chem-e8105 enzymaticandbiomimeticcatalysis · 2019-03-19 · aldolasebiomimetics...

Jan DeskaLaboratory of Organic Chemistry

CHEM-E8105Enzymatic and Biomimetic Catalysis

Lecture 6: Aldol chemistry

19.03.2019

Aldol-catalyzing enzymes

§ mainly involved in biosynthesis and degradation of sugars and related biomolecules

§ 2 major classes that differ in their basic activation mode

ü class I mechanism: enamine catalysis or class II mechanism: enolate catalysis

§ rather narrow scope of accepted donors (nucleophiles)

O2–O3PO

OH

+O

OHPO32–

fructose1,6-biphosphate

aldolase

FBA

OOPO32–

OH

OH

OHOPO32–

DHAP

HOOC

O+

O

AcHN

N-acetylneuraminicacid aldolaseOH

OH

OH

OHO

HOAcHN

OHHO

HOOH

COOH

H

O+

2-deoxyribose5-phosphate

aldolase

DERA

O

OHPO32–

OH

OHPO32–H

O

NH2

Lys

+HN

2-O3POO

OH

H2O

N

Lys

HO

HH

H2-O3PO

N

Lys

HO

H2-O3PO R H

O

RH

O

2-O3POO

R

OH

OH

H2O

* *

N

Lys

HO

H2-O3POOH

R* *

Lys or His

N

Lys or Hisphosphate bindingpocket

N

Lys or His

H+

+ N

Lys or His

General act ivat ion modes

class I aldolase: enamine catalysis

His

2-O3POO

OH

R H

O

2-O3POO

R

OH

OH

* *

phosphate bindingpocket

Zn2+His

HisHis

Glu

OO

HO

Tyr

Zn2+

His His

His

Glu

OO HO

Tyr

O2-O3PO

OHH H

Zn2+

HisHis

His

Glu

OHO O

Tyr

2-O3PO O

OH

HOR

Glu

OHO

Zn2+

His

HisO2-O3PO

OH

OHR

–OTyr

General act ivat ion modes

class II aldolase: enolate catalysis catalytic zinc

2-Deoxyr ibose-5-phosphate Aldolase

DERA (Lactobacillus brevis)

§ homo dimer, 259 amino acids per subunit

(other organisms exploit tetrameric DERAs)

§ class I aldolase

§ independent on cofactors or metal ions

§ physiological role: catabolism of glycosidesand deoxyribonucleotides

§ catalyzes the reversible cross-aldol reactionbetween acetaldehyde and other acceptoraldehydes

Aldolases: synthet ic appl icat ions

Synthesis of the statin core structure

Greenberg, Varvak, Hanson, Wong, Huang, Chen, Burk, Proc. Natl. Acad. Sci. 2004, 101, 5788-5793.

H

OCl +

H

O+

H

O DERACl

OH OH

H

O

O OH

OH

Cl

OH OH

OH

O

NNH

O

PhPh

F

atorvastatin(Lipitor)


Synthesis of azasugars

O

OH

OPO32–NH

H

O

BnO

O+

FBANH

OH

BnO

O

OH

OOPO32–

phosphatase

NH

OH

BnO

O

OH

OOH

H2

Pd/CNOH

HOOH

OH

OH

OOHH2N

H2Pd/C

NHOH

HOOH

D-fagomine

Dean, Greenberg, Wong, Adv. Synth. Catal. 2007, 349, 1308-1320.



O

OH

OPO32–NH

H

O

BnO

O+

FBANH

OH

BnO

O

OH

OOPO32–

phosphatase

NH

OH

BnO

O

OH

OOH

H2

Pd/CNOH

HOOH

OH

OH

OOHH2N

H2Pd/C

NHOH

HOOH

D-fagomine

DHAP expensive/elaborate synthesis





O

OH

ON3 H

O+

FBAN3

OH

OH

OOHB OH

HO OH

OHHO

borate buffer

OH OH

NHOH

HOOH

L-deoxymannojirimycinOH

Oin situ formed borate analoguesas cheap DHAP surrogates

Aldolase biomimeticsEnamine-based biomimetics as the mother of Organocatalysis

based on stoichiometric enamine chemistry

O NH

cat. TsOH–H2O

N 1) MeI

2) H2O

OMe

Stork, 1954:

Yamada, 1969:

O NH

cat. TsOH–H2O

N 1)

