Krische allylation

The Krische allylation involves the iridium-catalyzed enantioselective addition of an allyl group to an aldehyde or an alcohol, resulting in the formation of a secondary alcohol and a new carbon-carbon bond.[1][2] This method of asymmetric carbonyl allylation employs catalytic chiral iridium catalysts that can be generated in situ, thereby avoiding the necessity for preformed stoichiometric allyl metal reagents and stoichiometric chiral reagents, and significantly reducing waste production. The mechanism of the Krische allylation involves transfer hydrogenation, precluding the use of redox manipulations (alcohol to aldehyde oxidation) that are generally needed for such transformations.[1][3]

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Background

Enantioselective carbonyl allylations are significant for their application to the synthesis of polyketide natural products. In 1978, Hoffman described the first chiral allyl metal reagent, an allylborane derived from camphor.[4][5] Following his discovery, improved methods for the asymmetric carbonyl allylation emerged from Kumada, Roush, Brown, Leighton, and others.[6][7][8][9][10][11] Unfortunately, these carbon-carbon bond forming reactions have historically resulted in the formation of undesired and stoichiometric metal byproducts due to the necessity of preformed allyl metal reagents as allyl donors.

In 1991, Yamamoto paved the way for the first catalytic enantioselective methodologies with his Lewis acid-catalyzed carbonyl allylation. Such catalytic methods would circumvent the formation of the stoichiometric byproducts.[12] His work was followed by Umani-Ronchi[13] and Keck,[14] who also contributed enantioselective catalytic carbonyl allylation methodologies. While these contributions to the field were impactful, they did not circumvent the need for pre-formed allyl metal reagents. Catalytic variants of the Nozaki-Hiyama-Kishi reaction present another related method for carbonyl allylation, but they still rely on the use of stoichiometric metallic reductants to turn over the catalytic cycle.[15] In addition to the previously stated drawbacks of these allylation methods, many of them also require stoichiometric chiral starting materials (i.e. pinene, tartrates, etc.), anhydrous reaction conditions, and/or pre-formation of reagents that are not trivial to make or to work with. Polyketide synthesis based on first-generation technologies described above often end up being too long for large scale application due to the need for added redox manipulations (i.e. alcohol to carbonyl oxidations) and protecting group requirements.

Reaction features

The Krische allylation sets out to bypass some of these drawbacks through transfer hydrogenative carbon-carbon bond formation.[3][1] In a series of papers published in the early 2000s, Krische and coworkers developed a family of catalytic carbonyl allylation methods in which allenes, dienes, and allyl acetate are able to function as allyl donors and precursors to transient allyl metal nucleophiles.[16][17][18][19][20][21] Notably, this work allows for enantioselective carbonyl allylation without pre-formed organometallic reagents or metallic reductants. This circumvents additional preparative steps and the formation of undesired byproducts. An important feature of this reaction is that it can be done from the alcohol or aldehyde oxidation state without the usual need for redox manipulations. In the case of the aldehyde, isopropanol is added as a terminal reductant to turn over the metal catalyst. Remarkably, due to a kinetic preference for primary alcohols, protecting group manipulations are not necessary when performing this reaction on a substrate that contains both primary and secondary alcohols.[22]

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The figure below shows the different allyl donors[23][24][25][26][27] that have been successful in the Krische allylation reaction, along with their respective yields and enantiomeric excess.

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It is important to note that, although the Krische allylation addresses several key inconveniences of earlier allylation methods, the conditions of this reaction are often considered to be harsh. The use of high temperatures and the need for base in the reaction maybe lower the functional group tolerance in some cases.

Mechanism

The following two mechanisms have been postulated for Krische’s iridium-catalyzed transfer hydrogenative carbonyl allylation. In both mechanisms, in situ formation of the active catalyst occurs first through the complexation the chelating phosphine ligand and m-NO2BzOH with [Ir(cod)Cl]2 to give Iridium carboxylate complex 2a. This complex is proposed to be in equilibrium with the ortho-cyclometallated complex 1.[1]

Oxidative addition of allyl acetate to the iridium is immediately followed by ortho-metalation and formation of the six-membered transition state, 3a. Loss of acetic acid then gives the sigma-allyl C,O-benzoate complex 4, which quickly equilibrates to the pi-allyl haptomer 5.

