Claisen Variant to Accommodate VQCs

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3 Claisen Variant to Accommodate VQCs ~Source eaction: Cycloalkenyl Allyl Ether Claisen ' ' ' ' ' ' n = 0, 1 =, ' =, n C n *Very slow; side reactions (deallylation or aromatization) are competitive at required temps. *2 Carbonyl groups produced cannot always be distinguished easily in later chemistry. n ~Modified eaction: Carbomethoxyhydrazone derivative (and anionic version) ' ' n *6 to 31-fold rate increase for the hydrazone derivative, and a further 15 to 145-fold increase for the anionic version. This allows the reaction to be cooled to 66 C. a + vs. K + rates are not significantly different. *Prenyl ( = ) derivatives are slower, but not a huge difference. Complete allylic rearrangement is observed, verifying the [3,3]-sigmatropic nature of the transformation. *For the hydrazone, / 2 is the best solvent system. For the anionic version, heating in aprotic solvents is best. ' ' n ' ' n J. rg. Chem. 1983, 48,

4 Enediyne Cyclization ~A neat reaction, though not very general in its application. TP CpCo(C) 2, m-xylene hν, Δ, 60 % ( % 1) CoCp (air stable) Si 2 61 % 1 (eacts with 2 ) *eaction works with 1-mono; 1,1- or 1,2-di; and 1,1,2-trisubstituted patterns as well. *Proceeds with complete specificity relative to the starting olefin. J. rg. Chem. 1984, 49,

5 Michael Variant to Accommodate VQCs ~ "Electronic Compensation for Steric Congestion." Enolates Acceptors Products ** Li C C 2 Et C 2 Et C 2 Et Li C 2 Et C C ** C Li ** C C C 2 Et C C 2 C 2 Et C Ci-Pr Li ** C C SPh C 2 Et C 2 Et *** *** *un in TF with LDA. Aprotic conditions for Michael rxns only possible in cases where product enolate is more stable than the initial enolate. *Li + coordination may be accelerating cyanoester cases. *Yields generally in 90s, except in cases of remote steric interference. **Give double-michael products with 4 contiguous QCs. ***Unreactive in VQC-forming reactions. C C C C J. rg. Chem. 1986, 51,

6 Synthesis of examethylglutaric Acid ~ Based on QC methodologies with formation of a tertiary carbocation followed by C-C bond formation. This approach generally fails for VQCs because the entropic and steric costs outweigh the energy gained by σ-bond formation. Cl (> 2 equivs) TiCl 4, C 2 Cl 2-75 C, 72% Cl I 4, u 2 CCl 4, C 3 C 2 64% 40% K (aq)/ i-pr (1:1), 91% C C C 2 2, Et 2 87% C C *This approach is successful in this case because the reverse reaction in step 1 is prevented by fixing the 2 fragments in a ring. *The aromatic ring can be readily cleaved and the resulting anhydride opened to form a linear system. J. rg. Chem. 1988, 53,

7 Thio-Claisen earrangement ~Why the thio-claisen? Because they couldn't make the correct -allyl compound. Auxiliary provides selectivity as well. Ph S 1. LDA 2. Br Ph S [3,3] 140 C xylene Ph S Et 3 BF 4 DCE, 83 C Ph SEt BF 4-1. ed-al, 0 C 2. Cl 4 Et/ 2 (3:2) K 68%, >99:1 dr 77% from [3,3] pdt ~Transition state diagrams for selectivity vs. reactivity justification: Ph S Facile at room temperature. / interaction lowers selectivity to 3:1 dr. Ph eed high temperature to overcome interaction. o / interaction, allowing S for diastereoselectivity observed. J. Am. Chem. Soc. 1994, 116,

