The Petasis Reaction of Boronic Acids, Oxo Components and Amines (Pt-3CR)

The multicomponent reaction of boronic acids, oxo components and amines is named after its inventor, the Greek chemist Nicos A. Petasis (N. A. Petasis, I. Akritopoulou, Tetrahedron Lett. 1993, 34, 583. DOI: 10.1016/S0040-4039(00)61625-8). This 3-CR (3-component reaction) can also been described as a boronic acid Mannich variant.

Scheme 1 The Petasis reaction of boronic acids, amines and aldehydes. Throughout this article we use color coding in the schemes, blue for the amine component and red for boronic acid component.

Due to the immense potential scaffold variability, this non-isocyanide based MCR has become very popular in the synthesis of arrays of compounds for potential applications in drug discovery, plant protection and material science. Another major advantage of this MCR is that a large variety of organoboronic acids are readily available, some in isomerically pure forms. This can be ascribed to their widespread utility in Suzuki-Miyaura coupling. Several hundred alkyl, aryl and heteroaryl boronic acids are now commercially available and can be employed in this MCR process as well as in related syntheses. Interestingly, most of these compounds are also air- and water-stable as well as low-toxic and environmentally friendly. Importantly for a superior application in MCR chemistry, boronic acids also tolerate many functional groups, thereby allowing the facile synthesis of multifunctional molecules without the excessive use of protecting groups. (N. A. Petasis in Multicomponent Reactions (Eds: J. Zhu, H. Bienaymé), Wiley-VCH, Weinheim, 2005, pp. 204-205.)

Scheme 2 Use of organoboronic acids in organic synthesis beyond Pt-3CR. Above: N-Arylated sulfoximes according to Bolm et al. from boronic acids and sulfoximes (C. Bolm et al. Org. Lett. 2005, 2667. DOI: 10.1021/ol050816a). Middle: A solid phase biphenyl synthesis according to Suzuki-Miyaura in ionic liquids using aryl boronic acids and solid bound aryl iodide (A. Ganesan et al., Org. Lett. 2002, 4, 3071, DOI: 10.1021/ol0263292; A. J. Suzuki, Organomet. Chem. 1999, 576, 147. DOI: 10.1016/S0022-328X(98)01055-9). Below: Recent highly enantioselective, Rh-catalysed Michael addition of arylboronic acids (J. G. de Vries et al., Org. Lett. 2005, 2433. DOI: 10.1021/ol050734m).

 

Scaffold variability, scope and limitations

The Pt-3CR methodology allows the synthesis of a large variety of interesting molecules, including amino acids, amino ketones, amino alcohols, amino sugars and several types of heterocycles. Thus it was only recently found by Chang et al. that quinolines and isoquinolines activated by diethyl pyrocarbonate (DEPC) will react with electron-deficient boronic acids in dichloromethane (DCM) to provide the corresponding dihydroquinolines 9 and isoquinolines 10 in good to high yields (Y. M. Chang et al. Tetrahedron Lett. 2005, 46, 3053. DOI: 10.1016/j.tetlet.2005.03.008). Unnatural α-amino acids, e.g. 14 are amenable to performing a stereoselective Pt-3CR; chiral amino alcohol auxiliaries can be employed and hydrogenolytically removed afterwards (N. A. Petasis et al. J. Am. Chem. Soc. 1997, 119, 445. DOI: 10.1021/ja963178n). 1,4-Benzodiazepin-3-ones, e.g. 15 have been synthesized using a mono protected diamine in the Pt-3CR, with subsequent deprotection and ring closure. Regioisomeric 1,4-benzodiazepin-2-ones, e.g. 16 are similarly amenable in a 4-step sequence in good overall yield. A two-step approach was taken for the synthesis of benzopiperazinones 17 using N-monoprotected 1,2-phenylendiamine, a boronic acid and glyoxylic acid, with subsequent acidic Boc deprotection and in situ ring closure (N. A. Petasis et al. Tetrahedron Lett. 2000, 41, 9607. DOI: 10.1016/S0040-4039(00)01717-2). Salicylaldehydes react smoothly with secondary amines and boronic acids without phenol protection to provide compounds such as 18 (N. A. Petasis et al. Tetrahedron Lett. 2001, 42, 539. DOI: 10.1016/S0040-4039(00)02014-1). The substance P antagonist Apprepitant was convergently synthesized by Merck chemists employing a highly stereoselective Pt-3CR resulting in intermediate 19 (K. Rossen et al. Chem. Eur. J. 2002, 8, 1372. DOI: 10.1002/1521-3765(20020315)8:6%3C1372::AID-CHEM1372%3E3.0.CO;2-6).

Scheme 3 Scaffold variability and reaction conditions for Pt-3CR: A: DEPC, RB(OH)₂, DCM, RT; B: DEPC, RB(OH)₂, DCM, RT; C: 1. R-2-phenylglycinol, glyoxylic acid, boronic acid; 2. H₂, Pd/C, MeOH, HCl; D: 1. Pt-3CR, CH₃CN, 80°C; 2. conc. HCl, DCM; 3. EDC-HCl, iPr₂NH, CH₃CN; E: 1. Me₂C=CHCOCl, py, DCM; 2. 1M HCl, 3. Pt-3CR; F: 1. Pt-3CR; 2. conc. HCl, DCM; G: Pt-3CR, DCM; H: Pt-3CR, DCM.

