A Dash of proline to induce chirality Christian Perreault Literature Meeting February 6 th, 2006

Synthesis of (-)-Littoralisone  Enantioselective Organocatalytic α-Oxidation of aldehydes David W. C. MacMillan et Al. J. Am. Chem. Soc. 2005, 127,  1,4 Selective Michaël addition induced by proline  Aldol reaction catalyzed by proline

Nine-membered lactone in an heptacyclic framework Glycosidic unity : (β)-D-Glucose Elaborated optically active cyclobutane 14 stereocenters within a 24 carbon framework (-)-Littoralisone Challenge of the synthesis

Verbena littoralis (1) Castro, O., Umana, E. Int. J. Crude Drug Res. 1990, 28, 175 (2) Ohizumi, Y.,et al J. Org. Chem. 2001, 66, (-)-Brasoside 1 (-)-Littoralisone 2 Origins Verbena littoralis grows in Costa Rica It is a shrub widely used in folk medecine as an effective antidiarrhetic. It has also been claimed as a remedy for typhoid fever, for relieving inflammations from insects bites and for cancer. First isolation and structure elucidation of Littoralisone in 2001 This heptacyclic iridolactone glucoside shown activity on PC12D nerve cells.

(-)-Littoralisone retrosynthesis Intramolecular organocatalysed 1,4-addition Two steps approach carbohydrate synthesis

(-)-Littoralisone synthesis

Enantioselective α-Oxidation of Aldehyde Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am. Chem. Soc. 1963, 85, 207. R’= Alkyl-X, BzCl, Acrylonitrile  Stork identified the usefullness of a condensed secondary amine on a carbonyl, for α-alkylation on the molecule

Enantioselective α-Oxidation of Aldehyde (1) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1973, 38, (2) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. Engl. 1971, 10, 476. (1) (2)

Enantioselective α-aminoxylation of Aldehyde (1) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2002, 122, (2) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (3) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, (4) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, (Proposed transition state) (5) List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395 (Proposed transition state) (1) (3) (2) (4-5)

Enantioselective α-amination of Aldehyde (1) (1) List, B.; J. Am. Chem. Soc. 2002, 124, (2) Udodong, U. E.; Fraser-Reid, B. J. Org. Chem. 1989, 54,  First direct catalytic asymmetric α-amination of aldehyde  Good yield an ee  Product is a useful precursor for 2-oxazolidinones and other α-amino and α-hydrazino acid derivatives scheme 1 scheme 2 (2)

Enantioselective α-aminoxylation of Aldehyde Zhong, G. Angew. Chem. Int. Ed. 2003, 42, (June) MacMillan, D. W. C. et al. J. Am. Chem. Soc. 2003, 125, (July) Hayashi, Y.; Junichiro, Y.; Kazuhiro, H.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293 (August)  Broad scope of compatible functionnality (scheme 1)  Alternative for Aminohydroxylation and Dihydroxylation of terminal alkene (scheme 3) scheme 1 scheme 2 scheme 3

Enantioselective α-aminoxylation of aldehyde + olefination in situ (1) (1) Zhong, G.; Yongping, Y. Org. Lett. 2004, 6, (2) Momiyama, N,; Yamamoto, H. J. Am. Chem. Soc. 2003, 125, 6038  Eliminate problems of purification  Acceptable yield (for 2 steps) and good ee’s  Good method to create an allylic alcohol scheme 1 (1) scheme 2 (2)

Donna Blackmond’s et al observation (1) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43, (2) Nielsen, L. P. C. N.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, (3) Singh, U. K.; Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,  Rate is a lot faster (10min.) compared to other proline catalyzed reaction ex: Aldol reaction between acetone and isobutyraldehyde required 48h at 30mol% (1) (2-3)  Rate of the reaction accelerate over time process  Experiment suggest an autocatalytic or autoinductive reactions!  Experiment suggest that the reaction is mediated by a proline-product adduct

Donna Blackmond’s et al observation (1) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43,  Enantiomeric excess was higher than that expected for a linear relationship  Clue to establish a model for the evolution of homochirality through precursor of low optical activity (Rate acceleration + ee’s improvement in time) (1 )

