Nature Chemistry Year-in-Review: 2016

Zhen Liu 02/23/2016

Nature Chemistry

2

Abbreviated Title Nat. Chem.Discipline ChemistryLanguage EnglishEdited By Stuart CantrillPublisher Nature Publishing GroupPublish History 2009–presentFrequency MonthlyImpact Factor 27.893(2015)

2016 Events

3

Formal [2+2+1] Synthesis of Pyrroles

4

[LnTiII]IV

LnTiIVN

N

R'

R'N RLnTiIV

N

LnTiIV

R2

R1R

N

LnTiIV

R2

R1

R

R4

R3

V

I

II

III

Alkynetrimerization

RN NR

Diazenedisproportionation RN NR0.5

R1

R2

[2+2] addition

R3

R4

Insertion

N

R

R1

R2

R4

R3 Reductiveelimination

R3 R4+ RN NR0.5+R1 R2N

R

R1

R2

R4

R3

10% py3Cl2Ti(NPh)

PhCF3, 110 ºC

Gilbert, Z. W.; Hue, R. J.; Tonks, I. A. Nature Chem. 2016, 8, 63.

Formal [2+2+1] Synthesis of Pyrroles

5

Gilbert, Z. W.; Hue, R. J.; Tonks, I. A. Nature Chem. 2016, 8, 63.

Formal [2+2+1] Synthesis of Pyrroles

6

Gilbert, Z. W.; Hue, R. J.; Tonks, I. A. Nature Chem. 2016, 8, 63.

PhN NPh0.5+R1 R2N

Ph

R2

R1

R2

R1

10% py3Cl2Ti(NPh)

PhCF3, 110 ºC3

N

Ph

R1

R2

R2

R1

N

Ph

R1

R2

R1

R2

+ +

2 3 4 5 6when R1 ≠ R2

Entry Products (4:5:6) %Yield (NMR)Alkyne

MeMe

PhMe

Ph

tBu

Et

Et

nBu

N

Ph

Me

Me

Me

Me

76 (98)1

2N

Ph

Ph

Me

Ph

Me

N

Ph

Me

Ph

Ph

Me

N

Ph

Me

Ph

Me

Ph

N

Ph

Ph

Ph N

Ph

PhPh

N

Ph

tBu

tBu

3

4

5

6

N

Ph

EtEt

NnBu

Ph

60 (91)

(32)

55 (92)

65 (95)

50 (83)

(0.45:1.0:0.77)

(0.0:1.0:0.25)

Suzuki-Miyaura Coupling of Amides

7

Weires, N. A.; Baker, E. L.; Garg, N. K. Nat. Chem. 2016, 8, 75.

(Het)Ar1 N

O

R

Boc

+

(Het)Ar2

(Het)Ar1 (Het)Ar2

O

+ HNR

Boc

B(OH)2

or

(Het)Ar2 B(pin)

R = Me or Bn

[Ni(cod)2]SIPr

K3PO4, H2Otoluene, 50 ºC

N N

IPr

IPr

IPr

IPr

SIPr

Entry Ketone Product %Yield

511

2

3

4

5

59

64

80

82

OMe

O

OMeMe2N

O

OMeO

O

NN

Me

O

N

Me

Suzuki-Miyaura Coupling of Amides

8

[Ni(cod)2], SIPrK3PO4, H2Otoluene, heat

N

O

N

OBn

H Boc

Bn

O

(pin)B

O

N

OBn

HO

[Ni(cod)2], SIPr, toluene, heat

O

O

O

O

Me

MeMei. Boc2O, DMAP, CH3CN, rt.A

C

OH

Me

MeMe

(–)-mentholB

NH

O

O

O

Me

Me MeBni. Boc2O, DMAP, CH3CN, rt.ii. A, [Ni(cod)2], SIPr, K3PO4

H2O, toluene, heat

ii. B, [Ni(cod)2], SIPrtoluene, heat

Weires, N. A.; Baker, E. L.; Garg, N. K. Nat. Chem. 2016, 8, 75.

CuH-Catalysed Reductive Relay Hydroamination

9

L*CuOBzVI

I

II

III

+

L*CuH

R'' OR

CuL*

R'

R''

R' IV

V

R'' CuL*

R'

R'' OR

R'1

L*CuOR

L*CuHI

[Si]-H

[Si]-OR

[Si]-H

[Si]-OBz

Hydrocupration relay

NR2R1

OBz2

3

R'' NR1R2

R'Remote Chiral Amine

R'' OR

R'1

NR2R1

OBz2 3

R'' NR1R2

R'

Cu(OAc)2(R)-DTBM-SEGPHOS (1.1 eq.)

