16 nozaki hiyama kishi reaction

Myers

Chem 115

The Nozaki-Hiyama-Kishi Reaction, Asymmetric Additions to Carbonyl Compounds

Recent Reviews:

• super-stoichiometric amounts of CrII reagents are generally employed.

Lumbroso, A.; Cooke, M. L.; Breit, B. Angew. Chem. Int. Ed. 2013, 52, 1890–1932.

• aldehydes react markedly faster and with complete selectivity in the presence of ketones.

Hargaden, G. C.; Guiry, P. J. Adv. Synth. Catal. 2007, 349, 2407–2424.

• because of the low basicity of organochromium reagents, the reaction is compatible with an
array of functional groups.

Fürstner, A. Chem. Rev. 1999, 99, 991–1045.
• Coupling of an alkenyl halide or triflate wtih an aldehyde mediated by Cr(II) was first reported
in 1977 and was found later to be initiated by a catalytic amount of NiCl2.

• Examples:
O
MPMO
H3C
H3C

Generalized Reaction Scheme:
O

R' X

H

R

Typically:

+

CrII,

OH

NiII
R

H
O

H
MOMO

R'

CH3
OCH3

O

TfO H
H3C

Mechanism:

OBn
CH3

CrCl2 (90 mol%)
NiCl2 (10 mol%)
O

H
O

CrII, NiII

+

I

C4H9

Ph

I

Ni0

H3C

NiI

H3C

C4H9

O

OTBS

Ph

+
H

C4H9

transmetalation

H

O

O

H
SEMO

CH3

CH3

H

O
O
H

CH3

O

H3C

CH
CH3 3

H3C

Ph

H3C

Ph

C4H9

CH3

CH3

CH3

O
CH3

Br

O

O

BnO

OH

work-up

O

1% NiCl2/CrCl2
(14 equiv)
DMF, 64%
dr ~ 3 : 1

O

O
OCrIIICl2
C4H9

O

OTBS

O

CrIICl2

O

O

H
O

O

H

THF, DMF, 23 ºC

CH3
CH3

O

H3C

OBn
CH3

CH3
CH3

CH3

O

BnO
O

I NiII

Cl2CrIII

OMOM

Product was not formed in the absence of 4-t-butylpyridine.
Stamos, D. P.; Sheng, X. C.; Chen, S. S.; Kishi, Y. Tetrahedron Lett. 1997, 38, 6355–6358.

C4H9

oxidative
addition

CrIICl2
I

O

OH

C4H9

CrIIICl2I

OCH3
O

HO

4-t-butylpyridine

CH3
CH3

• A specific example:

H

O

•
H

• metal = Cr, Ni (sometimes Co)

• X = Cl, Br, I, OSO2CF3, phosphonate

O

H3C

DMSO, 23 ºC
92%
single diastereomer

CH3

Takao, K.; Hayakawa, N.; Yamada, R.; Yamaguchi, T.; Morita, U.; Kawasaki, S.; Tadano, K. Angew.
Chem. Int. Ed. 2008, 47, 3426–3429.

• R' = allyl, aryl, alkenyl, alkynyl, propargyl

Ph

I

O

•

OH

MPMO
H3C

NiCl2 (6 mol%)
CrCl2 (7.6 equiv)

OTBS

H

OTBS
O

O

H
SEMO

H

H3C

O
HO
H
O
O

Huckins, J. R.; de Vincente, J.; Rychnovsky, S. D. Org. Lett. 2007, 9, 4757–4760.

O

CH3
CH3

CH
CH3 3

Fan Liu

1


Myers
• Synthesis of a palytoxin intermediate:

O

Chem 115

The Nozaki-Hiyama-Kishi Reaction, Asymmetric Additions to Carbonyl Compounds

CH3

PMBO
OPMB

OTBS
CH3

+

I

H3CO

Catalytic in Chrominium: Addition of super stoichiometric amounts of the non-toxic metal
manganese allows the reaction to proceed with catalytic amounts of Cr.

