bk-2016-1236.ch009

Chapter 9

The Petasis Borono-Mannich Multicomponent Reaction Downloaded by IOWA STATE UNIV on December 6, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch009

Cessandra A. Guerrera and Todd R. Ryder* Department of Chemistry, Southern Connecticut State University, New Haven, Connecticut 06515, United States *E-mail: [email protected]

The Petasis borono-Mannich reaction is a multicomponent process that involves the addition of an organoboronic acid to an imine or iminium ion formed by the condensation of an aldehyde and amine. Since the initial report by Petasis in 1993, it has attracted significant attention from the synthetic community and a number of advances have been reported since the topic was last reviewed. Recent highlights include new catalysts and reaction conditions, asymmetric variants, diversity-oriented approaches, and applications to the synthesis of natural products and other biologically-relevant targets.

Introduction Amines are widely found in biologically-active molecules and have attracted the interest of chemists for many years. Indeed, the Wöhler synthesis of urea from ammonium cyanate is widely regarded as foundation of organic chemistry as a discipline (1). Since this time, numerous approaches to amines and amine-containing molecules have been described in the literature, including a variety of multicomponent reactions (MCR) that involve nucleophilic addition to an imine as the key step. One such reaction involving a vinyl or aryl boronic acid as the nucleophile was reported by Petasis and co-workers in 1993 (2). They discovered that vinyl boronic acids add to Mannich-type adducts formed from secondary amines and paraformaldehyde to yield allylamines in 75-96% yield (Equation 1).

© 2016 American Chemical Society Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Downloaded by IOWA STATE UNIV on December 6, 2016 | http://pubs.acs.org Publication Date (Web): November 30, 2016 | doi: 10.1021/bk-2016-1236.ch009

The reaction was run by heating equimolar amounts of the amine and aldehyde in dioxane or toluene at 90°C for 10 minutes, followed by addition of the vinyl boronic acid (1.5 equiv) and stirring at room temperature for several hours or 90 °C for up to 30 minutes. Excess boronic acid was removed by acid-base extraction to provide the allylamine product in good yield. The reaction was applied to a short synthesis of naftifine (1), a topical antifungal agent. The authors observed that the E-stereochemistry of the vinyl boronic acid was maintained during the reaction and mentioned that aryl boronic acids behave similarly to generate the corresponding benzyl amines. Although the mechanism was not fully elucidated, the authors noted that vinyl boronic acids do not readily add to pre-formed iminium salts, and that initial attack by the OH or NH2 group to form a boron “ate” complex likely activates the vinyl group as a nucleophile for addition (Scheme 1). In fact, the majority of examples in the literature employ an aldehyde with an adjacent heteroatom directing group that presumably participates in this fashion.

Scheme 1. Boron “ate” complex. A second paper by Petasis and Zavialov in 1997 on the reaction significantly increased its scope and utility (3). In this study, glyoxylic or pyruvic acid served as the aldehyde component, thus yielding α-amino acids (3) as the product (Equation 2).

Besides providing a new method to generate this important class of molecules, the amine component was expanded to include aromatic and primary amines 276 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


