14 asymmetric allylation reactions

Myers

Chem 115

Asymmetric Allylation Reactions

Brown Allylation and Crotylation Reactions

Enantioselective Allylboration
Et2O
–78 A 23 °C;

O

Reviews:

H + (–)-Ipc2B

R

R
NaOH, H2O2

Srebnik, M.; Ramachandran, P. V. Aldrichimica Acta 1987, 20, 9.
R
Roush, W. R. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon
Press: New York, 1991, Vol. 2, pp. 1-53.
Synthesis of B-Allyldiisopinocampheylborane

H 3C

CH3
CH3

CH3

CH3
=

(1R)-(+)-_-Pinene
91.3% ee

H3B•S(CH3)2
THF, 0 °C
h,72%
72 h,
72%

BH
BH

(–)-Ipc2BH

CH3OH, 1 h
0 °C, 100%

yield (%)

ee (%)a

ee (%)b

CH3

74

93

•99

n-C3H7

71

86

-

n-C4H9

72

87

96

t-C4H9

88

83

•99

C 6H 5

81

96

96

aAllylboration carried out without filtration of
Mg salts. bAllylboration carried out at –100 °C
under Mg-salt free conditions.

2

98.9% ee

OH

• The reaction is quite general; the stereochemistry of the addition is the same in all cases
examined.
• Lower reaction temperatures (0 A –78 A –100 °C) lead to increased enantioselectivity.

CH3

BB

CH3

MgBr

2

98.9% ee

BOCH33
BOCH
2

–78 A 25 °C
25 °C, 1 h

98.9% ee

• Only Mg-salt free reagent can be used at –100 °C because the reactive borane is
sequestered by ate complex formation with CH3OMgBr at this temperature.
• Allylboration of aldehydes is essentially instantaneous at –78 or –100 °C in the absence of
Mg salts.

• Prolonged incubation at 0 °C affords enantiomerically enriched Ipc2BH. This is due to
equilibration of tetraisopinocampheyldiborane with _-pinene and triisopinocampheyldiborane; the symmetrical dimer crystallizes preferentially.

H 3C
H 3C

• Both enantiomers of _-pinene are commercially available and inexpensive.(Aldrich:
(1R)-(+)-_-pinene, 91% ee, $100/500mL; (1S)-(–)-_-pinene, 87% ee, $42/100mL).
• B-Allyldiisopinocampheylborane can be prepared and used in situ after filtration of
the magnesium salts produced during its formation.

Brown, H. C.; Desai, M. C.; Jadhav, P. K. J. Org. Chem. 1982, 47, 5065-5069.
Brown, H. C.; Singaram, B. J. Org. Chem. 1984, 49, 945-947.
Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51, 432-439.

H

H
H
H

H
CH3 H
B

O H3C
H

CH3
CH3

• Allylation of aldehydes proceeds through a
chair-like TS where R occupies an equatorial
position and the aldehyde facial selectivity
derives from minimization of steric interactions
between the axial Ipc ligand and the allyl group.

R
H

Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092-2093.
Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-5923.
Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401-404.
M. Movassaghi

1


Diastereoselective Allylboration of Chiral, _-Substituted Aldehydes

Asymmetric Isoprenylation of Aldehydes

(+)-Ipc2BH

+

•

CH3

THF

CH3

–25 °C, 6 h

(+)-Ipc2B

• The diastereofacial selectivity of the B-allyldiisopinocampheylborane reagent typically overrides
any facial preference of the aldehyde for nucleophilic attack.

CH3
CH3

• Hydroboration of allenes is an efficient method for preparing B-prenyldiisopinocamphenylboranes.
B-allyldiisopinocamphenylboranes

O

allylboration

H3C
(+)-Ipc2B

CH3
CH3

RCHO, Et2O
–78 °C, 12 h;
NaOH, H2O2

R

yield (%)

ee (%)

CH3

73

91

n-C4H9

79

92

CH2=CH

70

95

(CH3)2C=CH

85

OH

H

OH
H 3C

+

Et2O, –78 °C

H3C

81%

R
H3C CH3

O
H 3C

H3C

(–)-Ipc2BCH2CH=CH2
(+)-Ipc2BCH2CH=CH2

MATCHED:
MISMATCHED:

96

OH
H3C

allylboration
H

:
:

96

5

4
95

OH
H 3C

Et2O, –78 °C

OBz

H3C

(92% de)
(90% de)

OH
H3C

+
OBz

OBz

80%
Brown, H. C.; Jadhav, P. K. Tetrahedron Lett. 1984, 25, 1215-1218.
Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51, 432-439.

MISMATCHED:

Methallylation of Aldehydes

CH3
(+)-Ipc2BOCH3 +

Li

(–)-Ipc2BCH2CH=CH2
(+)-Ipc2BCH2CH=CH2

MATCHED:

Et2O

CH3
(+)-Ipc2B

–78 °C, 1 h

R
CH3

RCHO, Et2O
–78 °C, 12 h;
NaOH, H2O2

yield (%)
56

OH

CH3

R

n-C3H7

54

90

n-C4H9

56

91

t-C4H9

55

90

CH2=CH

57

92

6
96

(88% de)
(92% de)

• Although the stereochemical outcome of the allylboration of aldehydes using B-allyldiisopinocampheylborane is typically reagent controlled, this selectivity may be challenged with certain
substrates:

ee (%)
90

:
:

94
4

O
H 3C

H
Ph

OH

allylboration
Et2O, –78 °C

OH

+

H 3C

H 3C

Ph

Ph

72%
MISMATCHED:
MATCHED:

(–)-Ipc2BCH2CH=CH2
(+)-Ipc2BCH2CH=CH2

67
2

:
:

33
98

(34% de)
(96% de)

• The yields for methallylation of aldehydes are generally lower than in simple allylation reactions.

Brown, H. C.; Jadhav, P. K.; Perumal, P. T. Tetrahedron Lett. 1984, 25, 5111-5114.
Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51, 432-439.

Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1987, 52, 319-320.
Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54, 1570-1576.
M. Movassaghi

2


Chair TS's Produce syn Adducts from (Z)-Crotylboranes and anti Adducts from (E)Crotylboranes.

(Z)-Crotylboranes

CH3

H3C

(–)-Ipc2BOCH3

n-BuLi, KOt-Bu

H3C

K CH
3

THF
–45 °C

CH3 OCH3
–
B
2

K

–78 °C

+

CH3

BF3•OEt2
–78 °C
H3C
H

H

H
H

B

H

Ipc

"(Z)-crotylborane"

H3C

H
H3C

H

H
CH3 H
B
O H3C

H

B
2

CH3
B

aldehyde

NaOH, H2O2

yield (%) A:B

CH3

ee (%)

"syn adduct"

H3C

H

CH3

R

CH3
A

CH3

CH3

O H3C
R
CH3

R

RCHO
–78 °C;

OH
+

R

CH3

CH3 H

H

OH

OH

OH
CH3

–

CH3CHO

75

+

CH3CHO

72

–

C2H5CHO

70

+

C2H5CHO

78

–

CH2=CHCHO

63

95:5

90

–

C6H5CHO

72

94:6

88

R

CH3

CH3

95:5
4:96
95:5
4:96

90
92
90
92

R
H
"(E)-crotylborane"

"anti adduct"

• The crotylboranes are used immediately after decomplexation of methoxide from the ate
complex by BF3•OEt2 at –78 °C to avoid crotyl isomerization.
"Superbases" for Organic Synthesis

• These adducts can be viewed as protected aldol products; "deprotection" is brought about by
dihydroxylation/periodate cleavage or by ozonolysis.

Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293-294.
Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-5923.
Roush, W. R. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon

Press: New York, 1991, Vol. 2, pp. 1-53.

• The "superbase" prepared by mixing n-butyllithium and potassium t-butoxide (1:1) can metalate
hydrocarbons of low acidity, in particular olefins.
• Allylic methyl groups are much more readily metalated than allylic methylene or methine
centers.
• cis-2-alkenes generally react faster than their trans-isomers.
K
R2
• The large atomic radius of potassium favors !3-bonding
in allyl, crotyl and prenyl derivatives:

R1

R1, R2 = H, CH3
Schlosser, M. Pure & Appl. Chem. 1988, 60, 1627-1634.
Schlosser, M.; Stahle, M. Angew. Chem., Int. Ed. Engl. 1980, 19, 487-489.
M. Movassaghi

3


(E)-Crotylboranes

H3C

CH3

Diastereo- and Enantioselective vic-Diol Synthesis

n-BuLi, KOt-Bu

CH3

THF
–45 °C

CH3 OCH3
–
B

(–)-Ipc2BOCH3

2

K

–78 °C

K

CH3

(–)-Ipc2BOCH3

s-BuLi

OCH3

+

THF, –78 °C

Li

OCH3

CH3 OCH3 Li +
–
B
2

BF3•OEt2
–78 °C
OH
+

R

B

R

CH3
C

2

CH3
D

Ipc

aldehyde

yield (%)

–

CH3CHO

78

+

CH3CHO

76

–

C2H5CHO

70

+

C2H5CHO

69

–

CH2=CHCHO

65

–

C6H5CHO

79

NaOH, H2O2

C:D
95:5

BF3•OEt2
–78 °C

CH3

RCHO
–78 °C;

OH

ee (%)

CH3

CH3 O
B
2

OH
NH2

B

RCHO, –78 °C;

+ R

+ R
OCH3
E

(crystalline)

CH3

OH

2

OCH3
F

• Treatment of the crude product mixture with ethanolamine allows for easy removal of the
reagent by-product as a crystalline adduct; this is an alternative to oxidative work-up.

90
Ipc

aldehyde

yield (%)

E:F

ee (%)

90

–

CH3CHO

57

95:5

90

92

+

CH3CHO

59

95:5

90

–

C2H5CHO

65

94:6

88

+

C2H5CHO

68

–

CH2=CHCHO

63

94:6

88

–

C6H5CHO

72

95:5

90

95:5
4:96

OCH3

HOCH2CH2NH2

92

4:96

OCH3

–78 °C

• The crotylboranes are used immediately after decomplexation of methoxide from the ate

complex by BF3•OEt2 at –78 °C to avoid crotyl isomerization.

4:96
96:4
5:95

92
92
90

• Other vinyl ethers may be used, such as methoxymethyl vinyl ether (affording the
MOM-protected vic-diol).
Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293-294.
Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919-5923.
Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988, 110, 1535-1538.

M. Movassaghi

4


Preparation of (E)- and (Z)-Crotylboronate Reagents

Roush Allylation and Crotylation Reactions
Roush, W. R. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon
Press: New York, 1991, Vol. 2, pp. 1-53.
Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112, 6348-6359.
Roush, W. R.; Halterman, R. L. J. Am. Chem. Soc. 1986, 108, 294-296.

O

B

• The stability of allylboronate reagents permits their purification by distillation. Allyl
diisopinocamphenyl reagents cannot be distilled.

+

O

THF
–78 A –25 °C
45 min

toluene

CO2i-Pr

yield (%)

ee (%)

n-C9H19CHO

86

79

c-C6H11CHO

77

78

C6H5CHO

78

71

HR

FAVORED

R

CH3

O

CO2i-Pr

3 •99% Z

70-75 %

H

O

R

OR
H
H

O
B O
O

H

OH

OR

DISFAVORED

OH
+ R

R
–78 °C, 4Å-MS

CH3

R

reagent

yield (%)

n-C9H19

2

90

n-C9H19

3

70

c-C6H11

2

94

c-C6H11

3

90

TBSOCH2CH2

2

71

TBSOCH2CH2

3

68

aee

CH3
anti:syn
95:5
1:>99
>99:1
2:98
•98:2
2:•98

ee (%)a
86
77
86
83
85
72

of major diastereomer.

