Dual Catalysis Using Boronic Acid and Chiral ... - ACS Publications

Aug 12, 2016 - Department of Chemistry, Centennial Centre for Interdisciplinary Science, University of ... Tristan Verdelet , Robert M. Ward , Dennis ...
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Dual Catalysis Using Boronic Acid and Chiral Amine: Acyclic Quaternary Carbons via Enantioselective Alkylation of Branched Aldehydes with Allylic Alcohols Xiaobin Mo, and Dennis G Hall J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 12 Aug 2016 Downloaded from http://pubs.acs.org on August 12, 2016

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Journal of the American Chemical Society

Dual  Catalysis  Using  Boronic  Acid  and  Chiral  Amine:                                                               Acyclic  Quaternary  Carbons  via  Enantioselective  Alkylation  of   Branched  Aldehydes  with  Allylic  Alcohols   Xiaobin  Mo,  Dennis  G.  Hall*   Department  of  Chemistry,  Centennial  Centre  for  Interdisciplinary  Science,  University  of  Alberta,  Edmonton,     Alberta,  Canada,  T6G  2G2    

Supporting  Information  Placeholder ABSTRACT:  A  ferrocenium  boronic  acid  salt  activates  allylic   alcohols   to   generate   transient   carbocations   that   react   with   in   situ   generated   chiral   enamines   from   branched   aldehydes.   The  optimized  conditions  afford  the  desired  acyclic  products   embedding   a   methyl-­‐aryl   quaternary   carbon   centre   with   up   to  90  %  yield  and  97:3  enantioselectivity  ratio,  with  only  wa-­‐ ter   as   the   by-­‐product.   This   noble   metal-­‐free   method   com-­‐ plements  alternative  methods  that  are  incompatible  with  C– halogen  bonds  and  other  sensitive  functional  groups.  

co-­‐workers   prepared   acyclic   quaternary   carbon   centers   with   a  clever  combination  of  palladium,  Brønsted  acid,  and  amine   6b catalysis   (Figure   1a).   Similarly,   Carreira   and   co-­‐workers   employed  dual  iridium  and  amine  catalysis  as  a  complemen-­‐ tary  strategy  to  obtain  the  branched  products  of  allylic  alkyl-­‐ 6d ation  in  high  enantio-­‐  and  diastereoselectivity  (Figure  1b).   Previous work (a) List; Pd + amine + chiral acid (ref. 6b)

O Ar

H

R1

Me

The   advent   of   new   strategies   for   the   catalytic   activation   of   organic   molecules   creates   new   opportunities   to   design   un-­‐ conventional   bond   forming   processes.   In   dual   catalysis,   two   mutually  compatible  catalysts  are  combined  to  independent-­‐ ly   activate   two   different   substrates   and   expand   the   scope   of   reactions  with  substrates  that  are  unreactive  under  tradition-­‐ 1 al   conditions.   In   this   perspective,   the   concept   of   boronic   acid   catalysis   (BAC),   which   exploits   the   ability   of   boronic   acids   to   form   reversible   covalent   bonds   with   hydroxyl   func-­‐ tionalities,   was   examined   by   our   group   and   others   in   the   2 catalytic   direct   activation   of   carboxylic   acids   and   alcohols.   For   instance,   we   recently   reported   direct   boronic   acid-­‐ catalyzed   Friedel-­‐Crafts   alkylations   of   neutral   arenes   with   readily  available  allylic  and  benzylic  alcohols  as  a  way  to  cir-­‐ 3 cumvent  the  use  of  toxic  organohalide  electrophiles.  With  a   view  to  extend  this  strategy  towards  other  classes  of  nucleo-­‐ philes  such  as  carbonyl  enolates,  we   envisaged  the  possibility   of  merging  BAC  with  chiral  amine  catalysis  to  achieve  alkyla-­‐ tion   of   enamines   with   carbocations   via   dual   activation   of   4,5 aldehydes   and   alcohols,   respectively.   A   priori,   the   com-­‐ bined  use  of  Lewis  acidic  and  Brønsted  basic  catalysts  poses   challenging   issues   of   chemoselectivity,   including   the   threat   of  catalysts’  inter-­‐annihilation.  Moreover,  the  use  of  alcohols   as   precursors   of   reactive   carbocations   can   lead   to   side-­‐ reactions   like   homoetherification   or   alkylation   of   the   amine   catalyst.  Cozzi  and  co-­‐workers  overcame  these  challenges  by   employing   InBr3   and   imidazolidinone   catalysts   to   alkylate   linear  aldehydes  with  secondary  allylic  alcohols  in  high  enan-­‐ 4b tioselectivities.  Similar  approaches  to  asymmetric  allylation   of   branched   aldehydes   with   allylic   alcohols   engaging   transi-­‐ 6 tion   metals   as   co-­‐catalysts   were   reported.   In   2011,   List   and  

