Bicyclic -Ring Systems

Complex, multi-ring systems figure prominently in many aspects of organic chemistry, from exotic tests of theory to equally exotic natural products. We will encounter such systems throughout the text. Here we mention some fundamental issues inherent to multi-ring systems, beginning with a bit of nomenclature. 

Indenes and Indenones Indenestrol was identified [69] as a metabolite originating from the use of the very potent estrogen diethylstilbesterol (DES). Fligh transcriptional activity and 10-fold ERp selectivity were observed for the R-enantiomer 39. 

Benzothiophenes 2-Phenyl-benzothiophenes were described as ERP-selective agonists by Organon [71]. It was found that dibutyryl analog 42 exhibits 15-fold ERP selectivity in a CHO cell-based transactivation assay. Similar observations were made by Novartis [72]. Receptor binding studies showed 12-fold ERP selectivity for 43. Introduction of substituents at C3 or C4 reduced ERP selectivity. 

Complementary to the work on benzoxazoles, Wyeth investigated the prospects of 7-substituted benzofurans [81]. Due to the structural similarity between benzoxazoles and benzofurans it is not much of a surprise that the 7-substituted benzofurans showed high ERp selectivity. ERP affinity was also quite comparable to the corresponding benzofurans. Best results were obtained with 7-acetonitril analog 52, which showed 80-fold selectivity for ERp. Incorporation of an additional bromine at the 4-position (53) resulted in improved ERp affinity and ERP selectivity. 

Pyrazolo[l,5- i]pyrimidines The University of Illinois examined the estrogenic properties of the pyrazolo[l,5-a]pyrimidine scaffold [82]. The 6-OH-pyrazolo[l,5-a]pyrim-idine derivatives synthesized (e.g. 54) showed low affinity for either ERa or ERp, 

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Pyrolysis mass spectrometry, which does not require a volatile derivative, has been applied to various penicillins (78MI51100). These spectra contained fragments arising from the bicyclic ring system (4,5-dihydro-5,5-dimethylthiazole at mje 115, 1- and 2-methylpyrrole at mje 81 and unidentified peaks at m/e 100 and 125) as well as a series of fragments characteristic of the C(6) side chain. 

In 1980, a Merck group disclosed the results of a model study which amply demonstrated the efficiency with which the strained bicyclic ring system of thienamycin can be constructed by the carbene insertion cyclization strategy.12 Armed with this important precedent, Merck s process division developed and reported, in the same year, an alternative route to carbene precursor 4.13 Although this alternative approach suffers from the fact that it provides key intermediate 4, and ultimately thienamycin, in racemic form, it is very practical and is amenable to commercial scale production. The details of this interesting route are presented in Schemes 4-6. 

In bridged bicyclic ring systems, two rings share more than two atoms. In these cases, there may be fewer than 2" isomers because of the structure of the system. For example, there are only two isomers of camphor (a pair of enantiomers), although it has two chiral carbons. In both isomers, the methyl and hydrogen are cis. The trans pair of enantiomers is impossible in this case, since the bridge must be cis. The... 

Scheme 10.17 illustrates allylation by reaction of radical intermediates with allyl stannanes. The first entry uses a carbohydrate-derived xanthate as the radical source. The addition in this case is highly stereoselective because the shape of the bicyclic ring system provides a steric bias. In Entry 2, a primary phenylthiocar-bonate ester is used as the radical source. In Entry 3, the allyl group is introduced at a rather congested carbon. The reaction is completely stereoselective, presumably because of steric features of the tricyclic system. In Entry 4, a primary selenide serves as the radical source. Entry 5 involves a tandem alkylation-allylation with triethylboron generating the ethyl radical that initiates the reaction. This reaction was done in the presence of a Lewis acid, but lanthanide salts also give good results. 

Longifolene is a tricyclic sesquiterpene. It is a typical terpene hydrocarbon in terms of the structural complexity. The synthetic challenge lies in construction of the bicyclic ring system. Schemes 13.24 through 13.33 describe nine separate syntheses of longifolene. We wish to particularly emphasize the methods for carbon-carbon bond formation used in these syntheses. There are four stereogenic centers in longifolene,... 

