Higher Order Cycloadditions in Synthesis

Transcription

1 'Malley igher rder Cycloadditions in Synthesis otes on Mechanism The cyclodimerization of alkenes and alkynes is a fundamental transition metal mediated process. This is the basic step in the mechanism of metal catalyzed or mediated higher order cycloadditions. For a detailed discussion, see egedus, L. Transition Metal in the Synthesis of Complex rganic Molecules, University Science Books, M M+2 Depending on the nature of the metal, this metallocycle can undergo many different reactions. For the purposes of this presentation, the most relevant are insertion reactions of alkenes, alkynes, and carbon monoxide to form expanded metallocycles. These metallocycles can then undergo reductive elimination to regenerate the active catalyst. M +2 M +2 M +2 -M Although the mechanisms of some higher order cycloadditions have not been exhaustively studied, it is believed that cyclization/insertion processes are generally responsible for these reactions. A further mechanistic point regarding metal mediated reactions is that photolysis is frequently used to aid in the dissociation of carbonyl ligands from metal centers. In metal mediated cycloadditions, irradiation is frequently used for this purpose, rather than to initiate a photochemically allowed concerted cycloaddition.

2 'Malley igher rder Cycloadditions in Synthesis [2+2], [3+2], and especially [4+2] cycloadditions are well established methods for ring synthesis. By contrast, the synthesis of larger rings through higher order cycloaddition reactions is far less common. Due to the breadth of this topic, this presentation is far from exhaustive and focuses mainly on synthetic applications of higher order cycloadditions. Some general references: Evans, P.A, ed. Modern hodium-catalyzed Chemistry, Wiley-VC, Yet, L. "Metal-Mediated Synthesis of Medium-Sized ings" Chem. ev. 2000, 100, Mehta, G.; Singh, V. "Progress in the Construction of Cyclooctanoid Systems: ew Approaches and Applications to atural Product Synthesis" Chem.ev. 1999, [4 + 3] Cycloadditions The initial report of a [4+3] cycloaddition came from Fort (JACS, 1962, ). Furan was used to capture the oxallyl species generated from chlorodibenzyl ketone. Cl 2,6-lutidine, furan DMF, rt, 18% This reaction was adapted for the synthesis of thromboxane analogs. (Bowers and Mann, Tet. Lett. 1985, 26(36) Br TFE, Et C(Me) % (incl.bromination) (15 eq) (C 2 )C 2 C 5 11 C(Me) 2 The intramolecular version of this reaction has been studied extensively with a range of precursors oxyallyl species. armata et. al. Tet. Lett. 1997, 38(46), ; Tetrahedron, 1997, 53(18), ; Acc. Chem. es. 2001, 34, C C + (Et) 2 ()P Li MM 58% C MM MeMgI 85% Me 2 S (Et) 2 ()P MM 1. LDA, C 2 MM Me S S I + Et 2. LiAl4 69%, 1:1 + 42% BuLi, TF; Et -78 C to rt, 83% S Et Me C 2 (+)-aphanamol 2 S MM C 2 MM Me S Tf 2, 2,6-lutidine DCM, -78 C 32 % TiCl 4 (inverse addn.) -78 C, 86% 1:1.1 (+)-widdrol Lautens has demonstrated the enantioselective opening of furan [4+3] adducts. JACS, 1997, 119, P i(cd) 2, ()-BIAP Trost has shown that trimethylene methane equivalents can undergo [4+3] cyclization with dienes. Due to the stepwise mechanism of this reaction, competing [3+2] reactions can pose a problem. Chem. Lett. 1994, P DIBAL % and >95% ee for multiple substrates, also works for adducts diastereomeric to the one shown. C 2 Me CtBu Pd(Ac) 2 /P(iPr) 3 /BuLi, TF, 60 C, 6h 48% (+33% [3+2]) C 2 Me 1