[Pd] + amine chiral phosphoric acid

R2

HO R1 ,

R2

O

= H, Me, Ph

R2

H Me Ar R1

66-98% yield up to 99.8:0.2 er

linear product

(b) Carreira; Ir + amine + acid (ref. 6d)

O Ar

H

[Ir] + amine chiral ligand acid activator

OH Ar

Me

42-86% yield >99.5:0.5 er, >20:1 dr

O

H Ar

H Me Ar branched product

This work (c) Boronic acid + chiral amine

O

O H

Ar Me

complementary functional group tolerance

HO Ar

Ar

boronic acid + chiral amine

noble-metal free, benign byproduct (H 2O)

54-90% yield up to 97:3 er stereogenic quaternary carbon centers

H

Ar Ar

Me Ar further product transformations, e.g. oxidative cleavage

 

Figure  1.  Methods  for  dual  catalytic  asymmetric  allylation  of   branched  aldehydes  with  allylic  alcohols     As  highlighted  through  these  key  contributions,  the  prepara-­‐ tion   of   acyclic   quaternary   all-­‐carbon   centers   remains   an   im-­‐ 7 portant  objective  in  organic  synthesis.  For  instance,  methyl-­‐ aryl  quaternary  carbons  are  present  in  a  number  of  bioactive   8 natural   products   and   drug   candidates   (Figure   2).   Although   9 several  methods  exist  based  on  the  use  of  chiral  auxiliaries,   there  are  relatively  few  strategies  available  through  asymmet-­‐ ric   catalysis.   Furthermore,   preparative   methods   based   on   palladium   catalysis   are   not   orthogonal   with   functionalities   like   aryl   halides   and   are   often   incompatible   with   nitro   or   other  basic  functional  groups.  Herein,  we  describe  a  concep-­‐ tually   novel,   noble   metal-­‐free   methodology   based   on   dual   BAC  and  amine  catalysis  that  is  compatible  with  these  func-­‐ tional   groups   and   provides   methylated   quaternary   carbon   centers  in  high  enantioselectivity  (Figure  1c).  

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Me

N Ph

Me

OMe H 2N

Me

2TFA

Cl

O N Me

O

O

N F

N

Me

O

N

Cl

Me

LY426965 serotonin antagonist

(+)-cuparene O 2N

Ph H N

N

O

O O S N Me

O N Me

O

NK1/NK3 receptor antagonist

CCR5 antagonist

 