2) H2O

OCO2tBuCO2tBu CO2Me

CO2Me

17%, 59% ee

Aldolase biomimetics

The Hajos-Parrish-Eder-Sauer-Wiechert reaction

§ first highly enantioselective organocatalytic reaction

O O

O

NH

COOH

L-proline(3 mol%) OH

O

O

cat. TsOH

O

O

93% ee

O NH

COOH

L-proline(3 mol%) O

cat. TsOH

74% ee

O

O OH

O

O

O

Wieland-Miescher ketone

proline + HClO4

proline + HClO4


The Hajos-Parrish-Eder-Sauer-Wiechert reaction

§ first highly enantioselective organocatalytic reaction

O O

O

NH

COOH

L-proline(3 mol%) OH

O

O

cat. TsOH

O

O

93% ee

O NH

COOH

L-proline(3 mol%) O

cat. TsOH

74% ee

O

O OH

O

O

O

Wieland-Miescher ketone

OH

H

H

cortisone OH

H

H

O

progesterone

OH

H

H

norethindrone

OHOOH


general aldol catalysis: List, 2000 & MacMillan, 2002

O

(solvent)

+H

O NH

COOH

DMF, 4 °C

O OH

97%, 96% ee

H

O+

H

O NH

COOH

DMF, 4 °C H

O OH

82%, 99% ee, 96% anti

high enantioselectivity

with a-substituted donors: high anti-diastereoselectivity

List, Lerner, Barbas, J. Am. Chem. Soc. 2000, 122, 2395-2396.Northrup, MacMillan, J. Am. Chem. Soc. 2002, 124, 6798-6799.

H

O L-Pro

H

HO NCOOH H–H2O

N+

H

O

O–

H

NO

OH

H

NO

OH



Houk, Martin, List, J. Am. Chem. Soc. 2003, 125, 2475-2479.

H

O

DMF, 4 °C H

O OHL-Pro2 x

donor activation favours anti-E-enamine

origin of stereoselectivity (simplified Houk-List model)

H

NO

OH

Me

+

H

O

Me

O H

N H

O O

Me

H

Me

H

O H

N H

O O

H

Me

Me

Hvs




H

O

DMF, 4 °C H

O OHL-Pro2 x

Zimmerman-Traxler-liketransition statefavours eq-eq-arrangement





H

O

DMF, 4 °C H

O OHL-Pro2 x

O H

N H

O O

Me

H

Me

H

OHN H

–O O

Me

H

Me

H+

+ H2O – L-Pro

OH

OMe

H

Me

H

=H

O OH



syn-selective aldol reactions

Ramasatry, Zhang, Tanaka, Barbas J. Am. Chem. Soc. 2007, 129, 288-289.

by stabilization of anti-Z-enamine

OHO

+NMP, 4 °C

O OH

81%, 92% ee, 88% syn

H

O H2N COOH

OtBu

OHCl Cl

O H

N

H

H

O O

Ar

H

H

OOtBu

H


syn-selective aldol reactions

Kano, Yamaguchi, Maruoka, Angew. Chem. Int. Ed. 2007, 46, 1738-1740.

by destabilization of Zimmerman-Traxler arrangement

H

O+

NMP, r.t.H

O

CO2Et

OH

99%, 95% ee, 72% syn

H CO2Et

O

C4H9C4H9

NH

NHSO2CF3

OrganocatalysisDOI: 10.1002/anie.200604640

syn-Selective and Enantioselective Direct Cross-Aldol Reactionsbetween Aldehydes Catalyzed by an Axially Chiral AminoSulfonamide**Taichi Kano, Yukako Yamaguchi, Youhei Tanaka, and Keiji Maruoka*

The aldol reaction has long been recognized as one of themost fundamental tools for the construction of new carbon–carbon bonds.[1] In this area, the cross-aldol reaction betweentwo different aldehydes is known to be often problematicbecause of undesired side reactions, including dehydration ofthe product, self-aldol reaction, and multiple addition of theenolate to the aldol product. To date, however, several cross-aldol reactions using aldehyde-derived metal enolates, includ-ing silyl enol ethers as nucleophile and/or non- or slowlyenolizable aldehydes as electrophile, have been reported,[2–9]

and some rare examples of the catalytic asymmetric version ofthis reaction have recently been developed.[10–16] For example,the diastereo- and enantioselective cross-aldol reactionbetween aldehydes and silyl enol ethers was first accom-plished by Denmark et al. with chiral Lewis base catalysts,[10]

and very recently Kobayashi and co-workers demonstratedthe chiral Lewis acid catalyzed diastereo- and enantioselec-tive reaction using aldehyde-derived enecarbamates as anactivated aldehyde nucleophile.[11] With these methods, boththe syn and anti diastereomers, respectively, were formed in ahighly enantioselective fashion. On the other hand, to the bestof our knowledge, most organocatalytic direct enantioselec-tive cross-aldol reactions of aldehydes, first reported byMacMillan and co-workers, provide predominantly anti aldoladducts,[12–17] albeit with only a few exceptions giving synadducts.[12d] In this context, we have been interested in thepossibility of developing a syn-selective direct cross-aldol

reaction between two different alde-hydes by using a chiral organocata-lyst. Herein we wish to report such asyn-selective and enantioselectivedirect cross-aldol reaction catalyzedby an axially chiral amino sulfona-mide of type (S)-1.

