Discovery of Eco-Compatible Synthetic Paths by a Multi-Catalysis Approach

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Submitted on 8 Oct 2018

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Discovery of Eco-Compatible Synthetic Paths by a

Multi-Catalysis Approach

Jean Rodriguez, Adrien Quintard

To cite this version:

Jean Rodriguez, Adrien Quintard.

Discovery of Eco-Compatible Synthetic Paths by a

Multi-Catalysis Approach.

CHIMIA, Schweizerische Chemische Gesellschaft, 2018, 72 (9), pp.580-583.

�10.2533/chimia.2018.580�. �hal-01890347�

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Multi-catalysis

Organo-catalysis catalysis

Metal-Org Org Met Met

A

B

C

+

D

A

B

C

Complex scaffolds

directly assembled

from raw materials

-Different mechanisms

-Improved kinetics/selectivities

-New synthetic paths

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O Ph O Ph O COOH HOOC ₊ N H Ar OSiR3 Ar cat1 (15 mol%) MeOH, rt without co-catalyst: 12% yield, 90% ee with 6 mol% Cu(i-BuCOO)2:

50% yield, >98% ee

R

N

Nu

Synergistic transition state:

1 2a 3a [Cu] + 2 CO2 cat1: Ar = (3,5-CF3)-C6H3, R= TMS O OH OH O O O O 5b 52%, 1:0.2:0.05 dr O OH OH O COOH HOOC O R + Fe(acac)3 or Cu(acac)2(15 mol%) THF, 22-25 °C, 15-20 h O R OH R OH 12 examples

Representative examples:

2 5a 60%, 1.2:1 dr 1 4 5

*

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N H N O OH N OH R3 R3 R3 R3 Ar OTMSAr Ar OSiR3 Ar Ar OTMSAr O TMS TMS Fe OC OC CO [Fe] Me3NO CO2 + Me3N O TMS TMS Fe OC OC OH TMS TMS Fe OC OC H H2O R2 OH O R1 N R3 OTMS Ar Ar OH O R2 O R1 O R3 O R2 O R1 H2O R3 O R2 O R1 OH H O H R3 R2 O _O R 1 + R1 O OH R3 R1 O R3 OH [Fe] (1-10 mol%) Me3NO (1.1-11 mol%) cat1 (2-20 mol%) toluene, 10-25°C 18-70 h * * O R2 R2 O cat1

a) Discovered multi-catalytic borrowing hydrogen:

b) Mechanism: if R1_{, R}2₌ alkyl or aryl R1 O R3 O * O R2 cascade up to 92% ee 8 9 10 11 cat1: Ar = Ph or Ar = (3,5-CF3)-C6H3.SiR3= TMS or TBDMS 9 2 10 Influence [2] Rate determining as soon as [2] is sufficient R OH O

4, NFSI, (S)-cat1 (20 mol%) MTBE, rt, 1 h 30 then 1 Cu(acac)2(15 mol%), rt, 6 h O HOOC R + O + F 4 NFSI COOH R OH F 2 R O F

-In situ catalytic preparation? -Stability? -Selective aldolization? Key intermediate: O [Cu] O H COOH H F R R2 H

Proposed transition state: 1 i-Pr OH O F i-Pr OH F 48% yield (24/1 dr) 98% ee 45% yield (24/1 dr) 98% ee

Selected example:

_{One-pot sequence:}

Cascade:

6

6a 7

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PhO2S _O

O

With Cu: 50% yield, 68% ee

Without Cu: 26% yield, 51% ee 11e + OH R4 8 9 [Fe] (6.5 mol%) Me3NO.2H2O (8 mol%) cat1 (13 mol%) Cu(acac)2(5 mol%) xylenes, 10-25 °C R1 O EWG R2 R2 OH EWG O R1 O EWG or R1 O 10 R2 11

Selected examples

O O O

Without Cu: 79% yield, 85% ee

11a

O

With Cu: 82% yield, 1.2:1 dr, 86% and 81% ee Without Cu: 78% yield, 1.2:1 dr, 72% and 72% ee

11d

O

Without Cu: 64% yield, 91% ee

11b

OMOM

With Cu: 60% yield, >(99:1 dr), 90% ee Without Cu: 59% yield, >(99:1 dr), 84% ee 10a O COOEt HO O n-C6H13 O O

Without Cu: 84% yield, 91% ee 11c EWG = COOR3_{, NO} 2 EWG = COR3_{, SO} 2Ph