OH

OH
R

2. 1N HCl, Et2O
3. DIPT, MgSO4

(R,R)-2 or (R,R)-3
toluene

O

H

OR
H

H

H 3C K

O
B

• Essentially identical results are obtained with a range of commercially available tartrate esters
(CH3, Et, i-Pr).

O

O
O B O O

1. B(Oi-Pr)3
–78 °C

• Competition experiments have shown that (E)-crotylboronates react faster with aldehydes
than the corresponding (Z)-isomers.

Proposed Origin of Selectivity in Tartarate
DerivedAllylboronate
AllylboronateAdditions
Additions
Tartrate Derived

H

70-75 %

• Tartrate
modified (E)- and (Z)-Crotylboronates can be stored for several months at –20 °C in
Tartrate-modified
neat form or in solution with little noticeable deterioration.

R

–78 °C, 4Å-MS

aldehyde

OR
H

H

2 •98% E

OH

• Enantioselectivities are typically moderate.
• 4Å-MS are necessary to achieve the highest levels of selectivity.

O

Pr
CO2i-Pr

O

• Crotylboronates are configurationally stable at or slightly above room temperature.

CO2i-Pr
H

H3C

2. 1N HCl, Et2O
3. DIPT, MgSO4

n-BuLi, KOt-Bu
CH3
CH3

R

THF
–78 A –50 °C
15 min

H 3C

O
B

CO2i-Pr

77%

O
B

n-BuLi, KOt-Bu

CO2i-Pr

1. B(Oi-Pr)3
–78 °C

CO2i-Pr

O

2. 2N HCl, Et2O

3. (+)-DIPT, MgSO4

O

CH3

CO2i-Pr

1. B(OCH3)3
Et2O, –78 °C

MgBr

H 3C

K

R

• The favored transition state is believed to minimize unfavorable lone-pair
lone-pair
lone pair-lone
pair
interactions.
Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985, 107, 8186-8190.

Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R. L. J. Am. Chem. Soc. 1990,
112, 6339-6348.
Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J. J. Org. Chem. 1987, 52, 316-318.
M. Movassaghi

5


(–)-Bafilomycin A1:

Reaction of Tartrate-Derived Allyl- or Crotylboronates with Chiral Aldehydes

MATCHED:

CO2i-Pr

CO2i-Pr

CH3
OTBS

OHC

O
B

+

CH3
CO2i-Pr

O

OTBS

OH
71%, 78% de

MISMATCHED:

CO2i-Pr

CH3

O
B

OTBDPS +

OHC

O

MATCHED:

+

H 3C

CH3

OTBS

OHC

+

O
B

H 3C

O

CO2i-Pr

MATCHED

H 3C

OTBDPS +

O
B

H 3C

O

CO2i-Pr

+

OHC

(R,R)-2

OPMB
CH3

1. (S,S)-2
(S,S)-1, Toluene
–78 °C
2. TBSOTf
MISMATCHED

85%, •96% de

(R,R)-1, Toluene
(R,R)-2
–78 °C, 8 h
92%, 70% de

OTBS
DMPO

OTBS

OH

H 3C

OPMB
CH3 CH3

CO2i-Pr

CH3

O
B

CH3 CH3
OH
80%, 94% de

MISMATCHED:

CO2i-Pr

DMP = 3,4-dimethoxyphenyl

CO2i-Pr

CH3

CO2i-Pr

O

(S,S)-2

OTBDPS
OH
72%, 74% de

OHC

CHO

H 3C

CH3
CO2i-Pr

O
B

DMPO

CH3 CH3

CH3 CH3
O

CO2i-Pr

OTBDPS
OH
85%, 76% de

MATCHED:

CO2i-Pr

CH3
OHC

OTBS

O
B

+

CH3 CH3
O

CO2i-Pr

OH
71%, 90% de

CH3
MISMATCHED:

TESOTBSO

OH

OH
B(OH)2

H3C
CH3

O
B

OTBDPS +

CO2i-Pr

CH3

1. Pd(PPh3)4, TlOH
THF, 23 °C, 30 min
65%
2. KOH, 1,4-dioxane;
2,4,6-trichlorobenzoyl chloride,
i-Pr2NEt, THF;
DMAP, toluene, reflux
52%

OTBS
OH
28% de

• All reactions were performed in toluene at –78 °C in the presence of 4Å-MS.
CH3O
O
O TBSO

Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985, 107, 8186-8190.
Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J. J. Org. Chem. 1987, 52, 316-318.

CH3 CH3 CH3 CH3 OCH3

CH3 OCH3

CH3 CH3
O

CO2CH3

I

+

CO2i-Pr

CH3
OHC

OTBS

CH3 CH3
OTES

O

H 3C

H 3C
CH3

CH3 OCH3

CH3
M. Movassaghi

6


CH3O

TBSO
H 3C

OTES

O
O TBSO

O
+

H

CH3 CH3

O

OH
OH

Catalytic, Enantioselective Addition of Allylsilanes to Aldehydes

H 3C

H 3C
CH3 OCH3

CH3

CH3 CH3

(S)-(–)-BINOL

CH3

1
O
1. TMSCl, Et3N, LHMDS
CH2Cl2, –78 °C, 30 min
2. 1, BF3•OEt2, –78 °C, 30 min

R

H

+

Si(CH3)3

1. (S)-(–)-BINOL (20 mol%)
TiF4 (10 mol%)
CH2Cl2, CH3CN, 0 °C

OH
R

2. Bu4NF, THF
aldehyde

time (h)

yield (%) ee (%)

85%
CHO

4

90

94

20

93

84

4

91

94

20

92

93

20

81a

74

PhCHO

4

85

80

c-C6H11CHO

4

72

60

PhCH2CH2CHO

4

69

61

H3C CH3
CH3O

TBSO
H 3C

O
OH OTBSO

CH3 CH3
OTES

O

H 3C

CH3 CH3 OCH3

CH3 CH3

(CH3)3CCHO
CHO
Ph

CH3

TASF, DMF, H2O
23 °C, 4 h

TASF = [(CH3)2N]3S[(CH3)3SiF2]

CHO
TIPSO
H3C CH3

O
O

93%

H 3C
H 3C
HO

CH3
O

CH3O
O

OH O

CH3 CH3
OH
H 3C

aBased

HO

CHO
CH3

CH3 CH3 OCH3

CH3

on 25% recovered aldehyde.