Our strategy is based on the recent observation that adirect asymmetric Mannich reaction is catalyzed by theaxially chiral amino sulfonamide (S)-1 to give the anti productpredominantly, which is a minor diastereomer in the proline-catalyzed reaction.[18] Since it would be difficult for antienamine A, which is generated from a donor aldehyde and(S)-1, to react with an acceptor aldehyde that is activated bythe distal acidic proton of the triflamide of (S)-1, the cross-aldol reaction catalyzed by (S)-1 would be expected toproceed through syn enamine intermediate B, thus giving thedesired unusual syn product as shown in Scheme 1.

We first examined the reaction between 4-nitrobenzalde-hyde and hexanal in the presence of 5 mol% (S)-1 in varioussolvents at room temperature, and the results are summarizedin Table 1. Unfortunately, the reaction in less polar solventssuch as dioxane, toluene, and CH2Cl2 gave the cross-aldolproduct 2 in poor yield with low stereoselectivities (Table 1,entries 1–3). In the case of acetonitrile, only a trace amount of2 was observed, although syn-2 was slightly dominant overanti-2 (Table 1, entry 4). While the use of DMSO, which is acommon solvent for aldol reactions catalyzed by proline orrelated organocatalysts,[13a, 15] led to the formation of thedesired syn-2 in a highly diastereo- and enantioselectivemanner, the yield was still low (Table 1, entry 5). When theamide solvents N,N-dimethylformamide (DMF) and N-meth-ylpyrrolidone (NMP) were used, the desired syn-2 wasobtained in moderate yield with excellent diastereo- andenantioselectivity (Table 1, entries 6 and 7). Accordingly,

Scheme 1. Possible transition states for the enantioselective directcross-aldol reaction catalyzed by (S)-1.

[*] Dr. T. Kano, Y. Yamaguchi, Y. Tanaka, Prof. K. MaruokaDepartment of ChemistryGraduate School of ScienceKyoto UniversitySakyo, Kyoto 606-8502 (Japan)Fax: (+81)75-753-4041E-mail: [email protected]

[**] This work was partially supported by a Grant-in-Aid for ScientificResearch on Priority Areas “Advanced Molecular Transformation ofCarbon Resources” from the Ministry of Education, Culture, Sports,Science, and Technology, Japan.

Supporting information for this article is available on the WWWunder http://www.angewandte.org or from the author.

Communications

1738 ! 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2007, 46, 1738 –1740


replacement of acceptor = other a-functionalizations of aldehydes and ketones

Imine acceptors = Mannich reaction

Hayashi, Tsuboi, Ashimine, Urushima, Shoji, Sakai, Angew. Chem. Int. Ed. 2003, 42, 3677-3680.

