Mitsunobu coupling

Hydroxyl group of 7-hydroxymethylperhydropyrido[l,2-u]pyrazines 382 was arylated by Mitsunobu coupling with phenols and 4-fluorothiophenol... 

Scheme 3) [30]. The pY + 3 diversity alcohols (Ri)-OI I (Fig. 15) were attached to the template through a Mitsunobu coupling to provide ether derivatives of 16. Palladium-mediated Alloc deprotection followed by amide formation using the phosphate-ester-containing diversity acids (R2)-C02H provided the fully coupled resin-bound products of 17. Cleavage from the resin with 95% TFA/H20, which also afforded benzyl phosphate deprotection, followed by reversed-phase (RP) semipreparative... 

Table 3 Carbonucleosides prepared by Mitsunobu coupling to acyclic alcohols...

Table 4 Cyclic carbonucleosides prepared by Mitsunobu coupling...

ABT-594 is reported to be in clinical trials for the treatment of neuropathic pain (Thatte, 2000 Sorbero et al. 2001). Its precursor (f )-N-Boc-azetidin-2-yl-methanol is accessible in a short sequence starting from commercially available D-aspartic acid dibenzyl ester. The synthesis is concluded by Mitsunobu coupling with 6-chloropyridin-3-ol and subsequent acidic deprotection. On a larger scale the primary alcohol is activated as a mesylate prior to coupling with 6-chloropyridin-3-ol in the presence of potassium hydroxide, so that Mitsunobu conditions can be avoided (Meyer et al., 2000). 

This potential mechanistic synergy made BSO an early candidate for conjugation to MGd. Thus, FMOC protection of the amine group of BSO 11 was carried out to give the corresponding carboxylic acid 12. Subsequent Mitsunobu coupling to MGd and deprotection afforded the desired conjugate 13 in 35% yield (Scheme 3). 

Fig. 4. Solid-phase phosphonopeptide synthesis using modified Mitsunobu coupling procedure.

In the penem series, 2-(heteroatom-substituted)-methyl derivatives have been similarly prepared via the 2-(hydro-xymethyl) key intermediate 71. Some examples of this C-2 functionalization are illustrated in Scheme 39 <1990H(30)799, 1995JME4244>. The reactions involved are O-acylation 72, O-arylation 73 by Mitsunobu coupling, and substitution by nitrogen nucleophiles 74 after OH activation by mesylation. 

Diastereoselective /3-lactone formation was also carried out by a tandem Mukaiyama aldol lactonization between an aldehyde 132 and a thiopyridyl ketene acetal 133 (Equation 46) <2005CCL1448>. This reaction gave the /3-lactone 134 as a 10 1 (transacts) mixture of diastereoisomers and the major isomer was converted into (-)-tetrahydrolipstatin by silyl deptotection followed by a Mitsunobu coupling to form the ester. 

On the other hand, N-alk-4-enyl-substituted maleimides, which can be readily synthesized using the maleimide-alkenol Mitsunobu coupling procedure, give rise to... 

A stereoselective synthesis of (-)-gallocatechin illustrates a general approach to flavan-3-ols. Mitsunobu coupling of a phenol and an epoxyalcohol provides access to a l-aryl-3-bromo-2-hydroxypropyl 2-iodoaryl ether which is cyclised to the flavanol by a halogen-metal exchange (Scheme 13) <06CL1006>. 

A synthesis of a-lipoic acid and derivatives has been reported. The pendant alkene of complex (111) was transformed to a primary alcohol (112) via hydroboration-oxidation sequence. Mitsunobu coupling of (112) with thiobenzoic acids to give (113), followed by desilylation and nucleophilic substitution again employing thiobenzoic acid gave the advanced intermediate (114) (Scheme 169). 

Cyclic phosphonate analogues of PMEA (36) have been obtained after stereoselective cyclisation of an acyclic phosphonyl intermediate to the phos-phonyltetrahydrofuran nucleoside derivative. A series of cyclopropylphos-phonate analogues (37) has been synthesised stereoselectively via intramolecular epoxide opening reaction of y,5-epoxyalkanephosphonates with subsequent Mitsunobu coupling reaction to purine bases. Acyclic phosphonate derivatives of thymine (38-43) have been prepared and evaluated as multisubstrate analogue inhibitors of Escherichia coli thymidine phosphor-... 

The mechanism of the Mitsunobu reaction of alcohols with phosphonic acids has been recently studied [ 109]. A typical Mitsunobu coupling reaction proceeds via Path A and it is generally recognized that the rate-determining step is the re-... 

The 2-oxabicyclo[3.1.0]hexane nucleoside 166 was obtained via a Simmons-Smith type cyclopropanation reaction of intermediate 164, followed by glycosidation with several natural heterocyclic bases <05JOC6891 05NNNA383>. A restricted version of puromycin built on a bicyclo[3.1.0]hexane template was synthesized by Choi via Mitsunobu coupling of a 3-azido-substituted carbocyclic moiety with 6-chloropurine to give compound 167 <02OL589>. 

Aryl 2-deoxy-p-D-glycosides.1 These glycosides (4) can be prepared in high /3-selectivity by Mitsunobu coupling of phenols with 2a-(thiophenyl)- or 2a-(sclcno-phenyl)-a-D-pyranosnes 2, prepared by reaction of C6HsSC1 or Cf,HMitsunobu conditions provides mainly fi-... 

Extension of this synthetic protocol was further investigated by Sarshar et al. by attaching the aldehyde or amine component to the Wang resin. Hence, functionalised polymers 215 and 217 were prepared by standard coupling methods of carboxybenzaldehyde 214 and N-Fmoc-6-aminohexanoic 216, respectively. Resin 219 was prepared via a modified Mitsunobu coupling of 4-hydroxybenzaldehyde 218 to Wang resin 84 (Scheme 4.3.2). 

The discovery route selected for compound 131 is outlined in Scheme 30.24. Commercially available (S)-(+)-hydroxymethyl-Y-butyrolactone (135) was chosen as the chiral synthon. Diisopropylazodicarboxylate/triphenyphosphine-mediated Mitsunobu coupling... 

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