Figure  2.  Examples  of  biologically  active  compounds  contain-­‐ ing  stereogenic  methylated  quaternary  carbon  centers   The  initial  optimization  was  performed  on  the  racemic  reac-­‐ tion   and   focused   on   selecting   the   best   boronic   acid   co-­‐ catalyst  and  allylic  alcohol  partner  with  aldehyde  1a  and  ben-­‐ 6d zhydrylamine   A1   (see   SI).   This   effort   identified   the   most   promising   conditions   with   ferrocenium   boronic   acid   B1   and   alcohol  2a  in  a  dichloromethane/hexafluoroisopropanol  mix-­‐ ture  (v:v=10:1)  at  40  °C  for  48  h,  affording  product  3a  in  88%   yield   (Table   1,   entry   1).   The   use   of   HFIP   was   critical   to   in-­‐ crease  the  solubility  of  ferrocenium  boronic  acid  B1  as  well  as   10 stabilizing   the   putative   carbocation   intermediate.   Allylic   alcohol   2a   with   para   fluorine   substituents   was   employed   to   best   suppress   the   boronic   acid-­‐catalyzed   1,3-­‐rearrangement   of   allylic   alcohols,   a   process   competing   with   the   desired   al-­‐ 11 lylation.   Even   though   a   limited   number   of   allylic   alcohols   were  suitable  (see  SI),  it  is  often  inconsequential  because  one   of  the  most  compelling  synthetic  transformation  of  the  diaryl   alkene  moiety  of  products  like  3a  is  oxidative  cleavage.    

Table   1.   Chiral   Amine   Optimization   in   the   Dual   Cata-­‐ lytic  Asymmetric  Allylationa   O Ph

H

Me

2a: Ar = 4-F-C6H 4

1a

O

B1 (20 mol%) amine (20 mol%)

Ar

HO Ar

Ar Ar

H

DCM:HFIP = 10:1, 40 °C, 48 h, 0.125 M

Me Ph

3a F 3C

CF3 CF3

Fe +

B(OH) 2

NH 2

SbF6

B1

entry  

a

Ph

Ph

A1

N NH 2

A2

amine  

R  

N H

N H

O TMS

O R

CF3

A4-8

A3 b

yield  (%)  

  c

er  

1  

A1  

-­‐  

88  

50:50  

2  

A2  

-­‐  

86  

76.5:23.5  

3  

A3  

-­‐  

n.r.  

n.d.  

4  

A4  

-­‐SiMe3  

20  

87.5:12.5  

5  

A5  

-­‐SiEt3  

34  

83.5:16.5  

6  

A6  

-­‐Si(i-­‐Pr)3  

51  

85.5:14.5  

7  

A7  

-­‐SiPh3  

31  

85.5:14.5  

8  

A8  

-­‐Si(t-­‐Bu)Me2  

47  

90:10  

Reactions  conditions:  0.25  mmol  of  aldehyde  and  0.50  mmol   of  alcohol  in  a  solvent  mixture  of  dichloromethane  (2.0  mL)   and  hexafluoroisopropanol  (0.2  mL)  under  nitrogen  at  40  °C   b 1 for  48  h.   Yields  were  determined  by   H  NMR  analysis  of  the   reaction   mixture   with   1,4-­‐dinitrobenzene   as   internal   stand-­‐ c ard.   Determined  by  chiral  HPLC  analysis  of  the  correspond-­‐ ing  alcohol  product  of  aldehyde  reduction  (see  SI).    

