Synthesis of Amphidinolide X and an Exploration of Key Reactions
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1 PJM 1/12/05 Synthesis of Amphidinolide X and an Exploration of Key eactions Lepage,.; Kattnig, E.; Furstner, A. JACS, 2004, 126, Produced by marine dinoflagellates, Amphidinium sp. that live in symbiosis with a flatworm, Amphiscolops spp. - Potent toxicity against various cancer cell lines, such as murine lymphoma and human epidermoid carcinoma - Amphidinolide X is unique to class of amphidinolides in that it lacks a characteristic exo-methylene group, or a 1,3 diene unit - nly naturally occuring macrolide containing a diester and a diol - Many synthesis of other amphidinolides, first synthesis of X
2 etrosynthetic Analysis Pd mediated Cross Coupling M P A X Yamaguchi esterification Yamaguchi macrolactonization P B P C P
3 Synthesis of Fragment A of Amphidinolide X TBDPS Ti(i-Pr) 4, L-(+)-DET t-bh, 97% H 83%ee Tetrahedron, 1999, 55, TBDPS H 1. (CCl) 2, DMS, Et 3 N 2. () 2 P()C(N 2 )C, K 2 C 3, H, 67% TBDPS H Synthesis of Alkynes from Aldehydes: Corey Fuchs: 1972 CH CBr 4, PPh 3 Br Br t-buli Gilbert Seyferth: 1979 CH n-buli or t-buk H P() 2 eactions must be run at -78 C using freshly prepared reagent under inert atmosphere N N hira Bestmann: 1989/1996 CH K 2 C 3, H eactions can be run at room temperature in a one-pot procedure w/o anhydrous conditions P() 2 N N Synlett, 1996, 521.
4 Synthesis of Fragment A of Amphidinolide X TBDPS LiHMDS, Tf, 95% TBDPS H TBDPS H TBDPS
5 Synthesis of Chiral 2,3-Allenols From Propargylic Epoxides Typically use Copper catalysts and Stiochiometric Grignard reagents: Anti diastereomer i-prmgbr, H 5% CuBr, PBu 3 100:1 anti/syn 80% yield "anti" product Anti isomer predominates in organocuprate additions Syn diastereomer i-prmgcl, 5% CuBr, TMSCl 84:16 syn/anti 100 % yield H "syn" product Syn diastereoselectivity dependent on presence of TMSCl and use of MgCl Also effective for acyclic substrates Alexakis, A.; Tetrahedron, 1991, 47,
6 Three Proposed chanisms A Cu (III) intermediate ' 2 CuLi ' ' Cu III H ' H An Addition / Elimination pathway ' 2 CuLi ' Cu ' H anti elimination Direct S N 2 displacement ' H ' 2 CuLi ' H syn elimination
7 Stiochiometric Addition to Propargylic Epoxides Stoichiometric use of organocuprates: Anti products predominate Suspect reactions proceed via an S N 2 pathway TBS ether led to decreased selectivities unclear as to reasoning Marshall; JC, 1993, 58, 7180.
8 Furstner s Catalytic Synthesis of Chiral 2,3 Allenols Early reports: 1976 Furstner, A.; ndez, M. Angew. Chem. Int Ed. 2003, 42, Br Ph MgBr Fe(acac) 3 (cat) Ph + Ph 78%ee = p-c 6 H 4 50%, 55% ee 12% C 6 H 13 93% ee C 6 H 13 MgBr Fe(acac) 3 (5mol %) 93%, syn/anti = 6:1 90% ee C 6 H 13 H + H 85% ee - very fast reactions - low catalyst loading (3-5 mol%) - insignificant attack of Grignard to epoxide Use of Fe(acac) 3 in cross-coupling reactions: Angew. Chem. Int. Ed. 2003, 42, 308.
9 Syn Selectivity 2 Fe 3 H syn relationship Complementary to organocuprate additions
10 Substrate Variability
11 Palladium Catalyzed Insertion eactions of Allenols Ar ' H Pd (0), Ar-X N 3 Pd (0) Ar-X, DMF/C 3 2- Pd (II), Allylic halides ' = H Ph '=H ' ' = H
12 Palladium Catalyzed Insertion eactions of Allenols Synthesis of α, ß-unsaturated ketones: path a H Pd (0) N 3, Ar-X Ar H Pd(dppe) 2, NMP 61%, 8:1 E/Z Br typically saw moderate E/Z ratios favoring E isomer Tsuji; JC, 1985, 50, 537.
