Cyclizations  of  Ynamides to  Generate  Novel  Ring  Structures

John  Milligan Frontiers  of  Chemistry  SeminarWipfGroup  Meeting July  23,  2016

1

N EWGR

TsNN

H Ph

OO

BocNMe CO2Me

NBn

Ts

NTs

O

Cl Ph

NBn

Ts

H

O

OHNO

CO2Me

R1N TsMe

R2

R3

MeO2C

MeO2C

N

CO2Et

O

NBoc

NO

NTs

H

NTs

OAc

n-BuPh

Ynamides

2

NR R

enamines:

First isolated in 1936

Storied history

Well understood reactivity

Ynamides

3

NNR R

enamines:

First isolated in 1936

Storied history

Well understood reactivity

RR

ynamines:

First isolated in1958

Infrequent and sporadic in theliterature

Major disadvantage:instability toward hydrolysis andpolymerization

Ynamides

4

NNR R

enamines:

First isolated in 1936

Storied history

Well understood reactivity

RR

ynamines:

First isolated in1958

Infrequent and sporadic in theliterature

Major disadvantage:instability toward hydrolysis andpolymerization

N EWGR

ynamides:

First isolated in1972

Of great interest inrecent years

Bench stable!

Synthesis  of  Ynamides:  State  of  the  Art  Before  2003• Elimination

• Isomerization

5Janousek,  Z.;  Collard,  J.;  Viehe,  H.  G.  Angew.  Chem.  Int.  Ed.   1972,  11,  917Huang,  J.;  Xiong,  H.;  Hsung,  R.  P.;  Rameshkumar,  C.;  Mulder,  J.  A.  Grebe,  T.  P.  Org.  Lett.  2002,  4,  2417

NHMe

OPh

NCl

ClCl

then NaHCO3NMe

NMe2

Ot-BuOK

THF, rt64%

NMe

NMe2

OPh

PhCl

t-BuOK(20 mol %)

THF, rt83%

N Ph

ON Ph

O

Discovery  of  Cu  mediated  coupling

6Dunetz,  J.  R.;  Danheiser,  R.  L.  Org.  Lett.  2003,  5,  4011Frederick,  M.  O.;  Mulder,  J.  A.;  Tracey,  M.  R.;  Hsung,  R.  P.;  Huang,  J.;  Kurtz,  K.  C.  M.;  Shen,  L.;  Douglas,  C.  J.  J.  Am.  Chem.  Soc.  2003,  125,  2368

Zhang,  Y.;  Husng,  R.  P.;  Tracey,  M.  R.;  Kurtz,  K.  C.  M.;  Vera,  E.  L.  Org.  Lett.  2004,  6,  1151

Br R2

CuSO4•5 H2O (cat.)1,10-phenanthroline

K3PO4

toluene, 60-95 °CN H

R1

EWGN

R1

EWGR2

Br R2

KHMDS, CuI

pyridine, rtN HR1

EWGN

R1

EWGR2

72003:  Hsung  and  Danheiser  each  publish   Cu-­‐mediated  ynamide  syntheses

0

10

20

30

40

50

60

70

80

90

1998 2000 2002 2004 2006 2008 2010 2012 2014 2016

Occurrence  of  "Ynamides"  in  the  Literature(SciFinder search,  7/18/16)

Reactivity  of  Ynamides

8

NR1

EWGR2 N

R1

EWG R2

additionto electrophiles

additionof nucleophiles

Major  achievements:  ca.  2002-­‐2010• Hydrofunctionalization• Hydroboration,  hydrostannylation,  etc.

• Additions• Control  of  regioselectivity

• Classic  alkyne  cycloaddition  chemistry• [2+2]/[3+2]/[4+2]/[2+2+2]

9DeKorver,  K.  A.;  Li,  H.;  Lohse,  A.  G.;  Hayashi,  R.;  Lu,  Z.;  Zhang,  Y.;  Hsung,  R.  P.  Chem.  Rev.  2010,  110,  5064-­‐5106Evano,  G.;  Coste,  A.;  Jouvin,  K.  Angew.  Chem.  Int.  Ed.    2010,  49,  2840-­‐2859

NR1

EWGR2

R3XN

R1

EWG

X

R3

R2

NR1

EWG

R3

XR2

(depending on nature of R3 and X,as well as conditions)

Where  has  the  ynamide frontier  grown  in  the  last  2-­‐3  years?

