Synthesis of Azadirachtin: A Long but Successful Journey

Similar documents
Studies toward the Synthesis of Azadirachtin: Total Synthesis of a Fully Functionalized ABC Framework and Coupling with a Norbornene Domain

Hennoxazole A. Philip Williams Group Meeting December 12, OMe. OMe 1 6 O H

SECTION 12. «POT-POURRI» in Organic Synthesis (2018)

Synthetic Developments Towards the Preparation of Erythromycin and Erythronolide Derivatives

Total Synthesis of Rapamycin

The Story of Azadirachtin. Weiwu Ren

Total Syntheses of Minfiensine

Studies Toward the Total Synthesis of (±)-Noelaquinone

Total Synthesis towards Maoecrystal V

James D. White. A very productive professor 64 students graduated from his lab 94 postdocs have worked in his lab. Education Experience

Comparative Synthesis of Ingenol. Tyler W. Wilson SED Group Meeting

O OH N. Me OMe N NH HO H Debenzoyltashironin NMe 2. Phalarine. Anne-Marie Dechert

Total Synthesis of the Proposed Structure of Briarellin J

An Analysis of the Total Syntheses of Aphidicolin

Total Synthesis of Oxazolomycin A

Total Synthesis of Peloruside A Through Kinetic Lactonization and Relay Ring-Closing Metathesis Cyclization Reactions

Introduction to Synthesis: Design (CHE686) Spring 2015 Exam #1 3/6/15

CHEM 330. Final Exam December 5, 2014 ANSWERS. This a closed-notes, closed-book exam. The use of molecular models is allowed

Total Synthesis of (+)-Sieboldine A J. Am. Chem. Soc. 2010, 132,

Strategies for Stereocontrolled Synthesis

Enan$oselec$ve Total Synthesis of Amphidinolide F

Supporting Information. The synthesis of cardenolide and bufadienolide aglycones, and related steroids bearing a. heterocyclic subunit

The Amphidinolide T-Series

Total Synthesis of Maoecrystal V: Early-Stage of C-H Functionalization and Lactone

Enantioselective Synthesis of (+)-Cephalostatin 1

Synthetic Efforts Toward Palau'amine

Short Literature Presentation 10/4/2010 Erika A. Crane

Ladderanes: Uses and Synthesis. Nicholas Anderson Denmark Group Meeting October 28, 2008

A Concise Synthesis of ( )- Aplyviolene Facilitated by a Stragetegic Ter<ary Radical Conjugate Addi<on

Towards Maoecrystal V: A Comparison of Recent Strategies

Reporter: Yue Ji. Date: 2016/12/26

CHEM 203. Final Exam December 18, 2013 ANSWERS. This a closed-notes, closed-book exam. You may use your set of molecular models

Synthesis of Amphidinolide X and an Exploration of Key Reactions

Massachusetts Institute of Technology Organic Chemistry Problem Set 1. Functional Group Transformations Study Guide

Nine-Step Enantioselective Total Synthesis of (+)-Minfiensine

Total Syntheses of Manzamine A.

11-Step Enantioselective Synthesis of ( )-Lomaiviticin Aglycon

Reduction. Boron based reagents. NaBH 4 / NiCl 2. Uses: Zn(BH 4 ) 2. Preparation: Good for base sensitive groups Chelation control model.

I. Introduction. II. Retrosynthetic Analysis. Andrew Baggett. Liu lab

CHEM 203. Final Exam December 18, This a closed-notes, closed-book exam. You may use your set of molecular models

[3,3]-sigmatropic Processes. [2,3]-sigmatropic Processes. Ene Reactions. Generalized Sigmatropic Processes X,Y=C, N, O, S X,Y=C, N, O, S

A New Strategy for Efficient Synthesis of Medium and Large Ring Lactones without High Dilution or Slow Addition

Synthesis of the Stenine Ring System from Pyrrole

Total Synthesis of (-)-Mersicarpine

Memory of Chirality: A Strategy for Asymmetric Synthesis

Total Synthesis of (-)-Anominine

Total Syntheses of Nominine

Chemistry 3720, Spring 2004 Exam 3 Name:

Only five of the molecules below may be prepared as the sole product of allylic halogenation of the respective alkene. Circle those five.

