Development of and Recent Advances in Pd-Catalyzed

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Development of and Recent Advances in PdCatalyzed Decarboxylative Asymmetric Protonation Cian Kingston, Jinju James, and Patrick Jerome Guiry J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02478 • Publication Date (Web): 30 Oct 2018 Downloaded from http://pubs.acs.org on November 1, 2018

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The Journal of Organic Chemistry

Development of and Recent Advances in Pd-Catalyzed Decarboxylative Asymmetric Protonation Cian Kingston,a,b† Jinju James,a† and Patrick J. Guirya,b* a Centre for Synthesis and Chemical Biology; b Synthesis and Solid State Pharmaceutical Centre, School of Chemistry, University College Dublin, Belfield, Dublin 4 (Ireland) † The authors contributed equally to the synopsis Abstract Graphic O

Pd, PPh3 HCO2H/NEt3

H

O

R

2006 2008

Pd(PPh3)4 (1R,2S)-(−)ephedrine O

O

H R

O

1985 Racemic R = H, alkyl carbocyclic

Pd (S)-t-Bu PHOX

O

R

Formic acid Meldrum’s acid up to 95% ee R= alkyl, allyl, Ph, Bn, Halogen

H R Development

1992

2018

up to 38% ee R= alkyl

up to 92% ee R= aryl

Enantiodivergence Applications

Abstract Decarboxylative asymmetric protonation (DAP) is a mild and efficient synthetic tool for the catalytic asymmetric formation of tertiary stereocentres adjacent to a carbonyl group. The development of the methodology from the initial racemic report to recent asymmetric examples are summarized. The discovery of an enantiodivergent Pd-catalyzed DAP, in which the choice of the achiral proton source determines the stereochemical outcome, is highlighted. Furthermore, the mechanism of Pd-catalyzed DAP, investigated since the initial report, is also discussed.

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1. Development of the Achiral Decarboxylative Protonation The development of new methods for the asymmetric synthesis of target molecules is a key area of organic chemistry.1 Transition metal-mediated asymmetric catalysis, wherein the stereoisomeric products are formed in unequal amounts, has many advantages and plays an important role in modern synthetic chemistry.2 Alkylation of β-keto esters, followed by hydrolysis of the ester and decarboxylation, is a convenient method for the regioselective generation of mono or di-α-alkylated ketones.3 In 1985 Tsuji reported the palladiumcatalyzed decarboxylative protonation as a mild alternative to the contemporary (often harsh) conditions to remove the ester moiety. Hydrogenolysis of a variety of cyclic and acyclic allyl β-keto esters 1 using a palladium catalyst and tertiary amine salts of formic acid was carried out in excellent yields of up to 92 % (Scheme 1).4 The mild reaction conditions proved tolerant of a variety of functional groups on the α-substituent including acetal, tetrahydropyranyl ethers and ester substituents. The methodology was subsequently extended to substituted allyl malonates to form the corresponding monocarboxylic acids and esters.5 Similarly levels of functional group tolerance were observed, with yields up to 96 %. Formic acid has displayed unique properties compared to other hydride donors when it comes to palladium chemistry.4e In the report by Tsuji, the choice of proton source was crucial to form the protonated products 2, as the use of sodium acetate or morpholine instead of ammonium formate led to the formation of α-allyl ketones.4a In a later report, Tsuji also proposed a catalytic cycle wherein oxidative addition of the Pd0 catalyst to the βketo allyl ester 1 forms an allyl Pd-carboxylate complex 3 (Scheme 1). Tsuji favoured Pdassisted decarboxylation to form a Pd-bound enolate 4, which is protonated by the ammonium formate 5 to generate the desired product 2.6 A second decarboxylation and reductive elimination regenerates the catalyst and expels propene 8 as a by-product.