+NH

COOH

DMF, –20 °C

then NaBH4

HO

HN

70%, 96% ee, 95% syn

H

O2 x

H2N

OMe

OMe

H

O

+

N

OMeH

formed in situ by condensation

N H

N H

O O

HMe

Me

L-Pro

OMe

imine forced into ax-ax orientation

syn-product

Modern enamine catalysis

proline as template for the development of next generation organocatalysts

NH OMe

NH O

CF3F3CCF3

CF3SiMe3

N

NH

Bn

O

· TFA

N

NH

O

· TFA

NH

COOHMe

NH

COOH

F

NH

· BzOH

NH2

NC3H7

C3H7

NNH2

N

MeO


alpha-functionalization of aldehydes and ketones

O+ Ph NO2

NH

COOH

94%, 23% ee

O H PhNO2

H

O+

NH

75%, 97% ee

H

OOMe

PhPh

OO

H

O

+BnO2C N

N CO2Bn

NH

COOH

94%, 97% ee

H

ON N

HCO2Bn

CO2Bn


alpha-functionalization of aldehydes and ketones

H

O

+ Ph NNH

COOH

71%, 99% ee

H

OO NHPh

H

O

+NH

95%, 96% ee

H

OFOTMS

ArAr

H

O

+

N

NH

71%, 95% ee

H

OCl

O

PhO2SN F

PhO2S Ar = 3,5-(CF3)2Ph

O Cl Cl

ClCl

Cl

Cl

O

Bn

Modern enamine catalysisenamine activation in radical chemistry

N

NH

O

BnH

O

R

+

± H2O

+ H+

N

N

O

Bn

R

+± H+ N

N

O

Bn

R

± e– N

N

O

Bn

R

iminium cationLUMO activation

enamineHOMO activation

radical cationSOMO activation


enamine activation in radical chemistry

H

O

N

NH

O

BnTFA

(NH4)2Ce(NO3)6LiCl

THF, –10 °C

CHO

H

Cl

85%, 95% ee, 8:1 dr

N

N

O

Bn

–H2O– e–

H

N N

Bn O

+

H

N N

Bn O

+

+ Cl–+ H2O

Beeson, Mastracchio, Hong, Ashton, MacMillan, Science 2007, 316, 582-584.

Remember the Acyloin react ion?

Acyloin reaction

§ PDCs also catalyze C-C-coupling between a-ketoacids and aldehydes

§ biochemical equivalent to the Benzoin reaction

H

O

2 x

O

OH

cat. NaCN

H

O–

CN

benzoin

OH

CN+ PhCHO

O–OH

CN

+ CN–

– cyanide-mediated benzoin reaction only homocoupling

– mostly limited to aromatic aldehydes

Remember the Acyloin react ion?

Acyloin reaction

§ PDCs also catalyze C-C-coupling between a-ketoacids and aldehydes

§ biochemical equivalent to the Benzoin reaction

H

O

2 x

O

OH

cat. NaCN

H

O–

CN

benzoin

OH

CN+ PhCHO

O–OH

CN

+ CN–

– formal addition of HCN yields cyanohydrines

– analogous to Stetter amino acid synthesis

OHNaCN

H2O

OH

CN

Ncyanohydrine

H+

OHNH2

OHR

or

O

R = H, alkyl, OH

Cyanohydrine-convert ing enzymes

§ hydroxynitrile lyases (EC 4.2.1.x) mainly found in higher plants

§ main role: defence mechanisms based on cyanogenesis

§ 2 major classes that differ in their dependence on FAD

ü FAD not acting as redox mediator in these enzymes

O

OR

HOHO

OHO

CN

Ph hydrolase

R = H:β-D-Glc:

prunasinamygdalin

– sugar

HO

CN

Phhydroxynitrile

lyase

– sugarPhCHO + HCN

§ cheap sources for HNLs: almonds, cherry, manioc, rubber tree

Serine-Hist id ine-Aspartate: Catalyt ic tr iade

Sharma, Nand Sharma, Bhalla, Enzyme Microb. Technol. 2005, 37, 279-294.

mechanism in e.g. manioc and Hevea sp.

NN

HOO

HO

His235

Asp207

Ser80Thr11N

HOH

CN

OH

NH3

Lys236

NN

HOO

HO

His235

Asp207

Ser80Thr11N

HOH

NH3Lys236

NC

OH

NN

HOO

HO

His235

Asp207

Ser80Thr11N

HOH

NH3Lys236

OH

C N

O

+HCN

Bracco, Busch, von Langermann, Hanefeld, Org. Biomol. Chem. 2016, 14, 6375-6389.

calcium pantothenate: important animal feed additive

sold as Cymbaltaselective serotonine reuptake

inhibitor (antidepressant)

O

HHOPrunus amygdalus

HNL (V317A)

HCN, bufferpH 2.5 OH

CNHOnitrile

hydrolysis

spontaneouslactonization O O

OH

(R)-pantolactone99% ee

Prunus aremeniacaHNL

HCN, bufferpH 4

duloxetine

S CHO SCN

OH

SO

NHMe

99% ee

Synthet ic use: Addi t ion of HCN to aldehydes

Synthet ic use: HCN-free appl icat ions

Bracco, Busch, von Langermann, Hanefeld, Org. Biomol. Chem. 2016, 14, 6375-6389.

acetone cyanohydrine as masked HCN

R H

O almond meal

iPr2O, bufferpH 4.5

CNHO

R CN

OH+ +

O

O

O C3H7

OHOH

OH

stagonolide B

O

H11C5 O

OH

cytospolide E

HO

chem-e8105 enzymaticandbiomimeticcatalysis · 2019-03-19 · aldolasebiomimetics...

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