• Allyltrimethylsilane initially reacts with the HF produced during catalyst preparation to give
propene and (CH3)3SiF.

(–)-Bafilomycin A1
• It is important that the reaction be conducted in the presence of small amounts of CH3CN
to solubilize the polymeric TiF4.
Scheidt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M. D.; Roush, W. R. Angew. Chem., Int. Ed.
Engl. 1999, 38, 1652-1655.
Roush, W. R.; Bannister, T. D. Tetrahedron Lett. 1992, 33, 3587-3590.

• _,_-Disubstituted aldehydes afford the highest enantioselectivities.

Gauthier, D. R. Jr.; Carreira, E. M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2363-2365.
M. Movassaghi

7


Enantioselective Allylation Using a Stoichiometric Chiral Controller Group

Catalytic, Enantioselective Addition of Allyltin Reagents to Aldehydes

O
R1

R2
Sn(n-Bu)3

H +

CF33
CF

(S)-(–)-BINOL (10 mol%)
Ti(Oi-Pr)4 (10 mol%)
4Å-MS

F3C
F

Ph

OH R2

FF33CC

R1
CH2Cl2, –20 °C

Ph
CF
CF33

S N B N S
O O
O
Br O
1

R1
C 6H 5

R2

time (h)

H

70

yield (%) ee (%)
88

95

R2
Sn(n-Bu)3

C 6H 5

CH3

60

75

91

c-C6H11

H

70

66

94

c-C6H11

CH3

48

50

84

(E)-C6H5CH=CH

H

70

42

89

(E)-C6H5CH=CH

CH3

12

68

87

PhCHO

C6H5CH2CH2

H

70

93

96

C6H5CH2CH2

CH3

40

97

98

i-C3H7

H

70

89

96

furyl

H

70

73

96

furyl

CH3

12

99

99

p-CH3OC6H4

CH3

48

61

93

p-CH3OC6H4CH2OCH2

H

70

81

96

BnOCH2

H

60

84

95

• Addition occurs to the re face of the aldehyde with the catalyst prepared from (R)-(+)-BINOL.

1. 1, PhCH3
23 °C

HO H R2
R1

2. R1CHO
–78 °C

aldehyde

yield (%)

ee (%)

H

92

96

PhCHO

Cl

80

90

c-C6H11CHO

H

84

92

c-C6H11CHO

Cl

76

88

R2

• Reagent 1 is produced from the corresponding (R,R)-bis-sulfonamide by reaction
with BBr3 in CH2Cl2.
• Transmetallation of allyltin reagents with the chiral B-bromoboron
B-Bromoboron reagent 1 in toluene
is complete in 3-20 h.

• This procedure allows for the efficient asymmetric methallylation of aldehydes, typically a
difficult transformation.

• The (R,R)-bis-sulfonamide can be recovered from the reaction mixture.

Keck, G. E.; Krishnamurthy, D. Org. Syn. 1998, 75, 12-18.

Corey, E. J.; Kim, S. S. Tetrahedron Lett. 1990, 31, 3715-3718.

Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467-8468.
Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993, 58, 6543-6544.
M. Movassaghi

8


Diastereoselective Allyltitanation of Chiral Aldehydes

Enantioselective Allyltitanation of Aldehydes
Ph Ph
O

HO
HO

CH3
+
Ti Cl
CH3
Cl
Cl

O

Ph Ph
(R,R)-TADDOL

Et3N, Et2O
23 °C

Ph
Cl

or
cyclohexane,
reflux

Ti O
O

Ph

Ph

O
Ph

Ph
O

O

Ph

Ph

Ph

Ph

R

O
O

Ph

M

Ti O
O

R

M = Li, MgX

CH3
CH3

Ph

Cl

Ti O
O

Ph

Ph

O
O

M

1. R1

Ph
Ti O
O

R1
Et2O, 0 °C
CH3
CH3

Ph

Ph

R1

R2

ee (%)

H
H
H
CH3
Ph
(CH3)3Si
EtO
CH3
(CH3)3Si

Ph

(CH3)2CH
CH2=CH
Ph
Ph
Ph
Ph
CH3(CH2)8
CH3(CH2)8

95
97
95
98
97
•98
95
•98
•98

H3C

H3C
:

95

5

• Exceptionally high reagent selectivity is observed in the mismatched allylation of (R)-2-phenylbutyraldehyde (90% de) (cf., (–)-Ipc2BCH2CH=CH2: 34% de).
Ph

O

2. R2CHO, –74 °C

CHO
O
H3C

yield (%)

97
•98
•98
75
•98
•98

93
88
79
89
54
68
77
86
69

• (E)-Crotyltitanation of aldehydes affords anti products, presumably by a chair-like TS.

+

O
N

H3C

Boc

CH3

R2

O 3. NH4F, H2O
CH3
O
CH3
de (%)

OH

OH
CH3
CH3

OH
Ph

OH
Ph

+

O

Ph
Ph

0.5

OH
Ph

MISMATCHED

reagent

Ph

H3C
:

99.5

H

H3C

• (E)-Crotyltitanium reagents are produced from (E)- or (Z)-crotyl anion precursors.

Ph

H3C

TiCpL(R,R)
91-94%
91–94%

Ph

+

MATCHED

• The chiral diol is readily available in both enantiomeric forms from the corresponding
tartrate esters.
• Complex formation is driven to completion by neutralization of HCl with Et3N, or by
removal of HCl by heating.
• The complex may be used in crude form, as prepared in solution, or the complex may
be crystallized and isolated.