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The   enantioselectivity   of   the   allylation   was   examined   by   screening   over   30   different   chiral   amines,   based   on   condi-­‐ tions   of   the   optimized   racemic   reaction   (see   SI).   Chiral   pri-­‐ mary   amines   were   investigated   first   because   they   are   less   12 sterically   hindered   for   branched   aldehydes.   Unfortunately,   these  amines  generally  provided  poor  performance,  as  exem-­‐ 13 plified  with  A2  affording  a  76.5:23.5  er  (Table  1,  entry  2).  The   more  common  chiral  secondary  amines  were  evaluated  even   though   α-­‐functionalization   of   branched   aldehydes   catalyzed   by   secondary   amines   is   generally   more   challenging   and   less   14 15 successful.   When   diphenylprolinol   trimethylsilyl   ether   A3   was   employed,   the   reaction   provided   no   product   (Table   1,   entry  3).  We  hypothesized  that  this  failure  may  be  due  to  the   nucleophilic  secondary  amine  center,  which  could  deactivate   the   ferrocenium   boronic   acid   B1.   To   our   satisfaction,   upon   using   the   less   nucleophilic   diarylprolinol   silyl   ether   A4,   the   desired   product   was   observed   in   high   enantioselectivity   (87.5:12.5  er)  albeit  with  low  yield  (20%).  Encouraged  by  this   result,  we  eventually  identified  A8  as  the  best  amine  catalyst   providing  47%  yield  and  90:10  er  (Table  1,  entry  8).  With  this   optimal   chiral   amine   in   hand,   we   turned   our   attention   to   the   optimization   of   other   reaction   parameters.   A   brief   solvent   screening   identified   toluene/HFIP   (v:v=10:1),   at   a   concentra-­‐ tion   of   0.25   M,   as   the   solvent   system   providing   the   highest   enantioselectivity  albeit,  in  32%  yield  (see  SI).  Additives  (wa-­‐ 16 ter,   acetic   acid )   provided   no   improvement.     According   to   Bräse   and   co-­‐workers,   the   use   of   microwave   irradiation   can   17 accelerate   enamine   formation   for   branched   aldehydes.   By   applying   the   same   strategy   with   a   catalyst   loading   of   30   mol%,  the  yield  of  3a  near  doubled.  Catalysts  ratio  other  than   1:1  B1:A8  led  to  no  improvement  (see  SI).  At  this  stage,  a  re-­‐ optimization   of   the   allylic   alcohol   showed   that   2b   can   serve   as   a   cheaper   and   more   effective   allylation   agent   providing   a   higher  yield  of  60%  while  maintaining  the  enantioselectivity.   The   remainder   of   the   mass   balance   consists   mostly   of   unre-­‐ acted  aldehyde  and  transposed  alcohol.     The   scope   of   aldehyde   substrate   was   assessed   under   the   optimal   conditions   of   (Scheme   1).   Branched   aldehydes   with  an  aryl  group  bearing  electron-­‐donating  substituents  (-­‐ OMe,   -­‐Me)   provided   products   4b   and   4c   in   slightly   lower   yield   and   enantioselectivity   compared   to   4a.   While   existing   6b methods  also  reported  high  yield  and  high  enantioselectivi-­‐ ty  for  select  aldehydes  containing  simple  aryl  substituents  (-­‐ OMe,   -­‐Me,   -­‐F),   we   were   delighted   to   observe   a   wider   func-­‐ tional   group   tolerance   with   our   reaction   system,   especially   for   electron   withdrawing   aryl   substituents.   Branched   alde-­‐ hydes  with  bromo/chloro  aryl  substituents,  which  are  partic-­‐ ularly   useful   for   derivatization   by   cross-­‐coupling   chemistry,   were   well   tolerated   and   gave   high   yield   and   high   enantiose-­‐ 18 lectivity  in  the  preparation  of  products  4d-­‐f.  Highly  enanti-­‐ oselective   catalytic   α-­‐functionalization   of   aldehydes   1g-­‐j   has   6f,14d,19 been   shown   to   be   challenging   with   other   methods.   In   contrast,  with  our  system,   polar  basic  functional  groups  such   as   -­‐CO2Me,   -­‐NO2,   and   CF3   fared   well   affording   products   4g-­‐ 20   j. An   aldehyde   with   a   naphthyl   group   afforded   product   4k   in  good  yield  and  enantioselectivity.  The  auspicious  applica-­‐ bility  of  this  method  towards  heterocyclic  substrates  is  high-­‐ lighted  with  indolyl  product  4l,  which  despite  a  lower  yield,   was  obtained  in  high  er.  Unfortunately,  the  α-­‐ethyl  aldehyde   1m  was  not  readily  applicable.  The  absolute  configuration  of   the  allylation  products  4a-­‐m  was  assigned  as  (S)  based  on  the   21   derivatization  of  4a  into  a  known  compound  (see  SI).

