1) Binaphthol catalysts enable stereoselective Petasis reactions between salicylaldehydes and arylboronate esters, providing chiral amines in high yields and enantiomeric excesses. 2) Investigation of the reaction mechanism found that the cyclic bidentate binaphthol phenylboronate ester was not an intermediate. Instead, the reaction likely proceeds through acyclic intermediates involving binaphthol, boronate ester, and amine components. 3) Quantum chemical calculations support a mechanism where the rate-determining step is rearrangement of an iminium intermediate, which determines the reaction stereochemistry.

1. Binaphthol-catalyzed Petasis Reaction of Salicyaldehydes and Boronate Esters and Mechanism
Xianglin Shi, Istvan Enyedy, Lauren Blair, Lloyd Franlin, John Guzowski, April Hou, William F. Kiesman, Donald Walker, Maria Wu
Chemical Process Research & Development, Biogen, Cambridge, Massachusetts
GRC Organic Reactions & Processes, Stonehill College, Easton, Massachusetts, July 17-22, 2016
Abstract
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4 Acknowledgements
Michelle Lynn Hall, Ph.D. Scheodinger
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Catalytic asymmetric Petasis reactions of salicylaldehydes with arylboronates and secondary
amines, in the presence of 4Å molecular sieves and (S)-3,3’-dimethylbinaphthol (20-mol%),
afforded the corresponding chiral amines in 47−97% isolated yield and up to 99% ee. Comparison
of the reaction rate and product ee of arylboronate esters with different electronic property
provided some insight into the reaction mechanism.
Binaphthols also catalyze stereoselective addition reactions of aryl-, vinyl-, allylboronate
esters to other electrophiles; therefore, the mechanism has wide implications. NMR experimental
and computational investigations showed the transesterification reaction between PhB(OBu)2 and
BINOL was unfavorable, contradictory to what generally believed, but occurred rapidly in the
presence of an amine. Furthermore, the cyclic bidentate BINOL phenylboronate ester was unlikely
an intermediate on the catalytic pathway due to its high energy. This investigation indicated the
catalytic reaction probably went via intermediates including acyclic [BINOL-PhB(OBu)2] .H2NEt2,
[BINOL-PhB(OBu)(salicylaldehyde)].H2NEt2, BINOL-PhB(salicylaldehyde hemiaminal), and
BINOL-PhB(OH)(salicylaldehyde iminium). The rearrangement of the iminium was probably the
rate and stereochemistry determining step.
Binaphthol-Catalyzed Asymmetric Petasis
Reactions of Alkenylboronates
Examples of the Asymmetric Reactions of Salicyaldehydes and
Arylboronate Esters
Reaction Characteristics and Mechanistic Consideration
• The ~99.5% ee indicated the reaction rate of the catalytic process was up to 500-folds
faster than the background reaction
• The OH on salicylaldehyde was critical; the OH was involved in the rate determining step
• The pinacol boroate ester was much less reactive, indicating that ester exchange reaction
between boronate ester and binaphthol was involved
• Electron rich arylboronate esters reacted faster than the electron poor ones; therefore, aryl
migration step was probably the rate determining step
• Binaphthols also catalyze the addition reactions of boronate esters to other types of
electrophiles and generally believed mechanisms included initial ligand exchange reaction
between the binaphthols and the boronate esters to form cyclic and acyclic intermediates
followed by stereoselectively delivery of the nucleophiles to provide the chiral products:
Ester Exchange Reaction of a Binaphthol with Boronate
Ester Seemed Slow and Catalyzed by A Lewis Base
• Partial reaction and release of EtOH were observed by 1H NMR at rt after 15 h, while the
catalytic reaction occurred at -15 oC in 35 h.