H

CH3

CH3
H3C

OPMB
OPMB
O

O

O

H
PMBO

OPMB

1/2 Mn(0)

OPMB

BzO
BzO

OTMS
C4H9

Ph

OPMB
OPMB
CH3
OCH3
O
OH

CH3

0.11% NiCl2/CrCl2
(~30 equiv)
DMSO, THF, 82%
dr ~ 3.6 : 1

• TMSCl + Mn(0): TMSCl serves to liberate CrIII from the product chromium alkoxide. Mn(0)
reduces CrIII to the catalytically active CrII species:

1/2 Mn(II)

CrIIICl3

CrIICl2

Ph

OBz

C4H9
I NiI

TMS-Cl

OH
OBz

I NiII

OCrIIICl2
C4H9

Cl2CrIII
C4H9
O
Ph

H

• Example:
O

CH3

PMBO
OTBS
CH3 OPMB

OPMB

OPMB
O

H3CO
CH3
H3C

CH3
O

OH

H
PMBO

OPMB
OPMB
OPMB
OPMB
CH3
OCH3
O
OH

CH3

O

BzO
BzO

OH
OBz
OBz

H3C

OTf

O

+ H

O

CrCl2 (15 mol%)
(doped with cat. NiCl2)
Mn (1.7 equiv)

OH
O

H3C

TMSCl (2.4 equiv)
DMF:DME, 50 ºC
80%

O

Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349–12357.
• Zr(Cp)2Cl2 + Mn(0): use of Zr(Cp)2Cl2 in lieu of TMSCl suppresses formation of TMS enol ethers of
aldehydes and increases the reaction rate.
• Example:

Armstrong, R. W.; Beau, J.-M.; Cheon, S. H.; Christ, W. J.; Fujioka, H.; Ham, W.-H.; Hawkins, L. D.;
Jin, H.; Kang, S. H.; Kishi, Y.; Martinelli, M. J.; McWhorter, W. W.; Mizuno, M.; Nakata, M.; Stutz, A.
E.; Talamas, F. X.; Taniguchi, M.; Tino, J. A.; Ueda, K.; Uenishi, J.; White, J. B.; Yonaga, M. J. Am.
Chem. Soc. 1989, 111, 7525–7530.

H3C

I

CrCl2 (15 mol%)
NiCl2(dppp) (2 mol%)
Zr(Cp)2Cl2 (1 equiv)

O

+
H

Ph

Mn (2 equiv)
LiCl, MeCN
23 ºC, 71%

OH

H3C

Ph

Namba, K.; Kishi, Y. Org. Lett. 2004, 6, 5031–5033.
Fan Liu

2


Myers

The Nozaki-Hiyama-Kishi Reaction, Asymmetric Additions to Carbonyl Compounds

Ligand Additives: Addition of supporting ligands often accelerates the reaction. Use of chiral ligands
affords enantiomerically enriched secondary alcohol products.

O

N
H

O

N

N

O
t-Bu

3

1 R = i-Pr
2 R = t-Bu

N

Ph

Ph

A

Cl

H

CH3 OH

n-C5H11

n-Bu

B

n-Bu

Ph

Ph

t-Bu

H

t-Bu

O
Br

C

H

+
H

Ph

2 (10)

23

84

71

1 (10)

23

83

96

3 (10)

23

90

92

3 (5)

23

–

93

4 (3)

23

90

98

4 (3)

23

71

94

17

94

OH
Ph

O

93

OH

• Ligands on Ni, although not believed to be involved in the enantio-determining C–C bond-forming
step, can have a dramatic influence on the enantioselectivity due to ligand scrambling:

I

89

OH

I

n-Bu

4

H3C

0

OH

B

O

Cr-4 (10 mol%)
Ni catalyst I (2 mol%)
Zr(Cp)2Cl2 (1 equiv)

1 (10)

n-C5H11

O

I

n-Bu

H

O
Cl Cr
O
N

ee
(%)

O

S

N

yield
(%)

