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Burke Group Mee+ng Hosted by Seiko Fujii and Pulin Wang
Oct. 1, 2011
Strategy in Organic Synthesis: Retrosynthe2c Analysis Part II
MeMe
Me
OHMe
OH
(+)-Allocyathin B2
all-‐carbon quaternary centers
5,6,7-‐fused tricyclic core
Exocyclic C atom connected to C(12)
Isopropyl side chain at C(3)
Order of events 9:30AM............ Each group will present their retrosynthesis (7 min)
followed by a brief Q&A (3 min)
Order of presenta2on The Figh(ng Woodwards
What element rhymes with moron? "the group formerly known as two”
Group 3 Synthe(c Destroyers
10:30AM...........Vote for the top two groups to advance to the next round 10:40AM...........Quick Break 10:50AM...........Top two groups will present their forward synthesis (15 min each)11:20AM...........Q&A for both groups 11:40AM...........Literature examples 11:50AM...........Final vote!
• selec+ve oxida+ve cleavage • cycloisomeriza+on to form 6-‐membered ring
• 19 total steps, 14 steps in longest linear sequence
Steve, Kaitlyn, Stevie, Tim, Tony
This synthesis is beaer than that +me I
made strychnine! Go Woodwards!
Figh+ng Woodward Retrosynthesis
Figh+ng Woodward Retrosynthesis
M. Hatano, K. Mikami, J. Am. Chem. Soc. 2003, 125, 4704. Fairlamb, I. J. S. Angew. Chem. Int. Ed. 2004, 43, 1048.
Figh+ng Woodward Retrosynthesis
What element rhymes with moron? Eric, Junqi, Josh, Dan, Jim
• 3 Aldol reac+ons • 11 total steps from commercially available materials
Group II
(The group formerly known as Two) DMK, EKD, BCW, NP, JR, AA
Group II - Retrosynthesis!
Robust chemistry, inexpensive starting materials" Early route highly precedented" Flexible (Noyori reduction selectivity)" Limited use of protecting groups"15 steps in forward synthesis"
GROUP 3 Retrosynthesis of Allocyathin B2
Ian, Greg, Laura, Hannah, Michelle 1 October 2011
Synthe+c Destroyers Jus+n, Brice, Maa, Adam, Adina, Maa
• 9–10 Steps from Racemic SM • Rh-‐Catalyzed Formal [4+3] to Construct the 7-‐Membered Ring • Topological Stereocontrol • Atom Economical • Protec+ng Group Free!
Forward Syntheses
Round 2!
Lions, and 49ers, and Bears… Oh My
Formerly known as synthe+c destroyers
Synthesis of (+)-Allocyanthin B2
Preparation of Bicyclic Enone: Snider et al J. Am. Chem. Soc. 1980, 102, 5872-5880 Suzuki-Miyaura Coupling of Vinyl Boronic Acids with Vinyl Triflates: Gonzalez, et al. WO 2010146125 (A1). 2010 Formal [4+3] : Sarpong et al. Angew. Chem. Int. Ed. 2009, 48, 2398-2402. Sarpong et al. J. Am. Chem. Soc. 2010, 132, 12422-12425
Synthesis of (+)-Allocyanthin B2
" 3o carbocation"
Selenide Step: Hopkins, et al. J. Org. Chem. 1986, 51, 5243-5252. Reduction: Cha, et al. J. Org. Chem. 1987, 52, 5486-5487.
Synthesis of (+)-Allocyanthin B2
9–10 Steps Overall from Readily Available Racemic Starting Material
Rhodium Catalyzed [4+3] Cylcoaddition to Construct the Seven-Membered Ring
Topological Stereocontrol of Epoxidation and Oxirane Opening
Protecting Group Free
Most Reactions suggested to be at or slightly below room temp.
The Highlights
Group 3
Synthesis of Subunit A
Ian, Greg, Laura, Hannah, Michelle 1 October 2011
Synthesis of Subunit B
Ian, Greg, Laura, Hannah, Michelle 1 October 2011
Synthesis of Subunit B (cont’d)
Ian, Greg, Laura, Hannah, Michelle 1 October 2011
CompleKon of Synthesis
Ian, Greg, Laura, Hannah, Michelle 1 October 2011
Literature Examples before the final vote
Pulin
Trost’s synthesis of Allocyathin B2
Trost, B.M., Dong, L., Schroeder, G.M.; J. Am. Chem. Soc. 2005, 127 (9), 2844-‐2845.
Aldol condensa+on Ru-‐based cyloisomeriza+on
Asymmetric allylic alkyla+on
Hydroxyla+ve knoevenagel reac+on
Nakada’s synthesis of Allocyathin B2
Takano, M., Umino, A., Nakada, M.; Org. LeF. 2004, 6 (26), 4897-‐4900.
Radical ring expansion
Aldol reac+on
Alkyla+on
Final vote!
The Figh+ng Woodwards
Figh+ng Woodward Forward Synthesis
Allen, P. R.; Brimble, M. A.; Prabaharan, H. J. Chem. Soc., Perkin Trans. 1, 2001, 379.
Figh+ng Woodward Forward Synthesis
Figh+ng Woodward Forward Synthesis
Figh+ng Woodward Forward Synthesis
Boron
What element rhymes with moron? Forward Synthesis
Forward Synthesis
(+)-‐Allocyathin B2
"the group formerly known as two"!
Group II - Forward Synthesis!
15 total steps!
