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Enantioselective protonation. protonation as the enantio-determining step. Brian M. Stoltz. Nature Chemistry, 2009 ,1, 359. Song jin 2010-12-18 Gong group meeting. Important factors in achieving enantioselective protonation.

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Enantioselective protonation

protonation as the enantio-determining step

Brian M. Stoltz

Nature Chemistry,2009,1,359

Song jin


Gong group meeting


Important factors in achieving enantioselective protonation

﹡ A fundamental method for generating a tertiary carbon stereocentre

is to deliver a proton to a carbanion intermediate.

﹡Principal: enantioselective protonations are necessarily kinetic processes, because under thermodynamic control a racemate would be formed.

match the pKa of the proton donor and the product to prevent racemization before product isolation


Approaches for non-enzymatic enantioselective protonation

opportunities for asymmetric induction:

1.The use of a chiral Brønsted acid

(Enantioselective protonation by a chiral proton donor)

2. Generation of a chiral protonacceptor intermediate

(Enantioselective protonation by a chiral Brønsted base).

1.Chiral proton

2.Chiral carbanionintermediate


Enantioselective protonation by a

chiral proton donor

1.Chiral proton

2.Chiral carbanion intermediate

1.stoichiometric chiral proton source

substrates :lithium enolates (a, b)

a: Kim's enolate protonation

﹡ A π–π-stacking interaction between the substrate and rigid proton source was proposed


J. Org. Chem. 2004, 69, 5104-5107


b: Eames's enolate protonation


enolates and proton sources

can form an organized transition state that is

guided by lithium chelation

Bull. Chem. Soc. Jpn.,2005,78, 906–909


1.stoichiometric chiral proton source

substrates : Enolate intermediates enolates accessed through decarboxylation(c)

c: Rouden's decarboxylative protonation

Proton donors :

derived from Cinchona alkaloids

alkaloid derivatives :dual-purpose reagents

1: they deprotonate malonate hemiester

substrates and promote a decarboxylation event

2: the formed B*H served as a proton donor



2. catalytic chiral proton source

Stoichiometric to catalytic ?

Choose an appropriate stoichiometric proton source

a :Levacher's enol silane protonation


form a cinchonium fluoride

﹡ Deuterium labelling studies

﹡ The fluoride anion of this active catalyst then activates the silyl group to facilitate proton delivery from the ammonium cation

Angew. Chem. Int. Ed.2007, 46, 7090 –7093


a :Levacher's enol silane protonation

Past :using a ‘latent source of HF’

Now :using a carboxylic acid

the same :activation silyl enolate 2by means of fluoride or carboxylate anion.



b: Yanagisawa's enol silane protonation



EtOH as a proton donor

i-PrOH as a proton donor


methanol as a proton donor



the chiral Lewis acidic Ag∙BINAP complex binds methanol to generate a potent chiral

Bronsted acid

Angew. Chem. Int. Ed. 2005, 44, 1546 –1548


c. Yanagisawa's lithium enolate protonation

A*H: 1.0eq A*H=1 ee:8-13

A*H=proline ee:1

BHT ee:76 -80

phenol ee:7

(S)-BINOL ee:9

2,2,6,6-tetramethyl-3,5-heptadione ee:56

﹡ using a chiral Brønsted acid (0.1 equiv) in DMF at -78 °C for 5 min. Then, a solution of an achiral proton source(1 equiv) in THF was added (over a period of 2 h) at -78°C.

OL. 2006, 8, 1721-1724


﹡ Higher reactivity of A*-Li than that of the lithium enolate toward A-H is the key to success in the catalytic cycle.

﹡ both the catalyst 1 and BHT possess appropriate pKa values and BHT also has enough steric bulkiness to avoid the quick reaction with the lithium enolate, the catalytic cycle is considered to take place smoothly.


d: Yamamoto's enol silane protonation

﹡In the absence of an achiral proton source, even though a stoichiometric amount of chiral Brønsted acid was used, no reaction was observed even after 2 days.

Without PhOH, the desilylation was very slow because the affinity of the resultant conjugate base [A]- to the silicon is quite low.

J. AM. CHEM. SOC. 2008, 130, 9246–9247


e: Rueping's quinoline reduction/protonation

﹡phosphoric acid: chiral proton souce

Hantzch ester :an appropriate achiral stoichiometric proton source

Adv. Synth. Catal.2008, 350, 1001 – 1006

Organocatalytic Transfer Hydrogenation of Quinolines

Angew. Chem. Int. Ed.2006, 45, 3683 –3686



H- (hydride ion) addition

in the chiral center generationstep

Angew. Chem. Int. Ed.2006, 45, 3683 –3686



H+addition in the chiral center generationstep

﹡Regeneration of the chiral proton source was made by using Hantzsch ester as the achiral proton source.