OH

A

O

CH3

S
N

O

temp
(ºC)

Ph

O
H

R

R

Ph

Br

NH
O S O

ligand
(mol%)

OH

A
H

OCH3

N

product

method

O

Br

OCH3
OCH3

Ph

Ph

aldehyde

nucleophile

Chem 115

O

H3C
Br

OH
H3C

90%, 92% ee

H

Ph

CH3
OH
Ph

Ph

Mn (2 equiv)
LiCl, MeCN, 23 ºC

C

CH3

Method A1: CrCl2 (10 mol%), Mn (2 equiv), DIPEA (30 mol%), TMSCl (2 equiv), THF; TBAF, THF
N
H3C

N

• NiCl2
I
(NiCl2•DMP)

Namba, K.; Cui, S.; Wang, J.; Kishi, Y. Org. Lett. 2005, 7, 5417–5419.
Liu, X.; Li, X.; Chen, Y.; Hu, Y.; Kishi, Y. J. Am. Chem. Soc. 2012, 134, 6136–6139.

Method B2: NiCl2•DMP (2 mol%), CrCl2 (10 mol%), Proton Sponge (11 mol%), LiCl (2 equiv), Mn (2
equiv), ZrCp2Cl2 (1 equiv), MeCN
CH3

Method C3: Mn (3 equiv), TESCl (1.1 equiv), DME:MeCN; TBAF, THF.
1Inoue,

M.; Suzuki, T.; Nakada, M. J. Am. Chem. Soc. 2003, 125, 1140–1141.; Inoue, M.; Nakada, M.
Org. Lett. 2004, 6, 2977–2980.
2Namba, K.; Cui, S.; Wang, J.; Kishi, Y. Org. Lett. 2005, 7, 5417–5419.
3Xia, G.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 2554–2555.
Fan Liu

3


Myers

The Nozaki-Hiyama-Kishi Reaction, Asymmetric Additions to Carbonyl Compounds

• Ligand 8 contains binding sites for both Ni and Cr and dramatically lowers the catalyst loading
required for asymmetric addition.
Cr-8 (1 mol%)

• catalysts can override inherent selectivities of the substrate:

+

O

I

OBz

Cr-Ligand (20 mol%)
NiCl2 (2 mol%)
LiCl (2 equiv)
Mn (2 equiv)

OBz

Cl
OTBDPS

H

R OH

3,3'-dimethyl2,2'-dipyridine
(S)-5
(R)-5
(S)-6
(R)-6
(S)-7
(R)-7

I

H3C

Cl

NiCl2 (1 mol%)
Zr(Cp)2Cl2 (1.2 equiv)
Mn (2 equiv)

O

+

Ph

H

OTBDPS

Zr(Cp)2Cl2 (1 equiv)
MeCN, 23 ºC
Ligands

O

dr (S : R)
H3C

1 : 8.0
8.1 : 1

N

8

CH3

CH3
Liu, X.; Henderson, J.; Sasaki, T.; Kishi, Y. J.
Am. Chem. Soc. 2009, 131, 16678–16680.
Peng, J.; Kishi, Y. Org. Lett. 2012, 14, 86–89.

Cl

16 : 1
• Ligands for the enantioselective allylation and propargylation of ketones have been developed:

1 : 21
24 : 1

CrCl3 (10 mol%)
Ligand (10 mol%)

O

+
R'

CH3

nucleophile

O

N

OCH3
N

N

i-Pr

NH
O S O
CH3

m-CF3Ph

N

i-Pr

NH
O S O

CH3

t-Bu

temp
(ºC)

yield
(%)

ee
(%)

9

0

63

91

R

CH3

i-Pr
O

0

69

88 (anti)
70 (syn)

O

N
H

N

9

Ph

Boc

Bn

CH3

NH
O S O

Cl

HO CH3

N

O

Cl

O

N

O

10a

25

70

70

H3CO

n-Bu
HO CH3

H

9

N

S

N
Cl

ligand

R'