(including the highly hindered trityl and adamantylamines) in addition to secondary amines as described in the initial report. Several other solvents (ethanol, CH2Cl2) could be employed and boronate esters (as well as acids) were shown to participate in the reaction. Last but not least, it was shown that the use of the chiral amine (S)-2-phenylglycinol (2) gave the product as a single diastereomer (>99% de) in good yield and the auxiliary could be smoothly removed by hydrogenation to reveal the free amino acid. The Petasis borono-Mannich (PBM) reaction is categorized as a type II multicomponent reaction since it involves a series of reversible steps in equilibrium, followed by a final, irreversible step that drives the reaction to completion (Scheme 1) (4). Although the exact details of the mechanism are not known with certainty, it is generally believed that formation of the boron “ate” complex 4 is followed by intramolecular delivery of the boron substituent with concomitant formation of the new carbon-carbon bond. As mentioned above, most examples in the literature involve substrates bearing a heteroatom adjacent to the carbonyl group (e.g., glyoxylic acid, salicylaldehydes, α-hydroxyaldehydes, etc.), although this is not strictly required. The reaction is compatible with both primary and secondary amines; for the boronic acid component, vinyl and aryl substituents are most common. Operationally, the PBM reaction compares favorably to other well-known multicomponent processes that can be used to prepare similar compounds. For example, cyanide is the nucleophile in the Strecker reaction and presents toxicity issues, while the widely used Ugi condensation uses isocyanides, which often have a pungent odor. Both of these reactions (and others such as the Bucherer-Bergs hydantoin synthesis) also require a subsequent hydrolysis step that proceeds under harsh conditions (e.g., refluxing 6 N HCl) and thus limits their functional group compatibility. In contrast, the PBM products can be deprotected or converted to the free amino acid under mild conditions. Further, a large number of boronic acids (as well as amines and aldehydes) are commercially available and do not require rigorous exclusion of air and moisture like highly reactive organometallic nucleophiles such as Grignard reagents and organolithiums. The Petasis reaction has been the subject of several excellent reviews that include a comprehensive discussion of the mechanistic and experimental details mentioned above, most recently in 2010 and 2011 (5–8). Since then, the field has continued to advance on a variety of fronts. Major themes include the development of new catalysts and reaction conditions, expanded scope both from a methodology perspective and via the application of the PBM reaction to problems in organic synthesis; diversity-oriented approaches that use both the multicomponent nature of the Petasis reaction as well as the functional groups in the products to generate large numbers of molecules in an efficient fashion; and a variety of asymmetric approaches using both chiral substrates and catalysts. In addition, a few miscellaneous reports have appeared and suggest that new contexts for the Petasis reaction remain to be discovered. It should be noted that many of the papers have aspects that touch on more than one category (some of which are mentioned in the text). A number of other examples can also be found in patent literature but are not covered here. This review is intended to highlight results reported after the preceding reviews through mid-2016. 277 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Catalysts, Reaction Conditions, and Methodology


Lamaty and co-workers reported the PBM reaction of secondary amines, salicylaldehyde, and a variety of boronic acids under solvent-free conditions using microwave (MW) irradiation (Equation 3) (9). The reactions proceeded cleanly and only an aqueous work-up was required to yield the desired products in pure form. For example, a labile benzofuran derivative (5) was prepared in 95% isolated yield without chromatography. Yields with primary amines were lower and no product was obtained with glyoxylic acid as the aldehyde component.

The use of solvent-free conditions was also investigated by Wang, who found that salicylaldehyde reacted with a range of boronic acids and amines under thermal rather than microwave conditions to give the PBM products in moderate to good yield (10). A temperature of 80 °C gave the highest yields and the reactions were complete after 2 hours. The Candeias group used glycerol as a solvent in the PBM reaction of salicylaldehydes and 2-pyridinecarbaldehyde with secondary amines (Equation 4) (11). In some cases, yields were similar to other solvents such as ethanol or acetonitrile. Density functional theory calculations suggested that a reaction pathway involving glycerol boronates is competitive with that of the free boronic acid. In a separate experiment, a pre-formed mixture of glycerol boronate esters gave the Petasis product in moderate yield.

Fluorous-tagged benzylic (f-Bn) hydroxylamines such as 7 were used by Kristensen and co-workers as the amine component in the Petasis reaction to generate N-alkyl amino acids with good results (Equation 5) (12). Yields for the cleavage of the tag by hydrogenolysis were found to be substrate-dependent, while use of the previously-reported Mo(CH3CN)3(CO)3 conditions and subsequent purification was non-trivial due to metal complexation by the amino acid product. However, this issue could be circumvented by preliminary esterification with TMS-CH2N2 before treatment with the molybdenum reagent. 278 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Jensen and co-workers demonstrated the use of an automated microreactor system to optimize and investigate the kinetics of multicomponent reactions (13). In particular, a tandem Petasis-Ugi sequence based on glyoxylic acid was examined both stepwise and in series to monitor and optimize the formation of product at various times and temperatures and to extract kinetic parameters such as activation energies. Mass spectrometry-based methods were applied by two groups to investigate the Petasis reaction. Thomson and co-workers rapidly screened >1800 conditions using a high-throughput self-assembled monolayer/MALDI-Tof mass spectrometry (SAMDI) platform (14). In these experiments, the aldehyde component was immobilized on a gold surface and product formation was quantified relative to an internal standard. The optimized reaction conditions were later successfully transferred to the solution phase. Meanwhile, the Neto group applied a charge-tag strategy to monitor intermediates in solution as part of mechanistic studies for a model PBM reaction using benzylamine, salicylaldehyde, and phenylboronic acid (15). Interestingly, they were also able to isolate and characterize by x-ray crystallography the methanol adduct of a cyclized zwitterionic intermediate (9) formed prior to transfer of the boronic acid substituent (Figure 1).

Figure 1. Zwitterionic Intermediate Characterized by X-Ray Crystallography.