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Journal of the American Chemical Society

Scheme   1.   Substrate   Scope   of   Dual   Catalytic   Asym-­‐ metric  Allylationa   H

F 3C O

CF3

H SbF6 Fe +

R1

1f (1.00 g, 4.95 mmol)

B(OH) 2 N H

1a-k

O TBS

R1 R2

2. NaBH 4 (10.0 equiv) DCM:MeOH = 10:1, 0 °C

Ph HO

Ph Ph

HO

Me

Ph

HO

Ph

Ph

HO

Br

4d 77% (70%) 95.5:4.5 er

Ph Ph

Ph

HO

Me

Me

Me

Me

Ph

Ph HO

Me Cl Cl

Br

4e 73% (68%) 96:4 er

EWG

Ph Ph

Me

Me

4i: EWG = CF3 90% (80%) 96:4 er

Ph Ph

HO

4h: EWG = NO 2 82% (79%) 97:3 ere

4g: EWG = CO 2Me 69% (58%) 95:5 er

4f 87% (82%) 96.5:3.5 er

Ph HO

Ph

HO

4c 62% (57%) 93:7 er

4b 54% (42%) 92.5:7.5 er

Ph Ph

HO Me

Ph

HO Et

CF3 F 3C

4j 70% (70%) 95.5:4.5 er

4k 76% (71%) 96:4 er

N Ts

4l 52% (49%) 94:6 er

Me

4m 24% (19%) 80:20 er

  Reactions  conditions:  0.25  mmol  of  aldehyde  and  0.50  mmol   of  alcohol  in  1.1  mL  of  solvent  in  a  microwave  reactor  under   b nitrogen  at  60  °C  for  12  h.   Yield  of  first  step  were  determined   1 by   H   NMR   analysis   of   the   reaction   mixture   with   1,4-­‐ c dinitrobenzene  as  internal  standard.   Isolated  yield  over  two   d steps,   of   the   alcohol   product   of   aldehyde   reduction.   Deter-­‐ mined  by  chiral  HPLC  analysis  of  the   alcohol  products  4  (see   e SI).   Enantiomeric  ratio  of  4i  was  obtained  by  Mosher’s  acid   analysis  of  the  reduced  alcohol  product.   a

  To  demonstrate  the  practicality  of  this  method,  a  gram  scale   reaction   with   aldehyde   1f   was   performed   (Scheme   2).   Even   though  a  lower  yield  was  observed  compared  to  the  explora-­‐ tory  scale  of  Scheme  1,  the  enantioselectivity  was  maintained.   Oxidative  cleavage  of  the  double  bond  of  product  4f  afforded   compound   5   as   a   key   building   block   possessing   correctly   differentiated  side  chains  for  the  quaternary  carbon  fragment   8d of   Servier’s   NK1/NK3   receptor   antagonist,   which   could   not   be  prepared  previously  in  catalytic  asymmetric  fashion.    

Scheme  2.  Application  of  Dual  Catalytic  Allylation      

H 2N 2TFA

Cl

5 (89%)

Ph

Me

OMe

4a (60%) c 94:6 erd

60%b

2. NaBH 4 (10.0 equiv) DCM:MeOH = 10:1, 0 °C

OH

TBSO

2. i. O3, DCM, -78 °C ii. NaBH 4 (10.0 equiv)

4a-m Ph

Me

2b (9.90 mmol)

1. TBSCl (1.1 equiv), imidazole (2.0 equiv) DCM, rt, 16 h (96%)

Ph

HO

toluene:HFIP = 10:1, 0.250 M, µw 60 °C, 12 h,

2b

Ph

toluene:HFIP = 10:1, 0.250 M, µw 60 °C, 12 h,

Ph

CF3

1. B1 (30 mol%), A8 (30 mol%)

Ph

HO Ph

HO Ph

Cl Me

CF3

R2

Ph

1. B1 (30 mol%), A8 (30 mol%)

Cl

O

Cl

Ph H N O

HO

Ph Me Cl Cl

4f (67%, 96:4 er)