OCH3
N

O

Et3N, TMSCl
Mn (2 equiv), THF

OH

HO CH3
Br

O

HO CH3

Br

H3C
CH3

product

nucleophile

5

3,3'-dimethyl-2,2'-dipyridine

O

Ph

N

NH
O S O

Cl

1 : 15

OH
H3C

LiCl, MeCN, 23 ºC
>90%, 82% ee

O
N

1.2 : 1

R X

H3C
H3C

Chem 115

10a

25

86

N
H
Boc

H
N

96

t-Bu

10

Cl

7

S

6

Guo, H.; Dong, C.-G.; Kim, D.-S.; Urabe, D.; Wang, J.; Kim, J. T.; Liu, X.; Sasaki, T.; Kishi, Y. J.
Am. Chem. Soc. 2009, 131, 15387–15393.

Cl

HO CH3

10a

25

75

92

a1

equiv of LiCl was added.

Ph

Miller, J.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 2752–2753.
Harper, K. C.; Sigman, M. S. Science 2011, 333, 1875–1878.

Fan Liu

4


Myers

TBSO
H3C

• Examples in synthesis:
• A one-pot NHK-Peterson elimination strategy was used for the large-scale synthesis of the
anticancer marine natural product discodermolide:

CH3 CH3 CH3
CH3

CHO
OTBS OPMB
CH3

H3C
OTBS

OTES

TBSO
OPiv

CH3

H

THF, 0–15 ºC

R

PMBO

OTBS
CH3

CH3 CH3 TMS

TBSO
H3C

OH

+

CH3
OTBS OPMB
CH3

H3C
OTBS

6 M KOH

PMBO

CH3OH, 23 ºC
81% (2 steps)

OBn

CH3

CH3 100%, dr = 4 : 1

O
H

H

Cr-11 (20 mol%)
NiCl2(P(CH3))2
(4 mol%)

O

ZrCp2Cl2, Mn
LiCl, MeCN, 23 ºC

OBn
OBn

dr = 30 : 1
yield not reported

TBSO
H3C

CH3 CH3

93%, dr = 18 : 1

6 steps

O

OH
H

OBn
OBn

O

OCH3
N

i-Pr

O

Liu, X.; Li, X.; Chen, Y.; Hu, Y.; Kishi Y. J. Am. Chem. Soc. 2012, 134, 6136–6139.

O
O

CH3

CH3

H3CO DMBOMO

CH3 OH

OAc

I

H3CO
CH3

H

OTr
CH3

O

CH3 CH3
OCH3
OCH3

O
O

O
CH3

H3CO DMBOMO

OTr
CH3

CH3 CH3

OCH3
N

OAc

H3CO
CH3

S

OMTM

76%, dr = 2 : 1

N
N

TBSO
H3C

OMTM

CH3 CH3

2,4,6-Cl3C6H4COCl
Et3N, DMAP, THF, quan.

CH3

TBSO
H3C

O

CH3

OTBS

ent-12 (10 equiv)
CH3CN

OAc
OTr

+

H3CO

OTBS

NH
O S O

HO H3CO DMBOMO
I

CH3

CrCl2 (10 equiv)
NiCl2(dppp) (4 mol%)
proton sponge

OBn

O
OH

CH3

S
OTBS

OMTM

OBn
BnO
O

+
I

OH OAc
OTr

8 steps

H3C

H3C

OBn
O

OCH3

(1.27 kg)

BnO
O

O

CH3 CH3

OTBS

OH

Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Schuerch, F.; Seger, M.; Schreiner, K.; Daeffler, R.;
Osmani, A.; Bixel, D.; Loiseleur, O.; Cercus, J.; Stettler, H.; Schaer, K.; Gamboni, R.; Bach, A.;
Chen, G.-P.; Chen, W.; Geng, P.; Lee, G. T.; Loeser, E.; McKenna, J.; Kinder, F. R., Jr.;
Konigsberger, K.; Prasad, K.; Ramsey, T. M.; Reel, N.; Repic, O.; Rogers, L.; Shieh, W.-C.; Wang,
R.-M.; Waykole, L.; Xue, S.; Florence, G.; Paterson, I. Org. Process Res. Dev. 2004, 8, 113–121.