Renaud Group Exercise Set

VINBLASTINE. H MeO 2 C MeO. OAc. CO 2 Me. Me H

CHEM 203. Final Exam December 15, 2010 ANSWERS. This a closed-notes, closed-book exam. You may use your set of molecular models

Stemona Alkaloids. tuberostemonol. OMe O O. neostemonine. OMe O O. protostemonine

Total Synthesis of Saxitoxin

CHEM 203. Final Exam December 16, This a closed-notes, closed-book exam. You may use your set of molecular models

Massachusetts Institute of Technology Organic Chemistry 5.512

Total Synthesis of the Chartellines

Concise, Asymmetric, Stereocontrolled Total Synthesis of Stephacidins A, B and Notoamide B

Chapter 5 Three and Four-Membered Ring Systems

Synthesis of the Phomoidrides (CP 225,917 & CP 263,114) Chem. Rev. 2003, 103, 2691.

Syntheses of Leucascandrolide A. Supergroup Meeting August 4 th, 2004 Yu Yuan

Progress toward the Total Synthesis of Pleurotin

A Unified Strategy to ent-kauranoid Natural Products: Total Syntheses of ( )-Trichorabdal A and ( )-Longikaurin E

Approaches to the Synthesis of Macquarimicins and Cochleamycins

Synthesis of Atisine-type Alkaloids

Suggested solutions for Chapter 27

ROC Exam Problem 1

2,3-Sigmatropic Rearrangements in Organic Synthesis

JACS 1982: A Survey of Papers with a Focus on Synthetic Organic Chemistry

Dr. P. Wipf Page 1 of 5 10/7/2009. Cl Ru. Kingsbury, J. S.; Harrity, J. P. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791.

Highly Cytotoxic, Structure Similar Polyke>des CO 2 H

A Review of Total Synthesis of Spirotryprostatin A and B. Jinglong Chen Supergroup meeting Princeton University June

Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, Daniel Tzvi Cohen Short Literature Feb. 23, MeO HO OH. COOH ( )-Plicatic Acid OH OH

Short Lit

Protecting Groups. Tactical Considerations

THE UNIVERSITY OF CALGARY FACULTY OF SCIENCE FINAL EXAMINATION CHEMISTRY 350

I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J. Yamaguchi, and P. S. Baran, Angew. Chem. Int. Ed. 2009, 49,

Baran Group Meeting 04/07/04 The Total Synthesis of (+)-Ryanodol

CHEMISTRY MIDTERM # 2 November 02, The total number of points in this midterm is 100. The total exam time is 120 min (2 h). Good luck!

Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide

STRATEGIES IN SYNTHESIS

Radical Reactions. Radical Stability!!! bond dissociation energies X Y X + Y. bond BDE (kcal/mol) bond BDE (kcal/mol) CH 3 CH 3 CH 2 95 O H R 2 C H

E. Dithianes (S,S-Acetals)

Protecting Groups in Organic Synthesis-1 Ready

CHEM 330. Final Exam December 11, This a closed-notes, closed-book exam. The use of molecular models is allowed. This exam contains 12 pages

Highlights in the Progress of Biomimetic Strategies for the Construction of Complex Natural Products. Chris Galliford 26 th August 2003

Stereocontrolled Chlorination in Natural Product Synthesis

CEM 852 Final Exam. May 6, 2010

Recent Total Syntheses! Published in Nature!

Silenes in organic synthesis: a concise synthesis of (±)-epi-picropodophyllin

I. Liu Lab. Ka<e Boknevitz 1

Total Synthesis of (+/-)-Goniomitine via a Formal Nitrile/Donor-Acceptor Cyclopropane [3 + 2] Cyclization

CuI CuI eage lic R tal ome rgan gbr ommon

Application of Two Direct C(sp 3 )-H Functionalizations for the Total Synthesis of (+)-Lactacystin

CHEM 203. Final Exam December 12, This a closed-notes, closed-book exam. You may use your set of molecular models. This test contains 11 pages

CHEMISTRY Topic #8: Oxidation and Reduction Reactions Fall 2018 Dr. Susan Findlay

A Stereoselective Synthesis of (+)-Gonyautoxin 3

Synthesis of Abyssomicin C. Marie-Caroline Cordonnier Litterature Review 23/01/2009

