Overview of Synthesizing Merrilactone A

Transcription

1 verview of Synthesizing Merrilactone A = Contents = I. Beginning II. Danishefsky's Route III. irama & Inoue's Route IV. Frontier's Route V. Conclusion 6th / Feb./ 2008 Literature Seminar ~ B4 part ~ Takafumi Yukawa

2 I. Beginning Merrilactone A extraction Illicium merrillianum Merrilactone A only 0.004% yield Biological Feature Neurotrophic Neuritogenetic Chemical Feature istory very interesting and challenging compound possibility for treatment of neuro-degeneration deseases (Alzheimer s and Perkinson s) potential alternative for nerve growth factor (NGF) and other expensive peptidal reagents Densely xygenated! ighly compact and caged skeleton! oxetane dilactone It is important to synthesize Merrilactone A in the place of both chemistry and biology. Isolation Racemic Chiral Y. Fukuyama et al. Tetrahedron Lett. 2000, 41, V. B. Birman and S. J. Danishefsky J. Am. Chem. Soc. 2002, 124, M. irama, M. Inoue et al. J. Am. Chem. Soc. 2003, 125, G. Mehta and S. R. Singh Angew. Chem. Int. Ed. 2006, 45, 953. A. J. Frontier et al. J. Am. Chem. Soc. 2007, 129, 498. Z. Meng and S. J. Danishefsky Angew. Chem. Int. Ed. 2005, 44, M. Inoue et al. Angew. Chem. Int. Ed. 2006, 45, M. Inoue et al. J. rg. Chem. 2007, 72, Chap. II Chap. III Chap. IV Chap. III isolate Racemic First Danishefsky irama, Inoue chiral Mehta Frontier Strategy for ~~ ow to construct the five rings (A~E) ~~ Danishefsky's Route : irama and Inoue's Route : Frontier's Route : D C A B E B and C D A E A and C B D E E B A C D 1 / 15

3 II. Danishefsky's Route Retrosynthetic Analysis R 2 xetane formation i ii iii R R R R 2 C iv v vi vii X R R R 1 Diels-Alder viii ix x xi Key Reaction 1 Diels-Alder Reaction Diels-Alder reaction didn't directly proceed with the retro-synthesized compounds. R direct Diels-Alder R R more powerful dienophile R necessary to conduct further reactions C D Scheme 1 Methylene blue : elimination of oxygen 15, 17 16, 19 : reduction under very mild condition with high chemoselectivity ( 1987, 647) ex ) TF / NaB 4 (3.0 equiv.) / drop addition of Me C 2 Et 1 h, 10 C ; Et 1N ~ 80 % X X X only carboxylic acid is reduced in the X :, Br, N 2 presence of halogen and nitro group. 2 / 15

4 2 xetane Formation Largely, three methods are known for building-up oxetane Payne Rearrangement R 1 R 2 R 3 R4 R 5 strong base protic solvent R 3 R 1 R 5 R 2 R 4 This time, the situation has been slightly changed forming oxetane ring structure. (Fukuyama et al. Tetrahedron, 2001, 57, 4691) PINT C7- is located near C1. Strong base will open lactone ring. C7- attacks C1 producing four-membered ring, not C2 doing five-membered ring. Acid condition solves this problem, for tertiary C1 carbon is likely charging plus. Peternò-Büchi Reaction ([2+2] Photocycloaddition) Review : J. Chem. Soc., Perkin Trans. 1, 2001, 2983 ex ) Greaney's synthetic study (rg. Lett. 2005, 7, 3969) A C E B E B C A cf ) oxetanocin synthesis ( 1998, 5, 683) oxetanocin PINT generally low yield difficult to control the position of olefin and carbonyl group From 1,3-Diol 1995, 5, 533 cf ) Taxol PINT Installation of 1,3-diol moiety should be prior to oxetane formation. 3 / 15

5 Total Ring C, D C D 22 23, 24 : aisen rearrangement by Johnson ortho protocol (J. Am. Chem. Soc. 1970, 92, 741) C 3 C(Et) 3 + R 1 R 2 Et Et R 1 R 2 Et R 1 R 2 Et R 1 R 2 (23 : α, 24 : β) Desired cf ) Danishefsky developed this strategy for asymmetric synthesis. (Angew. Chem. Int. Ed. 2005, 44, 1511) C 2 Me C 2 Me TBS cat. (S,S)-[Co III (salen)]-ac Me -78 C, 2 days; -25 C, 2days Me TF Me 2 C y. 86 %, 86 %ee A B C D E t-bu N N Co Ac t-bu t-bu t-bu (S,S)-[Co III (salen)]-ac Ring A A 23, 24 iodolactonization (from 24) (from 23) dead end! C-allylation by Keck reaction Ring B B 27 selenenylation and bromoselenenylation oxidative deselenenylation free radical cyclization 4 / 15