Grubbs and coworkers [238] used the ROM/RCM to prepare novel oxa- and aza-heterocyclic compounds, using their catalyst 6/3-15 (Scheme 6/3.9 see also Table 6/3.1). As an example, 6/3-35 gave 6/3-36, by which the more reactive terminal alkene moiety reacts first and the resulting alkylidene opens the five-membered ring. In a similar reaction, namely a domino enyne process, fused bicyclic ring systems were formed. In this case the catalyst also reacts preferentially with the terminal alkene moiety. 

This chapter covers bicyclic ring systems with one bridgehead N atom and one extra heteroatom at each ring, and their benzo-fused derivatives. It surveys the literature from 1995 to early 2006 and is the continuation of <1996CHEC-II(8)633>. 

This chapter provides an update of Chapter 8.33 in CHEC-II(1996) <1996CHEC-II(8)863>. The work carried out on the bicyclic ring systems with ring junction P, As, Sb, or Bi has focused primarily on phosphorus. Very little work has been done on the other heteroatoms and as such the synthesis and reactivity of these compounds have been reviewed as one section, Section 12.12.7. Most of the compounds in this class contain more than one heteroatom, the additional atoms usually being oxygen and nitrogen. 

Alder et al. have studied various nonfused bicyclic ring systems with differing ring sizes with respect to the in,out-geometry displayed by these compounds <2001 JCS(P2)>. Compound 293 was synthesized and was found to favor... 

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

Both natural and non-natural compounds with a 2ff,5ff-pyrano[4,3-fc]pyran-5-one skeleton are of interest in medicinal chemistry. Several natural products, such as the pyripyropenes, incorporate this bicyclic ring system. The group of Beifuss has described an efficient microwave-promoted domino synthesis of the 2ff,5H-pyr-ano[4,3-fo]pyran-5-one skeleton by condensation of a,/3-unsaturated aldehydes with 4-hydroxy-6-methyl-2]-f-pyran-2-one (Scheme 6.244) [428]. It is assumed that in the presence of an amino acid catalyst a Knoevenagel condensation occurs first, which is then followed by a 6jr-electron electrocyclization to the pyran ring. While the conventional thermal protocol required a reaction time of up to 25 h (refluxing ethyl... 

Similarly, in a 1,3-dipolar cycloaddition of DMAD to the conformationally locked cyclic a-alkoxycarbonylnitrone (727), bicyclic ring systems, containing a nitrogen atom at the bridgehead position have been synthesized. A mechanistic interpretation of the origin of the fused pyrroles (729) includes the intermediate formation of the aziridine ring in (728) (Scheme 2.303) (820). 

The [5,5]-fused bicyclic ring system with one fusion nitrogen atom and three additional heteroatoms in a 2 1 distribution over both ffve-membered rings (2N1) is the origin of a great number of structures. The additional heteroatoms are mainly nitrogen, oxygen, or sulfur, and less commonly phosphorus or silicon atoms. 

There has been no specific review published in this particular field of 5-5 bicyclic ring systems, so that attention has to be drawn to the earlier contributions produced in CHEC(1984) and CHEC-II(1996) <1996CHEC-II(8)227>. 

There are only a few new theoretical studies of new 5-5 bicyclic ring systems. In one study azido-tetrazole isomerization was investigated (Scheme 1) <1998JOC2354, 1998JA4723>. The model systems chosen were fully conjugated (10-7T-electrons) thiazolo[3,2-<7]tetrazole in its unsubstituted form as well as substituted derivatives. 

The newly synthesized 5-5 bicyclic ring systems are mostly completely characterized using standard analytical techniques. Nevertheless, some 5-5 bicyclic ring systems are only sparsely characterized. Accordingly, 13C and H NMR chemical shifts are reported for most of these new compounds. Figure 2 shows the structures of the new compounds which are especially characterized by 13C NMR spectroscopy and other analytical methods. 

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