8 "Desymmetrization" of Cyclic Ketones ~ing cleavage reaction involving an intermolecular aldol and subsequent ketalization and fragmentation. BF 3 Et 2, PhC Ph n n n K 2 C 3 n = (,)-C 6 4 = n = 0, 9% yield, 6% ee n = 1, 15% yield, 34% ee *xn without QCs gives 34% yield and 26% ee for the 5-membered ring case and 30% yield and 49% ee for the 6-membered ring case. *The ees are probably better for the non-qc case because there is better facial bias for the Aldol step. It is difficult to determine by models whether the convex face is still more open when it has VQCs on it. Tetrahedron 2004, 60,

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10 Arene-Alkyne Cycloadditions -- Total Synthesis of (+)-Silphinene ~ ta reactivity pattern dictates resultant framework(s). Although a 1:1 mixture of isomers is observed, the total synthesis is only 3 steps, and multi-gram quantities of the natural product can be prepared in a few days. 9 hν 9 Li 9 9 Li, 2 *Mode of reactivity (meta vs. ortho or para) is controlled by the electronics of the arene and olefin. *egioselectivity is "controlled" by the donor alkyl groups on the olefin. *Endo/exo control results from strain (orbitals for endo TS do not easily overlap). *C(9) stereocontrol: (1:1) (+)-Silphinene = aromatic ring (side view) 9 9 Wender, P.A. Pure & Appl. Chem. 1990, 62,

11 Arene-Alkyne Cycloadd'ns -- (±)-Subergorgic Acid and ( )-etigeranic Acid ~(±)-Subergorgic Acid Synthesis. Stereocontrol likely due to A 1,2 -strain. Could potentially be made asymmetric with the use of a chiral ketal. hν C ~( )-etigeranic Acid Synthesis: meta-photocycloaddition then IMDA. hν hν, 2 2 IMDA 2 2 >98% ee Wender, P.A. Pure & Appl. Chem. 1990, 62,

12 Arene-Alkyne Cycloadd'ns -- Towards the Synthesis of (±)-Grayanotoxin II Ac hν Ac Ac destabilized Ac Ac PhSeCl Cl Cl = TBS *Bicyclic arene substrate is converted to a single pentacyclic product with 7 stereocenters. *First example of stereoinduction by a homobenzylic stereocenter. *nly one vinyl cyclopropane isomer is formed. This is because the steric interaction between the methyl and methoxy groups is decreased by the longer bonds of the cyclopropane as compared to the normal σ- bond in the isomer. Wender, P.A. Pure & Appl. Chem. 1990, 62,

13 Total Synthesis of (±)-Cupraene and (±)-α-cupraenone ~Selenium-lithium exchange as an anion generation technique. p-tol 2 Se TiCl 4 Se Se 1. n-buli, TF, -78 C p-tol 2. Br, -78 C Se p-tol t-buli pentane, 20 C (±)-cupraene ~Building the 5-membered ring via sequential ring expansions, one quat. center at a time. Se Se Et 2 pts, Ph p-tol Li 85% 2 2, 80 C, 12h p-tol 2 CLiSe Se AgBF 4, Al 2 3 Et 2, -78 C 66% 3h, 69% Studies in atural Products Chemistry 1991, 8, (±)-α-cupraenone

14 Biomimetic Total Synthesis of thyl omosecodaphniphyllate ~Polycyclization of a squalene derivative is the key synthetic transformation. Bn 3 2 or 3 Bn Ac 3 Bn Bn 2 4 Ac 80 C, 10h 3 Bn 65-80% cannot be observed 3 Bn hydrolysis, hydrogenolysis, Jones oxidation, esterification *VQCs set by in-situ intramolecular aza-da, followed by acid-mediated cyclization to complete the core framework. *Mild conditions lend credence to the biomimetic nature of the synthesis. verman, L.E. Proc. at. Acad. Sci. 2004, 101, eathcock, C.. J. rg. Chem. 1992, 57, For a similar strategy in secodaphniphylline, see: eathcock, C.. J. rg. Chem. 1990, 55,