Several reports of novel metal-catalyzed variants of the PBM reaction have been disclosed. The Bergin group developed conditions using 4Å molecular sieves (MS) and a Cu(I) additive that promoted reaction of some substrate combinations with low reactivity such as 2-pyridinecarboxaldehyde with arylboronic acids (Equation 6) (16). The exclusion of air and moisture was required and the highest yields were obtained with a coordinating group on the aldehyde. Reactions with dicyclohexylamine or arylboronic acids lacking an ortho-substituent were unsuccessful. 11B-NMR studies suggested that the reaction mechanism included a transmetallation from boron to copper. 279 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The Arndsten group developed a Petasis-like multicomponent reaction of imines, acid chlorides, and tetraalkylborates (instead of boronic acids) catalyzed by CuCl and a Lewis base to give α-substituted amides (Equation 7) (17). The general reaction conditions (CH2Cl2, rt, 18 h) were compatible with a wide range of imines, including those lacking a directing group. One example with an enolizable imine was also reported under slightly different conditions.

Beisel and Manolikakes developed a Petasis-like reaction of amides, aldehydes, and aryl boronic acids (Equation 8) (18). Yb(OTf)3 hydrate was used as a Lewis acid catalyst to promote formation of the reactive acyl imine species and Pd(TFA)2/2,2-bipyridine activated the arylboronic acid for addition. The reaction scope was wide and included electron-deficient arylboronic acids and carbamates in place of the amide. Yields ranged from 34-93% and the reaction was compatible with air and water.

280 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The use of 4Å molecular sieves was shown by Shi and co-workers to accelerate the PBM reaction to prepare the core of BIIB-042 (13), a γ-secretase modulator of interest as potential therapy for Alzheimer’s disease (Equation 9) (19). In the absence of a dehydrating agent, the reaction required heating and reached only 70-80% conversion over a period of several days. During this time, significant epimerization of an enolizable chiral center was observed in both the starting material and product. The inclusion of molecular sieves accelerated the reaction and complete conversion was obtained after 24-48 hours at room temperature without loss of stereochemical integrity. In situ FTIR monitoring of the reaction mixture suggested that dehydration of a hemiaminal intermediate to the iminium ion was responsible for the observed effect. The reaction conditions were also applied to several other secondary amines and a variety of arylboronic acids.

As described in earlier reviews, a variety of additives have been reported to increase the rate of the Petasis reaction. Since then, recent studies have demonstrated modest rate enhancements in the presence of chitosan (20), cobalt ferrite nanoparticles (21), metal-doped molecular sieves (22), protonated trititanate nanotubes (23), and La(OTf)3 with microwave irradiation (24).

Synthetic Applications The utility of the PBM reaction is amply demonstrated by the number of synthetic applications that have continued to appear in the literature. In this section, the reports are loosely arranged from general to specific: expansions in the scope of the reaction and approaches to various classes of compounds are described first, followed by examples in the context of particular synthetic targets. A group at Syngene described the preparation of fused triazepinediones (15) and related systems using a three step procedure that started with the Petasis reaction of glyoxylic acid and an alkyl-substituted BOC-hydrazide as the amine component (Scheme 2) (25). The sequence proceeded in reasonable yield without purification of the intermediates.



Scheme 2. Synthesis of Triazepinediones. A following paper similarly presented a telescoped route to 1,2,3,4tetrahydrocarbazoles (17) in 20-50% overall yield starting instead with a BOC-protected phenyl hydrazine as the Petasis substrate to deliver an intermediate suitable for a subsequent Fischer indole synthesis (Scheme 3) (26).

Scheme 3. Synthesis of 1,2,3,4-Tetrahydrocarbazoles. Jurczak and co-workers prepared a series of hexahydropyrazino[1,2a]pyrazine-1,2-dione β-turn mimetics (20) using the Petasis reaction of a solid-supported (S)-piperazine-2-carboxylic acid (18) with glyoxylic acid as the key step (Scheme 4) (27). The same group also reported a related sequence that delivered fused benzodiazepine derivatives (28). 282 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 4. Solid-Phase Synthesis of β-Turn Mimetics.

