Studies towards the Synthesis of (+)-Dictyoxetane

Abstract

The dolabellane-type diterpene dictyoxetane represents a significant challenge to synthetic organic chemistry. Methodology directed towards the total synthesis of naturally occurring (+)-dictyoxetane is reported. Catalytic asymmetric synthesis of the trans-hydrindane ring system is achieved through chemoselective deoxygenation of the Hajos-Parrish ketone. An alternative to the Garst-Spencer furan annulation is developed for the synthesis of a 2,5-dimethyl, tetrasubstituted furan, employing a tandem 5-exo-dig alcohol to alkyne cyclisation/aromatisation reaction as a key step. The (4+3) cycloaddition reaction of an oxyallyl cation with a tetrasubstituted furan is established on a cyclohexanone-derived model system, and a range of related (4+3) cycloadditions investigated on a homochiral, trans-hydrindane-fused furan, where regio- and diastereoselectivity is required for the natural product synthesis. In an alternative (4+2) Diels-Alder approach, a C₂ -symmetric vinyl sulfoxide-based chiral ketene equivalent is used to prepare oxanorbornenes with the same oxygen bridge stereochemistry found in the 2,7-dioxatricyclo[4.2.1.0^3,8 ]nonane ring system of the natural product.

Keywords: cyclization; cycloaddition; diastereoselectivity; natural products; oxygen heterocycles.

Scheme 1

Structure of (+)‐dictyoxetane 1 and core ring systems, our previously reported synthesis of racemic trans‐hydrindane 7, and application in Hugelshofer and Magauer's asymmetric synthesis of dictyoxetane. Conditions: a) ethylene glycol, pTSA, toluene, reflux under Dean‐Stark; b) OsO₄, NMO, H₂O, THF, ^t BuOH, 54 % (over 2 steps); c) PPh₃, C₂Cl₆, ⁱ Pr₂NEt, MeCN, 0→82 °C, 80 %; d) CeCl₃, ⁱ PrMgCl, THF, 23 °C, 91 %; e) i) (S)‐(‐)‐α‐methylbenzylamine, pTSA, toluene, reflux under Dean‐Stark, then methyl vinyl ketone, 40 °C, then AcOH, H₂O, 23 °C; ii) KOH, EtOH, 78 °C, 49 % (over 2 steps); f) Stewart‐Grubbs cat. (25 mol %), 2,6‐dichloro‐1,4‐benzoquinone, toluene, 111 °C, 55 %, 25 % recovered 9; g) TMSI, CH₂Cl₂, 0→23 °C, 92 %; h) O₂, hυ, TPP, DCE, 0 °C; PPh₃, 23 °C, 71 %; i) MsCl, NEt₃, CH₂Cl₂, −78 °C; j) NaH, THF, 66 °C, 88 % (over 2 steps); k) NIS, CH₂Cl₂, 23 °C; l) H₂, Pd/C, THF, 23 °C, 80 % (over 2 steps); pTSA=para‐toluenesulfonic acid, NMO=N‐methylmorpholine‐N‐oxide, TPP=tetraphenylporphyrin, Ms=methanesulfonyl, NIS=N‐iodosuccinimide.

Scheme 2

Previous approaches to the dioxatricyclic core of dictyoxetane. Conditions: a) Zn, B(OEt)_3, THF, rt, then Zn, CuCl, NH₄Cl, MeOH, 15 °C→rt, 59 %; b) TBAF, THF, rt→reflux; c) MsCl, ⁱ Pr₂NEt, MeCN, reflux, 45 %, isomer ratio 10 : 1 : 1 (only major shown); d) NaH, THF, reflux, 88 %; e) TMSOTf, CH₂Cl₂, −78 °C, 53 % (over 2 steps); f) BF₃⋅OEt₂, CH₂Cl₂, 0 °C, 72 %; g) CCl₄, 80 °C, 92 %; h) NaOH, MeOH, rt; TBAF=tetrabutylammonium fluoride, Ms=methanesulfonyl, TMS=trimethylsilyl, Tf=trifluoromethanesulfonyl, NIS=N‐iodosuccinimide, Ts=para‐toluenesulfonyl, Ac=acetyl.

Scheme 3

Proposed approach to dictyoxetane via tetrasubstituted furan 13.

