This natural product is a representative member of the family of the C2-symmetric bispyrrolidinoindoline diketopiperazine alkaloids. The stereospecific incorporation of two C-N bonds was achieved using the Mitsunobu reaction to convert two secondary alcohol functionalities to the corresponding alkyl azides with inversion of configuration. The azides subsequently were reduced to the primary amines and cyclized to the desired ib/s-amidine functionality. 

The key asymmetric acetate aldol reaction was carried out using Carreira s conditions (Scheme 12-1) to give 4 in nearly quantitative yields and perfect enantioselectivity, followed by hydrolysis to acid ent-5. This is the enantiomer of the fragment present in the natural products. Because of later difficulties with the macrolactonization, that step was carried out under Mitsunobu conditions with inversion of the alcohol, hence necessitating the opposite stereochemistry in precursor ent-5. 

The total synthesis of ditryptophenaline (651) used stereoisomer 637, which was oxidized (—> 645) and reduced to give diol 646 (Scheme 10.5). Analogous to the previously described synthesis, 646 was subjected to a Mitsunobu reaction and reduction to furnish cyclization product 647. Benzyl deprotection and coupling with a Fmoc-protected W-methyl-(5)-phenylalanine derivative yielded tetrapeptide 648. TMSE-deprotection, two oxidations (—> 650), Fmoc-deprotection, and DCC-mediated cyclization finally led to the natural product ditryptophenaline (651). 

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