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

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Presentation on theme: "Total Synthesis of Longithorone A Literature Meeting March 11th 2008 Charette group Angelique Fortier."— Presentation transcript:

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

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

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

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

5 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 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 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 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,

9 9 Schmitz’ biogenetic retrosynthetic analysis

10 10 Schmitz’ biogenetic retrosynthetic analysis

11 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, PNAS 2004, 101,

12 12 Shair’s retrosynthetic analysis

13 13 Shair’s retrosynthetic analysis

14 14 Shair’s retrosynthetic analysis

15 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 16 Shair’s retrosynthetic analysis

17 17 Shair’s retrosynthetic analysis

18 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 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 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 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 22 Vancomycin

23 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 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 25 Total Synthesis protection oxidation Z selective Wittig via unstabalized ylide

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

27 27 Total Synthesis Lithiation Lithium alkoxide serves as highly competent chiral auxiliarly Stereoselectively orchestrates the uniion of aldehyde 14 and nucleophilic vinylzinc transmetallation Stable complex with lithium trans to Ar 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 TMS, TBS selective deprotection Partial reduction: hydrogenation via Lindlar’s catalyst selective for terminal alkyne, TIPS deprotection TBS protection

28 28 Total Synthesis Complete selectivity for both olefin geometry and atropisomerism. 42% yield due to formation of major byproduct. TBS deprotection Major by-product…loss of 1 carbon -propene formed with carbene Hydride displacement via NaBH 3 CN using TFA as benzylic alcohol activation into a good leaving group followed by reprotection. Grubbs

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

30 30 Total Synthesis First attempt failed. 15 h at RT, heating and LA’s also did not work 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 Desilylation of 2 phenolic TBS groups, followed by oxidation with iodosylbenzene to give rise to bis quinone Amazingly, adduct started to slowly convert into Longithorine A at RT without being isolated Ie.diels-alderase

31 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 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 33 Thank you


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