Back to Sugars: Enzymatic Synthesis

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1 Back to Sugars: Enzymatic Synthesis Zhensheng Ding ov. 04 orthrup, A. B.; M acm illan, D. W. C. Science 2004, 305, 1752 orthrup, A. B. and MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, orthrup, A. B.; M angion, I. K.; ettche, F.; M acm illan, D. W. C. Angew. Chem. Int. Ed. Engl. 2004, 43, 2152 List, B. Tetrahedron 2002, 58, 5573 Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K. B. Science 1983, 220, 949 List, B. ; Lerner, R. A. and Barbas III, C. F. J. Am. Chem. Soc., 2002, 122,

2 Introduction to exoses Play vital roles in biological process - signal transduction, cognition, immune response Synthetically challengeable to chemistry - 4 stereocenters with 5 similar hydroxyl groups

3 Common Methods toward Sugars Sharpless s reiterative two-carbon extension cycle - Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K. B. Science 1983, 220, Takeuchi, M; Taniguchi, T; gasawara, K. Synthesis 1999, 1999, 341 etero-diels-alder reactions - Danishefsky, S. J.; Maring, C. J. J. Am. Chem. Soc. 1985, 107, Boger, D. L.; Robarge, K. D. J. rg. Chem. 1988, 53, Tietze, L. F.; Montenbruck, A.; Schneider, C. Synlett. 1994, 1994, Bataille, C. et al., J. rg. Chem. 2002, 67, 8054 Iterative syn-glycolate aldol strategy - Davies, S. G.; icholson, R. L.; Smith, A. D. Synlett. 2002, 2002, 1637

4 Sharpless s Two-carbon Extension Cycle: the Idea Key step: Sharpless asymmetric epoxidation Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K. B. Science 1983, 220, 949

5 Completion of the 1st Cycle Ph Ph Ph Ph LA / AlCl 3 1 : 4 Bh [ ] 83 % 56 % Bh Bh Me Me 3 SPh 71 % SPh Bh 1) PhS a 1) mcpba S C 3 C 2 Bh 2) (C 3 C) 2 92 % yield > 90 % ee S SPh Ac Bh Pummerer rearrangement 2 Ac 2 L - DET Ti ( - i - Pr ) 4 DIBAL o C Ac C C Ac ab 4 Bh Bn Bn 84 % 93 % S S R S R R Ac 2 1 R Ac 1 1 Ac Ph 3 P 1) 6 2) ab 4 Bh 88 % E / Z = 20 : 1 Ph 3 P 1) 7 2) ab 4 Bh 91 % E / Z = 20 : 1 Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K. B. Science 1983, 220, 949

6 Completion of the 2nd Cycle to 8 exoses 6 7 Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K. B. Science 1983, 220, 949

7 Modifications to Sharpless s Strategy C C C 1) oxidative ring-expansion 2) acid cyclization P C C C 25 R AD-Mix reagent exoses C C 24 R The key step: C C 24 TBS mcpba C C pts TBS TBS C C 25 69% from 24 Takeuchi, M; Taniguchi, T; gasawara, K. Synthesis 1999, 1999, 341

8 Boger s etero-diels-alder Reactions toward exoses Boger, D. L.; Robarge, K. D. J. rg. Chem. 1988, 53, 5793

9 Me Bz TBDMS Me BM ther etero-diels-alder Reactions toward exoses Ce(Ac) 3 -BF 3. Et2-78 o C Bz Me BM Ac Ac Ac Ac 45% conversion, single isomer Tunicamycins Danishefsky, S. J.; Maring, C. J. J. Am. Chem. Soc. 1985, 107, 7761 Al -35 Bzl o Et CX Et Et C and DCM Ac Bzl Ac 97% endo/ exo: >50:1 27 Et Tietze, L. F.; M ontenbruck, A.; Schneider, C. Synlett. 1994, 1994, 509 R 50 o R Me C xidation Deprotection Reducti on 12kbar EtC EtC Me Me 40-69% endo/ exo: >99:1 (D, L)-mannose Bataille, C. et al., J. rg. Chem. 2002, 67, 8054

10 Iterative syn-glycolate Aldol Strategy P 1) Glycolate Aldol ) Protect R R R R DIBAL- Cleavage R P R 40 Iterative Glycolate Aldol 42 Cleavage Deprotection R P R R 41 R Bn Bn Et2BTf, ipr2et BnC 2 C TF, -78 o C R Bn Bn Bn 73%, 94% d.e. R= R=TBDMS 90% 1) DIBAL, DCM 2) K 2 C 3, Me, 2 Et2BTf ipr2et TF, -78 o C TBDMS Bn Bn 45 54% Bn Bn 48 65% 1) DIBAL, DCM 2) 2, Pd/C EtAc, Et Bn Bn 47 TBAF Ac, TF Bn 98% TBDMS Bn Bn Bn Bn 63%, >95% d.e. 46 Davies, S. G.; icholson, R. L.; Smith, A. D. Synlett. 2002, 2002, 1637

11 Disadvantages and Advantages of the ld Methods Disadvantages: Require protection-group manipulations eed for iterative oxidation-state adjustment Long synthetic pathways Advantages: exoses can be independently derivatized ydroxyl groups of hexoses are protected ydroxyl groups of hexoses are chemically discriminated Ready to couple with other sugars to produce polysaccharides and other derivatives Can hexoses be synthesized more efficiently by such de novo methods?

