asymmetric autocatalysis triggered by carbon isotope (13c

Asymmetric Autocatalysis Triggered by Carbon Isotope (13C/12C) Chirality

Hong Ren 06-19-09

Kawasaki, T.; Matsumura, Y.; Tsutsumi, T.; Suzuki, K.; Ito, M.; Soai, K. Science, 2009, 324, 492.

The Homochirality Remains a Puzzle…

Hong Ren @ Wulff Group

The Homochirality Remains a Puzzle…


All the 20 natural amino acids are left-handed.

1st step Shattering the mirror: Absolute Asymmetric Synthesis

2nd step Propagating the imbalance: Asymmetric Autocatalysis

A proposed theory to explain the origin of the homochirality:

Blackmond, D. G. PNAS, 2004, 101, 5732-5736.

Asymmetric Autocatalysis and Its Implications for the Chemical Origin of Life


N

N

OH2

ZnN

N

OZn H N

N

OH

N

N

CHO

+

2

Zn

with low enantiomeric enrichment

with hign enantiomeric enrichment

Soai, K.; Shibata, T.; Morioka, H.; Choji, K. Nature, 1995, 378, 767-768.

Asymmetric Autocatalysis Triggered by Carbon Isotope (13C/12C) Chirality

Hong Ren 06-19-09


Generation of Chirality by Carbon Isotope Substitution


12C C12

X Y

Achiral compound

12C C13

X Y

carbon isotope substitution

Isotopic enantiomers

Solution: Asymmetric Autocatalysis

Problem: Experimentally inaccessible: very small difference between 13C and 12C


Discrimination of the Carbon Isotopic Chirality by Asymmetric Autocatalysis


H3C

Ph OH

13CH3

13C

13C13C

13C

C1313C

H OH

(R)-1 (S)-3

H313CO OCH3

H OH

(S)-2

H313C CH3

Ph OH

H OH

(S)-1 (R)-3

H3CO O13CH3

H OH

(R)-2

13C

13C13C

13C

C1313C

Carbon Isotopic Enantiomers




N

N

CHO

+

4

2

Zn

N

N

OZn N

N

OZn

tiny ee tiny ee

asymmetric autocatalysis

asymmetric autocatalysis

4+ i-Pr2Zn 4+ i-Pr2Zn



N

N

OH

(S)

N

N

OH

(R)

Enhancement of Enantiomeric Excess

Highly Enantioenriched (S)-5 Highly Enantioenriched (R)-5



Synthesis of Compound 1---Route 1


Ph

O

13CH3

+ Me2Zn H3C

Ph OH

13CH3

(R)-1, 89% ee

H313C CH3

Ph OH

(S)-1, 93% ee

Ph

O

CH3

+ (13CH3)2Zn

ligand (-)-8

NH

NH

SHO2

SO2

OH

OH

Ti(Oi-Pr)4, toluene

Ti(Oi-Pr)4, toluene



Synthesis of Compound 1---Route 2

Ph

13CH2

OH

CO2i-PrHO

HO CO2i-Pr

DIPT

Ti(Oi-Pr)4, t-BuOOH,DCM

PhOH

H213C O

1) p-toluenesulfonic anhydride, DMAP, pyridine

2) LAH, ether

H3C

Ph OH

13CH3

(R)-1, 86% ee

H313C CH3

Ph OH

(S)-1, 90% ee



O

OCH3Na, 13CH3OH H3

13CO OCH3

H OH

(S)-2

1) Ph3P, diisopropyl azodicarboxylate,

p-NO2C6H4COOH, THF

2) K2CO3, MeOH

H3CO O13CH3

H OH

(R)-2

Na, 13CH3OH

O

OCH3

Synthesis of Compound 2


Synthesis of Compound 3

13C6H5CHO

N

CH3OH

PhPh

(p-Br)C6H4B(OH)2diethylzinc, toluene

13C

13C13C

13C

C1313C

H OH

(S)-3, 96% ee

H OH

(R)-3, 99% ee

13C

13C13C

13C

C1313C

Br

Br

1) TMSCl, TEA, THF2) n-BuLi, B(OEt)3, THF3) diethylzinc, toluene then H2O4) TBAF, THF

13C

13C13C

13C

C1313C

H OH

(S)-3, 96% ee

H OH

(R)-3, 99% ee

13C

13C13C

13C

C1313C

+

Hong Ren @ Wulff Group Kawasaki, T.; Matsumura, Y.; Tsutsumi, T.; Suzuki, K.; Ito, M.; Soai, K.

Science, 2009, 324, 492.

Entry Chiral alcohol Isolated yield ee configurition 1 (R)-1 (89% ee) 94 92 S 2 (S)-1 (93% ee) 95 96 R 3 (R)-1 (89% ee) 80 88 S 4 (S)-1 (93% ee) 94 96 R 5 (R)-1 (89% ee) 96 88 S 6 (S)-1 (93% ee) 97 94 R 7 (R)-1 (89% ee) ND 93 S 8 (S)-1 (93% ee) 92 93 R



Chiral Discrimination of the Isotopic Carbons Using Compound 1 from Route 1

Entry Chiral alcohol Isolated yield ee configurition 1 (R)-1 (86% ee) 94 94 S 2 (S)-1 (86% ee) 87 95 R 3 (R)-1 (86% ee) 93 94 S 4 (S)-1 (90% ee) 98 93 R 5 (R)-1 (86% ee) 85 92 S 6 (S)-1 (84% ee) 93 88 R 7 (R)-1 (86% ee) 88 89 S 8 (S)-1 (90% ee) 93 90 R



Chiral Discrimination of the Isotopic Carbons Using Compound 1 from Route 2

asymmetric autocatalysis triggered by carbon isotope (13c

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