Me(EtO)2SiH (3.5–5 eq.)THF (1.0 M), 40–50 ºC

O

O

O

O

PAr2

PAr2

Ar = 3,5-tBu2-4-MeO-C6H2(R)-DTBM-SEGPHOS (L1)

Zhu, S.; Niljianskul, N.; S. L. Buchwald Nat. Chem. 2016, 8, 144.

Conversion of Alkanes to Linear Alkylsilanes

10

R R'R'' R

tBu tBu

[Ir] [Ir]H2Transfer

dehydrogenation

[Fe]

Fast olefinisomerizatoin

R [Si]

[Fe]H[Si]

[Fe]H[Si]

Ineffective for internal olefins

R'R''

[Si]

Chemo- and regioselectiveα-olefinhydrosilylation

Jia, X.; Huang, Z. Nat. Chem. 2016, 8, 157.

Conversion of Alkanes to Linear Alkylsilanes

11

R R [Si]

1 equiv. TBE1 mol% 1

1.2 mol% NaOtBu

Neat or p-xylenet, 200 ºC

1 equiv. (Me3SiO)2MeSiH10 mol% [Fe]

20 mol% NaHBEt3

r.t., 12 h

Entry Alkane t (min) Solvent [Fe] Product Yield (%)

N

NN FeArAr Br Br

2b, Ar = 2,6-iPr2-C6H32c, Ar = 2,6-Et2-C6H3

1 n-octane 10 None 2c SiMe(OSiMe3)2n-heptyl 77 (67)

24

30 None 2c4 SiMe(OSiMe3)2

76 (63)

3 300 p-xylene 2d SiMe(OSiMe3)276 (63)Me3Si Me3Si

4 300 p-xylene 2dSiMe(OSiMe3)2

60

MeO MeO

R R BPin

1 equiv. TBE1 mol% 1

1.2 mol% NaOtBu

Neat or p-xylenet, 200 ºC

1 equiv. HBPin10 mol% 2a

20 mol% NaHBEt3

r.t., 12 h

Entry Alkane t (min) Solvent Product Yield (%)

N

NtBu2P FeCl Cl

2a

1 n-octane 10 None BPinn-heptyl 95

24

30 None BPin 90

3 300 p-xylene BPin 92Me3Si Me3Si

4

S O

P iPr2iPr2P Ir

Cl 1H

Jia, X.; Huang, Z. Nat. Chem. 2016, 8, 157.

Efficient Catalysis of A Cubic Coordination Cage

12Cullen, W.; Misuraca, M. C.; Hunter, C. A.; Williams, N. H.; Ward, M. D. Nat. Chem. 2016, 8, 231.

NO

H

O

N

+

HO

H2O

The Kemp Elimination Reaction

kcat/kuncat = 2 x 105

Host Cage [Co8L12](BF4)16

Enantioselective aldol reactions with masked fluoroacetates

13

R1

O

H+

C1 or C2 (20 mol%)

THF, 0 or 10 ºC

O

SHO2C

F

R2

racemic F-MAHT

O

S

F

R2OH

R1

NH

ONH

F3C

F3C

N OMe

N

HN

OHN

CF3

CF3

NMeO

N

C1C2

O

ArSCO2

F

O

ArS

F

+ CO2

N

N

O

R2

H

H

N

R3

R4

O

H

R1

HO

O

F

O

SAr

Saadi, J.; Wennemers, H. Nat. Chem. 2016, 8, 276.

Enantioselective aldol reactions with masked fluoroacetates

14

R1

O

H+

C1 or C2 (20 mol%)

THF, 0 or 10 ºC

O

SHO2C

F

R2

racemic F-MAHT

O

S

F

R2OH

R1

NH

ONH

F3C

F3C

N OMe

N

HN

OHN

CF3

CF3

NMeO

N

C1C2

Saadi, J.; Wennemers, H. Nat. Chem. 2016, 8, 276.

