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

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1 Asymmetric Synthesis of αsubstituted Allyl oranes and Their Application in the Synthesis of Isoagatharesinol Yuang Yu Fang and Varinder K. Aggarwal University of ristol, UK Angew. Chem. Int. Ed. 2007, 46, Stephan Elzner January 06, 2007 Stephan Wipf Group 1 1/14/2007

2 Introduction Allyl boron reagents Important tool in the synthesis of natural products Allyl addition of organoboron reagents to carbonyl compounds are highly diastereoselective 1 2 L n * H 1 2 A number of reagents for enatioselective allylation were developed with chiral ligands at the boron center H L 2 * H C 2 ipr C 2 ipr ( l Ipc) 2 Few protocols were developed in which the chiral center is a structural component of the allylic unit L V. Aggarwal, G. Y. Feng, A. T. Schmidt, J. Am. Chem. Soc. 2005, 127, Y. Yamamoto, N. Asao, Chem. ev. 1993, 93, Stephan Wipf Group 2 1/14/2007

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

4 Application: Synthesis of Alkaloids Coniine Neurotoxin found in poison hemlock entcorynantheidol Crispine A Alkaloid with antitumor activity T.. Wu, J. M. Chong, J. Am. Chem. Soc. 2006, 128, Stephan Wipf Group 4 1/14/2007

5 Examples for Enantioselective Allylboration in total synthesis (+)13Deoxytedanolide A.. Smith, C. M. Adams, S. A. Lodise, A. P. Degnan, A.. Smith, J. Am. Chem. Soc. 2003, 125, (+)rasilenyne S. E. Denmark, S.M. Yang, J. Am. Chem. Soc. 2004, 126, Stephan Wipf Group 5 1/14/2007

6 1,3Disubstituted Allylboronate Aldol addition to chiral αsubstituted allyl boronate compounds H Me Me MeC(Et) 3 cat. EtC 2 H 135 C * H C 2 Et CH Et * CH 2 Cl 2, rt single diastereomer Johnson rearrangement =Me : 78% =Me : 95% : 82% : 65% C 2 Et > 98% ee H MeC(Et) 3 cat. EtC 2 H 135 C, 48% C 2 Et CH CH 2 Cl 2, rt H C 2 Et 84%, 91%ee J. Pietruska, N. Schöne, Chem. Eur. J. 2004, Stephan Wipf Group 6 1/14/2007

7 αsubstituted Allylboronates nepot double allylboration with a 1,3bifunctionalized boron reagent for the diastereo and enantioselective synthesis of anti1,5diols ( d Ipc) 2 1 CH 2 CH H (0.82 equiv.) 1 (1.7 eqiv.) ( d H 2 Ipc) 2 CH 2 Cl 2, 78 C rt, 24h 1 αsubstituted allylboronate 1, 2 =, (CH 2 ) 2, (CH 3 ) 2 CH, C 6 H %, 91 95%ee Application: Synthesis of C(43)C(67) fragment of Amphidinol 3 TDPS CH CH 2 Cl 2, 78 C ( l Ipc) 2 TDPS ( l Ipc) 2 H H 43 H TDPS 50 CH 2 Cl 2, rt 70 80%, dr 9:1 E. M. Flamme, W.. oush, J. Am. Chem. Soc. 2002, 124, J. D. Hicks, E. M. Flamme, W.. oush, oush, rg. Lett. 2005, 7, Stephan Wipf Group 7 1/14/2007

8 Aggarwal: Preliminary work Enantioselective synthesis of secondary alcohols and amines using chiral organoboranes generated from sulfonium ylides F eq. LiHMDS dioxane, THF, 5 C H 2 2, NaH 1 H 70 87%, 95 96%ee NH 2 S 3 H 1 = Et, nu, = H, Me, Cl NH 2 Mechanism %, 9697%ee V. Aggarwal, G. Y. Feng, A. T. Schmidt, J. Am. Chem. Soc. 2005, 127, Stephan Wipf Group 8 1/14/2007

9 Main article: Synthesis and application of αsubstituted allyl boranes Synthesis of the sulfonium salt S 2 Cl 1) P 3 dioxane/h 2 reflux, 92% 2) CCH 2 Cl K 2 C 3, 82% Aldol addition to αsubstituted allyl boranes S h! S 76% S endo/exo 20:1 1) PdS/C, H 2 2) recryst. 84% S 48% overall nr NaF 4 (aq.) CH 2 Cl 2 F 4 F 4 1) LiHMDS, 78 C THF/CH 2 Cl 2 30 min 2) 100 C CH 100 C 9 H Excellent enantio and diastereoselectivity High Z selectivity Chiral sulfide recovered (>90%) Side reaction (< 20%): H H V. Aggarwal et al, Angew. Chem. Int. Ed. 2001, 40, V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007, 46, Stephan Wipf Group 9 1/14/2007

10 Mechanism Aggarwal, Angew. Chem. Int. Ed. 2007, 119, Stephan Wipf Group 10 1/14/2007

11 Expansion of Methodology ther enatiomer acessible via boraneisomerisation/aldol sequence F 4 1) LiHMDS, 78 C THF/CH 2 Cl 2 30 min 2) 100 C to 0 C CH 78 C H C 1,3 borotropic rearrangement: V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007, 46, Stephan Wipf Group 11 1/14/2007

12 Application: Total synthesis and structural confirmation of (+)isoagatharesinol (+)Isoagatharesinol: Norlignane, isolated from asparagus gobicus (2004) Confirmation of relative stereochemistry (racemic) F 4 1) LiHMDS, 78 C THF/CH 2 Cl 2 30 min H TS 1) LiH 4 H H 2) 2) TAF matched NM data Piv Piv TS H H 100 C 3) TSCH 2 CH TS 78% 1) DEAD, P 3 pn 2 C 6 H 4 C 2 H H H Asymmetric total synthesis 2) LiH 4 3) TAF H H F 4 Piv 1) LiHMDS, 78 C THF/CH 2 Cl 2 30 min 2) H TS 1) LiH 4 2) TAF H H 100 C TS 3) TSCH 2 CH Piv TS H H 81% 72%, > 99%ee V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007, 46, C.X. Yang, S.S.Huang, X.P. Jang, Z.J. jia, Planta Med. 2004, 70, Stephan Wipf Group 12 1/14/2007

13 Conclusion A stereocontrolled synthesis of αsubstituted allyl boranes was developed Subsequent aldol reaction yielded Zconfigured homoallylic alcohols in excellent enantio and stereoselectivity The methodology was expanded via 1,3borotropic rearrangement and subsequent aldol reaction Applied to the first total synthesis of (+)isoagatharesinol Stephan Wipf Group 13 1/14/2007

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