JACS ASAP Article: Published 3/12/08. Lei Jiao, Changxia Yuan and Zhi-Xiang Yu. Current Literature: 3/29/08. David Arnold

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1 Tandem h(i)-catalyzed [(5+2)+1] Cycloaddition/Aldol eaction for the Construction of Linear Triquinane Skeleton: Total Syntheses of (+)-irsutene and (+)-1- Desoxyhypnophilin JACS ASAP Article: Published 3/12/08 Lei Jiao, Changxia Yuan and Zhi-Xiang Yu Current Literature: 3/29/08 David Arnold David Wipf Group Page 1 of 15 6/25/2008

2 Linear Triquinanes: Target Natural Products (+)-1-desoxyhypnophilin (+)-hirsutene Lentinus crinitus Coriolus consors Polyquinane natural products were first isolated in Since then over 80 linear triquinane natural products have been isolated from plants, microbes and marine organisms. Biological activities of select linear triquinanes include antibiotic and antitumor activity. Tetrahedron Letters 2000, 41, 8985; Angew. Chem. Int. d. 2003, 42, David Wipf Group Page 2 of 15 6/25/2008

3 Background: Theoretically Suggested Mechanism for [h(c) 2 Cl] 2 Catalyzed Intermolecular (5+2) eactions between Vinylcyclopropanes and Alkynes + [h(c) 2 Cl] 2 h( C ) 2 Cl - C 1/2 [h(c) 2 Cl] 2 + C h( C )Cl h( C )Cl h(c)cl h(c)cl h(c) Cl Catalytic Cycle J. Am. Chem. Soc. 2004, 126, David Wipf Group Page 3 of 15 6/25/2008

4 Could the Intermediate Along the oute to a [5+2] Cycloaddition be intercepted by C to give a [5+2+1] Cycloadduct -C M Ln + C [5+2] product M Ln C insertion [5+2+1] Product J. Am. Chem. Soc. 2002, 124, David Wipf Group Page 4 of 15 6/25/2008

5 Yes With a Surprising esult! C 2 M e C (1 atm), [h(c) 2 Cl] 2 + DC, 60 o C; C 2 M e 13% 18 % 32% T ransannular A ldol condensat ion gives t he coresponding diquinane products Good yields of diquinanes with carbonyl activated alkynes ighly regio- and diastereoselective J. Am. Chem. Soc. 2002, 124, David Wipf Group Page 5 of 15 6/25/2008

6 Background: h(i)-catalyzed Two Component [5+2+1] Cycloadditon of ne-vinylcyclopropanes and C Computational considerations for the [h(c) 2 Cl] 2 catalyzed cycloaddition reaction ffect of VCP olefin geometry on the cis/trans stereochemistry of the bicyclic products X [h(c) 2 Cl 2 ] X hln X A : kcal/mol [5+2] cycloadduct X 5 mol % [h(c) 2 Cl] 2, 0.2 atm C atm N 2 X + X - C + C dioxane, 0.05 M, 80 o C X Ln h A : kcal/mol X X = C(C 2 Me) 2 /Z = 3:1 /Z = 1:3 X = NTs /Z = 3:1 /Z = 1:3 Cis Trans 16% 50% 52% 17% 15% 44% 31% 10% A : kcal/mol [5+2+1] cycloadduct Substrate Scope J. Am. Chem. Soc. 2007, 129, David Wipf Group Page 6 of 15 6/25/2008

7 Combination of Methodologies: Construction of the Linear Triquinane Skeleton Key Transformation h(i)-catalyzed [(5+2)+1] cycloaddition aldol condensation ene-vcp ' ' linear triquinane Initial Attempts i) C (1 atm), 5 mol % [h(c) 2 Cl] 2 dioxane, 60 o C, 32 h ii) Cl- 2 Complex mixture Me methoxyethoxy-ene-v CP i) C (0.2 atm), 5 mol % [h(c) 2 Cl] 2 dioxane, 80 o C, 24 h ii) Cl- 2 16% David Wipf Group Page 7 of 15 6/25/2008

