L. Gremaud, L. Palais, A. Alexakis* Department of organic chemistry, University of Geneva, CH-1211 Geneva 4, Switzerland

Acknowledgment: The authors thank the Swiss National Research Foundation (Grant No. 200020-113332), COST action D40 (SER Contact No. C07.0097) for financial support, BASF for a generous gift of chiral amines, all collaborators of Alexakis rescherch group and Audrey Mercier from Kundig group for a generous gift of 3,3’ BINOL derivatives.

Since 2003, asymmetric 1,4-additions to enals using Rh1 or Pd2 catalysis has been reported by Miyaura, Hayashi, and Carreira. In all of these enantioselective process, the 1,4-addition is limited to cinnamaldehyde derivatives. Despite than the Cu is known to be a very good metal to catalyzed 1,4 addition no direct methodology has been achieved to enals. Alternative indirect ways have been described by Hoveyda with amides3 and by Feringa with thioesters,4 where the resulting adducts could be converted to aldehydes in a further step. Herein, we report the first successful enantioselective copper-catalysed conjugate addition to several α,β-unsaturated aldehydes, with diorganozinc and Grignard reagents.5

[1] As a reference containing the results obtained for Rh-catalyzed ACA to enals, see: (a) Itooka, R.; Iguchi, Y.; Miyaura, N. J. Org. Chem. 2003, 68, 6000–6004. (b) Tokunaga, N.; Hayashi, T. Tetrahedron: Asymmetry 2006, 17, 607–613. (c) Paquin, J. F.; Defieber, C.; Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 10850–10851. [2] As a reference containing the results obtained for Pd-catalyzed ACA to enals, see: Nishikata, T.; Yamamoto, Y.; Miyaura, N. Chem. Commun. 2004, 1822–1823 [3] Hird, A. W.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 1276–1279. [4] Des Mazery, R.; Pullez, M.; Lopez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966–9967. [5] Palais, L.; Babel, L.; Quintard, A.; Belot, S.; Alexakis, A. Org. Lett. 2010, 12, 1988-1991.

Introduction Screening of chiral ligand for R2Zna

Entry R R’ Conv. (%)a,d ee (%)b

1 C7H5 Et >99 (75) 75, (R) 2 n-Bu Et >99 (60) 64, (R) 3 i-Bu Et 100 70, (R) 4c C7H5 Me 85 (79) 68, (R) 5c n-Bu Me 87 76, (R) 6c i-Pr Me 100 70, (S) 7c Ph Me 50 64, (S)

a Conversion determined by 1H NMR and up to 99% b Determined by 1H NMR c Determined by chiral GC or SCF d Performed with 5.25 mol% L9, 5 mol% CuTC, with Et2O during 6 h at -20°C.

ACA of R2Zn to various enals

Conclusion

a Determined by 1H NMR b Determined by chiral GC c Reaction performed at 0 °C over 16 h d Yield in parentheses.

Screening of chiral ligand for RMgBra

a Conversion determined by 1H NMR and up to 99% b Determined by 1H NMR c Determined by chiral GC or SCF d Reaction performed with 10 mol% of ligand e Not determined f Reaction performed with 1.3 equiv. of TMSCl.

ACA to various enalsa ACA of various RMgBr

a Conversion determined by 1H NMR and up to 99% b Determined by 1H NMR c Determined by chiral GC. a Determined by 1H NMR b Determined by chiral GC c Yield in parentheses.

We have described the first copper-catalysed conjugate addition of dialkylzinc and Grignard reagents to a large variety of α,β-unsaturated aldehydes with moderate to excellent 1,4-regioselectivities and ee’s up to 90%. Key feature for this reaction with Grignard reagents was the addition of TMSCl which accelerates the conjugate addition and prevents the formation of 1,2 products by trapping the enolate and forcing the conversion to β-carbon adduct. Further work is in progress to improve the specter of application.

O O *+ Et2Zn( 2 equiv.)

Cu(OTf)2 (5 mol%)L* (10 mol %)PhMe, 0°C, 3h

OP

ON

Ph

PhO

PO

N

Ph

Ph

Ph Ph

Ph Ph

OP

O

Ph Ph

Ph Ph

O

OO N Ph PPh2

PPh2

OP

ON

P NP N

Ph

Ph

2-naphthyl

2-naphthyl

OP

ON

Ph

PhPh

Ph

2-naphthyl

2-naphthyl

OP

ON

Ph

Ph

L11,4 : aldolb > 99 : 1

eec = 50%

L21,4 : aldol = 99 : 1

ee = 57%

L31,4 : aldol = 95 : 5

ee = 79%

L41,4 : aldol = 94 : 6

ee = 34%

L51,4 : aldol > 99 : 1

ee = 64%

L61,4 : aldol = 88 : 12

ee = 60%

L71,4 : aldol = 93 : 7

ee = 73%

L81,4 : aldol = 99 : 1

ee = 50%

L91,4 : aldol = 87 : 13

ee = 72%

L9c1,4 : aldol = 100 : 0

ee = 75%

O O (R)+ EtMgBr( 2 equiv.)

