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Synthesis of cis,cis,cis,cis-[5.5.5.5]-1-Azafenestrane

2002; Wiley; Volume: 41; Issue: 21 Linguagem: Inglês

10.1002/1521-3773(20021104)41

1521-3773

Scott E. Denmark, L.A. Kramps, Justin I. Montgomery,

Synthetic Organic Chemistry Methods

To provide an opportunity for X-ray analysis of an unsubstituted fenestrane, one of the ring-fusion carbon atoms was replaced with a nitrogen atom to facilitate salt formation; the key strategic step to the first 1-azafenestrane (see scheme) involves the tandem [4+2]/[3+2] cycloaddition of a nitrocyclopentene with butyl vinyl ether. The adduct with borane provided crystals suitable for X-ray analysis, which revealed the planar deformation of the central carbon atom to be modest (116.1 and 116.6°). The structural theory of organic chemistry is one of the most highly evolved constructs in natural science. The ability to explain and correctly predict the detailed molecular structure of millions of compounds naturally inspires research to test the limits of the theory. One important subset of this field of investigation probes the extent to which a tetracoordinate carbon atom (bearing all carbon substituents) can deviate from the van't Hoff/Le Bel tetrahedral geometry. The interesting family of compounds called fenestranes1 comprises molecules with planarizing distortion of the central carbon atom. The magnitude of the distortion is dependent on the size and configuration of the fused rings. Because the parent, unsubstituted fenestranes are low molecular weight hydrocarbons, they are not amenable to X-ray crystallographic analysis. The few X-ray structures on record are of substituted and functionalized derivatives.2 We were intrigued by the possibility of replacing one of the ring-fusion carbon atoms with a nitrogen atom to facilitate salt formation and provide an opportunity for X-ray analysis of an unsubstituted fenestrane. In addition to establishing the full molecular structure and the extent of the central carbon planarization, the pyramidal distortion of the nitrogen atom would also be of interest; to our knowledge, no monoazafenestranes have been prepared. An unusual tetraamino [5.5.5.5]fenestrane is known and it exists as an equilibrium mixture of (degenerate) open and closed forms when protonated.3 We describe herein the first synthesis of an unsubstituted 1-azafenestrane 1 along with the synthesis and X-ray crystallographic analysis of the borane adduct 1⋅BH31 . Analysis of the tetracyclic ring structure of 1 reveals that it contains an embedded pyrrolizidine unit fused to a bicyclo[3.3.0]octane system. In recent years, a large number of pyrrolizidine-based alkaloid natural products in the necine, alexine and australine families have been synthesized in these laboratories.4 The key strategic operation in all of these syntheses is the tandem [4+2]/[3+2] cycloaddition of nitroalkenes.5 This process allows for the facile and stereocontrolled construction of highly functionalized nitroso acetals that serve as precursors for pyrrolizidines upon catalytic hydrogenolysis. The application of the tandem cycloaddition strategy to the synthesis of 1 is outlined in Scheme 1. Constructing the core of 1 requires the creation of one of the four rings in the tandem [4+2]/[3+2] process by cycloaddition of a C2 dienophile (butyl vinyl ether (3)) with a cyclopentenyl nitro diene 2 (ring C) bearing the suitable dipolarophilic tether. The tetracyclic nitroso acetal 4 is then poised for hydrogenolytic unmasking to a tricyclic pyrrolizidine (third ring, c) which should undergo spontaneous lactam formation (→5; fourth ring, d) from the appended carboxylic ester. Thus, three of the four rings of [5.5.5.5]-1-azafenestrane can be assembled in two chemical manipulations. Two-stage reduction of the α-hydroxy lactam 5 leads to the target azafenestrane 1. This approach allows for a modular synthesis of fenestranes containing rings of different size at various positions. With regard to the configuration at the ring fusions, only one relationship was expected to be variable. In the [4+2] process, the approach of the dienophile can take place on the two diastereotopic faces of the nitroalkene to create cis and trans isomers. The [3+2] process is formally in the spiro mode family6 and thus is expected to proceed via an exo-mode pathway to create a cis ring fusion independent of the tether length. Retrosynthetic strategy for the construction of azafenestrane 1 by tandem [4+2]/[3+2] cycloaddition. Piv=pivaloyl, THP=tetrahydropyranyl. The side chain of nitroalkene 2 (that creates ring d) could be introduced by nucleophilic addition to the nitro allylation reagent 6.7 The required nucleophiles (alkyllithium reagents) could be obtained by halogen–metal exchange from the corresponding iodides 7 and 8. Each side chain precursor requires a different sequence to complete the construction of the desired α,β-unsaturated ester: 1) Horner-Wadsworth-Emmons (HWE) or Wittig reaction with aldehyde 9 and 2) oxidation of an allyl alcohol 10 to the acid followed by esterification. Both approaches were pursued in view of the unknown sensitivity of the nitroalkene to these