• The ester exchange was accelerated by a Lewis base PhCOMe
Lou, S. and Schaus, S. J. Am. Chem. Soc. 2008, 6922
The Ester Exchange Reaction of Binaphthols and Boronate
Esters did not Occur unless an Amine Bases were Present
• The reaction occurred rapidly at rt when an amine, for example, HNEt2 or EtN(iPr)2,
was added
• The amine components in the catalytic Petasis reaction catalyzed this transesterification
reaction
The Ester Exchange Reaction of Binaphthols and Boronate
Esters did not Occur unless an Amine Bases were Present
• The reaction occurred rapidly at rt when an amine, for example, HNEt2 or EtN(iPr)2,
was added
• The amine components in the catalytic Petasis reaction catalyzed this transesterification
reaction
11B NMR Showed Boron (III) and (IV) Species Formed from the
Ester Exchange Reaction in the Presence of an Amine Base
B NMR overlay with PhB(OBu)2 and 100016-11-7.esp
40 35 30 25 20 15 10 5 0
Chemical Shift (ppm)
-0.5
0
0.5
1.0
1.5
2.0
NormalizedIntensity
All spectra were taken in CD2Cl2.
H NMR Spectra Indicated Formation of Multiple Species
and Reversible Association of BuOH and HNEt2
NONAME00
9 8 7 6 5 4 3 2 1 0
Chemical Shift (ppm)
-1.0
-0.5
0
0.5
1.0
1.5
2.0
NormalizedIntensity
Broadening of the signals of BuOH and HNEt2 indicated their reversible association and disassociation
with B; up-field shift of HNEt2 signals showed it was located in the shielded magnetic field of the
BINOL
The signals of HNEt2 are broad and up-field shifted
BINOL+PhB(OBu)2+HNEt2 (~1:1:1 molar ratio);
BINOL+PhB(OBu)2
+iPr2NEt (~1:1:1
molar ratio)
n-BuOH
PhB(OBu)2
• Either the cyclic or acyclic BINOL
Phenylboronate esters are
unfavored thermodynamically
relative to BINOL and
PhB(OBu)2.
Cyclic BINOL Phenylboronate Ester and BINOL Afforded
Product in Similar ee and Same Stereoselectivity
Catalyst (equiv) Product ee
BINOL (0.2) 82-86
BINOL-B-Ph (0.2) 74-83
BINOL (1.0) 85-90
BINOL-B-Ph (1.0) 93-95
• Catalytic amount of BINOL gave higher ee than the cyclic BINOL phenylboronate ester, but
stoichiometric amount of cyclic boronate ester afforded highest ee
• Both resulted in the major product with (R)-configuration
• The cyclic BINOL phenylboronate ester was probably not the intermediate that determined
the stereochemistry
• Formation of acyclic and cyclic BINOL phenylboronate esters is thermodynamically unfavored
• Consistent with the NMR experimental results; V and VII may not be involved in the reaction
pathway
Quantum Chemical Calculations
Reaction Pathway Involved Low Energy BINOL Phenylboronate
Ester Amine Salts
The Hemiaminal Led to Iminium that Determined the Reaction
Stereoselectivity
Transition States and Activation Energies of XIVPreS vs. XIVPreR
TSR
65.3
XIVpreR
41.2
TSS
47.7
XVR
1.1
XVS
0.0
RelativeEnergy(kcal/mol)
Reaction Coordinate
XIVpreS
32.5
TSS TSR
The Roles of the Amine in the Reaction
• Amine stabilize the products via charge
and H-bond interactions
• Amine reduced the energy barrier of the
proton transfer step, rate determining step
of the transesterification reaction (Wulff,
G.; Lauer M.; Bohnke, H. Angew. Chem.
Int. Ed.Engl. 1984, 741)
BINOL+PhB(OBu)2+iPr2NEt
(~1:1:1 molar ratio);
BINOL+PhB(OBu)2+ HNEt2
(~1:1:1 molar ratio)
PhB(OBu)2
All spectra taken in CD2Cl2
All spectra taken in CD2Cl2
BINOL
PhB(OBu)2
BINOL-B-Ph + HOBu