Carbon-carbon bond cleavage in norbornane derivatives. Convenient route to novel carbocyclic rings

Various ways of ring opening of norbornane derivatives resulting in the stereoselective synthesis of substituted cyclopentanes, cyclohexanes, fused and bridged rings have been reviewed briefly.


Introduction
Norbornene and its dihydro derivative norbornane are considerably strained molecules. 1Because of the high ground state energy associated with these angle strained molecules, reactions that lead to ring opening proceed readily.The proclivity of the norbornane derivatives to undergo facile ring opening combined with their easy availability through stereoselective Diels-Alder reaction of readily available cyclopentadiene derivatives have made norbornanes useful synthetic intermediates.Ring opening of norbornene derivative can be achieved through scission of either of the four topographically different carbon-carbon bonds viz.'a', 'b', 'c' or 'd' (Chart 1).With the development of novel reagents and new methodologies for chemo-, regio-and stereoselective reactions it has become possible to realise cleavage of all these bonds.This has resulted in the synthesis of a variety of novel ring systems with defined stereochemistry such as substituted cyclopentanes, cyclohexanes, fused and bridged rings.The objective of this paper is to summarise the various ways 2 of ring opening of norbornane derivatives with illustrative examples.

Cleavage of Bond 'a' (path-1) (i) Synthesis of substituted cyclopentanes
Cleavage of bond 'a' in norbornane derivatives offers an easy access to cis-1,3-disubstituted cyclopentanes.cis-1,3-Disubstituted cyclopentanes have been used as intermediates in the synthesis of terpenoids 3 as well as in the synthesis of carbocyclic nucleosides. 4ing opening of norbornane derivatives through cleavage of bond 'a' dates back to 1906 when Semmler 5 demonstrated that fenchone 1a on treatment with sodamide gave the cyclopentane carboxylic acid amide 2a (Scheme-1).Subsequently it was shown that some other 2-norbornanones 6 such as 1b under similar condition produced the ring opened product 2b.

Me
Me R

Scheme 1
The carbon-carbon σ bond in succinic ester derivatives has been found to undergo cleavage 7 when treated with Na-NH 3 (l) at low temperature.This concept was employed by Gassman and Creary 8 to achieve ring opening of the norbornene derivative 3 to produce cis-1,3-disubstituted cyclopentene derivative 4 in excellent yield (Scheme-2).

Scheme 2
A reductive retrograde aldol C-C bond fission strategy was employed by Katagiri et al 9 for ring opening of the norbornane derivative 5 to produce stereoselectively the cyclopentane derivative 6 in quantitative yield (Scheme-3).The compound 6 has been employed for the synthesis of carbocyclic analogue of oxazinomycin.(ii) Synthesis of bridged rings Cleavage of bond 'a' in systems having a ring annulated at the bond 'a' of norbornene, provides a convenient route to novel bridged ring systems.For example, the 1,4-bis mesylates 9a and 9b underwent 11 a Grob-like fragmentation to afford bicyclo[3.2.1]octene 10a and bicyclo [4.2.1]nonene 10b (Scheme-5), respectively under reductive condition.

Scheme 5
Synthesis of eight-12 and nine-membered rings has been a long standing problem 13 because of difficulties arising out of the high degree of ring strain and transannular reaction present in them.An appropriately constructed norbornene derivative on ring opening can provide a facile access to these ring systems.Ghosh et al demonstrated 14 that when the 1,4-bis mesylates 11 and 13 were heated with zinc powder and NaI in HMPA, Grob fragmentation took place to afford the bridged eight-membered rings 12 and 14, respectively (Scheme-6).

