CYCLOBUTADIENE IN ORGANIC SYNTHESIS

Transcription

1 Lit. Seminar CYCLBUTADIENE IN GANIC SYNTESIS Usage of Unstable Intermediate: Cyclobutadiene as A Case 0. Introduction (C) 3 Fe 2 steps Kenzo YAMATSUGU (M2) (+)-Asteriscanolide difficulty to use in synthesis unstable species high reactivity unique reaction sequences Contents 1. General feature of cyclobutadiene 3. eaction sequences of cyclobutadiene 2. Stabilization by iron tricarbonyl complex 4. Total synthesis of (+)-Asteriscanolide Marc L. College 1. General feature of cyclobutadiene + antiaromataic + unstability from ring strain uckel orbital energy + rapid dimerization and oligomerization α 2β α 2β cf. stable cyclobutadiene α β α α + β α + 2β α α + 2β 2. Stabilization by iron tricarbonyl complex + in 1965, the first prepation of cyclobutadiene-iron tricarbonyl ref. JACS 1965, 87, 132. Fe 2 (C) 9 (C) 3 Fe stable pale yellow crystalline + Molecular orbital of C 4 4 Fe(C) 3 ref. Inorg. Chem. 1979, 18, b 1u tal d xy δ e g (1) e g (2) d zx, d yz π a 2u d z 2 σ 1/12

2 Molecular orbital diagram of C 4 4 Fe Molecular orbital diagram of C 4 4 Fe and C Molecular orbital diagram of C 4 4 Fe(C) 3 1. near equality of the cyclobutadiene e g level and Fe 3d (d zx and d yz ) level 2. Geometry of C allows only b 2, b 1, and a 1 (d z 2, d xy, and d x 2 -y 2 ) to participate in π back-donation. C Fe C C geometry of C 3. d 8 doesn't require metal-ring antibonding orbitals to be occupied. These three features make the complex stable. + compatible with many organic reactions *electrophilic reaction, Grignard reagent, reduction * cyclobutadiene-iron tricarbonyl complex is known to decompose oxidatively. (C) 3 Fe Ce 4+ + Fe 2+ + C + + liberated cyclobutadiene can be trapped with several unsaturated compounds. C (C) 3 Fe C CAN (C) 3 Fe CAN only activated dienophile can be used intermolecularly 2/12

3 3. eaction sequences of cyclobutadiene 3.1. Intramolecular cycloadditions between cyclobutadiene and alkenes (C) 3 Fe ref. JACS, 1996, 118, JACS, 2002, 124, CAN acetone, r.t., 15min y. 85% # ecedents pentane (C) 3 Fe CAN acetone y. 50% sealed tube 220 o C, 90min (C) 3 Fe 1. hν 2. CAN y. 83% Tetrahedron Lett. 1974, 28, # Scope and limitations substrate preparation + intramolecular = the key to success with unactivated olefin + intermolecular cycloadditions oligomerization + 11 & 14 transfer of stereochemical information ----concerted mechanism + 20: sterically restricted tether oligomerization higher temp. & short rxn. time works well + 23: sterically encumbered alkene two adjacent quaternary carbon centers # xidative decomplexation of (C) 3 Fe-cyclobutadiene complex substrates prone to undergo intramolecular cycloaddition = = CAN (5eq.), acetone(1-2mm), r.t., 15min substrates less prone to undergo intramolecular cycloaddition trimethylamine-n-oxide(tma, 8-20eq.), acetone(2-20mm), reflux, 6-24h 3/12

4 No involvement of Fe in the cycloaddition # Tether effect preliminary experiment CAN * Three-atom heteroatom-containing tethers * Three-atom all-carbon tethers * Four-atom heteroatom-containing tethers * Four-atom all-carbon tethers + Three-atom heteroatom-containing tethers A: CAN, acetone, rt B: CAN, DMF, 80 o C C: TMA, acetone, reflux A: CAN, acetone, rt B: CAN, C 3 CN, rt C: CAN, DMS- 2, rt D: TMA, acetone, reflux *hydrolysis *cinnamyl alcohol was recoverd allene sterically congestured unactivated olefins: K oxidant : CAN is K 4/12

5 + Three-atom all-carbon tethers A: CAN, r.t. B: TMA, reflux C: CAN, reflux unactivated alkene: CAN: X trans slightly activated alkene CAN: K secondary orbital interaction? cis trans activated alkene good yield secondary orbital interaction? cis restricted freedom of the tether A: CAN, acetone B: TMA C: CAN, overall yield (ketalization) sp 2 sp 3 gem-disubstituted cf. entry 1 + reactivy heteroatom-containg > all-carbon shorter C- lengths compressed C--C bond angles + how to solve this low reactivity *electronic activation of dienophile *socondary orbital interaction *restriction in the freedom of tether *geminal substitution *TMA 5/12

6 + Four-atom heteroatom-containing or all-carbon tethers A: CAN B: TMA less reactive trans freedom cis strongly activated + reactivity three-atom > four-atom + again, some activation (strongly in the case of all-carbon case) is essential # Theoretical calculations B3LYP/6-31G(d) as implemented in Gaussian 98 These reactivity was supported by theoretical calculations. (A) vs (B) heteroatom-containing all-carbon short C- bond = [4+2], not [2+2] All-carbon tether must be more compressed because of long C-C bond at the expense of angle strain that destabilizes the B-TS. 6/12