The PBM reaction of 2-pyridine-carboxaldehydes was explored by the Mandai group using a variety of cyclic and acyclic secondary amines and styrenyl vinylboronic acids or electron-rich arylboronic acids in refluxing acetonitrile (Equation 10) (29, 30). Yields were mostly in the 70-90% range except for several 6-substituted pyridines which were significantly lower. Other heteroaromatic aldehydes gave poor conversion or complex mixtures of products. In the case of dibenzylamine, the products could be further derivatized by treatment with CAN to deliver the mono-benzylamine or by catalytic hydrogenation to cleave the amine substituent entirely. Interestingly, the electron-rich 4-dimethylaminopyridine-2-carboxaldyde gave an unexpected side product in nearly quantitative yield by direct alkylation of the aldehyde.

The Nielsen group reported the Petasis reaction of acyl hydrazides with hydroxyaldehydes and aryl boronic acids in hexafluoroisopropanol (HFIP) to yield 1,2-hydrazidoalcohols 22 (Scheme 5) (31). These intermediates could be carried on via treatment with bis(trichloromethyl)carbonate (BTC) to either the corresponding oxadiazolones 23 or oxazolidinones 24 by varying the stoichiometry and reaction conditions.



Scheme 5. Synthesis and Cyclization of Hydrazidoalcohols. Li and co-workers prepared 2-arylimidazo[1,2-a]pyridin-3-ols by a PBM reaction of 2-aminopyridines with glyoxylic acid and aryl boronic acids under microwave irradiation (Scheme 6) (32). The initial Petasis adduct undergoes spontaneous cyclization followed by dehydration and aromatization to give the observed product.

Scheme 6. Reaction of 2-Aminopyridines. The Petasis reaction of cyclic amino alcohols, glyoxal, and arylboronic acids was used by Song and colleagues to prepare fused morpholine-pyrrolidine (27) or piperidine derivatives with good yields (Equation 11) (33). Several of the synthesized compound displayed insecticidal activity against armyworms and root-knot nematodes.



A series of 2-hydroxy-2H-1,4-benzoxazine derivatives (31) was generated through the PBM reaction of N-substituted 2-aminophenols with glyoxal and arylboronic acid (Scheme 7) (34). The authors suggest that addition of the aryl group to the iminium species 28 is directed by the acetal OH group, followed by equilibration to the more-stable trans stereoisomer.

Scheme 7. Synthesis of 1,4-Benzoxazines.

Verbitskiy and co-workers reported the synthesis of several 5-aryl-6heteroaryl-substituted 1,6-dihydropyrazine derivatives such as 32 by the addition of electron-rich (benzo)furan or thiophene boronic acids to the hydroxy adduct of pyrazinium salts (Equation 12) (35). The most active of the resulting compounds exhibited anti-tuberculosis activity comparable to standard drugs. A later study extended this methodology to trans-styrenyl boronic acids (36).



Aryl-substituted 1,4-benzodiazepine-3,5-diones (33) were prepared by Noushini and colleagues using the PBM reaction of 2-aminobenzamides with glyoxal and an arylboronic acid (Equation 13) (37). The reactions proceeded in 62-78% yield with 4Å molecular sieves at room temperature in CH2Cl2.

Shang and co-workers reported that the Petasis adducts can be converted to tetrahydro-1H-xanthen-1-ones (34) in 70-95% yield by FeCl3-catalyzed reaction with 1,3-diketones (Equation 14) (38). The authors propose that the FeCl3 coordinates the basic amine moiety and activates it for departure in a substitution reaction with the enol form of the diketone, followed by ring closure.

Mizuta and Onomura reported the diastereoselective addition of arylboronic acids to acylpiperidinium ions generated from N,O-acetals in the presence of BF3·OEt2 at low temperature to yield cis-2-aryl-3-hydroxypiperidines 35 (Equation 15) (39). The reaction was applied to a short synthesis of (±)-L-773,060, a piperidine neurokinin-1 receptor antagonist (Ar = Ph), by O-alkylation and deprotection of the Cbz group.



Jarvis and Charrette prepared pyrrolinol derivatives using the PBM reaction of optically-active α-hydroxyaldehydes and allylamines with styrenylboronic acid in ethanol at reflux, followed by ring-closing metathesis with the Grubbs second-generation catalyst (Scheme 8) (40). The sequence gave similar yields when run without purification of the intermediate PBM adduct. The pyrrolinols were subsequently carried on to an aziridination/nucleophilic ring-opening sequence to yield enantiopure substituted piperidines.

Scheme 8. Synthesis of Enantiopure Substituted Piperidines.

An impressive application of the PBM reaction was reported by the Yudin group, who reacted aziridine aldehyde dimers 40 along with cyclic or acyclic amines and vinyl, alkynyl, aryl, or heteroarylboronic acids in hexafluoroisopropanol to yield syn-α-amino-aziridines (41) in moderate yields (Scheme 9) (41). The intermediates could then be carried on by an anchimerically-assisted nucleophilic ring opening to syn-1,2 or -1,3 diamines 42-44 with up to three contiguous stereocenters.