Cl

O N Me

Cl Me

R 2N

NK1/NK3 receptor antagonist (see full structure in Scheme 1)

  Mechanistic  control  experiments  were  conducted.  Ferroceni-­‐ um  boronic  acid  B1  was  shown  to  be  a  superior  acid  catalyst   4a 4b 5b compared  to  TFA,  InBr3,  and  p-­‐TsOH  for  the  asymmet-­‐ ric   allylation   (Scheme   3,   top).   Though   it   provides   a   signifi-­‐ cantly   lower   yield,   the   ferrocenium   catalyst   devoid   of   a   bo-­‐ ronyl  group,  CpFe(III)CpSbF6,  is  also  active  (Scheme  3,  top).   This   result   indicates   that   cooperative   activation   involving   both  Lewis  acidic  sites  of  B1  cannot  be  ruled  out.  In  the  pres-­‐ ence   of   HFIP,   with   none   or   trace   water,   a   complex   dynamic   equilibrium   is   likely   to   establish   consisting   of   the   free   bo-­‐ ronic   acid,   the   bis(hexafluoroisopropoxide),   the   hydroxy   (hexafluoroisopropoxide)   hemiester,   and   the   corresponding   anionic   species   (Scheme   3).   Formation   of   boronic   anhydrides   was   not   detected   by   mass   spectrometry.   The   possible   exist-­‐ ence   of   inter-­‐catalyst   interactions   was   examined   by   NMR   spectroscopy   in   the   reaction   solvent   (10:1   d8-­‐toluene:HFIP).   11 In   the   presence   of   the   amine   catalyst,   a   new   B   NMR   reso-­‐ nance   appears   at   ~5   ppm,   possibly   indicative   of   reversible   catalyst   interactions   as   a   tetrahedral   amine-­‐borate,   or,   more   likely   a   base-­‐promoted   formation   of   the   tri(hexafluoroisopropoxy)borate   complex   observed   by   MS   11 (see   SI).   According   to   B   NMR   analysis,   catalyst   B1   appears   largely   transformed   at   the   end   of   the   reaction.     Although   a   slow  destructive  interaction  between  the  Fe(III)  ion  and  nu-­‐ 22 cleophilic   reagents   cannot   be   ruled   out,   reversible   interac-­‐ tion   of   the   catalyst   with   the   water   by-­‐product   or   unreacted   substrates  is  also  possible  and  would  require  further  studies.     Altogether,  based  on  these  preliminary  experiments  and  pre-­‐ 3b vious  work  with  catalyst  B1,  an  SN1  mechanism  is  proposed   with   the   dual-­‐catalyzed   cycles   depicted   in   Scheme   3.   Face-­‐ selective   attack   of   the   in   situ   formed   chiral   enamine   (H)   to   the  reactive  carbocation  (E)  results  in  the  allylation  product.   Substitution   of   boronic   acid   B1   for   a   mixture   of   2,3,4,5-­‐ F4HC6B(OH)2   and   Cp2Fe(III)SbF6   provided   a   lower   yield   (32%),   which   lends   further   support   to   an   ion   redistribution   mechanism  that  is  possible  only  with  ionic  boronic  acid  B1.     In  summary,  we  have  disclosed  the  first  application  of  BAC  in   asymmetric  dual  catalysis.  This  noble  metal-­‐free  method  for   allylation   of   branched   aldehydes   provides   moderate   to   high   yields   with   high   enantioselectivity,   and   it   displays   broad   functional  group  tolerance.  The   reliability  of  this  asymmetric   allylation  was  demonstrated  on  a  gram-­‐scale  for  the  prepara-­‐ tion   of   a   quaternary   carbon   fragment   of   Servier’s   NK1/NK3   receptor   antagonist.   A   dual   catalyzed   SN1   mechanistic   cycle   was   proposed.   We   envision   that   more   dual   catalyzed   trans-­‐ formations   of   synthetic   interest   can   be   developed   based   on   the  BAC  concept.  

