Alois Fürstner Group Meeting O'Malley 2/29/2005 Prof. Alois Fürstner was born in 1962 in Bruck an der Mur, Austria. He received his Ph.D. in 1987 from the Technical O University of Graz under Prof. Weidmann. In 1990-1991, he was engaged in postdoctoral studies with Prof. Oppolzer at the M O M O University of Geneva. He completed his habilitation in 1992 at O the Technical University of Graz and obtained a position as a M OR L OR professor at the Max-Planck-Institut für Kohlenforschung. In L 1998, he was promoted to director. He is also affiliated with the University of Dortmund. His contributions to chemistry have A B C been recognized with numerous awards, including the Dozentenstipendium of the Fonds der Chemischen Industrie (1994), the Arthur C. Cope Scholar Award (2002), and the Otto O Bayer Prize (2006). Grubbs I (3 mol%) O OTBS Ti(OiPr)4 (30%) Research in the Fürstner group focuses on organometallic chemistry and its application to the synthesis of complex natural OTBS O O CH2Cl2, 40 °C products. Specific areas of focus include alkene and alkyne 80% E:Z 2.7:1 metathesis, development of new metal catalyzed and mediated O H reactions, and the preparation and use of active metals. OH KMnO4, Ac2O; PCy Grubbs I: R = Ph H Cl 3 O Grubbs IA: R= CH=CPh2 Alkene Metathesis aq. HF, MeCN, 54% O O Ru Cl R PCy The Fürstner group has made impressive contributions in the field of ring-closing alkene metathesis, 3 particularly the areas of: (i) extension to the synthesis of medium and macrocyclic rings (ii) control of H product stereochemistry (iii) development of new catalyst systems (iv) application to the total synthesis (—)-Gleosporone of complex natural products. 8 steps, 18% It was initially believed that macrocylizations using RCM required either a directing group or a conformational predisposition towards cyclization to succeed. The Fürstner group disproved this in their The Fürstner group helped pioneer the use of RCM for the formation of medium and large rings. They synthesis of several natural odoriferous macrolactones. JOC, 1996, 61, 3942-3943. used RCM of a cyclooctene as the key step in their short synthesis of Dactylol. JOC, 1996, 61, 8746-9. O TMSO HO Gubbs IA (4 mol %); O Schrock catalyst (3%), O O 6 steps Y C6H14, 55 °C; TBAF, 92% H2, Pd-C X O X=8, Y=4; 79%; 94% X=3, Y=9; 62%; 95% Me H CF3 Ph TM F3C Dactylol (17% overall) Exaltolide O Mo Schrock In macrocyclizations where the double bond is to be retained rather than hydrogenated, E/Z selectivity of Catalyst RCM can pose a difficult problem. The Fürstner group reported that remote functionality can play a key O N role in obtaining selectivity. A hydrogen bond between the unprotected phenol and the ester carbonyl is believed to be responsible for this selectivity. Org. Lett. 2000, 2, 3731-4. F3C F3C OPMB OPMB OR O OR O Cl PCy3 It was discovered early on that the presence of a "directing" functional group greatly assisted the OMOM OMOM Ph formation of macrocycles (see structure A). However, such groups could also result in stable chelates O Grubbs II O Ru that sequester the catalyst (B and C). The Fürstner group found that the use of mild Lewis acids such as Cl Mes Mes Ti(OiPr)4 could overcome such chelation in their synthesis of (—)-Gleosporone. JACS, 1997, 119, 9130-6. N N R=H, 10% cat., 20h, 69%, 0:100 E:Z R=Me, 5%, 1.5 h, 93%, 66:34 R=MOM, 10%, 3h, 91%, 68:32 R=TBS, 5%, 1h, 91%, 40:60 1 Alois Fürstner Group Meeting O'Malley 2/29/2005 Alkene metathesis is an inherintly reversible process. This can particularly pose difficulties for the O O O O synthesis of medium sized cycloalkenes. However, the process can be driven towards ring closure O by evolution of volatile byproduct olefins (e.g. ethlyene) from the reaction medium. Also, when the CrO3, Ac2O O O product olefin is highly substituted, less active catalysts may be insufficiently reactive to initiate O AcOH, PhH, Ring Opening Metathesis. This reversibility also allows for equibilibration of olefin geometry. The 0 °C 54% Fürstner group exploited this phenomenon in their synthesis of the herbrumins, where the Z olefin was Cat. D (5%), 50 min 37%, 27% trimer, O O O O calculated to be 3.5 kcal/mol more stable than the desired E isomer. This is the first example of the 11 % oligomer; extended time favors selective synthesis of both isomers of