EWG EWG EWG EDG EDG EDG

Total Synthesis of (+)-Suaveolindole

Transcription:

ynthesis of Azadirachtin: A Long but uccessful Journey Gemma E. Veitch, Edith Beckmann, Brenda J. Burke, Alistair Boyer, arah L. Maslen, and teven V. Ley Angew. Chem. Int. Ed. 2007, Early View And Gemma E. Veitch, Edith Beckmann, Brenda J. Burke, Alistair Boyer, Carles Ayats, and teven V. Ley Current Literature Chenbo Wang @ Wipf Group Aug 18th, 2007 Angew. Chem. Int. Ed. 2007, Early View Chenbo Wang @ Wipf Group 1 10/29/2007

Azadirachtin Azadirachtin was isolated from the seed of Indian neem tree Azadirachta indica (0.2 to 0.8 percent by weight) in 1968. It acts as an antifeedant and growth disruptor against over 200 species of insect yet displays very low mammalian toxicity (LD 50 (rat) > 5g/kg). Its structure was elucidated in 1987. Commercially available: 10 mg@$137 Butterworth, J.. et al Chem. Commun. 1968, 23 24. Kraus, W et al Tetrahedron 1987, 43, 2817 2830 Chenbo Wang @ Wipf Group 2 10/29/2007

Azadirachtin: tructural Features ixteen contiguous stereogenic centers, seven quaternary carbons ighly oxygenated ensitive functionalities (enol ether and epoxide) Chenbo Wang @ Wipf Group 3 10/29/2007

Retrosynthesis Ac Me 2 C C 2 Me TB Me 2 C C 2 Me Bn Bn Me Me 2 C C 2 Me Bn Bn Me C 2 Me Bn C 2 Me Bn Me 2 C Bn Me Me 2 C Me Bn Me TE TE Me 2 C Key tranformations: C 2 Me Bn Methy acetal protection of the enol ether functionality Radical cyclization to provide the bridged ring system -alkylation followed by Claisen rearrangement to install the C8 quartenary center Chenbo Wang @ Wipf Group 4 10/29/2007 + Ms Me Bn Me

Preparation of Left and Fragment TB C Me + Me 1. BuLi, TMEDA, 54% 2. K, Me 2 C Me 2 i Br ime 2 60% TB C 2 Me Me Me 1. F, py, 86% 2. (CCl) 2,DM, Et 3 N, 93% 3. LiCl, DIPEA, Diethylphosphonobutyro -lactone: 95%, E:Z 5:2 Me 2 i C 2 Me Me Me 1. Tebbe reagent 2. DIPEA, ydroquinone Tol 85 o Me C, 57%, endo:exo 5:2 2 i Me 2 C Me Me 1. TA, 2 -Me, 63%, dr 7:1 Me 2 i Me 2 C 1. Piv-Cl, DMAP, py, 89% 2. NaB 4,96% Piv Piv 1. MeI, CaC 3, MeCN, 2, 100% Piv Me 2 i Me 2 C 2. DBU, 92% 3. g( 2 CCF 3 ) 2, TFA-Ac then C 3 C 3, Me 2 C 85% Kolb,. C. et al. J. Chem. oc. Perkin Trans. 1 1992, 2735 Chenbo Wang @ Wipf Group 5 10/29/2007

Preparation of Left and Fragment (cont.) Piv 1. C, PPT, 94% Piv 1. TBTf, 2,6-lutidine Me 2 C 1. Dess-Martin 2. L-electride, 97% 3. ptical resolution with (-)-Camphanic acid, 40% C Me 2 C 1. Zn(B 4 ) 2 2. Li 3. C 2 N 2 79% CN 1. TBAF Me 2 C TB CN 2. TBTf, TEA 3. 3 then P 3 74% Me 2 C TB 2. NCC 2 C 2, TsCl, py 95% Me 2 C TB 2. PDC 3. LMD 85% Me 2 C DMD PPT, Me C 2 Me 1. C, PPT, 74% C 2 Me Bn Me 2 C 70%, dr 4.4:1 Me 2 C 2. BnBr, Ag 2, 61% Me 2 C 30 steps, 0.12% overall yield Chenbo Wang @ Wipf Group 6 10/29/2007

Degradation tudy Ac Me 2 C C 2 Me 1. 2,Pd/C,76% 2. Ac 2, TEA, DMAP, 65% Ac Me 2 C C 2 Me Ac PCC, 50% Ac Me 2 C C 2 Me Ac Azadirachtin TEA, 2, 32% C 2 Me 1. C, PPT, 72% C 2 Me Bn Me 2 C 2. Ag 2, BnBr, 71% Me 2 C Ley,. V. et al Tetrahedron, 1993, 49, 1675 Chenbo Wang @ Wipf Group 7 10/29/2007

