Synthetic Developments Towards the Preparation of Erythromycin and Erythronolide Derivatives
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1 ynthetic Developments Towards the Preparation of Erythromycin and Erythronolide Derivatives Russell C. mith Denmark Group Meeting most extensive project in organic synthesis this phenomenon is not rational --J. Mulzer
2 Erythromycin A/B N(C 3 ) 2 N(C 3 ) 2 C 3 C 3 A B Produced from the fungus treptomyces erythreus Used as widespread antibiotic ynthetic Challenges 10 defined stereogenic centers 14 membered macrocyclic lactone Two hemi-acetal sugar moieties
3 Initial Retrosynthetic Analysis C lactonization N(C 3 ) 2 C 3 C N(C 3 ) 2 C 3 acylation of sugar moieties 1. Form macro-lactone and append sugar moieties 2. Attempt lactonization with sugar moieties appended
4 Total ynthesis of Erythronolide B- E. J. Corey (1978) lactonization C Bz Bz N Baeyer-Villiger Et I TB Bz Bz 6 1 TB 9 Et C-C bond formation 6 Bz Bz 1 TB 9 13 Bz C10-C13 Bz C C1-C9
5 Preparation of Cyclic Intermediate Bz Bz C 1. Br Br 2 / KBr Br 96 % 2. B 2 6 / TF K 3. 2 Cr 4 C 43 % over 3 steps aq. K 0-20 C Br 13 % epimer 93 % Bu 3 n AIBN 91 % Br 2 / KBr K 4 98 % J. Am. Chem. oc, 1978, 100, 4618.
6 Completion of Cyclic Intermediate Bz Bz C Al(g) TF C 1. Raney Ni/ 2 2. Cl R R * 14 % epimer Bz 76 % Bz 4 eq R = CPh 75 % over two steps 1. aq. Li * 1. LDA (1.02 eq)/ MPA Bz C 2. 2 Cr 4 Bz 2. MeI J. Am. Chem. oc, 1978, 100, 4618.
7 C10-C13 Fragment 10 I 1. Cl Et 13 TB 2 2 NaW 4 Et 3 N C 2. NaB 4 1. Me 2. PCl 3, CCl 4 Li 2 N N 2 TB 1. t-bume 2 icl, imidazole 2. LDA, TF MeI > 25 C 1. Amberlite IRC-50 Me 2. 2 Cl Me 1. Cp 2 Zr()Cl, 43 C 2. I 2, CCl 4 I py 3. Me 2 CuLi TB 84 % J. Am. Chem. oc, 1978, 100, 4618.
8 Total ynthesis of Erythronolide B: Fusion of two key intermediates Bz Bz Bz Bz C C 3 C 3 55 C Bz N 2 Ph 3 P Bz 65 % N 70 % MgBr TB Bz 1 Bz C 78 % 1. Ac, 55 C 2. aq. Li 30 % 2 2 Bz Bz TB Zn(B 4 ) 2 5 C Bz Bz % TB Et J. Am. Chem. oc, 1978, 100, 4620.
9 Preparation of macrocyclic core 1. K DME/ 2, 45 C 1. Me Br, C Bz Bz C 2. C 2 N 2 C 2 Me 86 % 2. Amberlite IRC-50 Me 3. K, Me/ 2 C 2 But N N ipr 2 PPh 3, toluene J. Am. Chem. oc, 1978, 100, 4620.
10 Pop Quiz What is the mechanism for activation? Provide an experiment to provide support for proposal! What are the side products? N N 2 PPh 3
11 Final teps- Erythronolide B 1. Mn , Pd-C , Na Me 2. cat. K 2 C 3 Me 98 % 1 N Cl 2 -TF Erythronolide B J. Am. Chem. oc. 1975, 97, 654.