Scheme 9. Petasis Reaction of Aziridine Aldehyde Dimers. More recently, Beau and co-workers described the diastereoselective PBM reaction of optically-active N-protected α-amino aldehydes with secondary amines and various vinyl and arylboronic acids to generate 1,2-trans-diamines 45 in moderate to good yields and up to 98% ee (Equation 16) (42). The substituents on the aminoaldehyde had a major impact on the success of the reaction, as did the choice of solvent and inclusion of 4Å molecular sieves. Conditions were also reported for orthogonal deprotection of the various N-protecting groups.

Another interesting example was disclosed by the Yang group, who reacted the unusual 4-substituted 1,2-oxaborol-2(5H)-ols 46 with salicylaldehydes and an amine promoter to yield the PBM product. This is turn underwent an intramolecular SN2 cyclization with loss of the amine to yield disubstituted 2,5-dihydrofurans 47 in 70-92% yield (Equation 17) (43).



Tao and co-workers synthesized an N-glycosyl amino acid in 88% yield via the PBM reaction of a protected glucosamine with a vinylboronic acid and glyoxylic acid in CH2Cl2 at room temperature (Equation 18) (44). Unfortunately, the stereoinduction at the newly formed amino acid chiral center was low.

The solid-phase synthesis of β-lactams substituted at the 3-position with α-amino acids was developed by the Mata group (Equation 19) (45). A polymer-supported methylamino-β-lactam (49) underwent a Petasis reaction with arylboronic acids and glyoxylic acid (both in excess) in CH2Cl2 at room temperature for 72 hours. The use of hexafluoroisopropanol (neat or as a co-solvent) gave lower yields resulting from partial cleavage of the substrate from the resin at longer reaction times. The authors suggested that this cleavage was promoted by the acidic nature of the solvent.

The Nielsen group reported that treatment of β,γ-dihydroxy-γ-lactams (51) with BF3·OEt2 in hexafluoroisopropanol generated N-acyliminium ions which reacted with vinyl and arylboronic acids and esters via a Petasis-like process in moderate yields (Equation 20) (46). Relatively electron-poor boronic acids gave the cis isomer, while more reactive ones gave a mixture of cis and trans isomers.



Mandia and co-workers reported the PBM reaction of optically-active lactol 53 prepared from D-araboascorbic acid to obtain polyhydroxy trans-1,2-amino alcohols (54) with three continuous stereogenic centers as chiral building blocks (Equation 21) (47). Chemistry was also developed to carry on the Petasis adducts using a variety of selective functional group transformations.

Bering and Antonchick presented a method to prepare 2-substituted quinolines (55) by N-oxidation followed by reaction with electron-rich aryl or alkenylboronic acids in DMSO at elevated temperature (Equation 22) (48). The authors proposed a Petasis-like mechanism in which the boronic acid is activated by coordination to the anionic oxygen of the N-oxide, followed by delivery of the nucleophile to the iminium carbon and subsequent rearomatization.

A two-step route to 2,3-diaryl-quinoxalines (57) was developed by the Hulme group (Scheme 10) (49). It involved the PBM reaction of a mono-protected orthophenylenediamine with an arylboronic acid and phenylglyoxal upon microwave irradiation in moderate to good yield. Deprotection was followed by cyclization in situ to give the heterocyclic product. The analogous reaction with BOC-protected ethylenediamine was unsuccessful.



Scheme 10. 2,3-Diaryl-Quinoxalines.

The Thomson group reported a PBM approach to allenyl alcohols (61) that relies on the reaction of an arylsulfonylhydrazide with glycoaldehyde dimer and an alkynylboron nucleophile (Scheme 11) (50). The initially-formed adduct undergoes loss of sulfinic acid to yield the diazene and a retro-ene process to give the allene. The reaction was also shown to proceed smoothly and with high stereoselectivity when other carbonyl components such as (D)-glyceraldehyde, α-hydroxyketones, and β-hydroxyaldehydes were used.

Scheme 11. Generation of Allenyl Alcohols.



Sun and co-workers disclosed the PBM reaction of formaldehyde with benzylamine and arylboronic acids in DCE at 45-60 °C (Equation 23) (51). In this work, the initially-formed hemiaminal proceeds to form an iminium species which is intercepted in situ by propiolic acid in a decarboxylative coupling process that leads to propargylamines 62 in moderate to high yields. Similar results were also reported by a different group using toluene at 80 °C (52).

