Chemospecific and diastereoselective synthesis of bis-dioxabicyclo[2.2.1]heptanone ring systems

This


Introduction
Achieving the maximum pertinent complexity increase while minimizing the number of steps is an ideal in synthetic organic chemistry. 1Reactions leading to multi C-C bond formations through tandem processes, which can rapidly generate the molecular complexity in a controlled and predictable manner, is a contemporary theme in modern organic synthesis and finds application in accessing newer entities.Tandem processes of diverse nature, promoted through catalysis, thermal or photochemical activation have already proven their utility in organic synthesis and found many applications in the acquisition of complexity in the form of functionalized carboand heterocyclic systems.Reactions based on carbenoid transformations are among the synthetically most useful to increase the molecular complexity. 2,3Rhodium(II) carbenoid generated from α-diazo carbonyl compounds and their subsequent reactions play an important role in synthetic organic chemistry to design various polycyclic compounds with regio-and stereocontrol.This methodology serves as an important protocol to construct bonds for the synthesis of complex molecules 3 and various natural products 4 with atom economy.Thus, this methodology generates considerable interest and intensive investigation in synthetic organic chemistry.Metallo-carbenoid cyclization with a carbonyl group represents a most important method for the generation of carbonyl ylides from α-diazo carbonyl compounds and their subsequent 1,3-dipolar cycloaddition reactions with C=C bonds have been well documented. 3rom a survey of the literature, only a few examples are known for the 1,3-dipolar cycloaddition of carbonyl ylides with heterodipolarophiles such as carbonyl group.For example, reactions of five-or six-membered-ring cyclic carbonyl ylides with o-quinones, 5 p-benzoquinones, 6,7 1,2diketones 8 and other carbonyl compounds 9 have been studied to afford 1:1, 2:1 or 3:1 cycloadducts without any selectivity in the presence of copper or rhodium catalysts.These tandem cyclization-cycloaddition protocols have been successfully utilized in the synthesis of important biologically active compounds such as brevicomins 10 and zaragozic acid A 11 using propionaldehyde and glyoxalate as heterodipolarophiles, respectively.Furthermore, the dioxabicyclo[2.2.1]heptanone skeleton is present in a wide range of natural products and exists as part of polycyclic frameworks e.g.loukacinols, 12 xanthane epoxide, 13 and isogosterones. 14But the chemistry and the selectivity of these reactions have not been investigated well.The control of the stereoselectivity in the cycloaddition reactions of carbonyl ylides poses a challenge with the prospect of applications towards the synthesis of natural products.In continuation of our interest in the synthesis of highly substituted epoxy-bridged poly-or spirocyclic frameworks, 6,8,15 we recently reported on the chemoselective synthesis of multiple dioxabicyclo[2.2.1]heptanone ring systems. 16We herein report the detailed investigation on the tandem cyclization-[3+2]cycloaddition reactions of five-membered-ring carbonyl ylides for the synthesis of bisdioxabicyclo[2.2.1]heptanone ring systems.

Results and Discussion
It was envisaged that the reaction of α-diazo ketones such as 1 or 4 with Rh 2 (OAc) 4 could generate the corresponding rhodium carbenoids 2 or 5 based on our earlier work. 6The respective transient five-membered-ring cyclic carbonyl ylides 3 or 6 could successfully be generated by nucleophilic attack of ring oxygen atom to electron deficient rhodium-carbenoid carbon atom present in intermediates 2 or 5 (Scheme 1).Thus, the required starting materials of type 1 or 4 were prepared according to the literature procedure 6 and the tandem cyclization-cycloaddition reactions of the diazo ketones 1 or 4 with the keto-functional groups as heterodipolarophile have been investigated (Table 1).Initially, we studied the reaction of cyclic diazo ketones 1 with the compound having two keto-groups placed in 1,4-fashion on a rigid cyclic system.For this purpose, an excess of cyclohexane fused diazo ketone 1a was added to a dichloromethane solution containing anthraquinone and a catalytic amount of Rh 2 (OAc) 4 under an argon atmosphere.The reaction afforded the symmetric bis-cycloadduct 7 in 60% yield (Scheme 2).The formation of bisdioxabicyclo[2.2.1]heptanone ring system 7 in a chemospecific and diastereoselective manner was confirmed by spectral and crystallographic analyses.Similarly, the reaction of diazo ketone 4a and cyclopropane fused acyclic diazo ketone 4c with anthraquinone afforded the respective symmetric bis-cycloadducts 8 and 9 16 in good yields (Scheme 2, Table 2) as a single isomer.
Consequently, we chose acenaphthenequinone as another dipolarophile, where keto-groups are placed in 1,2-fashion to investigate the above reaction in the presence of excess diazo ketones 1a and 4a.Thus, we performed the reaction of excess α-diazo ketone 1a with acenaphthenequinone in the presence of Rh 2 (OAc) 4 to furnish bis-dioxabicyclo[2.2.1]heptanone ring system 10a as a minor isomer along with mono-dioxabicyclo[2.2.1]heptanone ring systems 10b,c as a diastereomeric mixture.And the crude nmr spectrum showed the formation of products in the ratio of 1:1:1.5.Similarly, diazo ketone 4a with acenaphthenequinone afforded bis-epoxy-bridged cycloadduct 11a as a minor isomer along with mono-epoxy-bridged cycloadducts 11b,c as a diastereomeric mixture and the crude nmr spectrum showed the formation of products in the ratio of 1:1:1.5.The bis-cycloadducts 10a and 11a were obtained only in poor (20 and 25%) yields even in the presence of excess diazo ketones.A reason for this may be due to steric hindrance arising from the proximity of an already installed dioxabicyclo[2.2.1]heptanone ring system.