Scheme   3.   Mechanistic   Controls   and   Proposed   Cata-­‐ lytic  Cycle  of  Dual  Catalytic  Asymmetric  Allylation  

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Control experiments with other acid catalysts O Ph

H

HO Ar

Me

1a

O

Ar

acid catalysts, A8

Ar

H

Ar Me Ph

conditions

2a or 2b

3a or 4a

B1: up to 60%, 94:6 er

InBr 3: up to 21%, 93:7 er

CpFe(III)CpSbF6 : up to 35%, 93:7 er

TFA: up to 18%, 88:12 er

CpFe(III)CpSbF6 + 2,3,4,5-F4HC 6B(OH) 2: up to 32%, 94:6 er

p-TsOH : < 5%, er n.d.

Proposed catalytic cycle

SbF6 Fe +

Ion Exchange

Fe +

B(OR) 3

HO Ph

Ph

Ph

Ph C (tetra-ion)

B(OR) 3 Boronic Acid Cycle

SbF6 Fe +

D (zwitterion)

B(OR) 2

B(OH) 2

SbF6 Fe +

HFIP B1 (R = H or CH(CF3) 2)

B1

Ph SbF6

Ph

O

E (carbocation)

Ph

H R1

N

N

Ar

R2

H

+ H 2O

Me

H R1

Ph Me Ar

R2

H (chiral enamine)

Me

Ar G (imine)

F 3C R1

Chiral Amine Cycle

N H A8

CF3 CF3

R2 N H

O TBS

CF3

A8 H 2O

R2 R1 N OH

O Ar

H F

Me

H

Ar Me

 

ASSOCIATED  CONTENT     Supporting  Information   Experimental   details,   analytical   and   spectral   reproductions   for  the  prepared  compounds.  The  Supporting  Information  is   available  free  of  charge  on  the  ACS  Publications  website.  

AUTHOR  INFORMATION   Corresponding  Author   *E-­‐mail:  [email protected]    

Notes  

The  authors  declare  no  competing  financial  interests.    

ACKNOWLEDGMENT     This   research   was   funded   by   the   Natural   Science   and   Engi-­‐ neering   Research   Council   of   Canada   (Discovery   Grant   to   D.G.H.)   and   the   University   of   Alberta.   X.M.   thanks   Alberta   Innovate  −  Health  Solutions  for  a  Graduate  Studentship.  We   thank   Dr.   Angelina   Morales-­‐Izquierdo   for   help   with   mass   spectrometric   analyses,   and   Dr.   Tristan   Verdelet   for   sugges-­‐ tions  on  the  manuscript.    

REFERENCES  

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(20)  The  racemic  background  enol  allylation  did  not  undermine  the   17 enantioselectivity  as  proposed  by  Bräse  and  co-­‐workers.   (21)  Sonawane,  R.  P.;  Jheengut,  V.;  Rabalakos,  C.;  Larouche-­‐Gauthier,   R.;  Scott,  H.  K.;  Aggarwal,  V.  K.  Angew.  Chem.  Int.  Ed.  2011,  50,  3760.   (22)  Prins,  R.;  Korswagen,  A.  R.;  Kortbeek,  A.  G.  T.  G.  J.   Organomet.   Chem.  1972,  39,  335.  

 

  For  Table  of  Contents  Only   HO Ph

Boronic Acid Catalysis

Ph

Ar OH B HO OH Ph

O H

Ar Me

Ph

O R1

Me

N

R2

Me

H

Ar

H

Ph Ph up to 90% yield Chiral Amine Catalysis up to 97:3 er Ar

     

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TOC graphic 81x31mm (300 x 300 DPI)

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