Scheme 4

Asymmetric synthesis of benzyl‐protected trans‐hydrindanone 24 from 2‐methylcyclopentan‐1,3‐dione. Conditions: a) methyl vinyl ketone, AcOH, H₂O, 70 °C; b) (D)‐proline, DMF, 23 °C, then H₂SO₄, 73 % (over 2 steps), er 99.4:0.6; c) NaBH₄, MeOH, −20 °C, >99 %; d) Im₂CS, toluene, 110 °C, 87 %; e) NaH, CS₂, MeI, THF, 23 °C, 85 %; f) PhOC(S)Cl, Py, DMAP, CH₂Cl₂, 23 °C; g) ethylene glycol, pTSA, benzene, reflux under Dean‐Stark, 18 42 %; 20 75 %; h) ethylene glycol, pTSA, benzene, reflux under Dean‐Stark, 22 72 % (2 steps); i) (TMS)₃SiH, ACCN, toluene, 110 °C; j) K₂OsO₂(OH)₄, NMO, ^t BuOH, H₂O, 85 °C, 62 % (over 4 steps from 16); k) PPh₃, C₂Cl₆, ⁱ Pr₂NEt, MeCN, 0→82 °C, 96 %; l) ⁱ PrMgCl, CeCl₃, THF, 0 °C, 99 %; m) KHMDS, BnBr, THF, 0 °C; n) HCl, THF, 23 °C, 80 % (over 2 steps); Im=imidazole, Py=pyridine, DMAP=4‐dimethylaminopyridine, pTSA=para‐toluenesulfonic acid, ACCN=1,1′‐azobis(cyclohexanecarbonitrile), NMO=N‐methylmorpholine‐N‐oxide, KHMDS=potassium bis(trimethylsilyl)amide.

Scheme 5

Synthesis of model dioxatricyclic core precursor 30. Conditions: a) PBr₃, DMF, CH₂Cl₂, 88 %; b) Pd(PPh₃)₂Cl₂, CuI, Et₃N, TMSCCH, DMF, 82 %; c) MeMgBr, THF, −78 °C, 93 %; d) TBAF, THF, 66 °C, used crude; e) 29, TMSOTf, CH₂Cl₂, −78 °C, 87 % (over 2 steps), dr 7.7 : 1. TMS=trimethylsilyl, Tf=trifluoromethanesulfonyl, TBAF=tetrabutylammonium fluoride, TES=triethylsilyl.

Scheme 6

Attempted furan annulation on benzyl‐protected hydrindanone 24. Conditions: a) POCl₃, DMF, CH₂Cl₂, 75 %; b) CH₃CHO, LiHMDS, THF, −78 °C; c) CeCl₃, ⁿ BuLi, TMSCCH, THF, −78 °C, 43 % 36, 8 % 37, 7 % 38, 25 % 36+37 (over 2 steps); LiHMDS=lithium bis(trimethylsilyl)amide.

Scheme 7

Synthesis and furan annulation of TIPS‐protected hydrindanone 40. Conditions: a) KHMDS, TIPSCl, DMF, 0 °C; b) 4 M HCl, THF, 30 °C, 82 % (over 2 steps); c) PBr₃, DMF, 0→80 °C, 75 %; d) TMSCCH, Pd(PPh₃)₂Cl₂, Et₃N, THF, 65 °C; e) MeMgCl, THF, −78 °C, 91 % (over 2 steps), dr 3 : 1; f) K₂CO₃, MeOH, THF, 60 °C, 98 %; KHMDS=potassium bis(trimethylsilyl)amide, TIPS=triisopropylsilyl.

Scheme 8

Evaluation of a formal (4+3) cycloaddition approach to dictyoxetane using furan 43. Conditions: a) 45, Sc(OTf)₃, CH₂Cl₂, 0 °C, 18 % 46 2 % 47 15 % 48 9 % 49 ; b) 50 or 51, Et₃N, toluene, TFE, 16 °C; c) Zn dust, NH₄Cl, MeOH, 60 °C, 80 % from 50, dr 1.4 : 1, 59 % from 51, dr 4 : 1; d) 55, toluene, 23 °C, 91 % dr 1 : 1 or 56, toluene, −78 °C to 23 °C, 93 % dr 1 : 1; e) 56, toluene, 23 °C then 110 °C, 95 % combined yield of a 1 : 1 : 1 : 1 mixture of four isomers. Tf=trifluoromethanesulfonyl, TFE=2,2,2‐trifluoroethanol, Naph=2‐naphthyl, TES=triethylsilyl, TIPS=triisopropylsilyl.

Scheme 9

Alternative approach to intermediate 12.

Scheme 10

Diels‐Alder cycloaddition of furan 43 with chiral ketene equivalent 65. Conditions: a) 65, CH₂Cl₂, 0 °C, 82 % combined yield of 66 and 67, 3 : 4 ratio of regioisomers; b) TFAA, NaI, acetone, −78 °C, 73 % combined yield; c) MeI, CaCO₃, H₂O, THF, 60 °C, 41 % 70, 44 % 71; TFAA=trifluoroacetic anhydride.