Ti O
Cl O

91–94%
91-94%

OH

Ph

H

H3C

CH3
CH3

O

OH

TiCpL(R,R)

R1

N
CH3

O

H3C

Boc

N
Boc

CH3

yield

TiCpL(R,R)

93

98.1

1.9

TiCpL(S,S)

95

0.5

99.5

TiCp(Oi-Pr)2

89

37.3

62.7

MgCl

86

55.1

44.9

OH
CHO
O
H 3C

H 3C

TiCpL(R,R)

N
CH3

Boc

93%

O
N
CH3
CH3 Boc
a single diastereomer

H3 C

Hafner, A.; Duthaler, R. O; Marti, R.; Rihs, G.; Rothe-Streit, P.; Schwarzenbach, F. J. Am. Chem.
Soc. 1992, 114, 2321-2336.

Duthaler, R. O.; Hafner, A.; Riediker, M. Pure & Appl. Chem. 1990, 62, 631-642.
M. Movassaghi

9


Myers

Chem 115

Asymmetric Allylation Reactions
Proposed Catalytic Cycle:

Krische Allylation and Crotylation Reactions:
Hassan, A.; Krische, M. J. Org. Proc. Res. Devel. 2011, 15, 1236.
Han, S. B.; Kim, I. S.; Krische, M. J. Chem. Commun. 2009, 7278.

OAc

General Allylation Reaction:

OAc

[Ir(cod)Cl]2 (2.5 mol %)
(R)-BINAP (5 mol %)

OH

+

R
R = aryl, alkyl

m-NO2BzOH (10 mol %)
Cs2CO3 (20 mol %)
THF, 100 °C

NO2

O
P
P

IrIr O

R

OAc

+

R

H

R = aryl, alkyl

m-NO2BzOH (10 mol %)
Cs2CO3 (20 mol %)
i-PrOH (200 mol %)

THF, 100 °C

OH

III

P
P

NO2

Ir

CH3

+

R = aryl, alkyl

4-CN-3-NO2BzOH (10 mol %)
Cs2CO3 (20 mol %)
THF, 90 °C

O
O

OH
R
CH3
65-73% yield

86-97% ee
4:1 to 8:1 dr

OAc
CH3

[Ir(cod)Cl2] (2.5 mol %)
(S)-SEGPHOS (5 mol %)

O
+
H

R

R = aryl, alkyl

OH

O

O
O

O

I

NO2

Ir

Base

P
P
6

H
H

P
P

NO2

III

Ir

O
R

5

III

NO2

Ir

O
H

H

R

• The Ir catalyst 1 (generated in situ) undergoes addition to aldehyde 2 via a 6-membered chair-like
transition state to generate the IrIII alkoxide 3. This does not undergo further dehydrogenation as the
olefin is thought to occupy a coordination site, blocking !-hydride elimination.
• Ligand exchange with the reactant alcohol (or isopropanol) generates the homoallylic alcohol 4.
• The Ir alkoxide 5 undergoes !-hydride elimination to produce the IrIII hydride 6. Dissociation of the
aldehyde 2 produces an IrIII hydride which undergoes deprotonation by the base to provide the IrI
anion 7.
• Oxidative addition of allyl acetate to 7 regenerates "-allyl IrIII catalyst 1.

(S)-SEGPHOS

O

R

4

O
P
P

PPh2

PPh2

O

OH

R

R

O

7

R

NO2
O

2

General Crotylation Reaction:
[Ir(cod)Cl2] (2.5 mol %)
(S)-SEGPHOS (5 mol %)

H

OAc

III

Ir

R
3
Hexa-Coordinate
18 Electron Complex

R
O

55-80% yield
90-93% ee

P
P

O

H

R

• Couplings of primary alcohols or aldehydes with allyl acetate utilizing Ir catalysts generate
allylation products without the use of stoichiometric allyl-metal(oid) reagents.

OH

NO2

III

Ir

AcO–

TMBTP = 2,2',5,5'-Tetramethyl-4,4'-bis(diphenylphoshino)-3,3'-bithiophene

OAc

O

O

O
P
P

O

O

O

55-80% yield
90-93% ee

[Ir(cod)Cl2] (2.5 mol %)
(–)-TMBTP (5 mol %)

[Ir(cod)Cl]2

AcOH

OH

1 (X-Ray)
O

m-NO2BzOH

III

4-CN-3-NO2BzOH (10 mol %)
Cs2CO3 (20 mol %)
i-PrOH (200 mol %)
THF, 90 °C

OH
R

• To use aldehydes as substrates in lieu of an alcohol, the use of a terminal reductant (isopropanol) is
necessary for the catalytic cycle to proceed.
• Enantioselectivites are high for both alcohol and aldehyde reactants.

CH3
66-82% yield
96-98% ee
6:1 to 13:1 dr

Kim, I. S.; Ngai, M, -Y.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 6340-6341.
Kim, I. S.; Nagi, M. -Y.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 14891-14899.

Anne-Marie Schmitt, Fan Liu

10


Myers

Chem 115

Asymmetric Allylation Reactions

Stereochemical Model in Asymmetric Crotolation Reactions:
• Couplings of aldehydes display higher diastereoselectivities than with alcohols, as higher
concentrations of aldehyde promote rapid capture of the kinetically formed trans-crotyl iridium
complex.
H
R'
R'
R

[Ir] O

[Ir] O

H

R

Bis Allylation and Crotylation of Glycols

OAc

[Ir(cod)Cl]2 (5 mol %)
(S)-Cl,MeO-BIPHEP
(10 mol %)

OH OH

Cs2CO3 (40 mol %)
4-Cl-3-NO2-BzOH (20 mol %)
Dioxane (0.2 M)
90 °C

H

H

• Kinetically formed trans-crotyl
iridium complex generates the anti
diastereomer.

• Equilibration to the cis-crotyl iridium
complex causes erosion in
diastereoselectivity.

OH OH

70%, >30:1 dr
>99% ee

• Equivalent bis aldehyde counterparts are unstable or unknown.