6 Ring E E toal 20 steps 10.7 % overall yield < Free Radical Cyclization > Free radical cyclization is another key reaction for all synthesis route. Danishefsky irama and Inoue Frontier (90%) AIBN, Bu 3 Sn, Ph, reflux; p-ts, 2 (one pot) Important method to construct ring B B General Feature react under mild conditions attack the closest reactive site irreversible undamage the other functional groups high regio and stereoselectivity retro reaction doesn't occur Frontier Molecular rbital The reaction is accerated as LUM becomes lower by the effect of electron withdrowng group. rxn rate : EWG = -C > -C 2 R > -Ph 5 / 15

7 III. irama and Inoue's Route Retrosynthetic Analysis i ii iii R R R R R R R R iv v vi vii Desymmetrization R R by Transannular Aldol Reaction R R viii ix x xi Key Reaction Desymmetrization by Transannular Aldol Reaction Advantage of taking desymmetrization strategy making the process shorter possibility to achieve enantioselectivity by desymmetrization R R M R R enantioselective deprotonation M R R R R diastereoselective C-C bond formation R R (-)-5 Desired (+)-5 (-)-13 R R Undesired (+)-13 R R R R Condition Check optimization of base reagent optimization of protecting group (DCB) 6 / 15

8 Possible Mechanism d c b a d b From condition check entry 1 and 2 : LiN(TMS) 2 was better than DBU in selectivity Table 1 entry 2 and 3 : high selectivity under lower rxn temp. Diastereoselectivity is achieved under kinetic control. a c Table 2 entry 1~ 4 : selectivity was changed under protecting group Diastereoselectivity depends on the size of ortho-substituent. The mechanism (shown left) can be supported. Explanation of Possible Mechanism 1. nly 2 protons circled (a and c) in the chart will actually be deprotonated and stable cis- enolate (4A and ent-4a) should be formed. 2. After deprotonation, steric interaction occurs between C7- bond and C14 in the conformation of 4A to generate 4B. 3. Enolate flips downward kinetically before stabilization by chelation like 4C. b d a c R R Desired Undesired Moreover, irama and co-workers succeeded in synthesizing chiral Merrilactone A by using chiral base in desymmetrization process. (J. rg. Chem. 2007, 72, 3005) Asymmetric Desymmetrization Condition Check Apply to Total 7 / 15

9 Total Ring B, C B C [2+2] photocycloaddition metathesis by Grubbs catalyst first generation key Criegee oxidation : attack from down side because of the steric effect of DCB MgBr 10 attack from down side Ring A A DBU free radical cyclization 8 / 15

10 Ring D D 19β Methylation by Eschenmoser s reagent : stereoselective enolization C3 protons are hidden by DCB or ethyl moiety. C1 proton can be regioselectively deprotonated : oxidation of ketal reaction mechanism Et BF 3 (Tetrahedron lett. 1978, 19, 419) At this stage, the problem is how to reduce C7 carbonyl group. At first, they use DIBAL- for compound 22 (model substrate), but desired product wasn't selectively obtained. Desired Undesired : reduction by DIBAL : Ag 2 C 3 /Celite oxidation mechanism (, 1979, 401) Celite : easy to separate Ag residue from product Ketal blocks the attack of hydride from downward Undesired products (26, 27) advantage very mild condition (neutral) disadvantage excess amount of Ag 2 C 3 is needed low selectivity Then, try another reductant : Birch reduction. 9 / 15

11 34 31 : Birch reduction Sodium cation is chelated as shown in the chart above high stereoselectivity 31, : regioselective oxidation I II Desired oxidation easily cf ) if the alcohol is protected by TBS, the structure is changed that TBS directs pseudo-equatorial way. III oxidation easily IV Undesired Ring E E : epoxidation by dimethyldioxirane (DMD) reaction mechanism (Chem Rev. 1989, 89, 1187) total 23 steps 3.0 % overall yield not commercially available ; preparation by oxidation of acetone is inefficient (y. ~ 3%). however, advantage is larger. byproduct is only acetone good selectivity despite of high reactivity inexpensive for preparation 10 / 15