12 ummary- Erythronolide B ynthesis Themes Use of cyclic intermediates to set desired stereocenters Use of key resolutions to separate racemic products Conclusions Macrolactonization can be accomplished with use of activated acid/ alcohol sequence to form large ring lactones Bromo-lactonization can be used as a powerful tool to set stereocenters
13 Total ynthesis of Erythromycin A R. B. Woodward (1981) C 2 C Bn lactonization Erythromycin looks hopelessly complex, particularly in the view of its plethora of asymmetric centers --Woodward (1956)
14 Preparation of key dithiadecalin intermediate 3 C 2 C Bn Me Me 1 + Me C 2 Ms Me Bn 1. Na, TF 2. Ac/ 2 C Bn N C 3 CN A Bn (70 %, 82 % ee) 1. MsCl, py 2. Alumina EtAc 1. s 4 1. NaB 4, Me Me A Bn 2. Me 2 C(Me) 2 C 2 Me Bn 2. MeC 2 I, K Bn 12 % overall from 1 J. Am. Chem. oc. 1981, 103, 3211
15 ynthesis of two intermediates from the same reagent 1. Raney Ni Et 1. CF 3 C 3 C 2 C C 2. N 2 ecn Me Bn 2. (CF 3 C) 2 DM Bn C P(nBu) 3 3 i. 3, Me ii. Me 2 B J. Am. Chem. oc. 1981, 103, 3211
16 Two intermediates merge together 3 C 2 C C + Bn C 2. (CF 3 C) 2 DM Li Et Me Bn C B 1. K/ MPA AcCl 2. NaB 4 /Me 3. MsCl/ py 83 % from 1,3-diketone Et Me Bn Bn Bn nbuli Et Me Bn LiAl 4 Et Ac 2 92 % Me Bn Ac Bn J. Am. Chem. oc. 1981, 103, 3211
17 Completion of seco acid chain Et Me Bn Ac Bn 1. Raney Ni Et 2. N 2 ecn Et Me Ac C P(nBu) 3 3 3, Me Me 2 LDA Et Me tbu Ac What is the configuration?? Provide a model (hint..hint) J. Am. Chem. oc. 1981, 103, 3211
18 Lactonization: ow hard can it be?? There are 2 crucial aspects that Woodward discovered during his studies 1) The configuration at C9 MUT BE () 2) Cyclic protecting groups at C3-C5 AND C9-C Ms Me 1. LiN 3 / MPA 2. 2 / Pt 2 N 2 Me Me Me 1. NaC 3 Cl 2 N 2. N 2. Cl, K 2 P4 N Me Et 3 N N Me J. Am. Chem. oc. 1981, 103, N 2
19 Completion of Erythronolide A core Me Me N Me CF 3 C N Me N 1. EtLi, MPA 2. Cl N Et 3 N C Ph 3 P toluene, reflux N R R = N J. Am. Chem. oc. 1981, 103, 3213.
20 N Attachment of sugar moieties PBC N C 1. BPCCl Et 3 N, DMAP 2. aq. Na IPA, TF i 2 CF 3 C 2 PBC N R 2 R 1 1. D-desosaminide (5 eq) AgTf (6 eq) 2. L-cladinoside (5.5 eq) Pb(Cl 4 ) 2 (6.5 eq) PBC N R 1 R 2 D-desosaminide R NMe 2 L-cladinoside R Me J. Am. Chem. oc. 1981, 103, 3217.
21 ynthesis of Erythromycin A PBC N N 2 N Na-g/ Me 1. NC, py R 1 R 1 2. AgF, MPA R 1 R 2 R 2 R 2 R 1 D-desosaminide NMe 2 R 2 5 C R 2 L-cladinoside R Me R 1 40 % R 2 Erythromycin A J. Am. Chem. oc. 1981, 103, 3213.