The Pyne (53) and Petasis (54) groups independently reported in early 2015 that allenylboron species undergo component-selective reactions with aldehydes and amines to yield either allenyl (63) or propargyl (64) amino acid products in good yield depending on whether a primary or secondary amine is used (Scheme 12). In either case, the stereoselectivity was generally excellent.

Scheme 12. Synthesis of Allenyl or Propargyl Amino Acids. The use of aminophosphonates in the PBM reaction with electron-rich arylboronic acids and glyoxylic acid was disclosed in two reports by Khukar and co-workers (Equation 24) (55, 56). The reactions were run in refluxing ethyl acetate and the diastereoselectivity was higher (9:1) for secondary amines.



Two interesting examples of the PBM reaction were reported by the Carboni (57) and Song (58) groups. The former used Z-alkenyl 1,2-bis(boronates) 66 with glyoxylic acid and secondary amines in hexafluoroisopropanol at room temperature to generate unsaturated γ-boronated amino esters 67 upon esterification with diazomethane (Equation 25) (57). These products could be carried on to a Suzuki coupling or other transformations.

The latter generated tertiary aromatic amines (68) using a double Petasis reaction of aniline with two equivalents of formaldehyde and an aryl or styrenyl boronic acid in refluxing toluene (Equation 26) (58). Yields were generally in the 60-96% range for a range of substituted anilines. The aniline could be replaced with 2-aminopyridine (27%) or 2-aminopyrazine (34%) to give the corresponding PBM products, albeit in lower yield.

Pyne and co-workers applied the PBM reaction at the start of a ten step chiral pool synthesis of the alkaloid calystegine B4 (Scheme 13) (59). (–)-D-lyxose, benzylamine and [(E)-2-phenylvinyl]boronic acid gave the aminotetrol in 82% yield. This intermediate was carried on through a RCM (ring-closing metathesis) reaction to give a 7-membered ring precursor for the final intramolecular aminal formation. A concise synthesis of zanamavir congeners based on the PBM reaction was reported by Norsikian, Beau, and co-workers (Scheme 14) (60). The key step involved the reaction of a diallyl or dibenzylamine with a vinylboronic acid and an unstable α-hydroxyaldehyde derived from (R)-glycidol (both prepared in two steps) in CH2Cl2/HFIP under thermal conditions or in CH2Cl2 with microwave irradiation. The product was obtained in 95% yield and carried on to the final product via an FeCl3·6H2O-catalyzed cyclization. 293 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 13. Synthesis of Calystegine B4.

Scheme 14. Preparation of Zanamavir Congeners. Rozwadowska and co-workers efficiently prepared the tetrahydroisoquinoline alkaloid (±)-calycotomine and its N-methyl analog 75 using the PBM reaction of an aminoaldehyde acetal with glycoaldehyde dimer and an electron-rich arylboronic acid, followed by a Pomeranz-Fritsch-Bobbitt cyclization (Scheme 15) (61). The overall yield for the three step sequence was 61%. Recently, a following report from the same authors described the synthesis of the related 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid in optically-active form by a similar approach using a chiral amine (62). Moderate stereoinduction (70:30 dr) was observed and the major enantiomer was enriched by fractional crystallization. 294 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 15. Synthesis of Calycotamine. Seeberger reported the synthesis of orthogonally-protected legionaminic acids (77) using a PBM reaction between an aldehyde, (E)-styrenylboronic acid, and an allylamine (Scheme 16) (63). The reaction proceeded in 76% yield at room temperature in ethanol to give the anti amino alcohol which was carried on to the final products.

Scheme 16. Preparation of Protected Legionaminic Acids. The Scheerer group recently presented a second-generation synthesis of the endophyte-derived (+)-loline alkaloids (81) using the PBM reaction of a pyrrolidine derived from a chiral pool starting material, (S)-4-amino-2hydroxybutanoic acid (Scheme 17) (64). Treatment with BF3·OEt2 promoted formation of the N-acyliminium ion, which reacted with the interesting methylpentanediol vinyl boronate 78 to give the desired product 80 as single diastereomer in good yield. 295 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 17. Petasis Reaction in Synthesis of Loline Alkaloids. Norsikian and Beau reported the use of an intramolecular PBM reaction on an advanced intermediate in the synthesis of ent-conduramine A1 (Scheme 18) (65). A functionalized boronic acid (82) was prepared in 9 steps from a protected ribose derivative and reacted with diallylamine in 4:1 ethanol/water at 80 ºC for 192 h to effect an intramolecular PBM reaction. The cyclized product 85 was obtained in 72% yield as a single diastereomer and converted to the final product 86 by palladium-catalyzed deprotection of the allyl groups. A similar route led to the related conduramine C4 in a shorter, six step sequence.