15 Enantioselective Biomimetic Synthesis of Dammarenediol II ~Key step: cationic tricyclization of a triene epoxide TBS S S 1. AlCl 2, C 2 Cl 2, -95 C 2. F, AC 3. (CF 3 C) 2 IPh, 0 C 42% 2 steps 3 steps 79% 36% PhC *Epoxide stereochemistry dictates the correct formation of the next 5 stereocenters, including the VQCs. *Aldol cyclization forms the fused 5-membered ring and provides a handle with which to attach the homoprenyl group. verman, L.E. Proc. at. Acad. Sci. 2004, 101, Corey, E.J. J. Am. Chem. Soc. 1996, 118,

16 Total Synthesis of (+)-Valerane ~rthoester Claisen to set first QC, copper-carbene cyclopropanation to set second QC of the pair. C(Et) 3 EtC 160 C, 5d 80% C 2 Et 1. 10% a (aq), reflux, 75% 2. (CCl) 2 then C 2 2 Et 2, 71% 2 CuS 4, c-c 6 12 W-lamp, reflux, 57% 1. Li/ 3, 76% 2. 2, Pd/C, 98% ~First attempt to advance orthoester Claisen product was via radical cyclization. C 2 Et LDA, TF Br(C 2 ) 3 Br Br Ph, Bu 3 Sn AIB, reflux C 2 Et C 2 Et *nly des-bromo starting material was observed. Srikrishna, A. Tet. Lett. 1996, 37,

17 Total Synthesis of ( )-Trichodiene ~Thio-Claisen rearrangement of a chiral bicyclic lactam sets VQCs at the ring junctions. Ph DMF, 90 C Ph Et 3 BF 4 Ph S 60%, 1 recycle S C 2 Cl 2 EtS 1. ed-al, -78 C 2 steps 2. Bu 4 2 P 4 Et/ 2 54% 60% *Thiolactam is produced as a single diastereomer in the Claisen. *Steric destabilization of the VQCs prevents complete conversion to product, producing an equilibrium mixture of 36:64 or about 1:1.8 (SM:Pdt). easonable quantities of material are obtained via recycling. verman, L.E. Proc. at. Acad. Sci. 2004, 101, yers, A.I. J. Am. Chem. Soc. 1998, 120,

18 Formal Synthesis of (±)-α-pinguisene and (±)-Pinguisenol ~Proposed Biosynthesis: P i P i + olefin attack P i P i [1,2]- shift [1,2]- migration olefin reformation P i P i olefin attack allylic elimination of diphosphate alkyl shift alkyl shift B: ~Synthetic approach; VQCs formed via cyclopropanation and selective reduction. Cu-CuS 4 2 3:2 K 2 C 3 2, - + (±)-α-pinguisene (±)-pinguisenol 1. Li/ 3 2. Wolf-Kishner PCC *refs (±)-pinguisenol *TL 1995, 36, or *Tetahedron 1996, (±)-α-pinguisene 52, J. Chem. Soc. Perkin Trans ,

19 Total Synthesis of ( )-Chimonanthine ~Diastereoselective intramolecular eck cascade builds VQCs and sets their absolute stereochemistry. 10 mol% (Ph 3 P) 2 PdCl 2 I Bn Bn I TEA, DMA, 100 C Bn Bn I 90% steps 4 steps Bn Bn 81% Bn Bn 74% *A single enantiomer of the eck cyclization cascade is formed, with its stereochemistry controlled by the configuration of the acetonide in the C 2 -symmetric cyclization precursor. *ne of few examples of a catalytic reaction forming VQCs. verman, L.E. Proc. at. Acad. Sci. 2004, 101, verman, L.E. J. Am. Chem. Soc. 1999, 121,

20 Enantioselective Synthesis of (+)-Maritimol ~VQCs formed via transannular DA with concomitant decarboxylation. TBS I TBDPS 6 steps 28% 2 C C DMS, C C 2 C C 86% 6 steps 21% *Macrocycle elegantly prearranges the transition state, holding the required s-cis diene geometry and providing regiocontrol. *Cyano stereocenter completely controls the formation of the desired product. Two endo transition states can be drawn, but in the disfavored TS, the C protrudes into the macrocycle, causing steric problems. *The transition state for epimeric cyano compound is pictured to the right, and would provide the enantiomeric product after decarboxylation. verman, L.E. Proc. at. Acad. Sci. 2004, 101, Deslongchamps, P. J. Am. Chem. Soc. 2000, 122, Transition state for opposite C stereochemistry: C 2 C