Kim, I. S.; Han, S. B.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2514–2520.
O

Other allyl donors have been used with alcohols and aldehydes as reactants:

Ph2
Ir P
P
Ph2

O
O

O
Allyl Donor

Products Generated
OH

OBz

R

OBz

OH
OH

O

R = aryl, alkyl
58-74% Yield
93-99% ee

R

O
O

OH
OH

OBz

R = aryl, alkyl
57-80% Yield
87-99% ee

R

CF3

CF3

OH OH

CN

OH OH
R = aryl, alkyl
62-77% Yield
96-99% ee

O
O

OAc

NO2

CH3

CH3

CH3 CH3 CH3

THF:H2O (4:1, 1.6 M)
K3PO4 (100 mol %)
70 °C

pseudo-C2 symmetric
62%, >6:1 dr
>99% ee

• Predominantly 1 of 16 possible stereoisomers was formed.

• Chromatographic isolation of the pre-formed iridium catalyst allows crotylations to be run at lower
temperatures.
Application to the Total Synthesis of Roxaticin
• Catalyst Generation:
OH

OH

OBz

R = aryl, alkyl
58-78% Yield
90-99% ee

R
SiMe3

SiMe3

[Ir(cod)Cl]2

O

(R)-Cl,MeO-BIPHEP

O
Cl

OAc

NO2

Cs2CO3
Dioxane, 110 °C

Cl
OCH3

Ph2
Ir P
P
Ph2

OCH3
Cl

O
Cl
NO2

(R)-I
Generated in situ

O

O

EtO
OBoc

EtO

OH
R

R = aryl, alkyl
58-79% Yield
92-99% ee

Han, S. B.; Han, H. Krische, M. J. J. Am. Chem Soc. 2010, 132, 1760–1761.
Zhang, Y. J.; Yang, J. H.; Kim, S. H.; Krische, M. J. J. Am. Chem Soc. 2010, 132, 4562–4563.
Gao, X.; Zhang, Y. J.; Krische, M. J. Angew. Chem. Int. Ed. 2011, 50, 4173–4175.
Han, S. B.; Gao, X.; Krische, M. J. J. Am. Chem. Soc. 2010, 132, 9153–9156.
Hassan, A.; Zbieg, J. R.; Krische, M. J. Angew. Chem. Int. Ed. 2011, 50, 3493–3496.

O
O

OH
[Ir(cod)Cl]2

OAc

O

(S)-SEGPHOS
Cs2CO3
CN
THF, 80 °C
NO2

92%
(isolated via precipitation)

Ph2
P Ir
P
Ph2

O
O

O
O

(S)-II

NC
NO2

Anne-Marie Schmitt, Fan Liu

11


Myers

Chem 115

Asymmetric Allylation Reactions

Application to the Synthesis of Roxaticin, continued.
OH OH

OAc

Allylation of Epimerizable Aldehydes from the Alcohol Oxidation Level:
• Allylation of !-chiral aldehydes and "-chiral alcohols: the transiently generated aldehyde is prone to
epimerization under the reaction conditions:

OH OH

(R)-I

1.

Dioxane, 110 °C

OH OTBDPS

PPTS , (MeO)2CMe2
CH2Cl2 , 25 °C, 91%

70% Yield, >30:1 dr
>99% ee
2.

OH OTBDPS

O3, CH2Cl2:MeOH
–78 °C; NaBH4, 86%

OAc

Cs2CO3 (20 mol%)
3-NO2-BzOH (10 mol%)
THF, 100 °C

CH3

H3C CH3 H3C CH3 H3C CH3
O

OH O

O

O

O

O

OH

"Second Iteration"
1. (S)-I, Allyl Acetate, 71%
2. TBSCl, imidazole, 85%
3. O3; NaBH4, 85%
"Third Iteration"
1. (S)-I, Allyl Acetate, 78%

2. PPTS, (MeO)2CMe2, 93%
3. O3; NaBH4, 78%

3 steps

OH O

O

O

O

O

• Optimized Reaction Conditions:
"First Iteration"

OH OTBDPS
OH OTBDPS

HO

OAc

+

CH3
PMBO

OAc

K3PO4, H2O
THF, 70 ºC
85%, dr = 14 : 1

CH3

CH3

(S)-II (10 mol%)

CH3

H3C CH3 H3C CH3 H3C CH3
O

O

O

O

O

O
CH3

7 steps

HO

PMBO
CH3

OH OH OH OH OH
CH3
OH
HO

CH3

O
O

CH3

CH3
Roxaticin
20 Steps Longest Linear Sequence
29 Total Steps

Han, S. B.; Hassan, A.; Kim, I. S.; Krische, M. J. J. Am. Chem. Soc. 2010, 132, 15559–15561.

CH3
CH3

OH OTBDPS

CH3

Catalyst (5 mol%)

CH3

O

CH3
epimerized diastereomer

OH

H3C CH3 H3C CH3 H3C CH3
O

OH OTBDPS

H3C CH3

Three interations, 9 total steps

O

CH3
desired diastereomer
dr < 2 : 1

[Ir(cod)Cl]2 (2.5 mol%)
(S)-Cl-MeO-BIPHEP (5 mol%)

Cs2CO3 (1 equiv),

3,4-(NO2)2-BzOH (10 mol%)
H2O (10 equiv)
THF (0.4 M), 100 °C, 24 h
Catalyst

Yield (A : B : C : D)

III
ent-III

79% (97 : 2 : 1 : 0)
80% (4 : 94 : 0 : 2)

CH3

A

B

OH OTBDPS

OH OTBDPS

CH3

CH3
D

C

Cl
H3CO
H3CO
Cl

Ph2
P Ir
P
Ph2

O
O

O2N
• Increased loadings of base improve the yield of A while suppressing
III
epimerization of the transient !-chiral aldehyde.
• Water improves the yield of A, possibly by facilitating the exchange between
product and reactant alkoxide and by increasing the amount of Cs2CO3 in solution.

