Central de Concentrador Lineal Fresnel

Scheme 1.10: General reaction scheme for the Mitsunobu reaction.

The Mitsunobu reaction (Scheme 1.10) is an important and widely used reaction, in which phosphine plays a central role. It is a versatile reaction, which is utilised for the dehydrative coupling of alcohols with acids or an acidic pro-nucleophile (pKa < 15) via the combination of an azodicarboxylate oxidising agent such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) and phosphine which acts as a reducing agent. The Mitsunobu coupling reaction was first reported by Mitsunobu et al in 1967 detailing the reaction of benzoic acid with alcohols in the presence of PPh3 and DEAD giving the corresponding ester in excellent yield.56 Later it

was found that the procedure was general, versatile and could be used with a wide variety of different pro-nucleophiles, offering a route for the substitution of alcohols in an efficient manner.3 The Mitsunobu reaction is a procedure that has enjoyed great

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success over the years being utilised in many synthetic methods; the original paper has since been cited over 500 times (web of science) in over 180000 reactions (REAXYS).57 It has been employed in general organic synthesis and medicinal chemistry; as such there have been a number of detailed reviews.3,55 The method offers wide substrate scope, stereospecificity and mild reaction conditions for a multitude of different functionalities. One of its biggest advantages is that when chiral secondary alcohols are used as substrates, this results in complete inversion of stereochemistry,58 unless sterically constrained; this property has been widely applied and often consists a key step in the formation of medicinal and natural product targets.

Tertiary alcohols in general don’t react under Mitsunobu conditions but there has been at least one example in which a tertiary alcohol has been reported by Shi et al.59 In this report chiral tertiary alcohols with observed to couple with phenols where complete inversion of the (S)-alcohol to the (R)-ether. Forcing conditions of 100 oC in toluene were required resulting in 56% of the ether. Nucleophiles that can be used in this substitution reaction, a whole array of different examples have been demonstrated since its discovery. The only limiting factor in choice of nucleophile or pro-nucleophile is that they must contain either an OH, NH or SH group that has a pKa ≤ 15, best results however, are achieved when the pKa < 11. Common nucleophiles include carboxylic acids, phenols, thiols, thiocarboxylic acids and hydroxamates.60–62 The reaction can be also can be performed in a number of different solvents, however by far the most commonly used is tetrahydrofuran (THF) or toluene.63

A variety of different phosphines can be employed for this reaction but the most common are PPh3 and PBu3. Both of these phosphines are cheap and commerically

available. One of the biggest limitations of the Mitsunobu reaction is formation of the phosphine oxide as by-product (as in the Wittig reaction) which can be difficult to remove requiring silica chromatography. However, the Mitsunobu products can often have similar chromatographic behaviour as the oxide and so can be difficult to isolate. The use of solid-phase-resin bound PPh3 has been shown to be an, effective alternative

to PPh3 and PBu3. The use of a solid-supported reagent avoids the homogenous

formation of phosphine oxide in solution. The immobilised phosphine oxide by-product is simply removed by filtration allowing simple a work up of the resulting solution. Humphries et al employed resin bound PPh3 along with an a alternative azo reagent 1,1'-

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(azodicarbonyl)dipiperidine (ADDP) to efficiently couple a series of pyridine-ether PPAR agonists in good to excellent yields, most > +70% of which proved unattainable to synthesise using conventional Mitsunobu procedures (Scheme 1.11).64

Scheme 1.11: Humphries et al synthesis of pyridine-ether PPAR agonists using solid phase PPh3 and

ADDP.64

Alternatively, the use of phosphonium salts has been shown to aid control of by product solubility, thus facilitating product purification and isolation. Tetra-aryl phosphonium perchlorate and hexa-fluorophosphate salts for example, tend to be insoluble in diethyl ether; this allows them to be precipitated from reaction mixtures. Poupon et al. demonstrated the use of phosphine reagents containing phosphonium salts in their structure (19) can provide comparable yields to those offered by both PPh3 and solid

supported-PPh3 reagents. With the added advantage of the resulting phosphonium-

phosphine oxide salt (22) precipitating out upon addition of diethyl ether giving phosphorus free products, as determined by 31P NMR spectroscopic analysis (Scheme 1.12).65

Scheme 1.12: Mitsunobu reaction using phosphine and DEAD reagents containing a phosphonium salt

allowing solubility controlled removal of hydrazine 21 and oxide 22 by-products.65