Finding the active specie (1) (1) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem. Int. Ed. 2004, 43, (2) Puchot, C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem. Soc. 1986, 108, 2353 (first explanation for non-linear product enantioselectivity)  This scheme showes a general mechanism for a product-induced reaction in which both rate and selectivity improve over time for the case in which one enantiomer is present in excess concentration relative to the other.  First proposition for the improved catalyst: α-effect and bronsted acid

(1) (1) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126,  Rate enhancement is independent of the enantiomer of 3 and the proline utilized  No erosion of ee and final configuration dictated by the proline stereochemistry  Utilization of specie 6 improves efficiency (reaction rate) of other proline catalyzed transformations such as aldol and aminoxylation reaction. Finding the active specie

 This reaction presents same nonlinear effect than for the aminoxylation (1) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, (1) Finding the active specie

(1) Iwamura, H.; Wells, D. H.; Mathew, S. P.; Klussmann, M.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2004, 126, Reaction 2b a) 10mol% of 5b b) 10mol% of 5c c) 20mol% of 4L  a) and b) presents the same kinetics properties: active specie cannot be 5b or 5c but help the formation of the super catalyst  a) and b) as well as c), show an acceleration proportionnal to the product concentration: acceleration is not due to a solvatation of proline in time Finding the active specie (1)

 three-point hydrogen bonding help to increased the active specie concentration into the cycle  In aldol reaction, the two-point hydrogen bonding inhibited the formation of a more active species  Transition state (in this proposition) is similar to the first proposed by List and Houk (1)Blackmond, D. G. et al J. Am. Chem. Soc. 2004, 126, Blackmond theory DFT calculation using B3LYP/6-31G

(-)-Littoralisone synthesis

Anomeric effect VS 2 anomeric effects 1 anomeric effect

Organocatalyzed Michael addition Kinetic control

2 plausible reactive species Organocatalyzed Michael addition

3 parameter to look at: 1) enol / enamine geometry: trans favored Organocatalyzed Michael addition

2) enol / enamine reactive face a) Allylic strain b) Proline’s asymmetric induction / hydrogen bonding In DMSO, Hydrogen bonding activation is questionable! Organocatalyzed Michael addition

c) Relative orientation of nucleophile / electrophile 3) enone / eniminium reactive face a) Allylic strain Organocatalyzed Michael addition

b) Proline asymmetric induction c) nucleophile / electrophile relative orientation Organocatalyzed Michael addition

The two combinations implying proline can be operative to explain stereochemistry observed Hydrogen bonding to explain diastereoselectivity is questionnable Others kinetic datas necessary to identified the reactive specie:  Which active specie you think it is involved?  Any other ideas? Enol / EniminiumEnamine / Enone Organocatalyzed Michael addition

(-)-Littoralisone synthesis

α:β = 8:1

Glycosidic part done by a MacMillan methodology Alan B. Northrup, David W. C. MacMillan, Sciences. 2004, 305, ) Enantioselective organocatalyzed dimerisation of aldehydes 2) Mukaiyama aldol + Cyclisation

1) Enantioselective organocatalyzed dimerisation of aldehydes α-hydroxyaldehyde must readily participate as both a nucleophilic and electrophilic coupling partner product must be inert to enolization and or carbonyl addition Alan B. Northrup, David W. C. MacMillan, Sciences. 2004, 305, David W. C. MacMillan et Al. J. Am. Chem. Soc. 2003, 125, Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152 Carbohydrate synthesis in two steps via 2 selective aldol reactions

2) Mukaiyama aldol + cyclisation catalysed by a lewis acid Alan B. Northrup, David W. C. MacMillan, Sciences. 2004, 305, Carbohydrate synthesis in two steps via 2 selective aldol reactions

Alan B. Northrup, David W. C. MacMillan, Sciences. 2004, 305, 1752.

(-)-Littoralisone synthesis α:β = 8:1 α:β = 12:1β only

(-)-Littoralisone synthesis

Efficient and convergent synthesis 13 steps for the longest sequence 13% overall yield (average of 85% per step) 13 stereocenters installed, 14 th from chiral pool 6 steps of protection / deprotection Conclusion