NO2

• The enhanced Lewis acidity at iridium may strengthen the agostic interaction between the iridium
center and the carbinol C-H bond, facilitating alcohol dehydrogenation. It may also accelerate
carbonyl addition with respect to aldehyde epimerization.
• Inductive electron withdrawal by the 3,4-dinitro benzoate ligand may facilitate deprotonation of the
Ir(III) hydride intermediate, allowing for faster catalyst turnover.
Schmitt, D. C.; Dechert-Schmitt, A.-M. R.; Krische, M. J. Org. Lett. 2012, 14, 6302–6305.
Anne-Marie Schmitt, Fan Liu

12


Myers

Chem 115

Asymmetric Allylation Reactions
Enantioselective Addition to Acylhydrazones:

Leighton Silicon Allylation Chemistry:
Leighton, J. L. Aldrichimica Acta 2010, 43, 3–14.

Ph

Background:
• In 2000, Leighton reported an allylation reaction where a Lewis acidic silicon atom is embedded in
a strained five-membered ring:

H3C
H3C

N
Ph

Ac
N

H

O
Si
N Cl
CH3

H3C

CH2Cl2, 10 °C, 16h

H
(5 g)

1. PhCHO (6 equiv)
sealed tube, 130 °C

O
Si

Ph

N

1. PhCHO
PhCH3, 23 °C

N

H

Ph

80%, 98% ee

Bz
H N
H3C N H

CHCl3, 23 °C

OH
1. Ph

Ph

1. t-BuCHO
PhCH3, –10 °C
2. HCl
80%, 96% ee

H

H3C

O
Si
N Cl
CH3

78%, 94% ee

Bz
N

N

H3C

Bz
N

CH3

2. HCl, 52%

O
Si
N Cl
CH3

Ph

Recrystallization

Ac
N

Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596–9597.

• By incorporating another electronegative element bound to silicon, the reaction takes place at
room temperature. With a chiral ligand, the reaction becomes enantioselective:

Ph

H

H

88% ee

Zacuto, M. J.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 8587–8588.

H3C
O
H3C
Si
H3C
O Cl
H3C

N

Ac
N

Ph

2. HCl, 87%

CH3

OH

H

Ph

OH

H

CH3

(5 g)
t-Bu

H3C

O
Si
N Cl
CH3

CHCl3, 40 °C
2. HCl, Et2O
3. Recrystallize

Bz
H N •HCl
H3C N H

SmI2, THF

Ph

H3C NH2
Ph

86%

74%, 98% ee

Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686–5687.
Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124,
7920–7921.

Mechanism:

Preparation of Allylsilane

Ph

• Two diastereomers are generated upon complexation with pseudoephedrine, which converge on
a common complex prior to allyl transfer:

Ph

OH
+

H3C

NH
CH3

Et3N, CH2Cl2
Cl3Si

0–15 °C, 12h
(150-g scale)

Ph
Me

Ph
Me

O
Si
N Cl
CH3

92%, dr = 2 : 1

Ph
O
O Ph
Si
N
+
N

H
N Cl
Me
Ph
H

1. CH2Cl2, 23 ºC, 15min
2. PhCH3, 23 ºC, 12h
90%

H
N N
Ph Si O
O
N H
Ph
H
CH3
H CH3

Ph

Cl–

• A 5-coordinate trigonal bipyramidal silicon species is proposed.
• The strained silacyclopentane increases the Lewis acidity of silicon.
• Aldehydes and acylhydrazones react, but not ketones, aldimines, or ketimines.

Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596–9597.

Angela Puchlopek-Dermenci, Fan Liu

13


Myers

Chem 115

Asymmetric Allylation Reactions

A C2-symmetric Chiral Controller for Aldehyde Allylation and Crotylation:

Allylation and Crotylation of !-Diketones:

• The C2-symmetric N,N'-dialkylcyclohexanediamine silane shown below shows improved
selectivites in the allylation and crotylation of aldehydes:

• The first example of enantioselective nucleophilic addition to !-diketones was achieved
using the C2-symmetric N,N'-dialkylcyclohexanediamine silane reagent:

4-BrC6H4

4-BrC6H4

N
Si
N Cl

+

Ph

OH

CH2Cl2, –10 °C

O
H

90%, 98% ee

N
Si
N Cl

Ph

4-BrC6H4

Br

O

O

OCH3

+

Br

CHCl3, 23 °C

O HO

OCH3

89%, 92% ee
regioselectivity > 20 : 1

4-BrC6H4

4-BrC6H4
4-BrC6H4
N
Si
N Cl

CH3

+

CH2Cl2, 0 °C

O
BnO

H

83%, 99% ee

CH3
+

N
Si
N Cl

OH
BnO

O

O

Ph

CH3

75%, 97% ee
dr > 20 : 1
regioselectivity > 20 : 1

4-BrC6H4
CH3

4-BrC6H4

O HO CH3

CHCl3, 23 °C
Ph

CH3

Allylation and Crotylation of !-Diketones:

OH
4-BrC6H4
N
Si
N Cl

O
CH3 +

Ph

CH2Cl2, 0 °C
H

O

Si

Ph
4-BrC6H4

R2

R1

O

Si
R2

R2

Fast

NH

O

O
O

(2.09 g)

O

R1

CH3
+
79%, 97% ee

4-BrC6H4

O

NH
90% recovered

Si

4-BrC6H4

O

R1

Si

R1

O
R2

R1

Fast

O
R2

Fast

O

O

Si

R1

R2

Kubota, K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42, 946–948.
Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 6, 4375–4377.
R2

• Using 2-hydroxybenzene as an activating group, imines can be allylated or crotylated
with high selectivity:

O
HO
Ph
Me

O
Si
N Cl
Me

CH3
+

R1

HO
CH2Cl2, 23 °C

N
H

74%, 99% ee
dr = 96 : 4

Rabbat, P. M. A.; Valdez, S. C.; Leighton, J. L. Org. Lett. 2006, 8, 6119–6121.

HN

CH3

R1
O HO R2

Ar
O Si N H
Cl–
N
Ar H
H

O

R1
R2

HO R1 O
R2

Ar
O Si N H
N
Ar H
H

• Four possible diastereomers undergo fast interconversion.
• Regioselectivity is determined by Curtin-Hammett kinetics. Steric interactions are minimized and
conjugation is maximized in the lower energy transition state.