7 (C) (D) vs Unexpectedly, these activation energy is higher than A-TS or B-TS. (cf. A: 9.1 kcal/mol) > Ester tether is too short to connect two reacting groups without strain? And because s-cis conformer is unfavorable? Anyway, there is no inherent difference in cyclization reactivity between C and D. slightly Low yield of D might be due to 1. less propensity to be oxidized 2. more electrophilicity of ester carbonyl (α-cation is stabilized by the complex) (E) (F) vs sp 3 sp 2 E Z E Z clearly, sp 2 carbon makes the compressed TS difficult C 2 C 2 (G) 2 C Type I Type II vs () C 2 Type I Type II (E)-alkene C 2 (Z)-alkene C 2 7/12

8 The Type I transition structure is lower in energy than the Type II transition. (disagreement with experiment in -TS) Type I : Type II = 1.0 : 3.3 (Table 6, entry 5) E-alkene leads to lower energy transition structure compared to Z-alkene. A quantitative measurement of the factors (simplifed model) Transition energy difference I Dienophile's energy difference I Endo/exo energy difference = Strain in the cis-transition structure 2.8 I 1.6 I 0.6 = 0.6 (kcal/mol) Conclusions xidatively liberated cyclobutadiene could be trapped intramolecularly with olefins to afford functionalized cyclobutene-containing cycloadducts. This reaction was affected by several factors including 1) oxidant (CAN vs TMA) 2) electronical acitivation (conjugated olefin) 3) tether length (heteroatom-containing vs all-carbon, 3 atoms vs 4 atoms) 4) tether's freedom (sp 2 vs sp 3, restriction by phenyl group) 5) alkene configuration (E vs Z) 3.2. apid entry into functionalized bicyclo[6,3,0] ring system ref. JACS 1997, 119, PCy 3 u PCy 3 Ph TBS TBS 200 o C sealed tube 5 8 TBS bicyclo[6,3,0] preliminary study using ethylene model study using substituted alkene (substituted alkene: regio- & stereo-chemical issue) Z:E = 1:9 major C 6 13 C y. 66% (4:1) C 6 13 minor Z:E = 2:1 8/12

9 substituted alkene ( = 4-penten-1-ol) reconsideration of the steric factor little regiocontrol (1.5:1 & 1.4:1) conformation of the methoxy group may play a role in dictating the reaction outcome? clear contrast between 17 and 21. obstacle to u-center's access? Alkylidene complex was oserbed by 1, 13 C, 31 P NM, which does not undergo subsequent turnover. + PCy 3 u PCy 3 Ph u TBS ( ) 3 PCy 3 + u TBS ( ) 3 PCy [2+2] photocycloaddition/thermal retrocycloaddition; a new entry to functionalized ring system + hν o C sealed tube ring system ref. JACS 1999, 121, JACS 2005, 127, L 2001, 3, /12

10 regioisomer Table 2. Thermal Fragmentation of Photoadducts inversion inversion inversion inversion + enchance the regioselectivity + (steric repulsion?) improve yield (quaternary carbon prevents the carbonyl group from participating unproductive reation??) Figure 2. rtep plot of photocycloadduct 9. + stereochemical in entry 2 & in entry 4 & 5 cis,trans-1,5-cycloocatadiene X Y? chair relax X Y cis,cis-1,5- cycloocatadiene boat + Configuration of determines which pathway (A or A') is prevailed. favors exo face? + cis,trans-1,5-cyclooctadiene relaxes leading to cis,cis-1,5-cycloocatadiene through rearrangement Approach to bicyclo [5,3,0] ring system through cyclopropane opening C 2 I 2, Et 2 Zn r.t., 12h o C 7 5 ref. JACS 2001, 123, L 2005, 7, L 2006, 8, bicyclo [5,3,0] 10/12

11 + C1 substituent influence the facility of the rearrangement. inversion involvement of the bonds neghboring the C1 substituent + C10 boat chair + Lewis acid-mediated fragmentations are also possible. PCC r.t. * low temp. & short time * retention of configuration * β-substituent is K. BF 3. Et 2 0 o C min + C1 substituent: influence the formation and reactivity of diradical A' and A"? + inversion: B to C (preference for cis,cis - cycloheptadiene?) + entry 6: unfavorable A" or B? Table 1. Lewis Acid-diated Isomerizations of Cyclopropyl Systems β-substituted retention * approapriately positioned carbonyl is necessary * entry 7: acid sensitivity (epimerization & conjugation) * C3-C7 bond is weakened by Lewis acid-carbonyl interaction. * relaxation from boat 30 to chair 31 * strain releasing opening from 31 to 32 11/12

12 + xepines are also available. m-cpba 200 o C + 4. Total synthesis of (+)-Asteriscanolide ref. JACS 2000, 122, (C) 3 Fe (C) 3 Fe C (+)-Asteriscanolide [] exo X exo CBS red. cyclobutadiene Diels-Alder ring-opening metathesis sequence stability of cyclobutadiene-iron tricarbonyl complex Total Syntheis of (+)-Asteriscanolide 1) LDA, TMS, Et 3 N; Pd(Ac) 2 (10 mol%) benzoquinone 60% 2) B 3. Et 2, TF, (S)-B--CBS (10 mol%) 56%, 94% ee 1 2 C hν, Ph; Fe 2 (C) 9, 50 o C 64% (C) 3 Fe C 1) LA, BF. 3 Et 2 93% 2) 2 NC 2 N 2, 3 P 4, Ac 100 o C, 67% (C) 3 Fe N (C) 3 Fe PCC, Py. MS 4A C % 3 N, acetone ethylene, 8, 56 o C, 63% Ph, o C 74% ) ed-al, CuBr; Ac, TF, 89% 2) B. 3 TF, TF; PCC, MS 4A, C % I, TF; Na, 2, TF/DMF 50% N N s s u Ph PCy 3 y. 3.9% for 9 steps 9 10 (+)-Asteriscanolide 8 12/12