The most common azo-derivatives used in the Mitsunobu reaction are DEAD and DIAD they and often can be used interchangeably as both are commercially available. Another by-product of the Mitsunobu reaction is the hydrazines derived from the

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azocarboxylates; again, like the phosphine oxides, these can often contaminate the Mitsunobu product owing to similar chromatographic behaviour. Due to this problem, there has been some interest in the last couple of decades on the development of new DEAD analogues to facilitate purification of the reaction mixture. As part of the same study; Poupon et al. developed a phosphonium supported DEAD reagent (20) in an attempt to once again precipitate and remove the resulting hydrazine by-product (21). The combination of both phosphine analogue 19 and the DEAD analogue 20 led to the complete removal of both unwanted by-products of the Mitsunobu esterification, achieving the Mitsunobu ester product between 2-octanol with 4-nitrobenzoic acid in 89% yield. There are other alternatives to DEAD and DIAD; for instance ADDP as demonstrated by Humphries et al. in combination with the solid supported-phosphine (Scheme 1.11) contains strong electron donating piperidine groups in place of -OEt groups of DEAD.64 This increases the basicity of the resulting anion from the azo moiety allows the use of pro-nucleophiles which have a larger pKa (up to pKa= ~15).

In the generally accepted mechanism as presented by the Kumar et al. review.55 The

first step in the Mitsunobu reaction consist of the nucleophilic addition of PPh3 to

DEAD to form the Morrison–Brunn–Huisgen betaine 23 via attack of the phosphine across the N=N.66 This zwitterionic intermediate 23 contains a positively charged phosphorus and a negatively charged nitrogen. From this intermediate there are then 2 pathways that reactions can proceed by Path A involves the reactive intermediate 23 reacting with two molecules of the alcohol to produce dialkoxy-phosphonium species 24 and DEAD-H2. In presence of the pro-nucleophile species one of the hydroxy groups

can dissociate and become protonated, and hence phosphonium salt 26 forms.

In Path B the negatively charged nitrogen acts as base to deprotonate the acidic pro- nucleophile resulting in the phosphonium salt 25 and the newly formed anionic nucleophile. The alcohol reagent then attacks the positively charged phosphorus in an SN2 fashion, displacing the carbamate anion resulting in DEAD-H2 and

alkoxyphosphonium salt 26. The alcohol group is then activated towards nucleophilic attack; if the pro nucleophile is acidic enough (i.e. pKa < 11) the oxyphosphonium salt 26 undergoes SN2 attack from the anionic nucleophile resulting in the formation of a

strong P=O double bond (which is the driving force for this reaction) and the Mitsunobu reaction product 28 (Scheme 1.13).3

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However, if the pro-nucleophile is weakly acidic then a side reaction can occur in which the conjugate base of the azodicarboxylate (27) is too weak a base to deprotonate, the pro-nucleophile and instead attacks 26 to form species 29 (Scheme 1.13). To overcome these limitations alternatives to the azodicarboxylate reagent s such as azodicarboxyamides derivatives have been employed e.g. ADDP. The use of ADDP has shown to be effective for pro-nucleophiles in which pKa<15. These modifications to this component of the Mitsunobu reaction, however, can have a detrimental effect on the Michael acceptor abilities of the process and as such often require a phosphine that is more nucleophilic, such as PBu3.67

Scheme 1.13: generally accepted mechanism for the Mitsunobu reaction.

In regards to synthetic applications, there are a multitude of different examples of the use of the Mitsunobu reaction in the total synthesis of natural products and

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pharmaceuticals. One such recent example is that of the total synthesis of the macrolactones; (3R,5R)-sonnerlactone and (3R,5S)-sonnerlactone which are originally derived from the marine fungus Zh6-B1 found in the bark of Sonneratia apetala.68 these macrolactones show interesting biological activity including anti-bacterial, anti-fungi and anti-cancer properties and therefore have been the focus of a number of total synthesis. Sanabonia et al. reported the total synthesis of these two macrocycles with one of the key steps being the stereoselective esterification between acid 29 and secondary alcohol 30 in a 68% yield. The second key step was the ring closing metathesis of the resulting Mitsunobu product 31, via the use of the 2nd generation Grubbs catalyst.69

Scheme 1.14: The key Mitsunobu esterification step of Sanabonia et al. synthesis of (3R,5R)-

sonnerlactone and (3R,5S)-sonnerlactones.