• Development  of  functional  analogs  of  ynamides:

• Increasing  array  of  additions/hydrofunctionalizations

10

Lu,  T.;  Hsung,  R.  P.  ARKIVOC 2014,  127-­‐141Perrin,  F.  G.;  Kiefer,  G.;  Jeanbourquin,  L.;  Racine,  S.;  Perrotta,  D.;  Waser,  J.;  Scopelliti,  R.;  Severin,  K.  Angew.  Chem.  Int.  Ed.  2015,  54 (45),  13393-­‐13396Wang,  X.-­‐N.;  Yeom,  H.-­‐S.;  Fang,  L.-­‐C.;  He,  S.;  Ma,  Z.-­‐X.;  Kedrowski,  B.  L.;  Hsung,  R.  P.  Acc.  Chem.  Res.  2014,  47,  560-­‐578

NNH

BocR

Boc

NS

R

O

N RNN

Where  has  the  ynamide frontier  grown  in  the  last  2-­‐3  years?

• Development  of  Cycloadditions  and  Cyclizations:  focus  of  present  talk• Cycloadducts  of  increasing  complexity• Novel  modes  of  reactivity/mechanistic  aspects• Use  of  cheap  and  abundant  catalysts/reagents

11Wang,  X.-­‐N.;  Yeom,  H.-­‐S.;  Fang,  L.-­‐C.;  He,  S.;  Ma,  Z.-­‐X.;  Kedrowski,  B.  L.;  Hsung,  R.  P.  Acc.  Chem.  Res.  2014,  47,  560-­‐578

What  is  the  overarching  problem  to  which  ynamide cyclizations  contribute?

12

NHRHO

O

Solid phase peptide synthesis:

Established MethodologyNH

O

n

ORO

OR OROR

OROligosaccharide synthesis:

Challenging but a constantlydeveloping field

OO

OR OOR

OR

n

N

O

O

H

HH

H

N

strychnine

?

Polycyclic, complex molecules:

Strucure dependent, no general set of building blocks

A massive, long lasting problem!

What  Paradigms  Address  this  Problem?• Schriber-­‐ Diversity  Oriented  Synthesis:  Building  Rapid  Diversity  into  new  chemical  space

• Sharpless-­‐ Click  Chemistry:  Diverse  Chemical  Function  through  a  few  good  reactions

13

OOOH

HO

N3

N3

OH

HO

N

N

NN

N NR

R

Schriber,  S.  L.  Science 2000,  287,  1964-­‐1969.Kolb,  H.  C.;  Finn,  M.  G.;  Sharpless,  K.  B.  Angew.  Chem.  Int.  Ed.  2001,  40,  2004-­‐2021Burke,  M.  D.  et  al.    Science  2015,  347,  1221-­‐1226.

What  Paradigms  Address  this  Problem?• Schriber-­‐ Diversity  Oriented  Synthesis:  Building  Rapid  Diversity  into  new  chemical  space

• Sharpless-­‐ Click  Chemistry:  Diverse  Chemical  Function  through  a  few  good  reactions

• Burke-­‐ “The  Synthesis  Machine”:  Breaking  complex  molecules  into  simple  building  blocks

14

OOOH

HO

N3

N3

OH

HO

N

N

NN

N NR

R

X BOO

O

OMeN

A A B C complexmolecule

cyclization/functionalization

Schriber,  S.  L.  Science 2000,  287,  1964-­‐1969.Kolb,  H.  C.;  Finn,  M.  G.;  Sharpless,  K.  B.  Angew.  Chem.  Int.  Ed.  2001,  40,  2004-­‐2021Burke,  M.  D.  et  al.    Science  2015,  347,  1221-­‐1226.

