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Chiral anti-1,2-Diols from α-Oxyaldehydes

Gayan Abeykoon, Shreyosree Chatterjee, Jason Chen*Iowa State University

Abeykoon, G. A.; Chatterjee, S.; Chen, J. S. Org. Lett. 2014, 16, 3248 – 3251

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Chiral-1,2-Diols

• Common in natural products like carbohydrates and polyketides

• Important as chiral ligands used in asymmetric catalysis.

• Our goal is to develop a methodology to generate chiral-1,2-diols with stereoflexibility

OH

OH

OH

OH

Unnamed Oxylipins isolated from Dracontium loretense

OH

CO2H

OH

CO2H

3

Sharpless Asymmetric Dihydroxylatation (SAD)

• SAD converts trans alkenes to chiral syn-1,2-diols with high enantioselectivity.

• Modest enantioselectivities are observed when cis alkenes are converted to anti-1,2-diols.

nBu OEt

O

nBu OEt

OAD-mix-

OH

OH(99% ee)

OH

HOAD-mix-[DHQD-IND]

(56% ee)

Sharpless et al. J. Org. Chem. 1992, 57, 2768 – 2771.Sharpless et al. J. Am. Chem. Soc. 1992, 114, 7568 – 7570.Sharpless et al. Chem. Rev. 1994, 94, 2483 − 2547.

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Strategies to Construct anti-1,2-Diols

R2R1

OH

OH

R1H

OH

O

R1 H

O

R1

OH

ONu

Nu

X

OHO

or

X M

• Nucleophilic attack on an aldehyde setting both stereo centers same time

• Nucleophiles - α-Oxycarbonyl compounds - Functionalized allyl reagents

Nucleophilic attack on chiral hydroxy epoxide

• Nucleophilc attack on chiral α-oxyaldehyde• More appealing: broader substrate scope

Mukaiyama et al. Chem. Lett. 1984, 753 – 756.Brown et al. J. Org. Chem. 1995, 60, 4686 – 4687.Scolastico et al. Org. Chem. 1984, 49, 3784 − 3790.

Carreira et al. Org. Lett. 2001, 3, 3017 – 3020.Jamison et al. Org. Lett. 2005, 7, 2937 – 2940.Guiry et al. Med. Chem. 2007, 50, 5894 − 5902.

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Enantioselective α-Oxygenation• Addition to α-oxyaldehydes is appealing in diol synthesis because of

– broad range of nucleophiles– substrate-controlled stereoinduction

• TBS ether for polar Felkin–Anh control• Benzyl ether for chelation control

• Chiral α-oxyaldehydes often require multiple steps to prepare with suitable protecting groups at alpha position to alter the selectivity

• Direct aldehyde α-oxygenation– most convenient route – organocatalytic methods via enamine catalysis

• Proline Catalysis• Imidazolidinone Catalysis

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α-Oxygenation• Proline catalysis

• Imidazolidinone catalysis

Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247 – 4250. Macmillan et al. J. Am. Chem. Soc. 2003, 125, 10808 – 10809.Hayshi et al. Tetrahedron Lett. 2003, 44, 8293 – 8296.

OR

1.

L-Proline (cat.) 2. Reduction

NHPhO

OHR

Ph ON

• not reproducible• unstable α-oxyaldehydes

• reproducible• stable α-oxyaldehydes

Sibi et al. J. Am. Chem. Soc. 2007, 129, 4124 – 4125.MacMillan et al. Chem. Sci. 2012, 3, 58 – 61.

RO

R

O

NH

NO

R1

(cat.)·HX

Cu2+/Fe3+ (cat.), Air

O

O

N

N

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Chelation and Polar Felkin-Ahn Control

• Grignard addition: Chelation control• Aldol reaction: Polar Felkin-Ahn control• Stereochemical oddity

MacMillan et al. Chem. Sci. 2012, 3, 58 – 61.

MeMgBr, THF

(92%, 5:1 dr))

OLi

THF (87%, 13:1 dr)

(93% ee)

(93% ee)

O

OH

N

(93% ee)

O

O

N

O

OH

N

O

O

H

RO

HN Nu

R

O

H H

O

M

N

Nu

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Determination of Diol Configuration O

OH

OH

OH

OP

O

OP

nBu M

OH

OP

Polar Felkin-AhnControl

ChelationControl

Oxygenation

OH

OH

Deprotection

Meso diol C2 symetric diol

R

O

H H

O

M

N

Nu

O

H

RO

HN Nu

Deprotection

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Determination of Diol Configuration

• anti diol configuration was determined by– Optical rotation– 1H NMR

O O

N

NH

O

Ph·HBF4

TEMPO, CuCl2 (cat.),O2, acetone(77%, 78% ee)

(cat.)

