Asymmetric Synthesis of -Substituted Allyl Boranes and Their - - PowerPoint PPT Presentation

Asymmetric Synthesis of α-Substituted Allyl Boranes and Their Application in the Synthesis of Iso-agatharesinol

Yuang Yu Fang and Varinder K. Aggarwal University of Bristol, UK

• Angew. Chem. Int. Ed. 2007, 46, 359-362

Stephan Elzner January 06, 2007

Stephan Elzner @ Wipf Group 1 1/14/2007

Allyl boron reagents

• Important tool in the synthesis of natural products
• Allyl addition of organoboron reagents to carbonyl compounds are highly

diastereoselective

• A number of reagents for enatioselective allylation were developed with chiral ligands at

the boron center

• Few protocols were developed in which the chiral center is a structural component of the

allylic unit

Introduction

R1 R2 BLn* R H O O BL2* H R1 R2 R R OH R1 R2

R2 L2B R1

• V. Aggarwal, G. Y. Feng, A. T. Schmidt, J. Am. Chem. Soc. 2005, 127, 1642-1643
• Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207-2293

B 2 (lIpc)2B B O O CO2iPr CO2iPr

Stephan Elzner @ Wipf Group 2 1/14/2007

Allylboration of Imines

• T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2006, 128, 9646-9647

Proposed transition state

O O B CF3 CF3 CF3 CF3 N R2 R1 toluene

• 78°C to rt

NH R2 R1

• Enantioselective allylation of cyclic imines

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Application: Synthesis of Alkaloids

• Crispine A

Alkaloid with antitumor activity

• Coniine

Neurotoxin found in poison hemlock

• ent-Corynantheidol
• T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2006, 128, 9646-9647

Stephan Elzner @ Wipf Group 4 1/14/2007

Examples for Enantioselective Allylboration in total synthesis

• (+)-13-Deoxytedanolide
• A. B. Smith, C. M. Adams, S. A. Lodise, A. P. Degnan, A. B. Smith, J. Am. Chem. Soc. 2003, 125, 350-

351

• (+)-Brasilenyne
• S. E. Denmark, S.-M. Yang, J. Am. Chem. Soc. 2004, 126, 12432-12440

Stephan Elzner @ Wipf Group 5 1/14/2007

1,3-Disubstituted Allylboronate

• J. Pietruska, N. Schöne, Chem. Eur. J. 2004, 5011-5019

Aldol addition to chiral α-substituted allyl boronate compounds

R OH B O O R CO2Et B* MeC(OEt)3

• cat. EtCO2H

135°C Johnson rearrangement R=Me : 95% Ph : 65% R=Me : 78% Ph : 82% PhCHO CH2Cl2, rt OMe OMe Ph Ph PhPh single diastereomer R O B* OEt CO2Et Ph Ph OH > 98% ee R OH B O O Ph Ph Ph Ph MeC(OEt)3

• cat. EtCO2H

135°C, 48% R CO2Et B O O Ph Ph Ph Ph PhCHO CH2Cl2, rt CO2Et Ph Ph OH 84%, 91%ee

Stephan Elzner @ Wipf Group 6 1/14/2007

• E. M. Flamme, W. R. Roush, J. Am. Chem. Soc. 2002, 124, 13644-13645
• J. D. Hicks, E. M. Flamme, W. R. Roush, Roush, Org. Lett. 2005, 7, 5509-5512
• One-pot double allylboration with a 1,3-bifunctionalized boron reagent for the diastereo- and

enantioselective synthesis of anti-1,5-diols

• Application: Synthesis of C(43)-C(67) fragment of Amphidinol 3

α-substituted allylboronate

α-Substituted Allylboronates

O O CHO TBDPSO B O O Ph Ph Ph Ph B(lIpc)2 CH2Cl2, -78°C O O TBDPSO OB(lIpc)2 B O O Ph Ph Ph Ph O O TBDPSO OH OH O O CH2Cl2, rt 70 - 80%, dr 9:1 O O O H

43 50

B O O Ph Ph Ph Ph B(dIpc)2 CH2Cl2, -78°C R1 OB(dIpc)2 B O O Ph Ph Ph Ph R1CHO (0.82 equiv.) OH R2 OH R1 R1, R2 = Ph, Ph(CH2)2, (CH3)2CH, C6H11 72 - 95%, 91 - 95%ee R2CHO (1.7 eqiv.) rt, 24h