Ynamides:  Potential  Contributors  as  Tunable,  Reactive  Building  Blocks• A  “building  block”  approach  to  to  alkaloids  and  heterocycles

• R’s  can  be  be  linked  in  a  variety  of  ways:  many  novel  cyclic  structures  are  possible 15

R1 NH2

R2

R4XR5X

Cl R3

OR1 N R3

(cyclization/couplingpartners)

R2

OR1 N R3

O

R2

R5R4

Cyclizations  of  Ynamides

Gold  Catalyzed

Intramolecular

Intermolecular

Non-­‐Gold  Catalyzed

Intramolecular

Intermolecular 16

Part  1A:  “Gold  Free”,  intramolecular• Transition  metal  catalyzed  enyne/diyne  cyclizations• Lewis  acid  mediated  cyclizations

17

Rh-­‐catalyzed  asymmetric  cyclization

18

NO

O

TsNPh

RhClL2(2 mol %)

DCE, 30 °C

95%, 97% ee

TsNN

H Ph

OO

Fc

Fc

FF

F

F

L:

Nishimura,  T.;  Takiguchi,  Y.;  Maeda,  Y.;  Hayashi,  T.  Adv.  Synth.  Catal.  2013,  355,  1374-­‐1382    

Rh-­‐catalyzed  asymmetric  cyclization

19

Nishimura,  T.;  Takiguchi,  Y.;  Maeda,  Y.;  Hayashi,  T.  Adv.  Synth.  Catal.  2013,  355,  1374-­‐1382    

NO

O

TsNPh

RhClL2(2 mol %)

DCE, 30 °C

95%, 97% ee

TsNN

H Ph

OO

Fc

Fc

FF

F

F

L:

NO

O

TsNPh

[M]

TsNNR2

H Ph

[M]

Oxidative  Rh-­‐catalyzed  cyclization

20

N

[Rh(CO)2Cl]2 (5 mol %)P[OCH(CF3)2]3 (20 mol %)

dioxane, rt, 2 h88%

Ts

NCl

Cl

O

TsN

O

Liu,  R.;  Winston-­‐McPherson,  G.  N.;  Yang,  Z-­‐Y.;  Zhou,  X.;  Song,  W.;    Guzei,  I.  A.;  Xu,  X.;  Tang,  W.J.  Am.  Chem.  Soc.  2013,  135,  8201-­‐8204.

Anionic  rearrangement

21

Brioche,  J.;  Meyer,  C.;  Cossy,  J.  Org.  Lett. 2013,  15,  1626-­‐1629  

NBn

TsO

O NHBoc

Me

LiHMDSZnCl2

THF, –78 °C Me NBn

Ts

BocHNCO2Me

1. MeI K2CO3 DMF

2. AgNO3 (5 mol %) acetone, rt 70% (3 steps)

BocNMe CO2Me

NBn

Ts

diastereoselective anionicClaisen rerrangement

Lewis  acid  mediated  cyclization

22

Yeh,  M-­‐C.  P.;  Shiue,  Y.-­‐S.;  Lin,  H.-­‐H.;  Yu,  T-­‐Y.;  Hu,  T.-­‐C.;  Hong,  J.-­‐J.  Org.  Lett. 2016,  18,  2407-­‐2410

NTs

Ph FeCl2 (1.1 eq)

THF, 40 °Cdry air N

Ts

O

Cl Ph

Part  1B:  “Gold  Free”,  intermolecular• [2+2]  “Ficini” reactions• Lewis/Bronsted  acid  mediated  cyclizations

• Dipolar  cycloadditions

• Cyclizations  involving  azides  or  diazo  compounds 23

R

NEWG

NuE

R

NEWGY Z

X

Ficini [2+2]  addition

24

Ficini,  J.  Tetrahedron  1976,  32,  1449-­‐1486  

NEt2

via:

THF

O

ONEt2

O

NEt2

Modern  ynamide Ficini reactions

25Yuan,  Y.;  Bai,  L.;  Nan,  J.;  Liu,  J.;  Luan,  X.  Org.  Lett.  2014,  16,  4316-­‐4319Enomoto,  K.;  Oyama,  H.;  Nakada,  M.  Chem.  Eur.  J.  2015,  21,  2798-­‐2802

• Facile  addition  with  activated  alkene  partner:

• Enantioselective  addition:

N

Ph

Bn

Ts

H

HNTs Bn

Ph

O

NEt2

O

OMeDCE, 40 °C

then MeOH, rt70%

O

NEt2

O

BF4

NBn

Ts

H

NTs Bn

Cu(OTf)2–BOX ligand(20 mol%)

4Å MS

CH2Cl2, 0 °C97%, 96% ee

O

OHNO

CO2Me

O

OO

NH

MeO2C

Ficini adduct  opening

26Wang,  X.-­‐N.;  Krenske,  E.  H.;  Johnston,   R.  C.;  Houk,  K.  N.;  Hsung,  R.  P.  J.  Am.  Chem.  Soc.  2014,  