22 Conclusions- Total ynthesis of Erythromycin A Themes Recognition of 2 repeating subunits Use of one key intermediate to set 7 stereocenters Use of decalin (cyclic) system for stereocontrol Conclusions The use of inherent chirality of molecule to set adjacent centers (Aldol/ Cram model) The necessary protection of key positional hydroxyl groups The ability to attach sugar moieties easily
23 Total ynthesis of 6-deoxyerythronolide B-. Masamune (1981) chelation Aldol boron Aldol boron Aldol 11 C 13 TE But 5 boron Aldol
24 tereoselective Aldol Condensation: Chiral Boron Enolates Exclusive formation of Z-enolate electivity increases with larger substituents on boron (B) Presence of a-substitution proves problematic with large groups on B J. Am. Chem. oc., 1981, 103, 1566
25 ynthesis of C1-C10 fragment Me 2 C C TBDM Et Me DIPEA 40:1 diastereoselectivity *R 1. F- C 3 CN 2. NaI 4 1. (CCl) 2 R (But)Ph 2 i R = (tbu) 1. ClC 2 Et 2. tbu 3. K 4. Ph 2 (tbu)icl R * = TBDM cy TBDM 1. Et DIPEA 14:1 diastereoselectivity 2. TBAF 3. NaI Pd/ Ba 4 J. Am. Chem. oc., 1981, 103, 1568
26 Completion of C1-C10 fragment (But)Ph 2 i 1. Me 1. (CCl) 2, py R R = (tbu) CF 3 C 2. TBAF/ 2 2. Et 2 CuLi J. Am. Chem. oc., 1981, 103, 1568
27 Left and Right alves Brought Together R But 1. (Me 3 i)n-li 2. C TE TE 17:1 diastereoselectivity But 1. NaB 4 2. (CCl 2 C) 2, py 3. Ac But TE 1. CuTf DIPEA 2. K, tbu R 1. PCC 2. CF 3 C Cu R R = CCl 2 C J. Am. Chem. oc., 1981, 103, 1568
28 Conclusions- Total ynthesis of 6- deoxyerythronolide B Themes Use of aldol disconnects to form 8 out of 10 stereocenters Development of stereoselective aldol chemistry using boron enolates Improvement upon lactonization method using metal/sulfur activation Conclusions The power of aldol chemistry to form contiguous stereogenic centers (simplification) The ability for stereoselective formation of two chiral centers with 1 reaction
29 (9)-Dihydroerythronolide A- [3+2] Annulation of Allylic ilanes (K. A. Woerpel) [3+2] annulation J. Am. Chem. oc., 2003, 125, 6018.
30 Use of Mg mediated cycloaddition- ynthesis of Erythronolide A (E. M. Carriera) 1. tbucl, C 2 Cl 2 TB N -78 C TB N 2. IPA, EtMgBr ACIEE, 2005, 44, 4036.
31 Conclusions- Erythromycin/ Erythronolide yntheses Macrolactonization has been improved to easily access large ring lactones Formation of contiguous stereogenic centers has evolved to today s asymmetric protocols Erythromycin will continue to be a tool used to test developments in the area of asymmetric organic synthesis verview Corey- traditional organic chemistry to set contiguous stereocenters Woodward- recognition of key structural aspects for macrolactonization Masamune- development of asymmetric aldol chemistry to set chiral centers
32
33 X-Ray of levorotatory bromo lactone Br
34 Preparation of C10-C13 Grignard I 1. TBDM 2. MgBr Li MgBr TBDM MgBr Br Br + Mg
35 Mechanism: Double Activation Evidence for 1: 1. -deuterated (1) afforded lactone with N deuteride incorporation 2. Lactonization occurs with no a- for ketene formation Tetrahedron Lett. 1976, 38, 3405.
36 Preparation of hemi thio-acetal (1) 1. (C 2 ) 2, p-ts 2. NC Cl 2 N N 2 N 3 N 2 Cl aq. Na 1. aq. Cl Me Me 1 65 % 2. (C 3 ) 3 C pts, Me ACIEE, 1977, 16, 196.
37 Preparation of protected b,g-hydroxy butanal Bn 1. Me/ LDA, CMe Me C Bn 1. (C 3 ) 3 C pts 2. LiAl 4 Ms Me Me Bn 3. MsCl/ py 60 % J. rg. Chem. 1967, 32, 1844 Tetrahedron Lett. 1971, 2953
38 Completion of seco-acid Et Me Bn Ac Bn 1. Raney Ni Et 2. N 2 ecn Et Me Ac C P(nBu) 3 3 3, Me Me 2 LDA Ac Me eco acid A intermediate CMe 3 tbuli Ac Model: CRAM enolate Et Me Ac tb 3 C RL J. Am. Chem. oc. 1981, 103, 3211
39 Proposed transition state for boron enolate TBDM R B L L *R R () configuration TBDM R L B L *R R (R) configuration
40 Problems with lactonization again!! TE But CF 3 C But But
41 Preparation of ()-3- hydroxylisobutyrate oxime TBCl, Et 3 N TB 1. Red-Al TB N Me Me 2. N 2
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