Scheme 18. Synthesis of ent-Conduramine A1.



A formal synthesis of (+)-conduramine E and its enantiomer was reported by Ghosal and Shaw using a different PBM reaction (Scheme 19) (66). In this case, the α-hydroxyaldehyde 87 was prepared in five steps from methyl-α-D-galactopyranoside and reacted with t-butylamine and styrenylboronic acid in ethanol at 80 °C to yield diene intermediate 88. This intermediate underwent treatment with (BOC)2O and a subsequent ring-closing metathesis reaction to afford the conduramine core, followed by acid-catalyzed cleavage of the ketal protecting group to intercept an intermediate from a previous synthesis.

Scheme 19. Synthesis of Conduramine E.

Bouillon and Pyne synthesized the polyhydroxylated pyrrolidine alkaloids DMDP and DAB using the PBM reaction of a masked aldehyde (91) derived from L-xylose in four steps with E-styrenylboronic acid and benzylamine (Scheme 20) (67). The reaction proceeded with high diastereoselectivity to yield anti amino alcohol 92. Use of a fluorinated alcohol solvent such as hexafluoroisopropanol or trifluoroethanol was found to give higher yields than methanol or ethanol. Selective mesylation followed by cyclization provided a pyrrolidine which was smoothly carried on to the two natural products (93 and 94) via a 2 or 3 step sequence.



Scheme 20. Synthesis of DMDP and DAB Alkaloids. A group at Bristol-Myers Squibb reported the synthesis of phenylpyrrolidine phenylglycine derivatives as inhibitors of Tissue Factor/Factor VIIa (TF-FVIIa) using the PBM reaction of an aminoisoquinoline with arylboronic acids and glyoxalate (Scheme 21) (68). The reactions proceeded in moderate to good yield affording a racemic phenylglycine intermediate (95) that was resolved by chiral HPLC after the final step in the sequence.

Scheme 21. Aminoisoquinoline Petasis Reaction.

Asymmetric Methods Many of the examples described above include the induction of relative or absolute stereochemistry directed by chiral centers in the substrates. Alternatively, 298 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


some groups have reported new examples and approaches to asymmetric PBM reactions using a chiral catalyst or auxiliary. The Hutton group reported the PBM reaction of substituted styrenylboronic acids and glyoxylic acid with Ellman’s tert-butylsulfinamide auxiliary as a chiral amine equivalent to produce β,γ-dehydrohomoarylalanine derivatives (97) in a highly diastereoselective fashion (Equation 27) (69). The reaction displayed a sensitive dependence on concentration. Yields improved to >94% from 55% when the reaction was run in CH2Cl2 at 0.33 M rather than 0.2 M. The authors suggested that this may be due in part to second-order kinetic effects combined with precipitation of the products at higher concentrations. The use of 10 mol % InBr3 as a Lewis acid additive was later reported by a different group to result in slight increases in diastereoselectivity under very similar conditions (70).

Schreiber and co-workers found that the PBM reaction of α-hydroxyaldehydes with secondary amines could be biased using 20 mol % of a BINOL-derived catalyst to favor the syn amino alcohol over the anti stereoisomer that is typically observed (Equation 28) (71). The reaction gave moderate to excellent diastereoselectivity and a detailed study of the interplay between the chiral centers in the amine and aldehyde with matched or mis-matched catalyst stereochemistry was also presented.

The use of BINOL-derived catalysts to promote the enantioselective Petasis reaction was later extended to salicylaldehydes by Yuan (72) and Shi (73). The latter found that the stereoselectivity was improved by the addition of 4Å MS. 299 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The Takemoto group explored an asymmetric PBM reaction of vinylboronic acids with anilines and glyoxamides in the presence of a thiourea catalyst (Equation 29) (74). The α-N-arylamino amide products (99) were obtained in good yield and 80-93% ee for a wide range of substrates, including electron-poor boronic acids.

Yuan and co-workers also investigated enantioselective PBM reactions using a thiourea catalyst (Equation 30) (75). Salicylaldehydes and cyclic secondary amines were reacted with aryl or vinylboronic acids to give the products in good yields and moderate to excellent stereoselectivity. An adjacent hydroxyl group on the aldehyde was required and the reaction was limited to primary or acyclic secondary amines.

