Organocatalysis for Asymmetric Synthesis

Catalytic methods are key in the synthesis of complex molecules as it enables selective and rapid generation of molecular complexity. Historically, catalysis has been dominated by metal-based catalytic approaches. However, organocatalysis, often inspired by enzymology, offers some new and very real advantages especially for applications such as enantioselective synthesis and natural product synthesis.

5-Pyrrolidin-2-yltetrazole
While the proline-based asymmetric organocatalytic system is well-studied it is not without its problems, particularly its poor solubility in many solvents. We reasoned that a tetrazole derivative might provide a more soluble alternative. We therefore prepared the (S)- 5-pyrrolidin-2-yltetrazole (and later its enantiomer) from proline and used it in a series of Mannich-type additions of carbonyl compounds to N-PMP-protected α-imino ethyl glyoxalates: benchmarking it against proline itself [1]. We found that 5-pyrrolidin-2-yltetrazole compared very favourably to proline, with the added value that the reactions were faster and could be performed in non-polar solvents.We have since used 5-pyrrolidin-2-yltetrazole to catalyse a wide range of reactions. Published examples include:

• Mannich-type addition of carbonyl-containing compounds to N-PMP protected α-imino ethyl glyoxalate [1]
• Michael addition of enamines to nitro-olefins [2]
• Asymmetric synthesis of chiral dihydro-1,2-oxazines from achiral starting materials [3, 4]
• Asymmetric addition of nitroalkanes to cyclic and acyclic enones [4, 5]
• Asymmetric addition of malonates to enones [6, 7]
• Synthesis of chiral 3,6-dihydropyridazines from achiral starting materials via a one-pot procedure [8]
• Asymmetric reaction to access chiral 1,2-oxazines and chiral pyridazines [9]
• Enantioselective synthesis of nitrocyclopropanes from bromonitromethane and a variety of cyclic and acyclic enones [10, 11]

Other proline-derived catalysts
We have also investigated proline-derived acylsulfonamide organocatalysts in asymmetric Mannich, nitro-Michael and aldol reactions [12] and a homo-proline tetrazole derivative which performed excellently in the asymmetric Michael addition of carbonyl compounds to nitro-olefins [13].

Natural product synthesis (chloptosin)
We used 5-pyrrolidin-2-yltetrazole in the total synthesis of the dimeric cyclohexapeptide chloptosin [14, 15]. This work features an organocatalytic tandem process for the synthesis of the embedded piperazic acids, in which a differentially protected azodicarboxylate was used together with pyrrolidinyl tetrazole as the catalyst. The central biaryl bond was formed by a Stille coupling of two sterically demanding ortho-chloropyrroloindole fragments.

Ammonium ylides in cyclopropanation reactions
Ylides are known reagents for cyclopropanation reactions, where the ylide is usually prepared in a separate step. With an abundance of available tertiary amines, with M. Gaunt we developed a one-pot approach to cyclopropanation using ammonium ylide-catalysis. Our initial stoichiometric investigation identified a one-pot process in which the ylide was generated from the ammonium salt in situ (below) [16]. We developed this into a catalytic process based on the postulated catalytic cycle and achieved good results using catalytic base.

We first studied intramolecular process [17] then a more general intermolecular enantioselective cyclopropanation reaction via ammonium ylides. We developed a process that produced functionalized molecules with excellent diastereo- and enantioselectivity, and as either enantiomer [18]. Furthermore, cinchona alkaloids also catalysed the reactions [19].

Publications

1. 5-Pyrrolidin-2-yltetrazole: a new, catalytic, more soluble alternative to proline in an organocatalytic asymmetric Mannich-type reaction A.J.A. Cobb, D.M. Shaw, S.V. Ley, Synlett 2004, 558-560

2. 5-Pyrrolidin-2-yltetrazole as an asymmetric organocatalyst for the addition of ketone to nitro-olefins A.J. Cobb, D.A. Longbottom, D.M. Shaw, S.V. Ley Chem. Commum. 2004, 1808-1809

3. A highly selective, organocatalytic route to chiral dihydro-1,2-oxazines
S. Kumarn, D.M. Shaw, D.A. Longbottom, S.V. Ley Org. Lett. 2005, 7, 4189-4191

4. A highly selective, organocatalytic route to chiral 1,2-oxazines from ketones S. Kumarn, D.M. Shaw, S.V. Ley Chem. Commun. 2006, 3211-3213

5. An efficient, asymmetric organocatalyst-mediated conjugate addition of nitroalkanes to unsaturated cyclic and acyclic systems C.E.T. Mitchell, S.E. Brenner, J. Garcia-Fortanet, S.V. Ley Org. Biomol. Chem. 2006, 4, 2039-2049