a target by catalyst choice. JACS, 2002, 124, 7061-9. trimer and oligomers Pyrenophorin H H Cat. B (5%) gives 81% trimer 4 steps, 12% O HO Fürstner cat. aq. HCl, 90% O O CH2Cl2 reflux O HO 69% + 9% Z H H The Fürstner lab has also used RCM as a key step in the synthesis of a number of highly complex H O O O molecules, most notably glycolipids such as Tricolorin G. JACS, 1999, 121, 7814-7821. O herbarumin I O OH H H H O HO O O Grubbs II aq. HCl, 47% O O O HO O O O 1. Grubbs Ia HO H CH Cl reflux O HO O O O 2 2 O 2. H , RhCl(PPh ) , 93% HO H H Ph O O 2 3 3 HO 86% O O O BnO O O 3. TFA, CH2Cl2 O 4. H2, Pd/C, MeOH, TFA HO O Fürstner Catalyst: See Chem.-Eur. J., 2001, 7, 4811, and references therein. BnO 49% HO PCy3 O Cl BnO Ru O O Cl Ph PCy 3 O Tricolorin G The Fürstner group also discovered uses for the reversibility of RCM reactions in the formation of macrocyclces with trisubstituted olefins and dimeric macrocycles. Org. Lett. 2001, 3, 449-451. Alkyne Metathesis O O O The first effective catalyst for alkyne cross-metathesis was reported in 1968. However, this heterogenous O O O mixture of tungsten oxides and silica was only active at temperatures above 200 degrees, and so was not useful for organic synthesis. In 1974, Mortreux et. al. reported that a mixture of Mo(CO)6 and simple phenols catalyzed alkyne methathesis at high temperatures (ca. 150 °C). The active species in this system is unknown, but believed to be a metal carbyne. In 1982, the Schrock group reported the well- defined catalyst (tBuO)3W=CCMe3, which is active at temperatures as low as room temperature. For a review, see Chem. Comm. 2005, 2307-2320. 1 3 In 1998, Fürstner reported the first use of Ring Closing Alkyne Metathesis for the synthesis of cat. t(h) prod. macrocycles with 12 or more atoms in the ring. ACIEE, 1998, 37, 1734-5. A(10%) 17 2(79%) B(10%) 40 3(65%) O O O O C(3%) 4 1(25%) 2(29%) 3 (10%) O (tBuO)3W CMe3 C(6%) 40 3(57%) 2 O O 5 mol % O O D(6%) 40 3(57%) O exposure of 2 to catalyst C 80 °C, 73% for 28 h gives 3 (60%) Cl PCy3 Cl PCy3 Cl PCy3 PCy Ph Ph Ph Cl 3 Ru Ru Ru Ru Cl Cl Cl Ph Cl Mes N N Mes 2,6iPrPh N N 2,6iPrPh Mes N N Mes PCy3 A B C D 2 Alois Fürstner Group Meeting O'Malley 2/29/2005 The synthesis of conjugated dienes has thus far eluded alkene metathesis. In addition to the usual Alkyne Cross Metathesis has been almost unexplored, but was used in a synthesis of prostaglandins issues of product geometry, such reactions also face a question of selectivity with regards to which and prostaglandin analogues. JACS, 2000, 122, 11799-11805. alkene in the starting diene participates in the reaction. As a result, such reactions often generate intractable mixtures of geometrical isomers of both the desired and ring-contracted products. Alkyne metathesis catalysts react with alkynes chemoselectively, thus making enyne-alkyne metathesis an MeO O O O attractive method for the synthesis of macrocyclic dienes. The Fürstner group reported the use of an CO Me alkyne metathesis-trans hydrosilation/protodesilylation protocol for the selective synthesis of E- O OMe 2 cycloalkenes and E,E-cycloalkadienes. Tetrahedron, 2004, 60, 7315-7324. Catalyst A [Cp*Ru(MeCN) ]PF TBSO 51%, balance recovered SM TBSO 3 6 OTES OTES AgF or (1 mol%), HSi(OEt)3 Si(OEt)3 AgF(cat.)/TBAF The Fürstner group developed a well-defined Molybdenum complex that functions as a highly 90% (91:9 E:Z) 84% effective alkyne metathesis catlyst when activated with a wide variety of haloalkanes (often CH2Cl2) or TMSCl. This catalyst was then applied to a highly efficient synthesis of epothilones A and C. Unsymmetrical alkynes generally give mixtures of regioisomers; E:Z is generally > 98:2. The excellent yield obtained in the RCAM reaction contrasts with the poor E/Z selectivities in early The enyne-alkyne metathesis was then applied in a synthesis of Lantrunculin A. ACIEE, 2005, 44, 3462- epothilone syntheses which relied on alkene metathesis. Chem. Eur. J. 2001, 5299-5317. 3466. R tBu tBu X tBu tBu Mo tBu tBu tBu Mo tBu Mo tBu O O O Catalyst A O Potential Active Species O O Cat. A (10 mol%) 1. Lindlar, H2, 82% Note: the exact active species in this reaction are unknown. Multiple Mo complexs have been isolated and O O O possess varying degrees of reactivity in metathesis reactions. Also note that these Mo catalysts can 2.