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O

R

Method A: Pd(OAc)2 (2.5 mol%) PPh3 (5.0 mol%) HCO2H/NEt3, THF, rt

O O

O

R

Method B: Pd(OAc)2 (2.5 mol%) PPh3 (5.0 mol%) HCO2NH4 (2.0 eq.), dioxane, reflux

1

H

2 up to 92% yield

Proposed Mechanism O

R

O O

8

1

[Pd] Reductive elimination H

Oxidative addition O

[Pd]

R

O O

7

3 Decarboxylation

Decarboxylation

CO2

[Pd]

CO2 O

O [Pd] H

R [Pd]

O 6

4 Protonation O

R H

HCO2H/NR3 5

2

Scheme 1. Racemic decarboxylative protonation by Tsuji However, Shimizu reported a slightly modified reaction mechanism to Tsuji’s initial hypothesis in their work on the synthesis of α-fluoroketones 10 (Scheme 2).7 They favoured a mechanism where the formate (produced in situ from formic acid) displaces the carboxylate ligand from the Pd-centre in 11. The β-keto acid 12 formed by protonation of carboxylate in solution, is then proposed to undergo decarboxylation followed by tautomerization of the enol to produce the racemic ketone product 10. In support of their mechanism, they reported that the putative complex 6 was synthesized via anionic ligand exchange of palladium acetate with silver formate. This Pd-allyl formate 6 complex is proposed to undergo decomposition to yield CO2, propene and the active Pd catalyst.8 The Pd hydride species 7 was not isolated or observed, but this may be due to its transient nature. Tsuji also suggested an alternative mechanism, where the decarboxylation and

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reductive elimination is a concerted process that does not require the formation of a palladium hydride species (Scheme 3).9 O

F

Pd cat. (2.5 mol%) HCO2H/NEt3 (4.4 eq.)

O O

O

H F

dioxane

9

10 up to 93% yield

Proposed Mechanism O

F

O O

8

9

[Pd] Reductive elimination

Oxidative addition O

[Pd] H

F

O [Pd]

O 7

11

HCO2H

Ligand exchange

Decarboxylation

5

CO2 O

Decarboxylation

[Pd] H

O

O 6

F

O OH

O

-CO2

F H

10

12

Scheme 2. Racemic decarboxylative protonation of α-fluoroketones by Shimizu

O

H

[Pd] H

O

[Pd] O

O

-CO2 -[Pd]

6

8

Scheme 3. Alternative concerted decarboxylation and reductive elimination pathway. 2. Initial Progress Towards Decarboxylative Asymmetric Protonation (DAP) The first report of an asymmetric variant of decarboxylative protonation was by Muzart in 1992.10 This work was built on their previous experience with asymmetric protonation of

4


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simple photochemically derived enols.11 Chiral amino alcohols such as ephedrine 15 were used as the protonating agent to achieve enantioselective protonation of α-substituted allyl enol carbonates 13 or β-keto allyl esters 14. Variable yields and enantioselectivities (up to 50% ee) were obtained depending on the type of substrate used (Scheme 4).10, 12 Muzart also demonstrated that similar results could be obtained with catalytic amounts of amino alcohol by using a debenzylation strategy for benzyl enol carbonates.12 Subsequent papers on this topic by Muzart ruled out a kinetic resolution as a reason for the observed enantioselectivity because racemic β-keto allyl ester 14 was recovered when the reaction was carried out to incomplete conversion.13 Initial reports by Muzart described the enantioselective step occurring via a nine-membered ring intermediate 18 formed by polar interactions between the common enol intermediate 17 and ephedrine (Scheme 5, A, pathway A).10 Further mechanistic studies led them to propose a mechanism that involved an ammonium enolate 19 (Scheme 5, A, Pathway B).14 It was suggested that the discrimination between the two faces of the enolate (19a vs. 19b), through steric interactions between the bulky groups on ephedrine and the aromatic skeleton of the substrate, gave rise to the moderate enantioselectivities observed (Scheme 5, B). Pd Source (0.5 eq.) Me OCO2Allyl R

O

n

13

O

MeHN OH 15 (2.0 eq.)

