1 Literature Screening JACS Synthesis February 2 nd 2009 Thibaud Gerfaud

2 Oxidative Pd(II)-catalyzed C-H bond amination to Carbazole at ambient temperature James A. Jordan-Hore, Carin C. C. Johansson, Moises Gulias, Elizabeth M. Beck and Matthew J. Gaunt - Classical disconnection in C-N bond formation: C-X + NH (Pd(0) and Cu(I) couplings) - This work: C-H + NH Pd(II) catalysis - Interest: No prefunctionalization of the aryl group with an halide - Carbazole motif present in a lot of natural products and medicines: Gaunt & al., JACS, 2008, 130,

3 Previous work on C-H amination: Gaunt & al., JACS, 2008, 130, Via nitrenes, Rh catalysis Driver & al., JACS, 2007, 129, Allylic C-H amination, heterobimetallic catalysis White & al., JACS, 2008, 130, Acetanilide amination, Pd catalysis Inamoto & al., Org. Lett., 2007, 9,

4 Mechanistic hypothesis: Optimized reaction conditions: Gaunt & al., JACS, 2008, 130,

5 Scope of the reaction Complex Isolation Gaunt & al., JACS, 2008, 130,

6 Application to complex substrates Conclusion - New Pd(II) catalyzed intramolecular C-H amination to form carbazoles - Reaction occurs under mild conditions with a broad scope - Rare exemple of reductive elimination from a high oxidation state transition - A non polar solvent seems necessary to promote polynuclear palladacycles - Useful in natural products synthesis N-Glycosyl carbazolesTandem para-iodination, C-H amination followed by Suzuki coupling to give highly functionalized cabazoles Gaunt & al., JACS, 2008, 130,

7 Direct Catalytic Asymmetric Synthesis of Cyclic Aminals From Aldehydes Xu Cheng, Sreekumar Vellalath, Richard Goddard and Benjamin List - Phosphoric acid catalyzed synthesis - Stereogenic cyclic aminals: very common in drugs, catalysts and pharmaceuticals - Common synthesis protocol for benzo(thia)diazines: use of an achiral catalyst and HPLC separation List & al., JACS, 2008, 130,

8 Catalyst Screening: List & al., JACS, 2008, 130,

9 Scope of the reaction: Aldehyde Aminobenzamide

10 Conclusion: - First enantioselective direct synthesis of aminals from aldehydes catalyzed by chiral phosphoric acid - Catalyst structure: - Good aldehyde tolerance - All investigated amides gave excellent enantioselectivities - Methodology applied to different structures: List & al., JACS, 2008, 130,

11 Asymmetric Reductive Mannich Reaction to Ketimines Catalyzed by a Cu(I) Complex Yao Du, Li-Wen Xu, Yohei Shimizu, Kounosuke Oisaki, Motomu Kanai and Masakatsu Shibasaki - Asymmetric  -aminoacids: Mannich reaction is the most straighforward method - Reaction was limited to the use of aldimines and iminoesters to form  -amino acids - Low reactivity of ketimines - This work: expand the scope of previous work by the group Shibasaki & al., JACS, 2008, 130,

12 Previous work by the same group: - Method limited to acetate-derived enolates as donors - New method required to achieve the catalytic asymmetric synthesis of  -amino acids with a substituent at the  -position Shibasaki & al., JACS, 2008, 130, Shibasaki & al., JACS, 2007, 129,

13 Catalytic Diastereoselective Reductive Mannich Reaction of Ketimines Shibasaki & al., JACS, 2008, 130,

14 Catalytic Asymmetric Reductive Mannich Reaction of Ketimines Conversion to  2,2,3 -amino acids derivatives Without any racemization and epimerization Shibasaki & al., JACS, 2008, 130,

15 One-Pot Synthesis of  -Siloxy Esters Using a Silylated Masked Acyl Cyanide Hisao Nemoto, Rujian Ma, Tomoyuki Kawamura, Kenji Yatsuzuka, Masaki Kamiya and Masayuki Shibuya Nemoto & al., Synthesis, 2008, 23,  -Hydroxycarboxylic acids or esters usually prepared in multiple steps by C-C bond formation using carbanion chemistry Kirschning & al., Chem. Eur. J., 1999, 5, 2270

16 - One-pot reaction using MAC (Masked Acyl Cyanide) - Reminder on Passerini reaction: Nemoto & al., Synthesis, 2008, 23,

17 - Esters and tertiary amides which cannot be directly synthesized by Passerini reactions can be synthesized using MAC reagents - Amines can be used directly: no need to form an isonitrile Scope of the reaction (selected examples) R1R2TimeYield 4-MeC 6 H 4 H5 min96% 4-NCC 6 H 4 H2h98% (E)-MeCH=CHH2h79% Me 3 CH5h30% 4-O 2 NC 6 H 4 Me0.5h90% 4-MeC 6 H 4 Me24h77% Me 3 CMe48h0% Nemoto & al., Synthesis, 2008, 23,

18 - Electron density on aromatic rings did not influence the reaction - Sterically hindered aldehydes and ketones are not good substrates for the reaction - On cyclohexen-2-one; competition between 1,2 and 1,4 addition Alcohol scope R3Yield i-Pr90% Bn88% Allyl92% Ph93% t-Bu0% - No reaction with hindered tert-butyl alcohol Nemoto & al., Synthesis, 2008, 23,

19 Conclusion - One-pot reaction to afford  -siloxy esters - A tertiary amine is necessary, in case of sterically hindered substrates DMAP can improve the yield - Trialkylamines unsuitables for the reaction because of decomposition of the MAC reagents - MAC reagents are the only acyl anions equivalents that allow one pot reactions to create  -hydroxy carbonyl compounds Nemoto & al., Synthesis, 2008, 23,

20 A Concise Asymetric Total Synthesis of Aspidophytine K. C. Nicolaou, Stephen M. Dalby and Uptal Majumber Nicolaou & al., JACS, 2008, 130, Isolated from Haplophyton cimicidium in Structure disclosed in Acid-mediated degradation lead to the right-hand constituent aspidophytine: HaplophytineHaplophyton cimicidium - First total synthesis: Corey 1999

21 Retrosynthetic Analysis Nicolaou & al., JACS, 2008, 130,

22 Synthesis of A Nicolaou & al., JACS, 2008, 130,

23 Fragment coupling and elaboration to Aspidophytine Longest linear sequence: 12 steps 5% overall yield Nicolaou & al., JACS, 2008, 130,

24 Other interesting articles Communications: - Three Component Coupling of α-Iminoesters via Umpolung Addition of Organometals: Synthesis of α,α-Disubstituted α-Amino Acids Kozlowski & al., JACS, 2008, 130, Full Papers: -Total Synthesis of (−)-Pseudolaric Acid Trost & al., JACS, 2008, 130,