136,  9802-­‐9805Wang,  X.-­‐N.;  Krenske,  E.  H.;  Johnston,   R.  C.;  Houk,  K.  N.;  Hsung,  R.  P.  J.  Am.  Chem.  Soc.  2015,  

137,  5596-­‐5601

AlCl3 (0.4 eq)

toluene, 105 °C68%

ON

Bn

Ns

H

HO

NBn

Ns

O

cis-trans cycloheptadieneone

R2NAlCl3

4πringopening

R2N

H

O

1,2-shift

AlCl3

Acid-­‐mediated  quinoline/pyridine  syntheses

27Xie,  L.-­‐G.;  Niyomchon,  S.;  Mota,  A.  J.;  Gonzalez,  L.;  Maulide,  N.  Nat.  Commun.  2016,  DOI:  10.0138/ncomms10914

Zhang,  J.  Zhang,  Q.;  Xia,  B.;  Wu,  J.;  Wang,  X.-­‐N.;  Chang,  J.    Org.  Lett. 2016,  DOI:  10.1021/acs.orglett.6b

NPh

MeCN

DMF, rt70%

OO TfOH (1.1 eq)

N

NOO

N

MeCN (0.6 eq)

CH2Cl2, rt>95%

Bn

Ts

TMSOTf (0.5 eq)

N

N

NBn

Ts

BnTs

Lewis  acids:  DA  cyclopropaneactivation

28

Mackay,  W.  D.;  Fistikci,  M.;  Carris,  R.  M.;  Johnson,   J.  S.  Org.  Lett. 2014,  16,  1626-­‐1629  

NTs

MeR1

Sc(OTf)3(10 mol %)

CH2Cl2, rt

CO2MeMeO2C

R3R2

R1

N TsMe

R2

R3

MeO2C

MeO2C

via:

R3R2

OMeOO

MeO

LA

N TsMe

R1

Lewis  acids:  DA  cyclopropaneactivation

29

Mackay,  W.  D.;  Fistikci,  M.;  Carris,  R.  M.;  Johnson,   J.  S.  Org.  Lett. 2014,  16,  1626-­‐1629  

NTs

MeC5H11

Sc(OTf)3(10 mol %)

CH2Cl2, rt89%

CO2MeMeO2C

C5H11

N TsMe

MeO2C

MeO2C

1. Na naphthalide THF

2. 3 M HCl, 125 °C

83%, >20:1 dr

C5H11

OOMe

OMe OMe

Dipolar  cycloaddition

30

Brioche,  J.;  Meyer,  C.;  Cossy,  J.  Org.  Lett. 2015,  17,  2800-­‐2803.

NO

NBoc

CO2EtN

CO2Et

O

K2CO3

DMF, rtN

Boc

70%

via:

N

O

NBoc

EtO2C

Vinylketene cascade

31

Willumstad,  T.  P.  Bordreau,  P.  D.;  Danheiser,  R.  L.  J.  Org.  Chem.  2015,  80,  11794-­‐11805.

N2O

R1

R2 hνCH2Cl2, rt;

toluene, 110 °C

R3 NR4

R5

NCO2t-Bu

CO2t-Bu

R4

R5

HO

R2R1

R3

1. Tf2O, DMAP CH2Cl2; TFA

2. I2, NaHCO3, MeCN, rt

N R4HO

R2R1

R3

R5

I

Part  2A:  Gold  catalyzed,  intramolecular• Diyne  cyclizations• Enyne  cyclizations• Cyclizations  involving  azides

32

Diyne cyclization

33Liu,  J.;  Chen,  M.;  Zhang,  L.;  Liu,  Y.  Chem.  Eur.  J.  2015,  21,  1009-­‐1013

NTs

Ph

OAc

n-Bu

(Johnphos)Au(MeCN)SbF6 (5 mol %)4Å MS

CH2Cl2, rt, 83%

NTs

OAc

n-BuPh

Diyne cyclization

34Liu,  J.;  Chen,  M.;  Zhang,  L.;  Liu,  Y.  Chem.  Eur.  J.  2015,  21,  1009-­‐1013

NTs

Ph

O

n-Bu

NTs

OAc

n-BuPh

O

[Au]

NTs

Ph

OO

[Au]