12 The Idea: L-Proline Catalyzed Cross Aldol Reactions Both steps are not practically proved Product of step 1 must be inert to further aldol orthrup, A. B.; M acm illan, D. W. C. Science 2004, 305, 1752

13 First Proline-catalyzed Direct Asymmetric Aldol Reactions - Breakthrough + R 30mol% L-Proline DMS R R= Ar, "unbrached Alkyl + R 30mol% L-Proline DMS 22-94% yield 36-77% ee R R= "brached Alkyl 63-97% yield 84-99% ee + R 30mol% L-Proline DMS R 38-95% yield 67-99% ee 1.5:1-20:1 dr ot require the pregeneration of enolates or enolate equivalents Stereoselectivity is usually good ucleophilic partners are acetone and a-hydroxyl acetone Stereoselectivity is substrate-sensitive with a-brached alkyl aldehydes give better e.e.s. List, B. Tetrahedron 2002, 58, 5573 List, B. ; Lerner, R. A. and Barbas III, C. F. J. Am. Chem. Soc., 2002, 122,

14 Features of Proline as Catalyst R 3 2 R 3 ucleophilic attack ydrolysis 51 R 3 R1 47 Lewis base rigidity back bones R 1 50 Dehydration Bronst acid R Deprotonation 1) Bifunctional catalyst with increase lewis basicity and rigid back bones 2) ontoxic, inexpensive, readily available in both enantiomeric forms 3) o prior modification of carbonyls 4) Water soluble 5) o metal required 49 M 52 pen book structure List, B. Tetrahedron 2002, 58, 5573 List, B. ; Lerner, R. A. and Barbas III, C. F. J. Am. Chem. Soc., 2002, 122,

15 Direct Enantioselective Cross-Aldol of Aldehydes Elusive Transformations X + Y enantioselective catalyst X X X Y Y Y Y X aldehyde Polymer onequivalent aldehydes must selectively partition into two discrete components - nucleophilic donor and electrophilic acceptor The propensity of aldehydes to polymerize Can proline be used for direct enantioselective cross-aldol reaction of aldehydes? mol% catalyst DMF, 4 o C % yield, 4:1 anti: syn, 99%ee orthrup, A. B. and M acmillan, D. W. C. J. Am. Chem. Soc. 2002, 124,

16 First Proline-catalyzed Direct Asymmetric Cross-Aldol Reactions of Aldehydes a) Good yields with excellent ees b) Tolerate a large range of substrates c) Aldehyde donors must be added slowly d) Lower catalyst loadings and shorter reaction time compared with ketone substrates e) Scalable For sugar synthesis: a-oxyaldehydes as substrates: X + Y X X aldol 1 aldol 2 X X X X X Y orthrup, A. B. and M acmillan, D. W. C. J. Am. Chem. Soc. 2002, 124,

17 Step 1 toward Sugar: Direct Asymmetric Aldol Reactions of xyaldehydes 1) Greatly affected by electronic nature of oxyaldehydes 2) Bulky aldehydes with a-silyloxy group can work 3) Products are protected forms of naturally occurring sugar erythrose 4) Products are nonreactive in aldol union orthrup, A. B.; M angion, I. K.; ettche, F.; M acm illan, D. W. C. Angew. Chem. Int. Ed. Engl. 2004, 43, 2152

18 Direct Asymmetric Aldol Reactions of xyaldehydes with Alkyl Aldehydes Glycoaldehydes: 1) Electrophile when a-methylene exists 2) uceophile when carbonyl is next to a-methine group orthrup, A. B.; M angion, I. K.; ettche, F.; M acm illan, D. W. C. Angew. Chem. Int. Ed. Engl. 2004, 43, 2152

19 Step 2 toward Sugar: Metal Catalyzed Carbohydrate Construction X X 59 TMS + Y LA aldol 2 X X X 60 Y Effects of solvent and LA orthrup, A. B.; M acm illan, D. W. C. Science 2004, 305, 1752

20 Structural Variation: A Lot Sugars 1) Quick construct polysaccharides 2) Broad diversification of subs. at C4 & C6 of sugars 3) Unnatural sugar synthesis with heteroatoms X X 59 TMS + Y LA aldol 2 X X X 60 Y orthrup, A. B.; M acm illan, D. W. C. Science 2004, 305, 1752

21 A Little Extension: Enzyme Catalyzed Aldol Reaction -Aldolase I and Aldolase II 1) Aldolase I utilize an enamine based mechanism 2) Aldolase II uses zinc cofactor 3) ow Aldolase I works? offmann, T.; Barbas III, C. F. et al J. Am Chem. Soc. 1998, 120, 2768

22 A Little Extension: Proline, An Aldolase I mimics ucleophilic attack R1 R 2 47 Dehydration 2 48 R 3 Deprotonation 2 ydrolysis R 3 51 R 3 50 R 3 49 Proline, the simplest enzyme E.. Jacobsen M ovassaghi, M.; Jacobsen, E.. Science 2002, 298, 1904

23 Proline- A Universal Enzyme? ucleophilic attack R1 Dehydration 2 E ydrolysis 2 R1 * E Electrophilic attack Deprotonation E + = L-Proline R 3 R 4 R R 3 R 4 And More... R 4 R 3 R R 4 R 3 Aldol reaction Manich reaction E + R 3 Ph EWG R 3 EWG Ph Michael addtion "-Aminoxylation reaction List, B. Tetrahedron 2002, 58, 5573 M erino, P.; Tejero, T. Angew. Chem. Int. Ed. Engl. 2004, 43, 2995

24 Summary The strategy for the synthesis of differentially protected hexoses provides rapid enantioselective access to key building blocks in saccharide and polysaccharide synthesis. The approach efficiently yields isotopic and functional variants of the hexoses that have not been readily accessible for pharmaceutical study. Proline is a bifunctional catalyst that is efficient for many transformations