N

iPr

Ph R

CHOO

PhHN

O

ArSCO2H

F

R = 4-F-C6H4

11-1

C2 (20 mol%)THF, 10 ºC, 3dAr = 2-F-C6H4

N

iPr

Ph R

O

PhHN

OH

SAr

O

F

After recrystalization:50% yield, >99% e. e., d. r. >20:1

(R,R)-11-2

i. TBSOTf, pyridine,DCM, 2h (99%)

ii. Pd/C, 20 mol%, EtSiH, DCM, r.t., 1 h, then filtered and concentrated

N

iPr

Ph R

O

PhHN

OTBS

H

O

F

11-3

N

iPr

Ph R

O

PhHN

OH OH

FO

O

2

Ca2+

Fluorinated atovastatin>99% e. e., d. r. >20:1

i. THF, –78 ºC, 1 h (89%, d. r. 4:1)

tBuO

OLi

ii. Deprotection (94%)iii. CaCl2, MeOH (aq.) (91%)

Iterative Reactions of C–C Bond Formation

15

B

OH

OH R1

N2

HR1

N2

HR2

N2

HR3

BOHHO

R2

BOHHO

R1

BOH

OH

R3

R1R2

R3

R1R2

Protodeboronation

B1 B2 B3 B4 a–d

N

OMe

MeO

N

OMe

MeO

N

OMe

MeO

OMeO

Bra b c d

37% 30% 28% 20%

Battilocchio, C.; Feist, F.; Hafner, A.; Simon, M.; Tran, D. N.; Allwood, D. M.; Blakemore, D. C.; Ley, S. V. Nat. Chem. 2016, 8, 360.

BOHHO

R

1

+

N2

R1 R2

N

R1

R2

B OH

OH

R

N

BOHHO

R1R2

R

Protodeboronation

OxidationH2O2

H

R1 R2R

HO

R1 R2R

Iterative C–C bond formation

2

3

Iterative Reactions of C–C Bond Formation

16

Battilocchio, C.; Feist, F.; Hafner, A.; Simon, M.; Tran, D. N.; Allwood, D. M.; Blakemore, D. C.; Ley, S. V. Nat. Chem. 2016, 8, 360.

Parameterization of Phosphine Ligands

17

Me

(HO)2B +

Cl

OTf

Pd2dba3 (1.5%)Ligand (3%)

KF (3 equiv.)THF, 24 h, r. t. Me

OTf

ClMe

+

L = PtBu395% yield

L = PCy387% yield

Niemeyer, Z. L.; Milo, A.; Hickey, D. P.; Sigman, M. S. Nat. Chem. 2016, 8, 610.

Addition of Organoboron Reagents to Fluoroketones

18

G

O

NH

iPr

O

NMe2

OHtBu

(2.5 mol%)

allyl–B(pin)NaOtBu, MeOH22 ºC, 4–18 h

G = Me, 68:32 e. r.;G = iPr, 66:34 e. r.low enantioselectivity

F3C

O

NH

iPr

O

NMe2

OH

R(2.5 mol%)

1.1 eq. allyl–B(pin)NaOtBu, 1.3 eq. MeOH

toluene, 4 ºC, 4 h

cat-1 R = tBucat-1 R = H

cat-1

With cat-1, >98% conv., 93% yield,96:4 e. r.

With cat-2, 62% conv., 53% yield,90:10 e. r.

G

HO

F3C

HO

NB

HO

Me2N

O

O

F

FF

R

O=C–C–Cdihedral, ~32º

≠

F3C

O

NH

iPr

O

NMe2

OH

R(1.0 mol%)

1.1 eq. allenyl–B(pin)NaOtBu, 1.3 eq. MeOH

toluene, 22 ºC, 4 h

cat-1 R = tBucat-3 R = SiPh3

With cat-1, 98% conv., >98% allenyl,93:7 e. r.

With cat-3, 98% conv., 96% yield, >98% allenyl,95:5 e. r.

F3C

HO •

Lee, K.; Silverio, D. L.; Torker, S.; Robbins, D. W.; Haeffner, F.; van der Mei, F. W.; Hoveyda, A. H. Nat. Chem. 2016, 8, 768.

Addition of Organoboron Reagents to Fluoroketones

19

Lee, K.; Silverio, D. L.; Torker, S.; Robbins, D. W.; Haeffner, F.; van der Mei, F. W.; Hoveyda, A. H. Nat. Chem. 2016, 8, 768.

CF3

O

Cl

ClF1

(pin)B

NH

iPr

O

NMe2

OH(2.5 mol%)

Me

cat-4 F3C OHCl

Cl F2

>98% conv., 97% yield,95:5 e. r.

