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

Introduction Allyl boron reagents • Important tool in the synthesis of natural products • Allyl addition of organoboron reagents to carbonyl compounds are highly diastereoselective H BL 2 * R 1 O R R 1 O BL n * R 2 OH R 2 R H R R 2 R 1 • A number of reagents for enatioselective allylation were developed with chiral ligands at the boron center B CO 2 i Pr O B O CO 2 i Pr 2 ( l Ipc) 2 B • Few protocols were developed in which the chiral center is a structural component of the allylic unit L 2 B R2 R 1 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 Stephan Elzner @ Wipf Group 2 1/14/2007

Allylboration of Imines - Enantioselective allylation of cyclic imines CF 3 CF 3 R 1 R 1 O B N O NH toluene R 2 R 2 -78°C to rt CF 3 Proposed transition state CF 3 T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2006 , 128, 9646-9647 Stephan Elzner @ Wipf Group 3 1/14/2007

Application: Synthesis of Alkaloids • Coniine • ent -Corynantheidol Neurotoxin found in poison hemlock • Crispine A Alkaloid with antitumor activity 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 Aldol addition to chiral α -substituted allyl boronate compounds Ph Ph OMe R B* OMe OH MeC(OEt) 3 O cat. EtCO 2 H PhCHO O R R B O PhPh CO 2 Et Ph 135°C OEt CH 2 Cl 2 , rt B* Ph OH CO 2 Et single diastereomer R=Me : 95% R=Me : 78% Johnson rearrangement > 98% ee Ph : 65% Ph : 82% Ph Ph O OH MeC(OEt) 3 Ph R cat. EtCO 2 H PhCHO R B O CO 2 Et Ph Ph 135°C, 48% B CH 2 Cl 2 , rt OH Ph O O CO 2 Et Ph Ph 84%, 91%ee Ph Ph J. Pietruska, N. Schöne, Chem. Eur. J. 2004 , 5011-5019 Stephan Elzner @ Wipf Group 6 1/14/2007

α -Substituted Allylboronates - One-pot double allylboration with a 1,3-bifunctionalized boron reagent for the diastereo- and enantioselective synthesis of anti-1,5-diols OB( d Ipc) 2 Ph OH R 2 CHO R 1 CHO Ph O Ph (1.7 eqiv.) R 1 (0.82 equiv.) OH R 2 B( d Ipc) 2 B B Ph O CH 2 Cl 2 , -78°C rt, 24h O O R 1 Ph Ph Ph Ph R 1 , R 2 = Ph, Ph(CH 2 ) 2 , (CH 3 ) 2 CH, C 6 H 11 72 - 95%, 91 - 95%ee α -substituted allylboronate - Application: Synthesis of C(43)-C(67) fragment of Amphidinol 3 O Ph OH Ph H 43 O Ph OB( l Ipc) 2 O O O OH O O O B( l Ipc) 2 B 50 Ph O TBDPSO TBDPSO O TBDPSO CHO CH 2 Cl 2 , rt CH 2 Cl 2 , -78°C O B O O O O 70 - 80%, dr 9:1 Ph Ph Ph Ph 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 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 OH - - BF 4 BR 2 H 2 O 2 , NaOH S + R 1.2 eq. LiHMDS BR 3 S + R R 1 R 1 dioxane, THF, 5°C R 1 O R 1 70 -87%, 95- 96%ee O NH 2 OSO 3 H R 1 = Et, nBu, Ph R = H, Me, Cl NH 2 R R 1 Mechanism 68-72%, 96-97%ee V. Aggarwal, G. Y. Feng, A. T. Schmidt, J. Am. Chem. Soc. 2005 , 127 , 1642-1643 Stephan Elzner @ Wipf Group 8 1/14/2007

Main article: Synthesis and application of α -substituted allyl boranes - Synthesis of the sulfonium salt - BF 4 1) PPh 3 S S BnBr S + dioxane/H 2 O Ph 1) PdS/C, H 2 NaBF 4 (aq.) h � reflux, 92% O O 76% 2) recryst. O CH 2 Cl 2 O O O 2) PhCOCH 2 Cl S 84% SO 2 Cl S K 2 CO 3 , 82% Ph endo/exo 20:1 O 48% overall - Aldol addition to α -substituted allyl boranes - BF 4 1) LiHMDS, -78°C • Excellent enantio- and S + Ph R Ph THF/CH 2 Cl 2 OH 30 min PhCHO diastereoselectivity B Ph O -100°C 2) Ph R • High Z selectivity B • Chiral sulfide recovered (>90%) 9 • Side reaction (< 20%): -100°C R OH Ph HO 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 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 - Other enatiomer acessible via borane-isomerisation/aldol sequence - BF 4 1) LiHMDS, -78°C Ph R Ph R OH S + Ph THF/CH 2 Cl 2 PhCHO 30 min Ph B B -78°C O R Ph 2) -100°C to 0°C 15 B -100°C R 1,3 borotropic rearrangement: V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007 , 46 , 359-362 Stephan Elzner @ Wipf Group 11 1/14/2007

Application: Total synthesis and structural confirmation of (+)-iso-agatharesinol (+)-Iso-agatharesinol: Nor-lignane, isolated from asparagus gobicus (2004) Confirmation of relative stereochemistry (racemic) OH OH 1) LiHMDS, -78°C - BF 4 THF/CH 2 Cl 2 OTBS OH 1) LiBH 4 S + 30 min 2) TBAF 2) → matched NMR data B OPiv OPiv OH OTBS OH 78% -100°C OH OTBS OH 3) TBSOCH 2 CHO 1) DEAD, PPh 3 p-NO 2 C 6 H 4 CO 2 H 2) LiBH 4 3) TBAF OH OH Asymmetric total synthesis - BF 4 OH OH 1) LiHMDS, -78°C S + THF/CH 2 Cl 2 OTBS OH 1) LiBH 4 30 min OPiv O 2) TBAF 2) B OH OH OPiv OTBS 81% 72%, > 99%ee -100°C OTBS V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007 , 46 , 359-362 3) TBSOCH 2 CHO C.-X. Yang, S.-S.-Huang, X.-P. Jang, Z.-J. jia, Planta Med. 2004 , 70 , 446-451 Stephan Elzner @ Wipf Group 12 1/14/2007

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