CO2Allyl R

or

Ph H

n

n

14

16 up to 99% yield up to 50 % ee

Scheme 4. General scheme for amino alcohol-mediated DAP

R

*

5



Me

A MeN H H O

H

Pathway A

Ph O

Me n

18 O H

OH Me

Me n

17

Me

Ph

H2 MeN

n

OH

16

O

Pathway B

Me n

19 B Ph H O

O H Me n

H H O

Ph H O NMeH Me

Me O

NMeH Me

H

Me

n

(R)-16

O H Me

))

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H

n

n

19a

19b

(S)-16 minor product

major product

Scheme 5. Proposed pathways in the amino alcohol-mediated DAP by Muzart The development of the palladium-catalysed DAP now provided an alternative to existing methods of asymmetric protonation for the formation of α-tertiary stereocentres. This transformation is of particular interest to practitioners of total synthesis and medicinal chemistry due to the range of target molecules possessing this structural motif. There are many challenges associated with asymmetric protonation: (a) the requirement to match the pKa of the proton donor and the product to prevent racemization before product isolation; (b) the ability to generate pro-chiral, sp2 hybridized substrates for protonation; (c) lack of mechanistic details to assist in reaction development.15 Generally, asymmetric protonation is achieved via a chiral enolate, a chiral Brønsted acid or a combination of the two. By using βketo esters for the regioselective alkylation and then their enantioselective removal, the possibility of over-alkylation is diminished. However, the application of Muzart’s synthetic approach employing chiral amino alcohols was hampered by somewhat low enantioselectivities. In Tsuji’s proposed mechanism for the racemic protonation (Scheme 1), a synthetically

6


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useful transition metal enolate 4 is regiospecifically generated upon decarboxylation under neutral conditions.16 In 2006, the Stoltz group realized an opportunity to expand on their previous decarboxylative asymmetric allylic alkylation (DAAA)17 work by intercepting the intermediate enolate associated with the chiral Pd complex 21 with an alternative proton source (Scheme 6, A).18 In the enantiodetermining step, formic acid was used as an achiral proton source to intercept this highly organized Pd-enolate intermediate leading to the formation of tertiary centres with high enantioselectivities of up to 95 % ee (Scheme 6, B). A variety of chiral ligands were also examined and it was found that chelating P,N-ligands were most effective. Generally, an excess of formic acid was required to prevent allylated product formation. However, too much formic acid led to a decrease in enantiomeric excess. These factors were also affected by the quantity of molecular sieves (MS) in the reaction, added to sequester any residual water from commercially available formic acid. Large amounts of MS increased the production of allylated product while small amounts decreased the ee values. In the substrate scope studies, fused aromatic and monocyclic substrates produced moderate to excellent levels of enantioselectivity. A variety of alkyl, benzyl, allyl, and fluoro substituents were tolerated at the α-position. Mechanistically, the authors aligned with Tsuji’s initial proposal, which favoured protonation of a Pd-allyl enolate species. Deuterium labelling studies were inconclusive in determining the fate of the formyl proton or the exact reaction pathway due to low levels of D incorporation (Scheme 6, C).

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*

A

P O

R

O

O

Pd2dba3, chiral ligand

O

N Pd O

R

Me

20

21

22 O

DAP

R

H+

H

23 B O Ph2P

N tBu

24: (S)-t-Bu-PHOX

O

X

R

CO2Allyl n

Y

O

Me CO2Allyl

O

H

4Å MS, 1,4-dioxane, 40 °C R = Me, Et, F, allyl, Bn X = Me, OMe Y = CH2, NBn n = 1,2

25

C

Pd(OAc)2 (10 mol%) (S)-24 (12.5 mol%) HCO2H (5-8 eq.)

X

Y

R n

26 up to 99% yield up to 95% ee

Pd(OAc)2, (S)-24 Labelled formic acid

O

H/D Me

4Å MS, 1,4-dioxane, 40 °C 20a

23a HCO2D: 35% D incorporation DCO2H:

Development of and Recent Advances in Pd-Catalyzed

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