21 Synthesis of 1,15-Dihydroxyherbertene ~Enolate alkylation sets first QC, intramolecular eck adds the second. I Bn 1. Pd(Ac) 2 (10 mol%) dppf (20 mol%), DMF 2 equiv. Bu 3, 120 C Wolf-Kischner 2. 2, 10% Pd/C, Et 71% MM LA, TF MM 0 C, 83% Fukuyama, Y. Tetrahedron 2001, 57,

22 Formal Syntheses of (±)-α-erbertenol and (±)-1,13-erbertenediol ~VQCs formed via Claisen followed by metathesis to generate the 5-membered ring. LDA, TF, TMSCl TEA, -70 C T reflux, 77% 2 C 5 mol% Grubbs II C 2 Cl 2, 5h, 98% 2 C 10% Pd/C 1. BBr 3, C 2 Cl 2-40 C T Et, 2 100% 2 C 2. ef = prev. slide 1. LA, Et 2, 0 C T 2. PCC-Si 2, C 2 Cl 2, T Wolf-Kischner (±)-1,13-herbertenediol *BBr 3 58% C 2 Cl 2, 76% (±)-α-herbertenol Srikrishna, A. Tet. Lett. 2003, 44, *Synlett 2005, 7,

23 Synthesis of (±)-erbertenolide ~VQCs formed via decarbonylation with retention of relative stereochemistry. 1. a, I glyme, reflux 2. LDA, I TF, 0 C T LDA, Et 2 C C 2 hν, solid C 2 BBr nm filter 0 C, 76% yield (20% conv.) C 2 Cl 2 *Low conversion attributed to product melting after formation & causing soln phase side-product formation. *igh conversions should be attainable by the use of a different ester. Garcia-Garibay, M.A. rg. Lett. 2004, 6,

24 Ac F Pyr TF 51% des. isomer TBS Ac C 2 Total Synthesis of orzoanthamine ~First QC formed via IMDA, second one via enol ether methylation. C 6 3 Cl C Ac C 2 TES 72:28 exo/endo 98% yield Ac TBS D D TBS t-buli, TF MPA then I, 92% TES TBS D D t-buli, TF DMPU then I, 83% TES TBS D D Miyashita, M. Science, 2004, 305,

25 orzoanthamine, Zoanthamine and Zoanthenol Attempts ~Conjugate addition strategy: 1. 2 CuLi, Et 2, -25 C then TMSCl, TEA, -25 C 0 C 2. mcpba, hexane, T 3. CSA, acetone, T 73% ~Simmons-Smith cyclopropanation: Kobayashi, S. Tet. Lett. 1998, 39, MM MM MM I, DME/MPA pts, C 2 Cl 2, T TMS then SmI 2, ClC 2 I -78 C -20 C 61%, 2 steps ~Intramolecular alkylation: irama, M. Chem. Lett. 1999, MM Br Et MM TBS 1. Br, Ph 2 C 2 Cl 2, 57% TBS 2. t-buk, Ph, 71% (88%, 2 step...?) Et Theodorakis, E. A. Tet. Lett. 2005, 46,

26 Total Synthesis of (+)-Welwitindolinone A ~Second QC formed via "exceedingly facile oxidative ring contraction." C Cl t-bucl TEA, TF -30 C C Cl Cl then TFA, TF/ 2-30 to 0 C 28% C Cl ( )-fischerindole I 2 Cl Cl Cl C tautomerization C C (+)-welwitindolinone A 10:1 3-epi-welwitindolinone A Baran, P.S. J. Am. Chem. Soc. 2005, 127,

