Total Synthesis of ( )-imandrine M. Movassaghi,* M. Tjandra and J. Qi J. Am. hem. Soc. 2009, 131, 9648-9650 Bz Adam T. oye urrent Literature ctober 3, 2009 Adam oye @ Wipf Group Page 1 of 22 10/3/2009
Structure of ( )-imandrine Bz 2 Bz arbon Skeleton Simplification: Adam oye @ Wipf Group Page 2 of 22 10/3/2009
Galbulimima Alkaloids 28 isolated alkaloids categorized into lass I, II and III haracterized by piperidine moiety and caged structure -Isolated from bark of Galbumimia belgraveana native to northern Australia and Papua-ew Guinea -Biological Properties- potent muscarinic antagonist Papuans (who tend to use this drug the most) boil the bark and the leaves together with another plant, called omalomena[2], in order to make tea It is similar to strong marijuana which induces a similar slumber like feeling http://en.wikipedia.org/wiki/galbulimima_belgraveana Adam oye @ Wipf Group Page 3 of 22 10/3/2009
Galbulimima syntheses lass I syntheses (selected): art (hio State) 1995 hackalamannil (Schering-Plough) 1996 Baldwin (xford) 2005 lass III syntheses: Mander (Australian at. Univ.) : Galbulimima 13 (racemic) 2003 Movassaghi (MIT): (+)- and ( )-GB 13 2006 hackalamannil (Schering-Plough): ( )-imgaline 2006 Evans (arvard): (+)-GB 13 and (+)-imgaline (antipodes) 2007 lass II syntheses: Movassaghi: TITLE PAPER Adam oye @ Wipf Group Page 4 of 22 10/3/2009
Polyacetate Proposal (Taylor) lass I 2 2 2 imbacine etc. 3 imandrine imandridine 2 2 lass II imbadine GB 13 imgaline 2 lass III Mander, L..; Prager, R..; Rasmussen, M.; Ritchie, E.; Taylor, W.. Aust. J. hem. 1967, 20, 1705-1718 Adam oye @ Wipf Group Page 5 of 22 10/3/2009
Baldwin Type I Synthesis Linear polyketide precursor R Biological R Diels-Alder 2 iminium reduction lass I R R (R =, imgravine) Tchabenenko, K., Adlington, R. M.; owley, A. R.; Baldwin, J. E. rg. Lett. 2005, 7, 585-588. Adam oye @ Wipf Group Page 6 of 22 10/3/2009
Baldwin Boc P() 2 Boc DIPEA, Lil, 50% 1. TFA, DM, 0 to rt, then ab 3 2. Boc 2, Et 3, DM Boc 2, Pt 2, Et 22% (3 steps) TFA, DM, then, ab 4, Boc Boc 60% (+)-imbacine separable Tchabenenko, K., Adlington, R. M.; owley, A. R.; Baldwin, J. E. rg. Lett. 2005, 7, 585-588. Adam oye @ Wipf Group Page 7 of 22 10/3/2009
lass III: Galbulimima Alkaloid 13 Evans Approach Aldol (+)-GB 13 R X c IMDA adduct X c Bn R 2 All Ph, -30 81 % 2 R single diastereomer 1. LiSEt 2. DIBAL- A P Boc A ( 2 ) 3 Boc Evans, D. A.; Adams, D. J. J. Am. hem. Soc. 2007, 129, 1048-1049 Adam oye @ Wipf Group Page 8 of 22 10/3/2009
lass III: Galbulimima Alkaloid 13 Evans Approach Aldol (+)-GB 13 R X c IMDA adduct Roskamp reaction Boc 2 Boc 11 steps (+)-GB 13 Snl 2 62% (3 steps) Li, Lil 4 2 2 Et R Snl 2 R Et J. rg. hem. 1989, 54, 3258-3260 Allyl Boc Evans, D. A.; Adams, D. J. J. Am. hem. Soc. 2007, 129, 1048-1049 Adam oye @ Wipf Group Page 9 of 22 10/3/2009