10 mol% Zn(OMe)2, 1.3 equiv MeOH,3:1 pentane:toluene, 22 ºC, 6 h

+

F3C OHCl

Cl F3

O

H

O3, CH2Cl2, MeOH,–78 ºC, 5 min

Me2S, –78 ºC to 22 ºC, 12 h

i. 2.5 equiv. THF, –30 ºC, 3.5 h

ii. Dess–Martin periodinane, CH2Cl2, 0 ºC to 22 ºC, 3 h

Me

CO2Me

ClLi•ClMg

F3C OHCl

Cl F3

O

Me

CO2Me

O NMe

CO2MeCl

Cl

CF3

F4

i. HONH2•HCl, pyr., 50 ºC, 12 h

ii. PhI(OH)OTs, MeOH, 22 ºC, 0.5 hiii. P(OMe)3, 110 ºC, 2h

Ref.

O NMe

Cl

Cl

CF3

Fluralaner (Bravecto)

O

HNNH

O CF3

20

Cyclic Polymers From Alkynes

WO

OTHF

THF

tBu

tBu

tBu

WO

OTHF

tBu

tBu

tBu

tBu5 equiv. HCCtBu

Toluene25 ºC

Complex1 Complex2

WO

OTHF

tBu

tBu

R

tBu+ H R

+ THF – THF

WO

O

tBu

tBu

R

tBu

RA

WO

O

tBu

tBu

tBu

B

R

R

WO

O

tBu

tBu

tBu

CR

R

Rn

R

R

RR

R

R

n

H R

Insertion

H R

H Rn

Propagation

Roland, C. D.; Li, H.; Abboud, K. A.; Wagener, K. B.;Veige, A. S. Nat. Chem. 2016, 8, 791.

para-selective C–H Functionalization

21

Boursalian, G. B.; Ham, W. S.; Mazzotti, A. R.; Ritter, T. Nat. Chem. 2016, 8, 810.

HR

i. 1.5 equiv. Selectfluor, 2.5 mol% 1, 7.5 mol% Ru(bipy)3(PF6)2, MeCN, 23 ºC

ii. Na2S2O3, H2O, 100 ºC

NR

NH

+HN

NH

N

NH

Me

N

NH

OMe

CO2Me OMe

N

CO2Me

NH

N

NH

N SEtO2C

N NH

79% 89% 90% 54% 76%

N

N OPd

N

NO(BF4)2

1

R

+

NN

Cl

TEDA2+•

EA = 12.4 eV

N

N

Cl

R

N

N

Cl

R

≠

–e–

–H+

R

N

N

Cl

22

Dearomative DihydroxylationProposed Mechanism

R + R'N NR' R'N NR'* Arene

R R'N NR'

*Visiblelight and/

or

R'NNR'

R

*δ+

δ–

NR'

NR'R

Arene Arenophile Excitedarenophile

Exciplex:electron transfer

Exciplex:charge transfer

[Arene–arenophile adduct]

RN N

MeNO O

i. Visible light

ii. OsO4 (Cat.), NMOii. p-TsOH

R O

OX

1. N2H4 or KOH, then BzCl

2. SmI2

N2H4 or KOH, then CuCl2

R O

O

NHBz

NHBz

R O

O

MeO OMe

Southgate, E. H.; Pospech, J.; Fu, J.; Holycross, D. R.; Sarlah, D. Nat. Chem. 2016, 8, 922.

N

NNMe

O

O

X =

23

Fast and Selective Ring-Opening Polymerizations

CF3

F3C N

H

S

N

H

O

O

O

O

N

N

N

H

O

O

O

O

R3N

RO

HH

OR

CF3

F3C N

S

N

H

O

O

O

O

RO

M

H

a b c

Previous bifunctional organocatalysts This method

TU-amine: slow but selective TBD: fast but not selective Thioimidate: fast and selective

CF3

F3C N

H

S

N

H

O

O

O

O

d

TU–1

+

Me O M

DCM or THF, 25 ºC

M+ = Na+, K+,N NMes Mes

H

O

O

OH

O

MeOn

Mw/Mn < 1.1

Zhang, X.; Jones, G. O.; Hedrick, J. L.; Waymouth, R. M. Nat. Chem. 2016, 8, 1047.