3 'Malley igher rder Cycloadditions in Synthesis Fischer vinylcarbenes undergo formal [4+3] cycloadditions with a variety of dienes and hetero dienes. It is important to note that these reactions actually proceed via a [2+1] addition followed by Cope rearrangement of the resulting diallyl cyclopropane. This reaction is included here because the Cope rearrangement usually occurs at room temperature and the formal [4+3] adduct is obtained directly (Barlunga et. al. JACS, 1995, 117(37), ; J. Chem. Soc. Chem. Comm. 1994, 321-2). Me Me tbu Cr(C) 3 Me Cr(C) 3 Me MeC, rt; 3 Cl, 45% 86% ee Me TF, -78 to -40 C, 3h; Si 2, TF-Et 2, rt, 3h 90% 2 Me Me tbu Me TBS Ac Ac DBU, MeC 88% Ac TBS orbol Arenes undergo [5+2] cycloadditions with olefins under photochemical conditions. This served as the basis for Wender's three step synthesis of siliphinene. (Tet. Lett. 1985, 26, 2625). For a more complete treatment of this reaction, see the group meeting presentation "Cyclopentane Synthesis" and Wender, P. A.; Siggel, L.; uss, J. M. "[3+2] and [5+2] Arene-Alkene otocycloadditions" in Comprehensive rganic Synthesis, Trost, B. M. ed. Volume 5, Br Li, 1% a Et 2, 3, 87% Li, Me 2, 66% hυ, 70% (1:1) [5 + 2] Cycloadditions The participation of 3-oxidopyriliums on [5+2] cyclodditions was initially reported in (Ullman, E. F.; Milks, J. E., JACS, 1962, 84, ). Wender used an intramolecular version of this reaction in his syntheses of orbol and esniferitoxin (JACS, 1997, 119, , ). TBS Bn TBS Ac Ac Bn 1. B 4, 0 C, 100% 2. mcpbaa, 0 C, 100% 3. Ac 2, DMAP, py 0 C, 100% Ac Bn TBS TBS Ac Ac Bn (+)-esniferitoxin DBU, MeC 80 C, 84% Me (+)-siliphinene Wender has developed rhodium catalyzed [5+2] cycloadditions of vinylcyclopropanes with a variety of 2π components. Intramolecular cycloaddition with an allene served as the key step in the syntheses of (+)-dictamnol and (+)-aphanamol I. (rg. Lett. 1999, 1(1), 137-9; 2000, 2(15), ). tbuli, Et 2, cprc, a -78 C to rt, 82% (Et) 2 ()P Me Bn 2 h, 90% CBS red. 78%, 91% ee MeMgBr, 0 C, Et 2 50% 1:1 dr [h(c)cl] 2 (0.5%) Me, 110 C, 0.5 h, 93% Me (+)-dictamnol Bn 1. [h(c)cl] 2 (2.5%) DCE, 80 C, 7 h, 76% 2. DMP, DCM, 80% I (+)-aphanamol 2

4 'Malley Wender also found that alkynones are viable substrates for intramolecular [5+2] cycloadditions. This reaction was used in the synthesis of the allocyanathin core (rg. Lett. 2001, 3(13), ). [h(c) 2 Cl] 2 (5%) DCE, 80 C, 3.5h 90% igher rder Cycloadditions in Synthesis C (+)-Allocyathin B 2 Mascarenas has discovered a method using chiral sulfoxides to direct the diastereoselectivity of oxidopyrillium cycloadditions. The diastereoselectivity appears to result from the rotational preference of the sulfoxide (rg. Lett., 2002, 4(21), ). Et 2 C C 2 Et : S Ac ptol DBU, Me, -30 C 3 h, 86% 1 diastereomer Et 2 C : S ptol C 2 Et aney i, TF 60 C, 82% Et 2 C C 2 Et Wender has developed a protocol for hetero [5+2] cycloadditions using cyclopropyl imines. JACS, 2002, 124, Bn 2 2. [h(c) 2 Cl] 2, C 60 C, Me, 82% Bn trans Me 2 C C 2 Me C Me 2 C 2 Me [4 + 4] Cycloadditions [4+4] cycloadditions are photochemically allowed. owever, the substrate range is very limited and the reactions often require harsh conditions (e.g. solid state dimerization of pyrones, Tet. Lett., 1971, hυ, solid state 100% brsm TFA, 50% C 2 The natural product Alteramide A was observed to undergo an intramolecular [4+4] cycloaddition upon UV irradiation. JC, 1992, 57(15), Et hυ, 0 C, 100% Et Wender has developed i catalyzed intramolecular [4+4] cycloadditions (JACS, 1986, 108, ) and applied the methodology to a short total synthesis of (+)- astericanolide (JACS, 1988, 110, ). 1. isobutyric anhydride 99% C 1.LiAl 4 93% 2. Swern, 88% 3. Li 88% 4. Swern, 89% 5. LiAl 4, Darvon 97%, 98% ee BuLi; C 2-56% MgX 57% B 3 TF; PCC 48% ed-al; Me 3 SnCl 83% i(cd) 2, P 3 90 C, 67% (+)-astericanolide 2. LDA, -78 to 0 C 69% SnMe 3 ed-al + Darvon Alcohol C 2 SnMe 3 ed-al, CuBr 74% aal 2 (C 2 C 2 Me) 2 Work on enantioselective intermolecular variations of this reaction has also been done. Although impressive selectivity in heterodimeriztions has been achieved, albeit in moderate enantioselectivity (tom Dieck et. al., ACIEE, 1992, 31, 305-6). =Ac, C, Me, Et Ac, % Ac Ac 2, BF 3 Et 2-50 to -20 C 8h, 40% Cl 2 Fe.5% butadienemg2tf (.7%) -17 C, 14 d, 89%, 61 % ee, BF 3 Et 2 20% i(ii), EtAlCl 2, hex 55 C, 12h, 50% = Me 2 3