5 mol% CuTC5.25 mol% L*Et2O, -78°C, 8h

PPh2PPh2

MeOMeO

FePh2PFeCy2P

Cy2P

NMe2

PAr2PAr2

NN

HO

PF6-

OP

ON

Ph

Ph

P N

2-naphthyl

2-naphthyl

(R) PCy2

L1d1,4 : 1,2 : aldolb = 24 : 76 : 0

eec = 50%

L7d1,4 : 1,2 : aldol = 21 : 79 : 0

ee = 44%

L91,4 : 1,2 : aldol = 62 : 38 : 0

ee = 89%

L101,4 : 1,2 : aldol = 32 : 42 : 26

ee = 92%

PTol2PTol2

L111,4 : 1,2 : aldol = 21 : 59 : 20

ee = 68%

L121,4 : 1,2 : aldol = 2 : 97 : 1

eee = nd%

L131,4 : 1,2 : aldol = 16 : 64 : 20

ee = 88%

L141,4 : 1,2 : aldol = 8 : 99 : 3

eee = nd%

L10f

1,4 : 1,2 : aldol = 85 : 15 : 0ee = 90%

O RO R

R'

1,4/1,2 up to 100:0ee's up to 90%

O R

R'

1,4/1,2 up to 85:15ee's up to 90%

1.5 eq. R'MgBr1.3 eq.TMSCl5 mol% CuTC5.25 mol% L*Et2O, -78°C

2 eq. R'2Zn5 mol% CuTC5.25 mol% L*

Et2O, -20 or 0 °C

O RO R

R'5 mol% CuTC5.25 mol% L9Et2O, -20°C, 6hR'2Zn

(2 equiv.)+

O R O R

R'5 ml% CuTC5.25 mol% L101.3 equiv. TMSClEt2O, -78°C, 8h

R'MgBr(1.5 equiv.)

+

O

R' = EtYield = 75%

1,4 : 1,2 = 85 : 15ee = 90%, (R)

R' = MeYield = 40%

1,4 : 1,2 = 65 : 35ee = 81%, (R)

R'

O

R' = EtYield = 46%

1,4 : 1,2 = 60 : 40ee = 90%, (R)

R' = MeYield = nd

1,4 : 1,2 = 40 : 60ee = 86%, (R)

R'

O

R' = EtYield = 44%

1,4 : 1,2 = 71 : 29ee = 90%, (R)

R' = MeYield = 40%

1,4 : 1,2 = 43 : 57ee = 84%, (R)

R'

O

R'

O

R' = EtYield = 59%

1,4 : 1,2 = 77 : 23ee = 83%, (R)

R' = MeYield = nd

1,4 : 1,2 = 48 : 52ee = 88%, (R)

R'

R' = EtYield = nd

1,4 : 1,2 = 36 : 64ee = 74%, (S)

O

R' = EtYield = 51%

1,4 : 1,2 = 63 : 37ee = 80%, (S)

R' = MeYield = 49%

1,4 : 1,2 = 63 : 37ee = 80%, (R)

R'

O R O R

R'5 ml% CuTC5.25 mol% L101.3 equiv. TMSClEt2O, -78°C, 8h

R'MgBr(1.5 equiv.)

+

O RO R

O R

O R

R = EtConv. > 99% (50)c

1,4 : 1,2 = 67 : 33ee = 88%, (S)

R = MeConv. > 99%

1,4 : 1,2 = 45 : 55ee = 74%, (S)

R = MeConv. > 99%

1,4 : 1,2 = 36 : 74ee = 88%, (S)

R = EtConv. > 99%

1,4 : 1,2 = 53 : 47ee = 86%, (R)

R = MeConv. > 99% (60)c

1,4 : 1,2 = 71 : 29ee = 89%, (R)

R = EtConv.a > 99%

1,4 : 1,2a = 36 : 64eeb = 80%, (S)

R = EtConv. = 88%

1,4 : 1,2 = 33 : 67ee = 80%, (R)

O R

O R

R = EtConv.a > 99%

1,4 : 1,2a = 67 : 33eeb = 74%, (R)