24

Oxadiazole Grafts in Peptide Macrocycles

NH

HN

NH

O

NHN

NN

O

OO

O

NH

HN

NH

O

NHN

NN

O

OO

O

NH

HN

NH

COOHHN

O

O

O

O

NH

+

aH

O

N NC PPh3

DCE/MeCN = 1:1r. t., 3 h

M-1a M-1b

NN

N

P

O

HN

NH

O

O

O

RH

PhPh

Ph

Electrostaticattraction

NO

HN

HN

O

RH

O

O

N

NPPh

Ph

Ph

H

NO

HN

HN

O

R HNN

O

Frost, J. R.; Scully, C. C. G.; Yudin, A. K. Nat. Chem. 2016, 8, 1105.

25

Intramolecular C–H Amination

NHPA

H

R

Pd(OAc)2 (10–15 mol%)PhI(DMM) (2–3 equiv.)

Chlorobenzene, Ar, 12 h100 ºC or 110 ºC

RN

PA

+

NHPA

O

R

O

N O

NPA

CF3

NPA

I

NPA

CO2Me

BrN

PA

NCl NCl

NPA

1N (72%), 1O (9%) 2N (54%), 2O (18%) 3N (76%), 3O (9%) 4N (53%) + 4N' (32%)

I

O

O O

O

Ph

PhI(DMM)

He, G.; Lu G.; Guo, Z.; Liu, P.; Chen, G. Nat. Chem. 2016, 8, 1131.

26

Intramolecular C–H Amination

He, G.; Lu G.; Guo, Z.; Liu, P.; Chen, G. Nat. Chem. 2016, 8, 1131.

27

Decarboxylative Hydroarylation of Alkynes

H

R1

R2

R

RuLn

R1

R2

R

HX

+ LnRuX2

R1

R2R

LnRu

R1 R2

R RuLn

O

O

R1R2

RRuLn

O

OX

H

R1R2

R

OO

RuLnR2

R1

R2R1

2 HX

– CO2

HX

Parth A

Path A'

– CO2

– CO2

R

Path C

O

O

R

R1

R2

R1

R2

R1

R2

+ LnRu(0)

+ LnRu(0)

Path B

RO

O

RuLn

R2R1Alkyne

insertion

ROH

O

H

Carboxyl-assistedC–H activation

I

II

II'

III

IVV

ROH

O

R2R1+

2.0 equiv. 1.0 equiv.R1

R2

R

90% yield

+ CO2Ru(p-cymene)2(OAc)2 (10 mol%)

Dioxane/mesitylene/heptane (2:2:1)80 ºC, 48 h

RuOO

O

O

Ru(p-cymene)2(OAc)2

Zhang, J.; Shrestha, R.; Hartwig, J. F.; Zhao, P. Nat. Chem. 2016, 8, 1144.

Alkoxycarbonylation of Alkenes

28

Li, H.; Dong, K.; Jiao, H.; Neumann, H.; Ralf, J.; Beller, M. Nat. Chem. 2016, 8, 1159.

C4H9 C4H9 C4H9C3H7

C3H7

C4H9COOMe C4H9

C4H9

Pd-catalyzedisomerization

Pd-catalyzedcarbynylation CO, MeOH CO, MeOH

COOMe

COOMe

CO, MeOH CO, MeOH

e-1 e-2 e-3 e-4

C4H9

COOMe

C4H9 + ROH

1 mol% PdCl2,4 mol% L16

toluene, 100 ºC, 20 h,CO (40 bar), 5 µL H2O

C4H9

COOR

20–99% yield65–85% branched selectivity

N PR2

OMe

L15: R = PhL16: R = Cy

Hot Areas in Organic Chemistry

29

– Drug Molecule Synthesis • Heteroarene Synthesis• Amination• Fluorinated Molecules

– Conversion of Hydrocarbon Feedstocks • C–H Functionalization• Unsaturated Bonds Functionalization

– Peptides/Proteins Related • New Synthetic Method• Modification

Acknowledgements

30

Engle Lab: Keary Engle, Ph.D De-Wei Gao, Ph.D. Miriam L. O’Duill, Ph.D. Sri Krishna Nimmagadda, Ph.D. Joe DerosaJohn GurakAndrew Romine Mingyu Liu Rei MatsuuraVan Tran Mark Boulous Miranda Sroda Tian (May) Zeng Zichen (Forrest) Wang Carrie Gabaldon

David Hill

Other labs at TSRI