Typically Pt-3CR works satisfactorily with secondary or hindered primary amines, hydrazines and anilines in solvents such as DCM at room temperature. Alkenyl, electron-rich and electron-neutral (hetero-)aryl boronic acids can be employed. Several reports have appeared regarding microwave-assisted Pt-3CR, which obviously increases the scope of the reaction substantially. Workers from Evotech used design of experiment (DOE) methods to optimize the Pt-3CR rapidly (N. I. McLean et al. Tetrahedron Lett. 2004, 45, 993. DOI: 10.1016/j.tetlet.2003.11.092). Thus the optimal conditions involved the microwave heating of the reaction components in dichloromethane (1 M) at 120 °C for 10 min in a focused microwave (CEM Explorer). These conditions were successfully applied to a range of Pt-3CRs employing either glyoxylic acid or salicylaldehyde as the carbonyl component along with a number of aryl/heteroaryl boronic acids and amine components.

Substrates with a wide range of electronic and steric properties generally work well in Pt-3CR, although electron-poor (hetero-)anilines often gave unsatisfactory yields and conversions. However, recently Sanofi-Aventis chemists could show that even these problematic cases can be easily mastered under microwave conditions. Thus a variety of five and six-membered heteroaromatics gave very satisfactory yields, as in 20-25 (M. Follmann et al. Synlett 2005, 1009. DOI: 10.1055/s-2005-864817). The new protocol greatly extends the scope of the original boronic acid Mannich reaction and makes it now quite suitable for the parallel synthesis of arrays that employ even electron-poor amine inputs.

Scheme 4 Microwave conditions allow for the usage of even electron-poor (hetero)-aromatics in Pt-3CR.

 

Union of Ugi and Petasis Reaction

Recently workers from Procter & Gamble described an interesting example of the union of two very useful MCRs, the U-4CR and the Pt-3CR. This one-pot combination of two of the most useful MCR is noteworthy, due to the potentially very large chemical space available. For example, while the available boronic acids and isocyanides number in the several hundreds, thousands of aldehydes or ketones and primary amines are commercially available. Thus, virtually billions of compounds are accessible by this union of MCRs.

Two variations on the U-Pt union theme have been described. First, a Pt-3CR of glyoxylic acid, aldehydes and amines was performed yielding N-substituted α-amino acids, which serve as the carboxylic acid input in a subsequent U-4CR, finally resulting in highly substituted dipeptides. Several examples have been described that yield products such as 26 in good yields. Moreover the reaction has also been performed on solid support, where the Rink amide serves as a solid phase amine component (D. E. Portlock et al. Tetrahedron Lett. 2003, 44, 5121. DOI: 10.1016/S0040-4039(03)01119-5). The method is practical and as described in the general procedures, the intermediate Petasis amino acid can be used without purification.

Scheme 5 The Pt-3CR intermediate N-alkylated α-aminoacid serves as starting material in the subsequent U-4CR.

In an second example N-mono-Boc-protected N‘-monosubstituted hydrazines reacted with glyoxylic acid and aldehydes to yield α-hydrazino acids, which in turn serve as both the amino and carboxylic acid substrates with aldehydes and isocyanides in a U-3CR giving raise to the interesting class of aza-β-lactams such as 27 and 28. The intermediate Pt-3CR product can be isolated and characterized and the total conversion performed in two steps. Interestingly, however, the authors observed that the reaction is best performed as a one-pot procedure without any isolation of intermediates (D. Naskar et al. Tetrahedron Lett. 2003, 44, 6297. DOI: 10.1016/S0040-4039(03)01524-7).

Scheme 6 Highly substituted aza-β-lactams are accessible by the combination of Pt-3CR and U-4CR.

 

Applications of Pt-3CR in Natural Product Chemistry

A potent immunosuppressant ISP-I (myriocin, themozymocidin) was isolated from the culture broth of Isaria sinclairii (ATCC24400). This compound was structurally simplified to give FTY720 (32), which also possesses considerable immunosuppressive activity and is now being examined in clinical studies. A Japanese group synthesized the drug in two steps making use of a key Pt-3CR (S. Sugiyama et al. Chem. Pharm. Bull. 2005, 53, 100. Link, PDF). During the Petasis-Mannich reaction benzylamine (29), dihydroxyacetone (30) and the corresponding 2-(p-octylphenyl)vinylboronic acid (31) yield the target molecule after hydrogenation.

Moreover, the polyhydroxylindolizidine alkaloid uniflorine A (33) isolated from the leaves of the tree Eugenia uniflora L. and used as an antidiabetic agent in Paraguayan traditional medicine was synthesized using Pt-methodology (A. S. Davis et al. J. Org. Chem. 2004, 69, 3139. DOI: 10.1021/jo049806y). Reaction of L-xylose (34), allylamine (35) and boronic acid 36 gives an advanced intermediate in 73% yield, which can be further elaborated towards uniflorin A (33) using a ring-closing metathesis reaction.

Scheme 7 Use of Pt-3CR in the total synthesis of natural products.

Clearly the CCN motif, which is formed during Pt-3CR is abundant in the structures of many natural products. Therefore one can foresee many useful and convergent applications of this MCR in the total synthesis of diverse natural products.

Outlook

The Pt-3CR nowadays is an indispensable part of the MCR repertoire useful for combinatorial chemistry. Moreover, the first interesting applications of this still young reaction in the synthesis of natural products and drug candidates are now emerging. The rapidly growing interest can be traced back to the broad availability of hundreds of boronic acids as well as the other starting materials. Moreover the functional group tolerance plays an important role in the popularity of this MCR.

It can be predicted that in the near future, many novel scaffolds available through the Pt-3CR together with a suitable secondary reaction will be discovered, thus greatly enlarging the already impressive pool of accessible scaffolds.