Synthesis of Substituted 1,4-Dienes by Direct Alkylation of Allylic Alcohols Kolundzic, F.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129,

Transcription

1 Synthesis of Substituted 1,4-Dienes by Direct Alkylation of Allylic Alcohols Kolundzic, F.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, Total Synthesis and Structure Elucidation of (+)-orbasin C Macklin, T. K.; Micalizio, G. C. J. Am. Chem. Soc. 2009, 131, Total Synthesis of Lehualide B by Allylic Alcohol-Alkyne Reductive Cross-Coupling Jeso, V.; Micalizio, G. C. J. Am. Chem. Soc. 2010, 132, Becky Farmer Short Literature Presentation Group eting

2 Glenn C. Micalizio 1996 BS Chemistry Ramapo College of ew Jersey 2001 D Chemistry - William Roush University of Michigan - Ann Arbor Postdoctoral Fellow - Stuart Schreiber arvard University Assistant Professor Yale University 2008-Present Associate Professor The Scripps Research Institute

3 Current thods for Allylic Alkylation Copper-Catalyzed Asymmetric Allylic Substitution Cl MgBr CuBr (3 mol %) ligand (3.3 mol %) C 2 Cl 2, -78 C 96% ee (+)-naproxen, 93% ee ligand = P Coupling of Alkynes with Allylic Alcohols to Generate Unsaturated Ketones Yorimitsu,.; shima, K. Angew. Chem. Int. Ed. 2005, 44, mol % catalyst mol % 4 PF 6 neat, 100 C 50% catalyst = Ru Cl Trost, B. M.; Martinez, J. A.; Kulawiec, R. J.; Indolese, A. F. J. Am. Chem. Soc. 1993, 115, Iridium-Catalyzed Allylation of Enamines 1. 5 mol % ligand 2.5 mol % [Ir(cod)Cl] 2 2 C ml TF rt, 5Å MS ligand = 2. aac/ac, P 2 76% 99:1 branched to linear 96% ee Weix, D. J.; artwig, J. F. J. Am. Chem. Soc. 2007, 129,

4 thods for Synthesis of Skipped Dienes lefination Reactions for the Generation of 1,4-Dienes + S 2 LiMDS, DME -78 C 73%, Z:E = 98:2 3-furyl Aissa, C. Eur. J. rg. Chem. 2009, Synthesis of Z,Z-Skipped Dienes C EtMgBr, TF 2. CuC C 5 9 C Pd/Lindlar 2., + 94% C % I C 2 C 5 9 Durand, S.; Parrain, J. L.; Santelli, M. J. Chem. Soc., Perkin Trans. I 2000, 253. Thermal Rearrangements of Vinylcyclopropanes R 3 Si toluene, 110 C 96% R 3 Si Lin, Y.-L.; Turos, E. J. rg. Chem. 2001, 66,

5 Synthesis of Substituted 1,4-Dienes by Allylic Alkylation R n + PMB PMB 1. ClTi(iPr) 3, C 5 9 MgCl, toluene -78 to -35 C 2. add allylic alkoxide R n PMB PMB 65% PMB both 5- and 6-membered rings could be utilized PMB 61% PMB tertiary alcohols could be used to generate trisubstituted alkenes PMB 57% exocyclic alkenes were tolerated C-C bond formation occurs in a suprafacial manner across the allyl system PMB PMB TES 50% er=97:3 54% er = 96:4 PMB PMB reactions with stereodefined allylic alcohols proceed with minimal stereochemical erosion TES dr 20:1 PMB PMB

6 Coupling of Acyclic Allylic Alcohols and Alkynes R1 R3 + R 4 R 5 1. ClTi(iPr) 3, C 5 9 MgCl, toluene -78 to -35 C 2. add allylic alkoxide R 1 R 2 R 4 R 5 R 2 R3 R PMB PMB PMB R R =, 41% R =, 66% PMB primary allylic alcohols couple efficiently with more substituted coupling partners 59% substitution can be introduced on neighboring methylene utilizing substituted tertiary allylic alcohols PMB PMB 57% tetrasubstituted olefins can be prepared using this method PMB PMB 78% E:Z = 1:1 PMB secondary allylic alcohols generate an additional stereodefined double bond, but with no stereoselection for the unsubstituted case 72% Z:E 20:1 PMB 1,1-disubstituted alcohols produce 1,4 dines with a stereodefined ttrisubstituted Z olefin

7 Additional Scope of Coupling Reaction R1 R3 + R 4 R 5 1. ClTi(iPr) 3, C 5 9 MgCl, toluene -78 to -35 C 2. add allylic alkoxide R 1 R 2 R 4 R 5 R 2 R3 + 59% Z:E 20:1 unsymmetrical alkynes couple regioselectively 59% Z:E 20:1 neighboring unsaturation in allylic alcohol is tolerated PMB PMB R 1 R 2 R 1 =, R 2 =, 59%, E:Z = 8:1 R 1 =, R 2 =, 67%, E:Z = 1:1 PMB PMB Z-disubstituted olefins couple with higher selectivity than E-olefins R 1 R 1 Ti R 2 control by minimization of A1,2 strain R 1 R 1 Ti R 2 control by minimization of A1,3 strain