agents. The synthesis began by preparation of the key subunits (Scheme 2). Pivalate 6 was prepared by modification of procedures for the synthesis of the analogous cyclohexene derivative.7 Unfortunately, the cyclopentenyl case could not be optimized above 9 %, but the reactions could be scaled up by using inexpensive starting materials. The iodo acetal 78 and THP-protected iodide 89 were prepared directly and by adaptation of literature procedures, respectively. a) 1. HCl, 80 °C, 2. NaOH, MeNO2, H2O, MeOH, RT, 3. Al2O3, 40 °C; b) pivalic anhydride, H2SO4, 9 % (four steps); c) LiAlH4, Et2O, reflux, 70 %; d) TsCl, Et3N, CH2Cl2 0 °C, 90 %; e) NaI, acetone, reflux, 99 %. Ts=tosyl. The nitro allylating agent 6 behaved similarly toward the two organolithium nucleophiles derived from 7 and 8 by iodine–lithium exchange with tert-butyl lithium10 (Scheme 3). Both the aldehyde 9 and the primary alcohol 10 were obtained in comparable, synthetically viable yields after hydrolysis of the protective groups. Homologation of 9 by using either methyl (triphenylphosphoranylidene)acetate or trimethylphosphonoacetate (with nBuLi) afforded low (15–22 %) yields of 2. The oxidation of alcohol 10 could be effected with the Jones reagent, but low yields were obtained and the purification of the product proved to be difficult. Better results were obtained when [(H2bipy)Cl5CrO]11 in CH2Cl2 was used. This chromium(V) complex afforded a mixture of acid and acid chloride, which could be converted to the desired ester 2 simply by treatment with MeOH. The remaining carboxylic acid could be converted to 2 with diazomethane. a) 1. tBuLi, THF/hexane/Et2O, −100 °C, 2. 6, −50 °C, TsOH, aq. acetone, 61 %; b) trimethylphosphonoacetate, nBuLi, THF, −70 °C, 22 %; c) 1. tBuLi, THF/hexane/Et2O, −100 °C, 2. 6, −50 °C, TsOH, MeOH, 67 %; d) Dess–Martin reagent, CH2Cl2, 89 %; e) 1. [(H2bipy)Cl5CrO], CH2Cl2, 2. MeOH, 3. CH2N2, 36 % (three steps). The [4+2] cycloaddition of nitroalkene 2 and butyl vinyl ether (3) afforded two diastereomers of nitronate 13. Only one of these diastereomers underwent spontaneous [3+2] cycloaddition to give nitroso acetal 4 a (Scheme 4). Nuclear Overhauser NMR spectroscopic investigations of 4 a confirmed the relative configuration of this compound (Scheme 5). a) 3, Me3Al, toluene, −70 °C, 4 a (67 %) and 16 b (27 %); b) Raney nickel, H2 (1100 kPa, 160 psi), MeOH 72 %; c) benzene, K2CO3, 80 °C, 70 %. nOe analysis of nitroso acetal 4 a. The reaction has not been optimized to control the diastereoselectivity by the use of different Lewis-acids. Increasing the selectivity of the reaction would improve the yield of nitroso acetal 13 a. Nitronate 13 b is also a useful compound and the separation from the nitroso acetal 4 a was easy because of the high polarity of 13 b compared to that of 4 a. Preliminary investigations indicated that the nitronate 13 b can undergo [4+2] cycloaddition at elevated temperature (NaHCO3, toluene, 97 °C) to give the diastereomeric nitroso acetal 4 b, which can potentially be transformed to diastereomeric fenestrane 1 b (Scheme 4). Hydrogenation of nitroso acetal 4 a afforded hydroxy 1-azafenestranone 5 in 72 % yield. The yield of 5 from nitroalkene 2 is 48 %—remarkable for the formation of a fenestrane skeleton. Completion of the synthesis required two deoxygenation steps (Scheme 6). First, the hydroxy group was removed by conversion to the phenyl thionocarbonate 12, which was reduced with nBu3SnH/AIBN by a method originally described by Barton and McCombie.12 The resulting lactam 13 was reduced with LiAlH4 to give the target cis,cis,cis,cis-[5.5.5.5]-1-azafenestrane (1). a) Phenyl thionochloroformate, pyridine, DMAP, 77 %, b) nBu3SnH, AIBN, benzene, reflux, 98 %; c) LiAlH4, THF, reflux, 83 %. The spectroscopic data for 1 clearly support the structure and Ch symmetry of the molecule (seven 13C NMR signals).13 To secure the detailed molecular structure, we surveyed the formation of crystalline salts and found that treatment of 1 with a solution of borane in THF formed an adduct (as judged by 1H NMR analysis) which could be recrystallized from diethyl ether to afford 1⋅BH3 as colorless needles. X-ray crystallographic analysis14 of 1⋅BH3 (Figure 1) confirms the gross molecular structure but also reveals that the compound crystallizes in a chiral space group (P21) because of the twist of the five-membered rings (dihedral angle B-N(1)-C(13)-C(7)=11.6°).15 The planarization of the central carbon atom (C(13)) is only modest as defined by the two orthogonal bond angles: N-C(13)-C(7)=116.1° and C(4)-C(13)-C(10)=116.6°. This was not unexpected as these angles in the all-cis stereoisomer of the parent [5.5.5.5]fenestrane hydrocarbon are calculated to be 113°.1 SHELXTL plot of 1⋅BH3 from X-ray analysis (35 % thermal ellipsoids). In summary, we have demonstrated the feasibility of a tandem cycloaddition approach to 1-azafenestranes and the ability to obtain crystalline adducts suitable for X-ray analysis. The preparation of more strained and flattened congeners is underway and will be reported in due course. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2002/z19766_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.