5 'Malley igher rder Cycloadditions in Synthesis [6 + 2] Cycloadditions Feldman has studied the photochemical intramolecular cycloadditions of tropones. (JC, 1989, 54(3), ). This reaction was applied in a synthesis of (+)-dactylol (JACS, 1990, 112(23), ). Pd-C, 2-10 C, Me, 87% hυ, CCl 3, -60 C 41%, 11:1 dr 1. Acetylation 2. hυ, MPA, 2 50% * 1. C(Me) 2 2 Li 2. LiAl 4, 74% (+)-dactylol igby has developed Cr(0)-mediated [6+2] and hetero-[6+2] additions using Cr coordination complexes.this reaction was used to synthesize (+)-ferruginine (JC, 1995, 60, ). C 2 Me Tl( 3 ) 3 Me, 85% Me Cr(C) 3 Me Me 2 C Me C 2 hυ 1. Li, 84% 2.ClC 2 ibu, MM; --pyr-2-thione; tbus, hυ, 49% Me 2 C C 2 Me Me 2 C C 2 15%, >98%de 58%, >98%de Me 2 C Me ote: presence of exo product is very unusual. 1. TFA, 2 /acetone 2. MeMgBr; LiAl 4; DMP, 28% Wender has extended his h-catalyzed methodology to vinyl cyclobutanones (JACS, 2000, 122(32), ). X 1 h(i), (Ag(Tf)) X 2 Ts [h(c) 2 Cl] 2 Me, 110 C 0.75 h, 91% % for X=Ts,, C(C 2 Me) 2 ; 1, 2 =, Me Ts [6 + 4] cycloadditions igby has extensively studied both thermal and metal-mediated cycloadditions of a variety of partners (JACS, 1993, 115(4), ). (C) 3 Cr 140 C, 63% Me Me 1. hυ 2. P(Me) , 56% exo endo Interestingly, the electronic nature of the diene seems to have little effect on the yield of the metal-mediated reaction. Lewis acids appear to catalyze the thermal cycloaddition (Tet. Lett. 2002, 43, (+)-ferruginine FeCl 3 (0.25 eq), DCM, 4A mol. sieves 48 h, 85% Ti(iPr) 2 Cl 2 (0.3 eq), S-BIL (0.3 eq) DCM, 4A mol sieves, 36 h, 80%, 40% ee 4

6 'Malley igher rder Cycloadditions in Synthesis igby used the cycloaddition of a sulfone in a synthesis of estradiol (JACS, 1999, 121(36), ). 2 S 1.tBuK, -105 C Cr(C) 3 2. CS 3. tbuk, -105 C 60% TBS TBS 1. hυ 2. C, 70% 1. K(C 2 ) % 2. F 3. TES, TFA, 38% 4. Pb(TFA) 4, 80% S 2 (+)-estradiol Multicomponent Cycloadditions Lautens has reported enantioselective [4+2+2] cycloadditions with norbonadiene (JC, 1993, 58(17), , JACS, 1995, 117(26), ). Co(acac) 2, -Prophos Et 2 AlCl =Me, 66%, 72% ee =homoprenyl, 49%, 79% ee =(C 2 ) 3 Ac, 52%, 73% ee P. A. Evans, has done extensive work on [4+2+2] cycloadditions (JACS, 2002, 124, ). 3 P P 3 Ts [h(p 3 ) 3 Cl] (10%) butadiene, AgX Ts Ts Ts Me, reflux X=Tf: 85% 3% X=SbF 6 : 2% 89% Ts(Li) p Ts C 2 Me [h(p 3 ) 3 Cl] (10%) AgTf, Me, t; heat, 87% [h(p 3 ) 3 Cl] (10%) butadiene, AgX Me, reflux 91%, dr>19:1 Ts Ts p Prophos= TBS jima has discovered a method for intramolecular carbonylative [ ] cycloadditions (JACS, 2005, 127(50), Y X h(acac)(c) 2 (1%) C, TF, rt 50-90% (usually >80%) for =, X,Y=, Ts, C(C 2 Et) 2, C(C 2 P) 2, C(C 2 ) % for =Me,, (often includes [2+2+2] product) igby has discovered that Cr complexes can participate in [6+2+2] cycloadditions with alkynes. This process appears to be a [6+2] cycloaddition followed by a [4+2+2] cycloaddition. This was applied to a synthesis of 9-epi-pentalenic acid. (JC, 2004, 69, 6751) 2 C Cr(C) 3 9 TIPS hυ, DCE 70% X TIPS 9-epi-pentalenic acid Wender has extended his vinylcyclopropane methodology to carbonylative [5+2+1] cycloadditions for the synthesis of bicyclo[3.3.0]octanes (JACS, 2002, 124, ). E P E Y + Multiple examples: E=CMe, C 2, C, C 2 Me, =alkyl,, (C 2 Me works, but gives 48%) Ito has reported a carbonylative [4+4+1] dimerization of ene-allenes (ACIEE, 1998, 37(24), Pd(P 3 ) 4 (5%) C, TF, 40h, 61% E

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