O

OH

OH

nBuLi,hexanes-78 °C(84%,12:1 dr)

Zn, AcOH(76%)

N

OH

ON

meso not C2 symmeric

O

H

RO

HNnBu

Li

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Optimizing the Diastereoselectivity

Entry M Solvent Temp. / °C dr Yield / %

1 MgCl Et2O 0 4:1 60

2 MgCl THF 0 6:1 70

3 MgCl THF –78 10:1 86

4 Li THF –78 6:1 81

5 Li hexanes –78 12:1 84

O

O

nBu M

Solvent, Temperature

N

OH

ON

O

H

RO

HNnBu

M

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Scope of Carbon Nucleophiles

Entry R dr Yielda / %

1 nBu 10:1 86

2 iPr 10:1 35

3 CH=CH2 >20:1 89 (78)b

4 C(Me)=CH2 >20:1 84 (79)b

5 Ph 14:1 77 (73)b

6 C≡CH 8:1 83 (67)b

a Isolated yield of a mixture of diastereomers. b Isolated yield of a single diastereomer.

O

O -78 °C, THF

R MgBr

N

OH

ON

R

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Effect of Chelation

O

O-78 °C, THF

iPr MgBr

N

OH

ON

ON

OH

OH

ON-78 °C, THF

iPr MgBr, CeCl3,

(35%, 10:1 dr)

(85%, 6:1 dr)

(65%)

R

O

H H

O

M

N

Nu

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Determination of Diastereoselectivity Using NMR

• Chemical shift of hydroxyl proton of masked 1,2-diols in CDCl3,

– ca. 2 ppm anti-diastereomer (major)– ca. 7 ppm syn-diastereomer (minor)

• This is general and holds for most of the NMR solvents

Major

Minor

O

OH

NO

OH

N

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Oxylipins from Dracontium loretense

• Oxylipin 2 has shown immunostimulatory effect.• Absolute configuration of chiral centers were not assigned.• Four total synthesis of oxylipins has been reported.

Pizza et al. J. Nat. Prod. 2009, 72, 813 – 817.Sharma et al. Tetrahedron: Asymmetry. 2011, 22, 367 – 372.Narsaiah et al. Tetrahedron Lett.2012, 53, 3955 – 3958.Barua et al. Tetrahedron 2013, 69, 2157− 2166. Reddy et al. Helv. Chim. Acta 2014, 97, 546−555.

1

2

OH

OH

OH

OH

OH

CO2H

OH

CO2H

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Application in the Synthesis of Oxylipins

O NH

N

Ph(cat.)

·HBF4

TEMPO, CuCl2 (cat.), O2, Acetone, -20 °C (79%, 72% ee)

SnBu3Bu3Sn nBuLi, THF,

SnBu3Li (79%, 72% ee,

in 5 steps

OH

OHOxylipin (6R,9S,10R)

O

OH

CO2H

O

ON

OH

ON

SnBu3

0 °C 8:1 dr)

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Application in the Synthesis of Oxylipins

SnBu3

OH

O

1. IBX (96%)

OH

OH

in 5 steps

Oxylipin(6R,9S,10S)

OH

CO2H

N

SnBu3

OH

ON

2. NaBH4, CeCl3,, MeOH, THF (82%, 12:1dr, 72% ee)

(72% ee)

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Conclusions

• Developed a method to – access anti-1,2-diols with high diastereoselectivity.– with differential protection.

• Built-in stereochemical probe using 1HNMR to determine the diastereomeric ratio of masked syn and anti-1,2-diols.

• Currently, we are working on optimizing the Grignard addition to α-oxyaldehydes to get syn-1,2-diols.

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Acknowledgment

• Department of Chemistry, Iowa state University• Prof. Jason Chen• Chen group members

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OTMP

O

(72% ee)

Cl

O

CO2Me

N

NHPh

O Me

Me

Me

(cat.)

TEMPO, CuCl2 (cat.),O2, acetone (79 %)

SnBu3

OTMP

OH

Bu3SnSnBu3 SnBu3

Li (8:1 dr)

CO2Me

OOTMP

OTES

(79 % single isomer,72% ee)

OH

OH

2. acid chloride 1, Pd2(dba)3 (cat.), PCy3 (cat.), PhMe (89 %)

1. TESCl, imid., DMF (86 %)

1. BH3·SMe2, (S)-Me-CBS, THF, 6:1 dr

a natural oxylipin (6R,9S,10R)

2. Zn, AcOH, THF, H2O (59 % single isomer, 2 steps, 96% ee)

LiOH, THF,H2O (69 %)

OH

CO2Me

·HBF4

nBuLi

THF

O

1

109

OH

OH6

OH

CO2H