Finally, a sui generis report emerged from the Hutton group describing variable stereoselectivity in synthesis of functionalized homoarylalanine derivatives via the PBM reaction of N-benzylphenylglycinol, glyoxylic acid, and styrenylboronic acids (76). The issue was traced to an unidentified impurity in the boronic acid sample purchased from a commercial vendor that afforded improved diastereoselectivity over cleaner batches prepared in-house. 300 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Diversity-Oriented Approaches Along with other multicomponent processes, the modular nature of the PBM reaction has been exploited to efficiently generate libraries of analogs. Some of these approaches take advantage of the functional groups in the products by using them for subsequent reactions in domino or cascade sequences. In this way, large numbers of compounds with diverse molecular structures can be rapidly accessed. The Schreiber group reported using the Petasis reaction followed by intramolecular 1,3-dipolar cycloadditions to prepare functionalized isoxazoles, isoxazolines, and isoxazolidines (Scheme 22) (77). The reaction of a lactol, aminoacetal, and aryl boronic acid in CH2Cl2 at room temperature proceeded in 79% yield with good diastereoselectivity. From here, alkylation of the amine and allylic alcohol rearrangement set the stage for nitrone or nitrile oxide generation and subsequent intramolecular cycloadditions to generate the products.

Scheme 22. Synthesis of Isoxazolidines.

Nielsen and co-workers employed a build-couple-pair strategy in which various alkene-containing components underwent PBM reactions to generate intermediates (103) that were then subjected to ring-closing metathesis (Scheme 23) (78). This yielded cyclic compounds (104-107) whose structure varied according to the placement of the alkenes in the starting materials. Two azepine products were further subjected to palladium-catalyzed isomerization to yield vinyl pyrrolidines. 301 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 23. Build-Couple-Pair Approach Using the Petasis Reaction.

The same group reported a second application of this approach using the PBM reaction of hydrazides, α-hydroxyaldehydes, and boronic acids to give acylhydrazido alcohols (Scheme 24) (79). These intermediates could be carried to the products (109-113) by RCM reactions as before, or via an intramolecular Diels-Alder (IMDA) reaction using a tethered furan moiety as the diene. Most recently, the Nielsen group has reported a new application of this methodology in which the initial furan cycloadduct (115) undergoes oxidative cleavage to a tetrahydrofuran dialdehyde (116) which is in turn a substrate for reduction and Mitsunobu reaction or reductive amination with a primary amine to give a bridged azepine (Scheme 25) (80). Further elaboration of these compounds was also presented. Using this methodology, a library of 1617 analogs was prepared and submitted for high-throughput screening. Meanwhile, the Beau group has explored tandem reactions of PBM adducts (119) derived from dienylboronic acids, α-hydroxyaldehydes (including sugars), and diallylamine (Scheme 26) (81, 82). Here, an intramolecular Diels-Alder reaction yielded bicyclic structures (120) with pendant moieties that were used for further transformations: cross-metathesis reaction of the second N-allyl group 302 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


with methyl vinyl ketone was followed by intramolecular conjugate addition to give the interesting polycyclic products (121) shown below. This sequence could be carried out in an impressive one-pot procedure with only moderate diminution in yield compared to the stepwise process. A subsequent paper expanded the scope of this approach to include a wider range of secondary amines and dienylboronic acids. NMR studies and DFT calculations were used to assign and explain the observed stereochemistry in the Diels-Alder reactions. Finally, a handful of miscellaneous reports have appeared recently in the literature. One used the Petasis reaction as a derivatization method for the HPLC analysis of glyoxylic acid in urine samples (83). Two others presented adaptations of the reaction for use in the undergraduate organic teaching laboratory, a development that speaks clearly to its reliability and ease of use (84, 85).

Scheme 24. Synthesis and Reaction of Acyl Hydrazido Alcohols. 303 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 25. Oxidative Cleavage of Petasis Product and Cycloaddition.

Scheme 26. Petasis Sequence with Tandem Reactions. 304 Coca; Boron Reagents in Synthesis ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

Conclusion The Petasis borono-Mannich reaction has emerged over the past two decades as a valuable method for the synthesis of biologically-relevant molecules. The favorable features that led to its adoption by the synthetic organic chemistry community will continue to recommend it for extensive use in the future. Further advances in the scope of the reaction, asymmetric variants, and applications to challenging synthetic problems will undoubtedly follow as well.


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