Demethylation of the C-8 Position C 2 Me Bn 1. TsNN 2,Ts,60% Ac C 2 Me Bn 1. e 2, tbu, 60% Ac C 2 Me Bn 1. s 4,83% Me 2 C 2. C(Me) 2, PPT 3. MeNa, 79% 4. 2 4, 2, 93% 5. Ac 2, TEA, DMAP, 92% Ac Me 2 C 2. RhCl(P 3 ) 3,70% Ac Me 2 C 2. C(Me) 2, PPT, 90% Ac Me 2 C Ac C 2 Me Bn NB, hv, 2, 50% Ac Me 2 C Ac C 2 Me Bn 2 C PCC, 84% mi 2,79% Ac Me 2 C Ac C 2 Me Bn 1. MeNa 2. (Me) 2, PPT 83% C 2 Me Bn Me 2 C Koot, W. J. et al Tetrahedron, 1995, 51, 2077 Chenbo Wang @ Wipf Group 8 10/29/2007

Methylation of the C-8 Position 3 steps, 46% Chenbo Wang @ Wipf Group 9 10/29/2007

Preparation of Right and Fragment 1. Bu 2 n, then MMCl, 82% 2. 3. py, DIPEA 3. AllylMgCl, 85% 4. BnBr, Na, 87% MM Bn 1. NB, 60% 2. Zn, N 4 Cl, 99% 3. 3, then P-P 3 4. TPAP, NM, 95% MM Bn 1. TFA, 2, 99% MM Bn Me 2 C 2. TBCl, TEA, 90% 3. C 2, NaMD, then MeI, 99% TB 1. AIBN, Bu 3 n, 70% 2. TFA, 2, 80% 3. 3. py, DIPEA 4. tbuk, 3 PCBr 2. Br 80% Br MM Bn Br PMB Bn 1. TMBr, 82% 2. PMBTCA, La(Tf) 3,90% 3. DIBAL- 4. Amberlyst 15, Me, 70% Br Br PMB Bn 1. MeLi, LiBr, 80% 2. iprmgbr, (C 2 ) n,80% 3. Ms 2, DIPEA, 90% Ms Me 22 steps, 4.1% Veitch, G. et al Angew. Chem. Int. Ed. Early View Chenbo Wang @ Wipf Group 10 10/29/2007

Fragment coupling 8 steps, 17% Chenbo Wang @ Wipf Group 11 10/29/2007

A Relay Route to Azadirachtin Ac Me 2 C C 2 Me 1. NB, Me, quant. 2. Bu 3 n, AIBN, 91% 3. BnBr, Ag 2, 60% Ac Me 2 C C 2 Me Bn Bn Me 1. DMP, 99% 2. TEA, Me, 2, 99% 3.TBTf,DIPEA,90% TB Me 2 C Azadirachtin C 2 Me Bn Bn Me 1. TBAF, quant. 2. 2,Pd/C, :99%, :80% Me 2 C C 2 Me Bn Me Amberlyst 15, 49% Chenbo Wang @ Wipf Group 12 10/29/2007

End Game Me 2 C C 2 Me Bn Me 1. Ac 2, TEA, DMAP, 74% 2. Cl Cl Cl Cs 2 C 3,80% Ac Me 2 C C 2 Me Bn Me 1. NaB 4,CeCl 3,49% 2. 2, Pd/C, 81% Ac Me 2 C C 2 Me Me, PPT, 70% Ac Me 2 C C 2 Me DMD, 67% Ac Me 2 C Azadirachtin C 2 Me 6 steps, 11% Chenbo Wang @ Wipf Group 13 10/29/2007

ummary The authors have demonstrated a feasible pathway for the synthesis of azadirachtin: 22 years in the making. 47 linear steps, 0.0010% overall yield Key steps include a Claisen rearrangement for the formation of C8-C14 bond and a radical cyclization to form the bridged ring system. End game relies on an intermediate prepared by the degradation of the target molecule. Chenbo Wang @ Wipf Group 14 10/29/2007

2024 © sciencedocbox.com Privacy Policy | Terms of Service | Feedback