NTs

Ph

OAc

[Au]n-Bu n-Bu

NTs

Ph

OAc[Au]

Indole  cyclization  with  tethered  alcohol

35

Zheng,  N.;  Chang,  Y.-­‐Y.;  Zhang,  L.-­‐J.;  Gong,  J.-­‐X.;  Yang,  Z.  Chem.  Asian  J.  2016,  11,  371-­‐375

NBn

NTs

OH

PPh3AuSbF6(5 mol %)

DCE, 25 °C89% N

Bn

O

NTs

H

Indole  cyclization  with  tethered  alcohol

36

Zheng,  N.;  Chang,  Y.-­‐Y.;  Zhang,  L.-­‐J.;  Gong,  J.-­‐X.;  Yang,  Z.  Chem.  Asian  J.  2016,  11,  371-­‐375

NBn

NTs

OH

PPh3AuSbF6(5 mol %)

DCE, 25 °C NBn

O

NTs

H

NBn

NTs

OH

[Au]

NBn

NTs

OH

Gold  Cyclization  of  Aryl  Azide

37

Tokimizu,  Y.;  Oishi,  S.;  Fujii,  N.;  Ohno,  H.  Org.  Lett.  2014,  16,  3138-­‐3141

N3

NTs

Ph

P(p-CF3Ph)AuCl (5 mol %)AgOTf (5 mol %)

(ClCH2)2, rt94% N

NTs

HPh

Part  2B:  Gold  catalyzed,  intermolecular• Alkyne  partners• Heterocyclic  partners• Azide  partners

38

Alkyne  coupling

39

Shen,  C.-­‐H.;  Li,  L.;  Zhang,  W.;  Liu,  S.;  Shu,  C.;  Xie,  Y.-­‐E.  Yu,  Y.-­‐F.;  Ye,  L.-­‐W.  J.  Org.  Chem.  2014,  79,  9313-­‐9138

HN

n-C6H13

IPrAuNTf2 (5 mol %)

H2O, 80 °C, 3 h70%

N

Br

O(2 eq)

N

PhPh

Ts

Nn-C6H13

PhNPh

TsO

Isoxazole coupling

40

O N

O

Ph

(ArO)3PAuNTf2(5 mol %)

NO

N

Ph

N

O

O

O

DCE, 80 °C83%

Xiao,  X.-­‐ Y.;  Zhou,  A.  H.;  Shu,  C.;  Pan,  F.;  Li,  T.;  Ye,  L.-­‐W.  Chem.  Asian  J.  2015,  10,  1854-­‐1858

Azide coupling

41Shu,  C.;  Wang,  Y.-­‐H.;  Zhou,  B.;  Li,  X.-­‐L.;  Ping,  Y.-­‐F.,  Lu,  X.;  Ye,  L.-­‐W.  J.  Am.  Chem.  Soc.  2015,  137,  9567-­‐9570

BrN3

PhN

MsPh

IPrAuNTf2(5 mol %)

4Å MSDCE, rt

85%NMs

NH

PhBr

Summary

Gold  Catalyzed

Intramolecular

Intermolecular

Non-­‐Gold  Catalyzed

Intramolecular

Intermolecular 42

Final  thought:  Black  Swans• Widely  accepted  conventional  wisdom  in  1976:• Gold  is  too  unreactive  to  be  of  catalytic  use• Palladium-­‐catalyzed  cross  coupling  can  achieve  C-­‐C  bond  formation  but  not  C-­‐N  bond  formation

• Olefin  metathesis  is  an  ill-­‐defined  reaction  of  olefinic  hydrocarbons  and  is  of  little  use  in  synthesis

• Plausible  addition:  Molecules  with  a  nitrogen  connected  to  a  triple  bond  (aka  ynamide)  are  too  unstable  and  reactive  for  widespread  adoption  in  practical  synthetic  chemistry

43

Nugent,  W.  A.    Angew.  Chem.  Int.  Ed.   2012,  51,  8936-­‐8949

Final  thought:  Black  Swans

Nugent’s  concluding  remark:  

“One  can  only  imagine  what  extraordinary  developments  those  of  you  currently  beginning  your  careers  in  chemistry  will  witness  in  the  next  35  or  40  years.    In  this  regard,  I  envy  you.”

44

Nugent,  W.  A.    Angew.  Chem.  Int.  Ed.   2012,  51,  8936-­‐8949