Scheme 6
Appropriately chosen functional groups on the norbornane derivatives and reducing agent give rise to ring opened products with chemodifferentiated functional groups for further elaboration.For example, the dimethyl esters 15a,b when treated with Na-NH 3 (l) at -55 o C underwent C-C bond cleavage 15  Ring strain, functional groups and reducing agent have been found to have profound influence on the reaction course in these systems.The chloro-ester 18 underwent a smooth radical induced bond fragmentation 16 when treated with Bu 3 SnH to produce the ring opened product 19 in 88% yield (Scheme-8).However, C-C bond cleavage did not take place in the relatively less strained chloro-esters 20 and 22 under similar condition and gave exclusively the reduced products 21 and 23 (Scheme-8), respectively. 17n contrast to these observations, SmI 2 has been found to be very effective in C-C bond fragmentation 10 in both norbornene and norbornane systems 24 and 26 to produce the bridged eight-membered rings 25 and 27 (Scheme-9) in excellent yields.Based on these findings of Haque and Ghosh, Williams et al 18 recently showed that bridged nine-membered ring 29 could also be formed albeit in low yield from the norbornene derivative 28 (Scheme-10).In an approach to cyclopentitols, Mehta and Mohal 22 employed the cleavage of bond 'b' in the 2,7-disubstituted norbornane derivative 37 through a Grob-like fragmentation to afford the substituted cyclopentene derivative 38 as the major product (Scheme-14).

Scheme 17
Haller-Bauer cleavage of 7-norbornenone derivative 46 having an eight-membered ring has also been employed 30 for the synthesis of cis-bicyclo [6.4.

Scheme 20
A tandem ring opening-ring closing metathesis in the norbornane derivatives has been of great use in the synthesis of multicyclic compounds.For example, Grubbs and coworkers have shown that the norbornene derivative 54 on heating in benzene with a catalytic quantity of the catalyst 50 afforded the fused tricycle 55 (Scheme-21) via ring opening of the norbornene ring followed by a double ring closing metathesis.

Scheme 23
Ring opening of norbornene through a sequence of ring opening metathesis and cross metathesis using a chiral molybdenum carbene complex has recently been shown by Hoveyda et al 34 to be an extremely efficient process for enantioselective synthesis of substituted cyclopentanes.A representative example involves treatment of the norbornene derivative 58 in benzene solution with 2 equivalent of styrene in the presence of 5 mol% of the catalyst 60 at 22°C to afford the substituted cyclopentane 59 (Scheme-23) in 57% yield with 96% ee.Even >98% ee was observed during such transformation when vinyl silane was used for cross metathesis.

Conclusions
The results discussed here show that C-C bond scission of norbornane derivatives has proven to be an efficient approach for the stereoselective synthesis of substituted cyclopentanes, cyclohexanes, fused rings and novel bridged rings.Since norbornene derivatives can be prepared stereoselectively through Diels-Alder reaction of cyclopentadiene derivatives, synthetic strategy involving Diels-Alder cycloaddition and subsequent fragmentation provides great application opportunities in organic synthesis.
© ARKAT USA, Inc 16a,b 31dodecane 47 present in taxanes (Scheme-18).Blechert et al31demonstrated that symmetrical norbornenes such as 48 in presence of a slight excess of terminal alkene produced only the tetrasubstituted cyclopentene 49 (Scheme-19) in excellent yield using the Ru-catalyst 50.Regioselectivity in ring opening of unsymmetrical norbornenes during ring opening metathesis was also observed.Thus, reaction of dicyclopentadiene 51 with allysilane afford a 3:1 mixture of the two regioisomeric products 52 and 53 (Scheme-20).The advantage of this ring opening cross metathesis reaction is the conversion of norbornene derivatives with defined configuration into substituted cyclopentanes of defined configuration.
Reaction of norbornene derivatives with a metal-carbene complex leading to ring opening (popularly known as ring opening metathesis) and subsequent coupling with an acyclic alkene (cross metathesis) provides a novel way of cleaving olefinic bond in norbornene derivatives.© ARKAT USA, Inc

Scheme 21 Issue in Honor of Prof. S. V. Kessar ARKIVOC 2002 (vii) 8-20 ISSN 1424-6376 Page 18
33ragies and Blechert33have accomplished the synthesis of [n.3.0]bicycles using a domino process involving ring closing-, ring opening-and cross metathesis.Thus, the norbornene derivatives 56 on treatment with a catalytic quantity of the Ru-catalyst 50 in the presence of a terminal alkene, allyl trimethly silane or ethylene, provided the bicycles 57 (Scheme-22).Higher yields of the products were obtained with Schrock's molybdenum complex PhMe 2 CCH=Mo=N[2,6-(isoPr 2 C 6 H 3 ] [OCMe(CF 3 ) 2 ] 2 The facile synthesis of the carbocyclic eight-membered ring 56 (n=3) is noteworthy as this ring system is particularly difficult to construct by other methods including ring closing metathesis.