8 ptimization: Changes at the -substitutent thoxy- and siloxy-ene-vcp ethoxy-ene-vcp i) C (0.2 atm), 5 mol % [h(c) 2 Cl] 2 dioxane, 80 o C, 24 h ii) Cl- 2 Complex mixture i) C (0.2 atm), 5 mol % [h(c) 2 Cl] 2 dioxane, 80 o C, 24 h siloxy-ene-vcp TBS ii) Cl- 2 19% David Wipf Group Page 8 of 15 6/25/2008

9 Model eaction Study on the Tandem TwoComponent [(5+2)+1]/Aldol eactions Different tether groups on the siloxy-enevcps have a minor effect on the reaction Methyl substituted (Z)-siloxy-ene-VCPs produce the correct cis-anti-cis configuration of the linear triquinane core diastereoselectively Methyl substituted ()-siloxy-ene-vcps produce the trans fused 5-8 bicyclic compounds and do not undergo the tandem aldol reaction David Wipf Group Page 9 of 15 6/25/2008

10 ational for the Stereochemistry of the [(5+2)+1] Cycloaddition Mechanism: VCP cleavage, alkene insertion, C insertion, reductive elimination David Wipf Group Page 10 of 15 6/25/2008

11 ational for the Stereochemistry of the Aldol Condensation The stereochemical outcome of the tandem two-component [(5+2)+1]/aldol reaction diastereoselectively sets the tricyclic core of hirsutene and 1-desoxyhypnophilin David Wipf Group Page 11 of 15 6/25/2008

12 etrosynthetic Analysis for the Natural Products: hirsutene and 1-desoxyhypnophilin Both natural products can be synthesized by elaboration of the common linear triquinane intermediate resulting from the tandem h(i)-catalyzed [(5+2)+1]/aldol reaction methodology. David Wipf Group Page 12 of 15 6/25/2008

13 Synthesis of Key linear triquinane intermediate and (+)-irsutene C P (C 2 CF 3 ) 2 K Bu t, 18-C-6 TF, -78 o C->rt, 6h (87% Z: = 7:1) TBS Tf t 3 N ther, 0 o C, 3h (100%) C 2 I 2 t 2 Zn C 2 Cl 2, rt, 2h TB S ( 86%) TB S i) C (0.2 atm), 5 mol % [h( C ) 2 Cl] M, dioxane, 80 o C, 48 h TBS ii) Cl- 2 (62%) K ey Intermediate M e 2 CCCl, DMA P C 2 M e n- Bu 3 Sn, A IB N C 2 Cl 2, 20 o C, 1h ( 92%) Toluene, 100 o C, 45 m in ( 68%) Ph 3 P=C 2 tb u - Benz ene, r ef lux, 1h ( 63%) Concise 8 step synthesis of (+)-hirsutene with an overall yield of 11% (+)-hir sutene David Wipf Group Page 13 of 15 6/25/2008

14 Synthesis of (+)-1-Desoxyhypnophilin Ph 3 P=C 2 S e 2, TBP K ey Intermediate tbu-b enzene, r ef lux, 2h ( 85%) C 2 Cl 2, r t, 2h + (83%) (16%) 1. (CCl) 2, DM S, C 2 Cl 2, -78 to -40 o C (52%) 2. t 3 N, -78 to rt, 2h (26%) 2 2, NaC 3 I 2 (+)-1-desoxyhypnophilin TF- 2, 0 o C, 5h (73%) Benzene, reflux, 2h (83%) (+)-1-desoxyphypnophinin synthesized in 9 steps with 13% overall yield David Wipf Group Page 14 of 15 6/25/2008

15 Conclusions The authors have developed an efficient tandem two-component rhodium(i) catalyzed [(5+2)+1] cycloaddition/aldol condensation reaction. This methodology was showcased by diastereoselectively establishing, in a single step, the correct placement of all stereocenters, including the two quarternary centers, contained in the core structure of the linear triquinanes: hirsutene and 1- desoxyhypnophilin. This paper represents the first application of the h(i)-catalyzed [(5+2)+1] methodology in natural product synthesis. (+)-1-desoxyhypnophilin (+)-hirsutene David Wipf Group Page 15 of 15 6/25/2008