6. Asymmetric organocatalytic conjugate addition of malonates to enones using a proline tetrazole C.E.T. Mitchell, K.R. Knudsen, C.E.T. Mitchell, S.V. Ley Chem. Commum. 2006, 66-68

7. A general organocatalytic enantioselective malonate addition to unsaturated enones V. Wascholowski, K.R. Knudsen, C.E.T. Mitchell, S.V. Ley Chem. Eur. J. 2008, 14, 6155-6165

8. An enantioselective organocatalytic route to chiral 3,6-dihydropyridazines from aldehydes A.J. Oelke, S. Kumarn, D.A. Longbottom, S.V. Ley
Synlett, 2006, 2548-2552

9. A sequential enantioselective organocatalytic route to chiral 1,2-oxazines and chiral pyridazines S. Kumarn, A.J. Oelke, D.M. Shaw, D.A. Longbottom, S.V. Ley
Org. Biomol. Chem. 2007, 5, 2678-2689

10. A new asymmetric organocatalytic nitrocyclopropanation reaction
H.M. Hansen, D.A. Longbottom, S.V. Ley Chem. Commun. 2006, 4838-4840

11. A general organocatalytic enantioselective nitrocyclopropanation reaction
V. Wascholowski, H.M. Hansen, D.A. Longbottom, S.V. Ley Synthesis 2008, 8, 1269-1275

12. Organocatalysis with proline derivatives: improved cataysts for the asymmetric Mannich, nitro-Michael and Aldol reactions A.J. Cobb, D.M. Shaw, D.A. Longbottom, J.B. Gold, S.V. Ley Org. Biomol. Chem. 2005, 3, 84-96

13. A homo-proline tetrazole as an improved organocatalyst for the asymmetric Michael addition of carbonyl compound to nitro-olefins C.E.T. Mitchell, A.J.A. Cobb, S.V. Ley Synlett, 2005, 611-614

14. Total synthesis of chloptosin: a dimeric cyclohexapeptide A.J. Oelke, F. Antonietti, L. Bertone, P.B. Cranwell, D.J. France, R.J.M. Goss, T. Hoffman, S. Knauer, S.J. Moss, P.C. Skelton, R.M. Turner, G. Wuitschik, S.V. Ley Chem. Eur. J. 2011, 17, 4183-4194

15. Total synthesis of chloptosin A.J. Oelke, D.J. France, T. Hofmann, G. Wuitschik, S.V. Ley Angew. Chem. Int. Ed. 2010, 49, 6139-6142

16. Organic-catalyst-mediated cyclopropanation reaction C.D. Papageorgiou, S.V. Ley, M.J. Gaunt Angew. Chem. Int. Edn. 2003, 42, 828

17. An intramolecular organocatalytic cyclopropanation reaction N. Breymer, S.C. Smith, S.V. Ley, M.J. Gaunt Angew. Chem. Int. Ed. 2004, 43, 2681-2684

18. Enantioselective organocatalytic cyclopropanation with ammonium ylides
C.D. Papageorgiou, M.A. Cubillo de Dios, S.V. Ley, M.J. Gaunt Angew. Chem. Int. Ed. 2004, 43, 4641-4644

19. Enantioselective catalytic intramolecular cyclopropanation using modified cinchona alkaloid organocatalysts C.C.C. Johansson, N. Bremeyer, S.V. Ley, D.R. Owen, S.C. Smith, M.J. Gaunt Angew. Chem., Int. Ed. 2006, 45, 6024-6028

Overviews and reviews

A versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones C.E.T. Mitchell, S.E. Brenner, S.V. Ley Chem Commun. 2005, 5346-5548

Practical organocatalysis with (S)- and (R)-5 pyrrolidin-2-yl-1H-tetrazoles
D.A. Longbottom, V. Frankevicivus, S. Kumarn, A.J. Oelke, V. Wascholowski, S.V. Ley
Aldrichimica Acta, 2008, 41, 3

(S)- and (R)-5-Pyrrolidin-2-yl-1H-tetrazoles: Enantiomeric Organocatalysts of Broad Utility in Organic Synthesis D.A. Longbottom, V. Franckevicvius, S.V. Ley, Chimia, 2007, 61, 247-256.

Asymmetric Organocatalysis S.V. Ley in “Asymmetric Synthesis – The Essentials”. M. Christmann and Ed. S. Bräse. Wiley-VCH. 2006 ISBN-978-3-527-31399-0, 211-216

New Strategies for Organic Synthesis: The First Highly Enantioselective Organocatalytic Diels-Alder Reaction Commentary by E. Diez and S.V. Ley,Chemtracts, 2000, 592.