Stephan Elzner @ Wipf Group 7 1/14/2007

Aggarwal: Preliminary work

• Enantioselective synthesis of secondary alcohols and amines using chiral organoboranes

generated from sulfonium ylides

• V. Aggarwal, G. Y. Feng, A. T. Schmidt, J. Am. Chem. Soc. 2005, 127, 1642-1643

Mechanism

S+ O BF4

• R1

BR3 1.2 eq. LiHMDS dioxane, THF, 5°C R R1 BR2 R R1 OH H2O2, NaOH R R1 NH2 70 -87%, 95- 96%ee NH2OSO3H 68-72%, 96-97%ee R1 = Et, nBu, Ph R = H, Me, Cl S+ O R1

• Stephan Elzner @ Wipf Group

8 1/14/2007

Main article: Synthesis and application of α-substituted allyl boranes

• V. Aggarwal et al, Angew. Chem. Int. Ed. 2001, 40, 1430-1433
• V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007, 46, 359-362
• Aldol addition to α-substituted allyl boranes

OH Ph HO

• Excellent enantio- and

diastereoselectivity

• High Z selectivity
• Chiral sulfide recovered (>90%)
• Side reaction (< 20%):
• Synthesis of the sulfonium salt

SO2Cl O S O 1) PPh3 dioxane/H2O reflux, 92% 2) PhCOCH2Cl K2CO3, 82% S O h Ph O S O 76% S O endo/exo 20:1 1) PdS/C, H2 2) recryst. 84% S+ O Ph 1) LiHMDS, -78°C THF/CH2Cl2 30 min 2) B R

• 100°C

BF4

• B

Ph R PhCHO

• 100°C

Ph R Ph OH 9 BnBr NaBF4 (aq.) CH2Cl2 S+ O Ph BF4

• 48% overall

Stephan Elzner @ Wipf Group 9 1/14/2007

Mechanism

Aggarwal, Angew. Chem. Int. Ed. 2007, 119, 363-366

Stephan Elzner @ Wipf Group 10 1/14/2007

Expansion of Methodology

• V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007, 46, 359-362

1,3 borotropic rearrangement:

• Other enatiomer acessible via borane-isomerisation/aldol sequence

S+ O Ph 1) LiHMDS, -78°C THF/CH2Cl2 30 min 2) B R

• 100°C

BF4

• B

R PhCHO

• 78°C

Ph R Ph OH 15 Ph B R Ph

• 100°C to 0°C

Stephan Elzner @ Wipf Group 11 1/14/2007

Application: Total synthesis and structural confirmation of (+)-iso-agatharesinol

• V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007, 46, 359-362

C.-X. Yang, S.-S.-Huang, X.-P. Jang, Z.-J. jia, Planta Med. 2004, 70, 446-451

Confirmation of relative stereochemistry (racemic)

1) LiHMDS, -78°C THF/CH2Cl2 30 min 2) B

• 100°C

OTBS 3) TBSOCH2CHO OTBS OH OTBS OPiv 72%, > 99%ee 1) LiBH4 2) TBAF OH OH OH OH S+ O BF4

• OPiv

81%

→ matched NMR data

S+ OPiv BF4

• 1) LiHMDS, -78°C

THF/CH2Cl2 30 min 2) B

• 100°C

OTBS 3) TBSOCH2CHO OTBS OH OTBS OPiv 78% 1) LiBH4 2) TBAF OH OH OH OH OH OH OH OH 1) DEAD, PPh3 p-NO2C6H4CO2H 2) LiBH4 3) TBAF

Asymmetric total synthesis (+)-Iso-agatharesinol: Nor-lignane, isolated from asparagus gobicus (2004)

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Conclusion

• A stereocontrolled synthesis of α-substituted allyl boranes was

developed

• Subsequent aldol reaction yielded Z-configured homoallylic

alcohols in excellent enantio- and stereoselectivity

• The methodology was expanded via 1,3-borotropic

rearrangement and subsequent aldol reaction

• Applied to the first total synthesis of (+)-iso-agatharesinol

Stephan Elzner @ Wipf Group 13 1/14/2007