Adv. Synth. Catal.2008, 350, 1001 – 1006


f: Deng's conjugate addition/protonation

﹡protonation for the generation of 1,3-stereocenters with excellent ee and dr

﹡higher diastereoselectivity afforded by QD-1a than DABCO(dr =1.2:1) and other cinchona alkaloids ,the stereoselective protonation is due to catalyst control by QD-1a, not thesubstrate control by the quaternary stereocenter formed in the nuclephilic addition.

J. AM. CHEM. SOC. 2006, 128, 3928-3930


Cinchona alkaloid derivative is proposed to serve two functions:

1.activating the Michael acceptor for addition

2.serving as the chiral Bronsted acid for the protonation of the nitrile-stabilized carbanion intermediate.


g: Tan's conjugate addition/protonation

Angew. Chem. Int. Ed. 2008, 47, 5641 –5645

h: Hénin/Muzart Norrish type II fragmentation/protonation

loss of isobutylene

﹡ An unusual technique to generate an enol in situ

Tetrahedrm , 1994, 50, 2849-2864.


i: Fu's addition of hydrazoic acid to ketenes followed by Curtius rearrangement

Curtius rearrangement

the protonated catalyst serves as a chiral Bronsted acid

Problem: rapid uncatalysed background reaction even at low temperatures,

Solution: use sterically large ketenes

Angew. Chem. Int. Ed. 2007, 46, 4367 –4369


Enantioselective protonation by a chiral Bronsted base

﹡The use of nucleophilic heterocycle catalysts to generate chiral proton acceptors.

a: Fu's addition of alcohols to ketenes

chiral proton acceptors

J. Am. Chem. Soc. 1999, 121, 2637-2638


﹡ catalyst did not appreciably

deprotonate methanol in solution.

﹡ catalyst did deprotonate HN3 in solution.

﹡Cat Bronsted basicity :2<1

acidity of the [H-catalyst*]:2>1

ee <5%



b :Rovis' protonation of chloroenolates

J. AM. CHEM. SOC. 2005, 127, 16406-16407


c :Scheidt's protonation of homoenolate equivalents

﹡the site of protonation is relatively distant from the chiral control element.

Synthesis. 2008,1306–1315


Conjugate addition/protonation sequences

catalysed by chiral metal complexes

a :Conjugate addition/protonation reactions catalysed by Rh•bis(phosphine) complexes


Metal-catalysed 1,4-additions


b :Divergent pathway consisting of β-hydride elimination, H-transfer, andprotonation

Angew. Chem. Int. Ed.2004, 43, 719 –723

(Article) J. AM. CHEM. SOC.2008, 130, 6159–6169


﹡ Deuterium labelling studies

﹡did not proceed via a direct protonation

of the rhodium enolate

Improved mechanism:

Hydride transfer

Chiral center generation

β-hydride elimination


(Article) J. AM. CHEM. SOC.2008, 130, 6159–6169


c :Conjugate addition/protonation with a nitrogen nucleophile catalysed by palladium

OL, 2005, 7, 2571-2573

d :Friedel–Crafts-type conjugate addition followed by enantioselective protonation

Sibi . Angew. Chem. Int. Ed. 2008, 47, 9913 –9915


Transition metal-catalysed enantioselective protonation reactions by means of chiral metal enolates

a :Trauner's Nazarov cyclization/enantioselective protonation

﹡pericyclic reaction :A distinct method of accessing a chiral metal enolate

a chiral metal enolate

﹡ R ≠ H, low diastereoselectivity

low stereoselectivity in the electrocyclization step

but high selectivity in the protonation step

Dirk Trauner. J. AM. CHEM. SOC. 2004, 126, 9544-9545


Contrast reaction:

Adv. Synth. Catal.2009, 351, 78–84


b :Palladium-catalysed decarboxylative protonation reactions

﹡decarboxylation of β‑ketoesters: a method accessing a chiral metal enolate.

intercept this intermediate

with an alternative electrophile, namely, a proton.

Brian M. Stoltz

J. AM. CHEM. SOC. 2004, 126, 15044-15045

J. AM. CHEM. SOC. 2006, 128, 11348-11349


c :Gadolinium-catalysed protonation reactions

﹡ the reaction proceeds via transmetallation from Si to Gd, and that this step is rate-limiting.

﹡ conjugate addition of cyanide to N‑acryloyl pyrroles

J. AM. CHEM. SOC. 2009, 131, 3858–3859



﹡ Useful transformations including natural products such as

α‑ andβ‑amino acids

﹡ Mechanistic understanding remains immature.