H3C
H3C

OTr

TBSO

CH3

HO

R

OAc

H

TBSO

OPiv

CH3 CH3 TMS
PMBO

O

OTES

CH3
CH3 CH3 CH3

+

CrCl2 (10 equiv)

NiCl2(dppp) (1 mol%)
proton sponge
12 (10 equiv)
CH3CN

CH3

I

(1.52 kg)

I

TBSO

+
O

TMS
CrCl2 (4.3 equiv)

OCH3

CH3

Br
PMBO

Chem 115

The Nozaki-Hiyama-Kishi Reaction, Asymmetric Additions to Carbonyl Compounds

t-Bu

NH
O S O
CH3
12

11
Kobayashi, K.; Fujii, Y.; Hayakawa, I.; Kigoshi, H. Org. Lett. 2011, 13, 900–903.
Kobayashi, K.; Fujii, Y.; Hirayama, Y.; Kobayashi, S.; Hayakawa, I.; Kigoshi, H. Org. Lett. 2012, 14,
Fan Liu
1290–1293.

5


Myers

Chem 115

The Nozaki-Hiyama-Kishi Reaction, Asymmetric Additions to Carbonyl Compounds

• Application to the synthesis of the anticancer drug Halaven!:

TBSO

O

OCH3
N
CH3

CrCl2, NiCl2
Et3N, 13

CH3
O
Br

OH

OTs

KHMDS, THF
TBSO
TBSO

O
HO
MsO

H3CO

+

O

OPiv

(1.48 kg)

OPiv

SO2Ph
O
H

TBSO
TBSO

CH3

O

H

•
CH3

n-BuLi
THF-heptane
<–50 ºC
75–95%

O

H

OH

•
O
•
O

H

OTBS
OTBS
O

CH3
OPiv

OTBS

4 steps

O

O

H

I
H

H

OTBS

H3CO
I

H

OTBS
OTBS

CH3O2C
H

OPiv

SO2Ph

O

O

H

O

•

(1.2 kg)

TBSO
TBSO

NH
O S O
CH3
13

O

(1.17 kg)

SO2Ph

O

H3CO

H3CO
CH3

O
TBSO
TBSO

OTBDPS

TfO
MsO

THF, 25 ºC

O

CH3
N

6 steps

CrCl2 (4.7 equiv)
NiCl2 (12 mol%)
Et3N, ent-13 (4.7 equiv)

SO2Ph

O

i-Pr

O

OTBDPS

H3CO

toluene, –20 ºC
65% (2 steps)
dr = 20 : 1

OCH3

N
CH3

O

CH3

i-PrOH, 25 ºC
60% (2 steps)
dr = 8 : 1

OTs
OTBDPS

TBSO

SiO2

CH3

THF, 25 ºC

+

H

TBSO

OCH3
N

CH3

O

2 steps

O

•
O
•

O
O

TMS
H

OH

H

DMSO, CH3CN
30 ºC, 45%
dr = 10 : 1

O

I
H

OTBS

H
O

(929 g)

1. CrCl2 (10 equiv)
NiCl2 (1 equiv)

O
O

Et3N, ent-13 (10 equiv) TBSO
MeCN, THF, 25 ºC
TBSO
H3C
2. DMP, CH2Cl2
60–80% (2 steps)

O
H
O

H

H
H

O

H

H

OTBS
OTBS

CH3

O

O

CH3O2C

H3CO

O

O
TBSO
TBSO

H

TMS
Br
CrCl2, NiCl2

O

O
O

H
H

O

OTBS
OTBS
O

OTBS
H

O

O

(580 g)

Synlett 2013, 24, 323–326.; Synlett 2013, 24, 327–332.; Synlett 2013, 24, 333–337.

Fan Liu

6