12 IV. Frontier's Route Retrosynthetic Analysis i R ii R R R R R X R R iii iv Nazarov Cyclization v vi vii Key Reaction Nazarov Cyclization Lewis acid-catalyzed Nazarov cyclization Ref. J. Am. Chem. Soc. 2008, 130, 300. general Lewis acids : Fe 3, BF 3 Et 2, Sn 4, Cu(Tf) 2, Pd 2 (MeCN) 2, Al 3, Sc(Tf) 3, etc Eisenberg and Frontier developed more powerful Lewis acid ; Ir (III) complex. synthesis of Ir (III) complex (Inorg. Chem. 2002, 41, 2095) Ir (III) comlex 4 C I Ir Ph 2 P P Ph 2 MeI (excess) a b c d Feature ex) Strong Lewis Acid increase the reactivity lessen byproducts under mild condition mechanism 11 / 15

13 Reactivity compared to Cu(Tf) 2 active spieces substrates coordinate to Ir (III) by, ' chelation. or dicarbonyl type (2a) 1 : Ir (III) complex (Tetrahedron 2005, 61, 6193) monocarbonyl type (2c, 2d) compound 2a, 2c, 2d short reaction time low temperature high yield In Merrilactone synthesis, 15j is the substrate for the key reaction forming ring C. TIPS TIPS TMS 15j Ir (III) complex is superior to Cu(Tf) 2 compound 2b Cyclization didn't proceed with 2b. The possible chelate structure is shown right. Ir (III) complex C 2 2, rt TBS 87 % TMS 23j TBS possible structure of Ir (III) chelation TIPS : triisopropylsilyl cyclization can't proceed in this binding A C owever, Ir(III) complex can not be the only catalyst of Nazarov cyclization. TIPS + produced is also thought to be a catalyst. This presumption is suggested by these experiments. entry Ir(III) complex TIPSTf TIPS + BAr f-. reaction BAr f- : 2 B CF 3 CF 3 4 entry 0 : using Ir (III) for general substrate (unprotected by TIPS) entry 1 : using Ir (III) for 15j (protected by TIPS) entry 2 : using TIPSTf for general substrate entry 3 : using TIPS. + BAr f- for general substrate Total entry 0 : Ir (III) complex works as a catalyst. entry 2 : TIPSTf doesn't work as a catalyst. entry 3 : TIPS + BAr f- works as a catalyst. They examined three procedures, and only No.3 was gone well. TIPS TIPS 1. TMS 2 TMS 3 TIPS TIPS TMS TIPS TMS 15i 15j TBS TBS TMS TMS 23i TIPS 23j TBS TBS Possibility 1. Ir (III) initiates and catalyzes. 2. Ir (III) initiates only and TIPS + catalyzes, in stead. 3. Both Ir (III) and TIPS + catalyze TBS TBS 33 Merrilactone A 12 / 15

14 Ring A, C A C key reaction 23j 7 8 : lactonization by higher-order stannylcuprate high stereo- and regioselectivity compared with general stannylcuprate 1,4-addition of tributylstannane high temp. : E-isomer (3'b) low temp. : Z-isomer (4'b) The metal is strongly chelated by the amide moiety. make it possible not to overadd to the substrate, producing a tertiary alcohol. cf ) TIPS TMS TIPS 2 TMS 3 Using a variety of Lewis acids, all attempts were failed and only hydrolyzed compound 13 was obtained. Ring B, D B D 13 / 15

15 23i 44 : selective desilylation of alkyne R TMS AgN 3 Ag KCN / 2 R Ag R TMS 2 R Ag R N C 23i 44 : free radical cyclization TIPS TBS AIBN Bu 3 Sn Bu 3 Sn TIPS TBS Ts 2 TIPS TBS cf ) When Me group was pre installed (31), desired lactone formation didn't proceed. 31 TBS 33 Failed What is the difference? In the case of R=, stabilization makes the equilibrium shift rightward. Ring E E 48 total 17 steps, 14.4 % overall yield : methylation 14 / 15

16 V. Conclusion Evaluate these three routes by Baran's 8 rules see Mr. Kuramochi's lit. seminar By Baran, short synthesis is defined as follow. short synthesis : maximized C-X(C) bond forming, minimized redox and protection-deprotection. This time, three total synthesis are summerized Route Total Steps Yield (%) C-X Forming (steps) Ratio (%) Redox (steps) Ratio (%) protection & deprotection (steps) Ratio (%) Danishefsky irama & Inoue Frontier Frontier's route will be good. Danishefsky : Formation of A ring by Diels-Alder is difficult. Stereoselective direct Diels-Alder would be nice. irama & Inoue : After desymmetrization, formation of ring B was problematic. Frontier : Smart synthesis, but asymmetric Nazarov cyclization should be the key for asymmetric total synthesis. 15 / 15