8 Lehualide B The lehualides are a family of pyrone-containing natural products isolated from a awaiian sponge Plakortis sp. lehualide B lehualide A Lehualide B shows nanomolar inhibition of IGRV-ET ovarian cancer cell proliferation, while its isomer lehualide A was inactive The lehualides share structural similarities with the peiricidins, which are inhibitors of mitrochondrial electrontransport chain Complex I There are no stereocenters in lehualide B, but it possesses a synthetically challenging skipped diene with two trisubstituted alkenes piericidin B 1

9 Retrosynthetic Analysis of Lehualide B Reductive Cross-Coupling lehualide B Claisen rearrangement and 2 C=C()MgCl

10 Synthesis of Allylic Alcohol Coupling Precursor I(Ac) 2 BF 3 Et 2 70% LDA (2.2 equiv), 2 S 4 24% over two steps mcpba, then Et 3 94% Se LiMDS, then 78% Se 1. g(ccf 3 ) 2. Toluene, 150 C 90% Claisen rearrangement MgBr E:Z = 10:1 TF, -78 to -25 C 59%

11 Reductive Coupling Endgame of Lehualide B LiMDS (2.5 equiv) TF, -78 C Li Li pyrone was masked as dianion to prevent reactivity at the carbonyl group ClTi(iPr) 3, c-c 5 9 MgCl toluene, -78 to 0 C 50% natural product was obtained in a 50% yield from reductive coupling, but relative ratio of regioisomers was only 1.3:1 lehualide B

12 Reductive Coupling Endgame of Lehualide B LiMDS (2.5 equiv) TF, -78 C Li Li ClTi(iPr) 3, c-c 5 9 MgCl toluene, -78 to -40 C 61% 1. IS, ClC 2 C:EtAc (2:1), 93% 2. BnZnBr, Pd(P 3 ) 4 TF, rt, 68% Z:E = 7:1 lehualide B E:Z 20:1 rs 20:1

13 (+)-orbasin C * R phorbasin B, R = phorbasin C, R = Ac carvotacetone skeleton The phorbasins are a class of diterpenes isolated from the Australian marine sponge orbas sp. Structurally related to carvotacetone monoterpenes and carvone The phorbasins demonstrate growth inhibitory activity against Gram positive bacteria such as Staphylococcus aureus and Micrococcus luteus, as well as selective growth inhibition of several human cancer cell lines (e.g., A549 lung adenocarcinoma, T29 colorectal adenocarcinoma) The relative stereochemistry of all of the phorbasin family members at C11 is undefined, while the absolute stereochemistry was assigned based on analysis of the CD spectra

14 Retrosynthetic Analysis of (+)-orbasin C Ac * phorbasin C Suzuki-Miyaura Cross-Coupling Ac I + (R) 2 B * 2R or 2S Br + Reductive Cross-Coupling TP

15 Synthesis of Vinyl Iodide Coupling Partner Br 1. 2,2-DMP, PTSA 2. s 4, M 3. Bu 3 Sn, AIB 65% over three steps Radical dehalogenation 1. nbuli, TF 2. Ti(iPr) 4 c-c 5 9 MgCl, Et 2 dr 20:1-78 C to rt (L) n M Ti 1. V(acac) 2, TBP benzene, 50 C, 63% 2. (CCl) 2, DMS Et 3, C 2 Cl P=C 2, TF 0 to 5 C + 79% over two steps Swern oxidation and Witting olefination dr 20:1 47% M Ti(L) n-1 1. Pd(P 3 ) 4 Ac, TF 2. Ac 2, pyridine DMAP, C 2 Cl 2 90% over two steps 1. IS, C 3 C, 77% 2. TFA, 2, TF 3. IBX, DMS I Sc(Tf) 3, 2 I Ac Ac 75% over two steps Ac Ac 80% Ac

16 Synthesis of Vinyl Iodide Coupling Partner TP 1. DMS, (CCl) 2 Et 3, C 2 Cl 2 2. KMDS, DME S Julia-Kocienski olefination TP B 51% over two steps E:Z 20:1 1. PTSA,, C 2 Cl 2 2. DMP, C 2 Cl 2, 2 3. CrCl 2, CI 3, TF 44% over three steps E:Z 20:1 Takai olefination I tbuli, B ipr 76% chanism of Modified Julia-Kocienski lefination TP KMDS S B S K TP S TP TP S TP S K K

17 Endgame of Synthesis and Structure Confirmation I B 2S Pd(P 3 ) 4, Tl 2 C 3 TF, 2 Ac 63% Ac Suzuki-Miyaura cross-coupling B 2R 67% Ac [α] 20 D +124 (c 0.18 ) Ac phorbasin C [α] 22 D -131 (c 0.18 )