Chalifoux, W. A.; Reznik, S. K.; Leighton, J. L. Nature 2012, 487, 86–89.
Angela Puchlopek-Dermenci, Fan Liu

14


Myers

Chem 115

Asymmetric Allylation Reactions
Mechanism:

Hoveyda Boron Allylation Chemistry:
• The Hoveyda group demonstrated that Cu-complexed C1-symmetric ligands I and II, can effect
enantioselective allylation of phosphinoylimines:

Ph

Ph

Mes N

Ph
Me

N

BF4

O

H

+

Br

N

Ar1 N

N Ar
2

H3C

P Ph
N
Ph

+

H

H3C

O
P Ph
N
Ph
Ph

H

+

N

P

O

Ph Ph

iPr Mes
H3CO B(pin)

II

H3C CH3
O
H3C
B
H3C O

MeOH, THF, –50 °C
92%, 97% ee

Ph
Mes
N

O

I (5.0 mol%)
CuCl (5 mol% )
NaOt-Bu (12 mol%)

HN

P Ph
Ph

Ar1 N

N Ar

2
Cu

O

OCH3

Br

I (2.5 mol%)
CuCl (2.5 mol% )
NaOt-Bu (6 mol%)

H3C CH3
O
H3C
B
H3C O

H3C CH3
O
H3C
B
H3C O

MeOH, THF, –50 °C
61%, 92% ee

II (5 mol%)
CuCl (5 mol% )

NaOt-Bu (12 mol%)
CH3
MeOH, THF, –50 °C
96%, 90% ee

CH3OH
R

O
H3C

P Ph
HN
Ph

H3C

O
Ph P NH
Ph

R

H
N

P

O

Ph
R2
N
Cu H3C
R
N

R1

Ph P
Ph
Ar1 N

O

R

Cu
I

P Ph
Ph

B(pin)

N

BF4 Mes

N

Ph

N

N Ar
2
Cu
O

P
Ph Ph

Ph Ph

• Allylation is driven by the formation of an energetically favorable B–O bond.
CH3

Ph

• Methanol releases the product alkoxide from the NHC–Cu complex. <5% conversion was observed
in the absence of methanol.

• The product phosphinoylamides can be convered to free amines under aqueous acidic conditions.
• High selectivity is observed with aromatic, heteroaromatic, conjugated, and some aliphatic
phosphinoylimines. Crotylation reactions proceed with modest yield and enantioselectivity but low
diastereoselectivity.

Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133, 3332–3335.

Angela Puchlopek-Dermenci, Fan Liu

15


Myers

• Simple amino alcohol catalysts III and IV were found to promote stereoselective boron allylation of
phospinoyl imines and isatins:

i-Pr

t-Bu

N
H
OH

O
t-Bu

III

O
P Ph
Ph

+

N

O

O

N(CH3)2

N
B

HO

HN

P Ph
Ph

t-Bu

P Ph
N
Ph

III (6.0 mol%)
NaOt-Bu (8.5 mol%)

H3C CH3
O
H3C
B
H3C O

+

H

P Ph
HN
Ph

N(CH3)2

N
H
OH
t-Bu

O

III

H3C
(H3C)2N

CH3
O

t-Bu

O

N

O

OH

O Bpin
H3C

P Ph
Ph

N
O

i-Pr

H3C CH3
O
H3C
B
H3C O

H

O

CH3
CH3

O

t-Bu

IV

MeOH, PhCH3, 22 °C
75%, 96% ee

N

H3C
H3C

i-Pr

III (3.0 mol%)
NaOt-Bu (2.5 mol%)

H3C CH3
O
H3C
B
H3C O

H

Mechanism:

i-Pr

N(CH3)2

N
H
OH

N

Chem 115

Asymmetric Allylation Reactions

O

R

N B

O

H

H3C
(H3C)2N

H

CH3
O

R

N B N
H O

H

P

Ph
Ph

MeOH, PhCH3, 22 °C
71%, 95% ee
t-Bu

O

O

P Ph
N
Ph
S

H
N

CH3

+

H3C CH3
O
H3C
B
H3C O
D D

H3C

IV (3 mol%)
NaOt-Bu (20 mol%)
MeOH, PhCH3, 22 °C
S
86%, 91% ee
dr = 39 : 1
H3C

P Ph
Ph

HN

N H3C

D D

O
H3C

(H3C)2N

CH3
O

N B
O
H
H3C

t-Bu

B
pin

MeOH
O

t-Bu
O

O
N
Ph

P Ph
Ph

+

H

H3C CH3
O
H3C
B
H3C O
Cy CH3

III (6.0 mol%)
Zn(Ot-Bu)2 (8.5 mol%)
MeOH, PhCH3, 22 °C
70%, 90% ee
dr = 8 : 1

O

P Ph
HN
Ph

O

P Ph
HN
Ph
Bpin

Ph
H3C Cy

H3C
(H3C)2N

CH3
O

R

N B
H

H3C
(H3C)2N

CH3
O

R

N B N
H O

H

P

Ph
Ph

OCH3

• <2% conversion was observed in the absence of methanol.
O
O
N
TBS
( an "isatin")

+

H3C CH3
O
H3C
B
H3C O

1.

•

III (0.25 mol%)
NaOt-Bu (0.4 mol%)

MeOH, PhCH3, 22 °C
2. aq. HCl, MeOH, 22 ºC

90%, >99% ee

HO

• The internal hydrogen bond between the protonated amine and the amide carbonyl rigidifies the
complex and increases the Lewis acidity of the boron center to facilitate substrate binding.
•
O

N
H

• Substrate release is accelerated by intramolecular protonation.
Silverio, D. L.; Torker, S.; Pilyugina, T.; Vieira, E.; Snapper, M. L.; Haeffner, F.; Hoveyda, A. H.
Nature 2013, 494, 216–221.
Angela Puchlopek-Dermenci, Fan Liu

16