27 Towards the Total Synthesis of Daphnilactone B ~etrosynthetic analysis 2 C FG 2 FG 1 [4+2]/ 2 FG 1 [3+2] FG 2 C 2 *FG 1 and FG 2 should maintain reactivity of nitroalkene as well as synthetic availability. (FG 1 =EWG, FG 2 contains ) ~Intramolecular [4+2] Cycloaddition of itroalkenes -60 C 0 C SnCl 4, C 2 Cl 2 68% Major *Model [4+2] reaction occurs in up to 68% yield with dr varying from 1:1 to 6:1. Both were characterized by X-ray. *Dipolarophile for [3+2] is not included in the model study for simplicity. *At lower than -60 C, side products were formed. *Stereoselectivity at the VQCs is excellent. The lactone tether, providing a rigid backbone, is attributed with this accomplishment. Minor Denmark, S.E. rg. Lett. 2005, 127,

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29 Synthesis of an Aphidicolone Derivative ~Diastereoselective intermolecular Michael addition forms VQCs TBS 1. LDA C, TF tol S TBS S tol Li TBS S tol F, S tol a 45% S()tol *Intermolecular Michael is organized by chelation between sulfinyl and enolate oxygen atoms. (7.4 : 1 dr) *Subsequent in situ vinyl lithium addition, dehydration, and extended conjugate addition allow for a one-pot synthesis of the complex tricyclic lactone. TBS 6 steps 55% 4 steps 48% t-bu aphidcolone verman, L.E. Proc. at. Acad. Sci. 2004, 101, olton,.a. J. Am. Chem. Soc. 1987, 109,

30 Synthesis of FG-ing Lactone Precursor towards Penitrem D Bn Bn Bn 1. MgBr, CuI (cat) TMEDA, TF, -78 C Burgess eagent % Bn 1. t-buk, TF Ph 2 S, 0 C 2. I, 0 C 42-59% 1. PPTS, acetone 2. Zn, icl (C 2 ) 2, 82-94% Bn ~Copper-catalyzed Grignard addition sets first QC, extended enolate formation with I trapping gives second one. *Alcohol elimination gives a single olefin isomer, confirmed by E. *Alkylation of the extended enolate occurs from the top face because in order for the vinyl and C 2 Bn groups to be pseudo equatorial, the methyl group is psuedo-axial and blocks the bottom face approach. Penitrem D Smith, A.B. III J. rg. Chem. 1995, 60,

31 TBS Total Synthesis of (±)-rrilactone A ~Use of endo DA to install the VQCs at an early stage...like the first step. mesitylene, collidene methylene blue 165 C 74% TBS 3-4 steps 78% TBS 1. 3; PPh3 2. Bn 2 TFA Ph, 65 C 94% TBS 2 steps 92% Et 2 C TBS TBS 3 steps 44% *DMMA was chosen as a more reactive version of the corresponding dimethyl butenolide dienophile. owever, it is reactive only with the most reactive dienes, hence the conditions. % *verall, the synthesis is completed in 20 steps and 10.7% yield "The use of dimethylmaleic anhydride as a dienophile leading to the incorporation of two angular methyl groups has broad potential implications which warrant follow-up." ~Prof. Sam Danishefsky Danishefsky, S.J. J. Am. Chem. Soc. 2002, 124,

32 Total Synthesis of ( )-Idiospermuline ~Dienolate dialkylation simultaneously forms both quaternary centers. Bn Bn Tf Tf LMDS, 9:1 TF:MPA, -40 C 75% Bn Bn 12 steps 30% I Tf SnBu 3 Pd 2 dba 3 CCl 3 P(2-furyl) 3, CuI MP, T 94% Ts Tf Ts 4 steps 46% *Stereoselectivity in dialkylation step is determined by the tartrate-derived dielectrophile. The high yield acheived in this step is attributed to a high level of stereoselection in the first alkylation. It also requires that the second alkylation proceeds via a transition structure where the carbonyl and enolate oxygens are oriented away from each other. (Much like the DA in an Evans aldol orienting itself to minimize the dipole.) verman, L.E. Proc. at. Acad. Sci. 2004, 101, verman, L.E. Angew. Chem. Int. Ed. 2003, 42,

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