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
﹡ A fundamental method for generating a tertiary carbon stereocentre
is to deliver a proton to a carbanion intermediate.
H+
X
Z
Y
﹡ 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
E
transition state
material
product
kinetic processes
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 H+
X
Z
2.Chiral carbanion intermediate
Y
Enantioselective protonation by a
H+
X
chiral proton donor
1.Chiral proton
Y 2.Chiral carbanion intermediate
Z
1.stoichiometric chiral proton source
substrates :lithium enolates (a, b)
a: Kim's enolate protonation
OH
OTMS
CH3Li
Et2O,CH2Cl2,-78℃
then cat
O
O
Cl
H
CH3
Cl
cat
﹡ A π–π-stacking interaction between the substrate and rigid proton source
was proposed
ee:3
J. Org. Chem. 2004, 69, 5104-5107
b: Eames's enolate protonation
ee:69
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
OL.2007,9,2621-2624
2. catalytic chiral proton source
Stoichiometric to catalytic ?
Choose an appropriate stoichiometric proton source
a :Levacher's enol silane protonation
ee:85
form a cinchonium fluoride
﹡ Deuterium labelling studies
RCOF + R'OD
O
Me
H(D)
Conv>95%
D%>95%
﹡ 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 2 by means of fluoride or carboxylate anion.
Snylett,2008,2447-2450
b: Yanagisawa's enol silane protonation
ee:62
EtOH as a proton donor
ee:14
i-PrOH as a proton donor ee:34
methanol as a proton donor
ee:98
ee:97
﹡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
A*H=proline
ee:8-13
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.
Possible mechanism:
HA*
OH
HA
O
OLi
HA*
1.0eq
OLi
+
*
A*Li
ee:8-10
OH
OLi
HA*
+
0.1eq
0.9eq
big enough to
prevent racemic product
racemate
HA
OLi
+
0.1eq
A*Li
0.1eq racemic product
0.1eq
1.0 eq HA
slow addition over a period of 2 h
A*
O
OLi
O
Li
H O
A
O
*
+
A*Li and ALi
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
Mechanism:
R
N
HO
O
P
ArO
OAr
N
H
H
R
O O
P
ArO
OAr
H- (hydride ion) addition
in the chiral center generation step
Angew. Chem. Int. Ed. 2006, 45, 3683 –3686
Mechanism:
+
H addition in the chiral center generation step
﹡ 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 the substrate 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%
ee:96
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
Normal Mechanism:
Ar
ORh
X
Y
Metal-catalysed 1,4-additions
b :Divergent pathway consisting of β-hydride elimination, H-transfer, and protonation
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
1,2-addition
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
Conclusion
﹡ Useful transformations including natural products such as
α- andβ-amino acids
﹡ Mechanistic understanding remains immature.