Table 2. Reaction of carbonyl ylides 3 or 6 with anthraquinone and acenaphthenequinone
a Yields (unoptimized) refer to isolated and chromatographically pure compounds.b Ref. 16. c Only the yield of bis-cycloadduct is provided.
After studying the tandem reaction of diazo ketones with 1,2-and 1,4-diketo functionalities placed on a rigid ring system, we extended the reaction of cyclic carbonyl ylides 3 and 6 with substrates having 1,4-diketo-functionalities on a flexible ring system.Thus, an excess of diazo ketone 1a was reacted with 1,4-cyclohexanedione in the presence of a catalytic amount of Rh 2 (OAc) 4 under an argon atmosphere.The crude reaction mixture was investigated by 1 H NMR spectroscopy, which indicated formation of the bis-dioxabicyclo[2.2.1]heptanone ring system as a mixture of diastereomers in the ratio of 1:3.These diastereomers were separated by column chromatography to afford products 13a and 13b in 45 and 17% yield, respectively (Scheme 3, Table 3).The IR spectrum of compound 13a showed a band at 1763 cm -1 for the presence of a keto-functionality in a strained ring.The 1 H NMR spectrum of compound 13a exhibited two singlets for both the bridgehead protons (H a ) at 4.23 and 4.21 ppm.Characteristically, 13 C NMR spectrum of the product 13a showed a single resonance at 87.2, 214.1 ppm for the bridgehead 17 (C-H a ) and the carbonyl (C=O) carbons, respectively.Further, the single crystal X-ray crystallographic analysis 18 of compound 13a (Figure 1) clearly revealed that the stereochemistry of the interesting bis-cycloadduct 13a has the trans-geometry on cyclohexane ring system.Based on the interrelated spectroscopic analyses, the minor isomer was tentatively assigned as biscycloadduct 13b with cis-geometry.

ISSN 1424-6376
Page 150  It is apparent that two consecutive 1,3-dipolar cycloaddition reactions took place with carbonyl groups of 1,4-cyclohexanedione rather than at the carbonyl groups present on dioxabicyclo[2.2.1]heptane ring system of the initially formed dioxabicyclo[2.2.1]heptane ring system of the mono-cycloadduct 12 to eventually yield the bis-cycloadducts 13a,b in a chemospecific manner.After the first cycloaddition, the keto-group present on the cyclohexane ring of product 12 (obtained via mono-cycloaddition of carbonyl ylide 3a) constitutes a platform, which led to two possible reaction pathways as shown in Scheme 3. Route a shows that the reaction of the carbonyl ylide dipole via equatorial addition to the keto-group of compound 12 leads to the trans isomer 13a.The alternative pathway, route b, indicates reaction of the carbonyl ylide dipole via axial addition to the keto-group of compound 12 to furnish the cis-isomer 13b.A similar reaction was performed with diazo ketone 4a to afford products 14a,b in 23 and 45% yield, respectively.The spectroscopic analyses revealed that the products 14a,b were derived from the double cycloaddition of carbonyl ylides to the carbonyl groups of 1,4cyclohexanedione as a diastereomeric mixture in the ratio of 1:2.The stereochemistry of product 14b is unequivocally confirmed as the cis-geometry on cyclohexane ring system based on the single-crystal X-ray analysis 19 (Figure 2).The stereochemistry of compound 14a is tentatively assigned as the trans-geometry based on the interrelated spectral analysis.Interestingly, we did not observe any other cycloadducts arising from the carbonyl groups present in the oxanorboranane ring system.The trans-and cis-isomers were predominant, when the diazo ketones 1a and 4a employed, respectively (Table 3).A reason for this may be due to the preference of approach of the respective carbonyl ylide intermediates 3a and 6a (path a and b, Scheme 3).This interesting observation encouraged us to further investigate to achieve a single isomer.To this end, we planned to replace H a in products 13 and 14 by an ethyl ester group.Thus, reaction was conducted between 1,4-diketocyclohexane and diazo ketone 1b.Interestingly, this reaction afforded bis-cycloadduct 16a as a single isomer in good yield (Scheme 4, Table 4).Singlecrystal X-ray crystallographic analysis 20 of bis-cycloadduct 16a confirmed its trans-geometry.Similarly, the reaction of diazo ketone 4b having ester functionality also furnished compound 17a as a single isomer and its stereochemistry is also assigned the trans-geometry based on the spectral similarities to 16a.  a Yields (unoptimized) refer to isolated and chromatographically pure compounds.
The formation of the alternative cis-isomers of type 16b and 17b (Figure 4) have been ruled out in the above reactions (Scheme 4) because of the prevailing steric hindrance when the ester substituent present in compound 15 completely restricts the axial approach of carbonyl ylide dipole.Thus, multiple tandem reactions of diazo ketones 1b and 4b having the ester substituent afforded the bis-cycloadducts 16a and 17a in good yield via equatorial addition of carbonyl ylide dipole with high stereoselectivity and chemospecificity.Essentially, in all the above reactions, there was no formation of such 2:1 or 3:1 cycloadducts such as compound 18 (Figure 4) even in the presence of an excess amount of diazo ketone.

Figure 4
In conclusion, tandem reactions of diazo ketones were demonstrated on examples having 1,2and 1,4-diketo-functionalities placed on rigid as well as flexible frameworks.The transient fivemembered-ring carbonyl ylides generated from α-diazo ketones underwent 1,3-dipolar cycloaddition reactions with keto-functionality to afford various bisdioxabicyclo[2.2.1]heptanone ring systems in a chemospecific and diastereoselective manner.In this process, construction of many stereocenters and up to 6 chemical bonds is attained in a single synthetic operation.