Mitsunobu coupling alcohol

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... 

In the case of the thiazolidinedioxides (38), the increased acidity of the cyclic sulfamide determines the reactivity. Metallation (NaH) occurs at N—H producing an anion which is readily alkylated <93TL4705>. Treatment with triphenylphosphine produces a stable betaine which can be used to couple alcohols and acids in a variant of the Mitsunobu reaction <94JOC2289>. 

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

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). 

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). 

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-... 

This reaction was first reported by Mitsunobu in 1967. It is the alkylation of compounds with active protons by using primary or secondary alcohols as the alkylating agents in combination with triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), to form molecules like esters, ethers, thioethers, and amines. Therefore, this reaction is generally known as the Mitsunobu reaction or Mitsunobu coupling. In addition, the specific reaction for forming esters by means of DEAD (or DIAD) and PPhs is generally referred to as the Mitsunobu esterification." Occasionally, the Mitsunobu reaction is also called the Mitsunobu transformation (for the conversion of alcohol into amines) or Mitsunobu cyclizafion (for the formation of cyclic compounds). Because of its intrinsic features of stereospecificity, as well as its occurrence in neutral media and at room temperature without a prerequisite activation of alcohol, this reaction has been extensively studied and used to synthesize a variety of compounds since 1970. 

Intriguing strategies have been developed for the stereocontrolled assembly of complex alkaloid structures. Brian M. Stoltz of Caltech prepared (/. Am. Chem. Soc. 2008, 130, 13745) the enantiomerically-pure alcohol precursor to the secondary amine 1 by enantiose-lective oxidation of the racemic alcohol. Intramolecular Mitsunobu coupling of 1 then led to (-)-Aurantioclavine 3. 

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. 

An alternative strategy for the synthesis of 9-alkoxypurines is via the coupling of a suitably functionalized 9-hydroxypurine with protected alcohols such as 1014 under the Mitsunobu condition or with halides under base-catalyzed conditions to give after deprotection 998 or its adenosine analog 1015 (90TL2185). 

The Mitsunobu reaction is usually only suitable for the alkylation of negatively charged nucleophiles rather than for the alkylation of amines, and only a few examples of such reactions (mainly intramolecular N-alkylations or N-benzylations) have been reported (Entry 15, Table 10.2). Halides, however, are very efficiently alkylated under Mitsunobu conditions, and it has been found that the treatment of resin-bound ammonium iodides with benzylic alcohols, a phosphine, and an azodicarboxylate leads to clean benzylation of the amine (Entry 9, Table 10.3). Unfortunately, alkylations with aliphatic alcohols do not proceed under these conditions. The latter can, however, also be used to alkylate resin-bound aliphatic amines when (cyanomethyl)-phosphonium iodides [R3P-CH2CN+][r] are used as coupling reagents [62]. These reagents convert aliphatic alcohols into alkyl iodides, which then alkylate the amine (Entry 10, Table 10.3). 

The p-sulfanyl amides 28 are synthesized from N-protected amino acids 24 via amino alcohols 25, which are converted into (5-acetylsulfanyl amides 26 by a Mitsunobu reaction. The (5-amine disulfide 27 is subsequently coupled with a variety of carboxylic acids, followed by reduction with tributylphosphine in aqueous THF in the presence of pyridine to produce the free thiol 28 (Scheme 5).1211 Detailed experimental procedures for these compounds have not been reported. 

This reaction is somewhat similar to the Mitsunobu Reaction, where the combination of a phosphine, a diazo compound as a coupling reagent, and a nucleophile are used to invert the stereochemistry of an alcohol or displace it. 

Another example employed Mitsunobu reaction for the inversion reaction (Figure 10(b)).A single enantiomer of a (stereo)chemically labile allylic-homoallylic alcohol was obtained in 96% yield and 91% ee from the racemate through a lipase-catalyzed kinetic resolution coupled with in situ inversion under carefully controlled (Mitsunobu) conditions. Using this reaction, the algal fragrance component, (S)-dictyoprolene, was synthesized. 

There are two problems. Enolates of primary amides are not very practical as the NH protons are more acidic than the CH protons. The solution is to use the nitrile and hydrolyse it later to the amide. A more serious problem is that the Sn2 reaction we want to use to couple the two together will go with inversion and that will give the biologically inactive enantiomer of darifenacin. The solution is a double inversion. Protection of the amine by tosylation 67 is followed by tosylation of the alcohol with inversion using a Mitsunobu-style reaction. This unusual esterification goes reliably with inversion.20... 

C-Sucrose. A key step in a synthesis of this saccharide involves as the first step the coupling of a vinyl iodide with an aldehyde mediated by CrCl2 and a trace of NiCl2 (14, 97-98). Thus coupling of the vinyl iodide 1 with the aldehyde 2, derived from D-arabinose, provides an allylic alcohol, which on Mitsunobu inversion provides the threo alcohol 3 as the major product. This is converted to C-sucrose... 

In a process resembling the Mitsunobu reaction (Chapter 17), alcohols and acids can be coupled to give esters, even macrocyclic lactones as shown below. In contrast to the Mitsunobu reaction, the reaction leads to retention of stereochemistry at the alcohol. Propose a mechanism that explains the stereochemistry. Why is sulfur necessary here ... 

One of the most widely used procedures for dehydrative coupling and cyclization reactions is the Mitsunobu reaction in which the components are treated with triphenylphosphine and diethyl azodicarboxylate (DEAD, EtOaC—N=N—COiEt). The overall equation for reaction of an alcohol 67 with an acid 68 to form the ester 69 is as shown and the active species is the zwitterionic... 

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