13 Palladium Catalyzed Insertion eactions of Allenols Insertion Cyclization eaction: path c Very high selectivities for the trans epoxides H Pd(PPh 3 ) 4 Ar-X, DMF, K 2 C 3 Ar Ma; JACS, 1999, 121,
14 Palladium Catalyzed Insertion eactions of Allenols Formation of 2,5 Dihydropyrans: path b nly works with 2,2-disubstituted allenols In the absence of allylic halides. Ma; JC, 2002, 67, 6104.
15 Silver Catalyzed Cyclization of Chiral 2,3 Allenols JC, 1993, 58, JC, 1996, 61, Can also use gold catalysis. rg. Lett. 2001, 3, 2537.
16 earrangement of Allenols w/ syl Chloride Proposed chanism Application to fused ring systems
17 Trost; JACS, 2001, 123, Allenol Addition to Aldehydes
18 Fragment A cont. TBDPS Fe(acac) 3, PrMgBr 62%, 8:1 syn/anti TBDPS H AgN 3, CaC 3, Acetone, H 2 90% TBDPS 1. NBS, DMF, H 2 65% 2. AIBN, (TMS) 3 SiH TBDPS 1. NaHC 3, H, 90% 2. PMBC(=NH)CCl 3, PPTS 76% H TBDPS PMB 1. TBAF, 97% 2. PPh 3, I 2, 92% I PMB
19 Synthesis of Fragment B + Ms Et 2 Zn, Pd(Ac) 2 (cat) PPh 3 (cat), 65% 4.5:1 anti/syn H Early work: Marshall Marshall; JC, 1995, 60, Best results with BF3-Et and bulky aldehydes
20 Transmetallation to Allenyl Tin Chlorides
21 Proposed mechanism: Pd-catalysed Formation of Allenic Esters
22 Synthesis of Allylic Zinc Intermediates via Transient rganopalladium Species Decent selectivity only with cyclic or secondary allylic benzoates Tamaru; ACIEE, 1995, 34, 787 eview of transient Pd intermediates: Marshall, J. A. Chem. ev. 2000, 100,
23 Proposed chanism + Ms Et 2 Zn, Pd(Ac) 2 (cat) PPh 3 (cat), 65% 4.5:1 anti/syn H Proposed chanism of rganozinc reagent Ms H 2 C CH 2 H 3 C CH 3 Pd(PPh 3 ) 4 2 PPh 3 2 PPh 3 Zn Ms H Et 2 Pd(PPh 3 ) 2 (Ph 3 P) 2 Pd Ms H Et 2 Zn (Ph 3 P) 2 Pd EtZnMs Et H EtZnMs Chem. ev. 2000, 100,
24 Proposed chanism cont. Ms Zn H 2 anti H 2 typical selectivities are 3:1 7:1 favoring anti product Aldehyde w/ α-stereocenter α-stereocenter does not effect outcome, but does lead to increased diastereoselectivity
25 ther Examples Can get very high selectivity with trifluoromethyl propargylic mesylates: Can also form organoindium reagents:
26 B (cont.) Completion of Fragments B and C H 1. PMBCl, NaH, 94% 2. LiHMDS, I, 95% PMB 1. Cp 2 ZrHCl; I 2, 61% 2. DDQ, 89% H I Synthesis of Fragment C Ph H N + I TIPS LDA, LiCl 89% Ph H N TIPS LDA, NH 3 -BH 3 99% H TIPS 1. TPAP, NM 2. (Et) 2 P()CH 2 C, LiCl, DBU, 94% TIPS 1. HF-Pyr, pyr (quant.) 2. (CCl) 2, DMS, Et 3 N 3. NaCl 2, NaHP 4, 2-methyl-2-butene, 92% H
27 Coupling of Fragments B, C, and A H + H I 2,4,6-trichlorobenzoyl chloride, Et 3 N, DMAP 96% I I PMB t-buli, 9--9-BBN B Li PMB Pd(dppf)Cl 2, Ph 3 As, K 3 P 4, 74% PMB C
28 Alkyl Boronates From rganometallics Tetrahedron, 1995, 51, PdCl 2 (dppe), K 2 C 3 discodermolide
29 Completion of Amphidinolide X PMB C 1. LiI, pyr. 2. Aq. AcH 3. DDQ 4. 2,4,6-trichlorobenzoyl chloride, Et 3 N, DMAP
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