Total Synthesis of Longithorone A

1. Total Synthesis of Longithorone A Literature Meeting March 11th 2008 Charette group Angelique Fortier

2. Longithorone A Key Concepts • Biomimetic synthesis • Atropisomerism • Enyne metathesis • Organozinc reagents • Transannular Diels-Alder reactions

3. Longithorone A • Marine natural product • Found on island of Palau in 1994

4. ¿Desirable synthetic target? Isolate of tunicate Aplydium longithorax; sponge It’s low cytotoxicity and lack of biological activity is over compensated by its attractive conglomeration of rings and its stereochemical complexity.

5. Logistics • 5x 6-, 10-, and 16 membered rings • 2 types of chirality • Stereogenic centers • Atropisomerism • 6 stereogenic centers • 2 of which are quaternary

6. Biomimetics - Structural Harmony • Amalgamation of two smaller macrocyclic subunits • These subunits are comprised of • Farnesyl units conecting position 2 and 5 of • Paraquinone moiety • One aspect to beware of…

7. Atropisomerism • Severely strained sequential 6-memered rings • None can adopt the most stable chair conformation • B-ring is cis fused to with C-ring, trans fused with A-ring, and has attachment point to D-ring • Forces A- and B-rings in distorted boat conformation • Forces C- and D-rings in mutated half-chairs • Spacial constraints give rise to an element of chirality known as atropisomerism

8. Longithorone A First isolated in 1994 by Professor F. J. Schmitz and co-workers at the University of Oklahoma J. Am. Chem. Soc.1994, 116, 12125-12126

9. Schmitz’ biogenetic retrosynthetic analysis

10. Schmitz’ biogenetic retrosynthetic analysis

11. Longithorone A First chemically synthesized in 2002 by Professor Matthew Shair and two of his graduate students at Harvard University J. Am. Chem. Soc.2002, 124, 773-775 PNAS2004, 101, 12036-12041

12. Shair’s retrosynthetic analysis

13. Shair’s retrosynthetic analysis

14. Shair’s retrosynthetic analysis

15. Shair’s retrosynthetic analysis It is interesting to note that the diene and dienophile are obtained from the same precursor, and is subject to similar chemistry

16. Shair’s retrosynthetic analysis

17. Shair’s retrosynthetic analysis

18. Ene-yne metathesis • Intramolecular ene-yne metathesis affords 1,2-disubstituted dienes • Intermolecular ene-yne metathesis affords 1,3-disubstituted dienes • What will happen for a macro-intramolecular?…

19. Ene-yne metathesis control • Assumed macrocyclization would resemble intermolecular reaction • Hence a 1,3-disubstituted diene • Since the resulting [12]-paracyclophane is less strained than a [11]-paracyclophane (from a 1,2-disubstituted diene)

20. Ene-yne metathesis • 1,3 observed especially for ring sizes of 12 and greater • Only 5 to 8 membered had been tested previously • First report of macro-ene-yne RCM • But how to control which atropisomer is obtained…

21. Vancomycin • Nicolaou successfully used removable directing groups to direct an atropselective macrocyclization. • Evans group also used the same strategy • Directing groups govern the transition state adopted during enyne metathesis • The A(1,3) interaction is worth several kcal/mol more and hence will be the disfavored conformer

22. Vancomycin

23. Atropisomerism control • Strategic benzylic hydroxyl groups should favor A & C and disfavor B & D due to A(1,3) strain • Benzylic hydroxyl groups can then be removed reductively • Absence of this control group led to non-selective ring closure

24. Negishi-type cross-coupling • Directing group installed via asymmetric alkenylation of an aldehyde • Can then be removed by hydride displacement or acid-mediated lysis • This starting material was derived from a Negishi-type Pd cross-coupling reaction

25. Total Synthesis oxidation protection Z selective Wittig via unstabalized ylide

26. Total Synthesis Halogen metal exchange reduction Conversion to zinc bromide species quench Exchange of BzOH for Br Aryl lithiation Pd-Negishi cross-coupling reaction Differentiation of two aryl methoxy groups!!! quench Usually nearly impossible! …but aldehyde can coordinate with L.A. catalyst, directing it to its’ adjacent methyl ether hence activating it for preferential cleavage!!! reprotection Also, increases the electronic effect. The lone pair of the adjacent oxygen can be delocalized into aldehyde

27. Total Synthesis Lithium alkoxide serves as highly competent chiral auxiliarly Stable complex with lithium trans to Ar Lithiation transmetallation Partial reduction: hydrogenation via Lindlar’s catalyst selective for terminal alkyne, TIPS deprotection Stereoselectively orchestrates the uniion of aldehyde 14 and nucleophilic vinylzinc TBS protection TMS, TBS selective deprotection Transition state: aldehyde coordinates to lithium trans to the distal pphenyl ring. Alkenyl transfer occurs via 6-membered transition state. -recovery of auxiliary via extraction. Completion achieved with equimolar aldehyde and bromozinc hence material economy

28. Total Synthesis Grubbs Major by-product…loss of 1 carbon -propene formed with carbene TBS deprotection Complete selectivity for both olefin geometry and atropisomerism. 42% yield due to formation of major byproduct. Hydride displacement via NaBH3CN using TFA as benzylic alcohol activation into a good leaving group followed by reprotection.

29. Total Synthesis Install vinyl iodide side chain as before Global desilylation, followed by alcohol protection Macrocyclization provide exclusively the 1,3 disubstituted diene product Lithiation, transmetallation, stable complex Alcohol protection, allylation However, less atropselective (less steric differentiation) and failed to completely control endocyclic olefin geometry oxidation Ionic type reduction of benzylic directing group via H- (silane) H+(TFA), PPTS deprotects alcohol Thermally stable up to 100°C …implies can activate Diels Alder reaction at higher temperatures

30. Total Synthesis First attempt failed. 15 h at RT, heating and LA’s also did not work Desilylation of 2 phenolic TBS groups, followed by oxidation with iodosylbenzene to give rise to bis quinone After much screening, reaction conditions were found giving complete endo selectivity but not facially selective, giving rise to both diastereomers (aldehyde and H down) favoring the non-natural configuration -this supports possibility of enzymatic assistance proposed by Schmitz Ie.diels-alderase Amazingly, adduct started to slowly convert into Longithorine A at RT without being isolated

31. Summary • Total synthesis • 32 operations overall • 19 steps in the longest linear sequence • Unique example of chirality transfer in complex molecule synthesis • Stereogenic centers are used to control planar chirality • Removal of chiral centers • Planar chirality is then in return used to regenerate stereogenic centers

32. Summary • Challenges overcome • Biosynthesis is feasible • Atropselectivity acheived • Macrocyclic ring closing enyne metathesis gave disubstituted 1,3 diene (first example) • Diels-Alder reaction gave endo product only • But was not facially selective (hence 2 diastereoisomers) • Benzylic alcohols were installed highly enantioselectively via vinylzinc additions

33. Thank you