Biosynthetic Proposal (Movassaghi) Adam oye @ Wipf Group Page 10 of 22 10/3/2009
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(+)- and ( )-GB 13 Movassaghi (+) and ( ) configuration? Br Pd(PPh 3 ) 4, Tl 2 3 Br TF, 2 B() 2 ui, K 2 3, 75% TBS Ph, 110 TBS Br 95% TBS 1. TBAF 2. Mn 2 3. TBSTf, Et 3, DM, -78 93% (3 steps) TBS 4,5- dihydrols l 2 Ru=(o = i Pr)Ph acrolein 2 l 2 85% TBS toluene 90 82% >20:1 endo:exo arbonyl protection TBS (±) Movassaghi, M.; unt, D. K.; Tjandra, M. J. Am. hem. Soc. 2006, 128, 8126-8127 Adam oye @ Wipf Group Page 13 of 22 10/3/2009
(+)- and ( )-GB 13 Movassaghi I 53% Boc MVK, AIB, n Bu 4 Sn, DIPEA, Ph, reflux Boc l, 2 69% Li 1. n BuLi l TBS TF, 85% 2. Martin sulfurane 81% TBS 1:1 d.r. BS, a 3 ; n Bu 4 Sn, AIB, benzene, 90 55% (2 steps) TBS 5-exotrig TBS (F) 3 Et 3 Aldol then ab 4 34% 36% separable Movassaghi J. Am. hem. Soc. 2006, 128, 8126-8127 Adam oye @ Wipf Group Page 14 of 22 10/3/2009
(+)- and ( )-GB 13 Movassaghi 1. bzl, 65% 2. IBX, Ts, Ph, DMS 80% bz TMSI; l; a 89% [α] D = -64 (c 0.06, l 3 ) lit. [α] D = -84 (l 3 ) Absolute stereochemical configuration of ( )-galbulimima alkaloid 13 confirmed Movassaghi J. Am. hem. Soc. 2006, 128, 8126-8127 Adam oye @ Wipf Group Page 15 of 22 10/3/2009
lass II vs. lass III Bz ( )-GB 13 ( )-imandrine Adam oye @ Wipf Group Page 16 of 22 10/3/2009
Title Paper TBS from MacMillian's D-proline cat.!-oxidation 5 steps Br Br B Pd(PPh 3 ) 4, Tl 3, 97% TBS Br B B() 2 2- azetidinone, ui, 85% TBS 1. TBAF 2. S 3 pyr 3. TBSTf, Et 3 67% (3 steps) TBS [Ru], acrolein 85% TBS BT,,-diethylanaline, 95 75% 5:1 d.r. TBS 1. Til 4, DM, -78 2. Martin sulfurane 57% (2 steps) Mukaiyama aldol Adam oye @ Wipf Group Page 17 of 22 10/3/2009
Title Paper 1. Li ubr S 2 Aldol 2. ab 4 3. Bzl bz Ts 81% bz Pl 3, DMF Vilsmeier reagent bz l l 71% bz Adam oye @ Wipf Group Page 18 of 22 10/3/2009
Title Paper bz 1. DDQ 2. al 2 3.; 2 2 61% bz (3 steps) 1. TMSI, DM, 66% 2. (F) 3 Et 3, 90% S 89%, rt, 45 min 1. ab 4, 90% 2. Bzl, pyr, 87% Bz ( )-imandrine 26 steps Adam oye @ Wipf Group Page 19 of 22 10/3/2009
chanistic Investigation Proton delivery assisted by amine (9) stereochem. config. preserved D D 3 D D 9 9 D 3 l l allylic displacement Light-sensitive l Isolable, disappears over course of rxn Adam oye @ Wipf Group Page 20 of 22 10/3/2009
chanistic Investigation 9 l D 3 D D 9 l o (9) exchange (supports intramolecular deprotonation) l Intermolecular transfer of l Adam oye @ Wipf Group Page 21 of 22 10/3/2009
onclusions -The first enantioselective total synthesis of a class II Galbulimima alkaloid has been reported in 26 overall steps -Late-stage spirocyclic -(9) bond construction -2 key concepts- synthetic design and mechanistic investigation - Biologically inspired synthesis -Sensitivity of intermediates Adam oye @ Wipf Group Page 22 of 22 10/3/2009