Catalytic cycle 1-2

Coordination of the aldehyde to the iridium results in the formation of a closed chair-like transition state with the allyl moiety, followed by generation of the homoallyl iridium alkoxide 6. This species is presumed to be stable due to coordination of the double bond with the metal, disabling beta-hydride elimination. Exchange of the homoallyl alcohol with another molecule of the reactant alcohol or with another alcohol (isopropanol, or an alcohol that can act as a terminal reductant and turn over the catalytic cycle) opens a coordination site on the iridium (7) and allows for beta-hydride elimination, giving 8 and turning over the catalytic cycle. Finally, dissociation of the aldehyde gives the starting catalyst complex 1.[1]

Another plausible mechanism is shown in the second figure, shown below. Proton loss from complex 1, followed by oxidative addition of allyl acetate to the iridium gives complex 3b. Loss of the acetate anion results in formation of complexes 4 and 5, after which the catalytic cycle is identical to the one described previously.[1]

A catalytic cycle of Krische allylation 1

Catalysts

Iridium and ruthenium complexes are used in these metal-catalyzed transfer hydrogenative asymmetric alcohol C-C couplings. Krische and coworkers have developed cyclometalated π-allyliridium(III) ortho-C,O-benzoate complexes derived from [Ir(cod)Cl]2, allyl acetate, various 4-substituted-3-nitro-benzoic acids, and axially chiral bis(phosphine) ligands for these transformations. These catalyst complexes are often generated in situ, but they can also be pre-generated and isolated as they are robust and air-stable. Shown below are syntheses of two catalysts used for these transformations.[28]

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Applications in Synthesis

Krische and others have applied this iridium-catalyzed, transfer-hydrogenative carbonyl allylation method to the synthesis of polyketide natural products. Some examples are shown below. In every case, the target compound was prepared in significantly fewer steps than was previously achieved.

In his synthesis of roxaticin, Krische repeated a sequence including his bisallylation, followed by acetonide formation, and then ozonolysis in three consecutive iterations.[29] The synthesis was completed in a significantly lower number of steps than had ever been achieved before,[30][31][32][33] made possible in part by Krische's use of his allylation methods. This is shown in the scheme below.

Krische allylation applied to the syntheses of (+)-roxaticin

The synthetic utility of these methods is also shown in Krische's synthesis[34] of bryostatin 7, a more efficient synthesis than those of Hale[35] (2008), Keck (2013), Masamune[36] (1990), and others.

Krische allylation in Krische's bryostatin 7 synthesis

In 2012, De Brabander applied the Krische bisallylation to his synthesis of psymberin in 17 LLS and 32 total steps, as shown below.[37] Through the use of the Krische allylation, this synthesis was accomplished via a much shorter route than previous syntheses of the molecule.

De Brabander synthesis of Psymberin

In 2016, Tao employed the Krische allylation to his synthesis of callyspongiolide using the chiral SEGPHOS catalyst complex.[38]

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References
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  2. Strategies and Tactics in Organic Synthesis, Volume 10 Michael Harmata Ed.
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  37. Feng, Yu; Jiang, Xin; De Brabander, Jef K. (2012-10-17). "Studies toward the Unique Pederin Family Member Psymberin: Full Structure Elucidation, Two Alternative Total Syntheses, and Analogs". Journal of the American Chemical Society. 134 (41): 17083–17093. doi:10.1021/ja3057612. PMC 3482988. PMID 23004238.
  38. Zhou, Jingjing; Gao, Bowen; Xu, Zhengshuang; Ye, Tao (2016-06-08). "Total Synthesis and Stereochemical Assignment of Callyspongiolide". Journal of the American Chemical Society. 138 (22): 6948–6951. doi:10.1021/jacs.6b03533. PMID 27227371.
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