Synthetic Efforts Towards Anthracyclines Using the Asymmetric Diels-Alder Reaction

Transcription

1 1 Synthetic Efforts Towards Anthracyclines Using the Asymmetric Diels-Alder Reaction D C B A Me Me N 2 Figure 1: Doxorubicin (DX) 1. Introduction Doxorubicin (1) is an effective drug used in chemotherapy, although other types of drugs are being developed and used with the anthracyclines 1 such as the taxanes. DX has the 3-D structures below (Figures 2-3); notice in DXa that the rings-a to D are nearly flat, but slightly buckled and the special half chair geometry of the ring-a in DXb reveals the chair conformation of the daunosamine (sugar) auxiliary. KEY: In all 3-D structures, the atoms are not shown, however the bonds surrounding oxygen are red, the bonds surrounding carbon are grey, the bonds surrounding nitrogen are blue, the bond attaching hydrogen is light blue and the bonds surrounding silicon are dark blue.

2 2 Figure 2: DXa Figure 3: DXb Crucial to the synthesis and a method for inducing the stereochemistry into the ring-a, is the asymmetric Diels-Alder reaction and has been extensively developed by the Stoodley group, Manchester, U.K. The D-glucose based diene (as type 2 or 3), a modified Danishefsky s Diene, used the -D-glucose moiety to control the stereochemistry of the cycloaddition; its 3-D structure is shown on the right (Figure 4). Notice the chair formation of the sugar group, which is its most stable form.

3 3 SiMe 2 Bu t Ac Ac Ac Ac Figure 4: D-Glucose based Diene In all cases, the major cycloadduct arising from the cycloaddition is a result of bond formation to the less sterically hindered top face of the diene 3 (Figure 5) and there is secondary orbital overlap 2 between the M of the diene and LUM of the dienophile in the transition state resulting in in endo adducts obtained under kinetically controlled conditions. The energy of this transition state is lower compared to the exo transition state. t BuMe 2 Si Favoured approach of dienophile Ac Ac Ac 3 Ac Figure 5: Model of Cycloaddition

4 4 An x-ray crystallographic study has shown that D-glucose based dienes of type (3) exist in the s-trans geometry (4). An NED spectroscopic study by NMR in deuteriochloroform solution showed that mainly one conformer of type (4) was present. Presumably 3, the steric interaction (green lines) between x and z in the conformer (5) outweighs that between x and y in conformer (4) and tips the balance in favour of the latter (Figure 6). z SiMe 3 y Ac x Ac Ac Ac Ac Ac Me 3 Si y Ac z x Ac 4 5 Figure 6: NMR Solution Studies of the Diene The adoption of conformations (4) and (5) is in accord with expectation based on the exo-anomeric effect 3, in which the -1 (between the diene and sugar) is sp 2 hybridised and it s p-orbital overlaps with the * antibonding orbital of the diene moiety 6 and the * antibonding orbital as a result of the bond between C-1 and -1 (Figure 7); when -1 is SP 3 hybridised (in C-1, -1 saturated systems) there is a more favourable gauche (60 o ) relationship! p * C 2' * 1' C 1 1' 6 Figure 7: Exo-anomeric Stereoelectronic Effects

5 5 2. Asymmetric Diels-Alder Approaches to Anthracyclinones SiMe 3 + Ph, 5 o C Ac 7 Ac Ac Ac Quinizarin 8 Ac 9 Ac SiMe 3 Ac Ac 10 SiMe 3 Scheme 1: Asymmetric Diels-Alder Reaction In 1984, Stoodley 4 reported a synthesis of (+)-(4)-demethoxydaunomycinone using an oxirane dienophile (7) and the D-glucose based diene (8) in an asymmetric Diels-Alder reaction and the ratio of the major cycloadduct (9) and minor cycloadduct (10) was 4:1 as observed by 1 NMR spectroscopy; the major diasteroemer (9) was isolated in 74% yield after recrystallisation. In order to undergo a Diels-Alder reaction, the s-cis geometry of the diene must exist (cf. Figure 5), as shown in Figure 7. The dienophile approaches the sterically less-hindered top face of a diene of type (11) to avoid an unfavourable syn-1,3-interaction between the C bond in the sugar group. Me 3 Si SiMe 3 SiMe 3 Ac Ac Ac Ac Ac Ac Ac Ac Ac 11 Ac Ac Ac 4 12 Figure 8: Conformations of the D-Glucose based Dienes The minor cycloadduct (10) arises from addition to either the top face of the unfavourable cis-conformer of type (12) or bottom face of the preferred conformer of type (11). The choice of silyloxy substituent is unlikely to affect the stereoselectivity.

6 6 SiMe 3 Ac Ac 10 Ac Ac Figure 9: Minor Diastereomer 3. Bicyclic Dihydroxydione Dienophile Approaches towards unreported anthracylines were attempted 5 and their syntheses would follow the typical asymmetric Diels-Alder reaction using a D- glucose-based auxiliary (Scheme 2). The dihydroxydione (12) reacted with the D-glucose-based diene (2) at elevated temperatures. NMR spectroscopy revealed a 60% diastereomeric excess of 13 when the reaction had gone to completion; unfortunately, at elevated temperatures, the cycloadducts are unstable and aromatization products are produced. The cycloadduct (13) was isolated in 36% yield after recrystallisation. Using a bicyclic oxirane was less rewarding. SiMe 2 Bu t SiMe 2 Bu t 12 PhMe + 98 o C Ac Ac Ac Ac Ac Ac 2 13 Ac Ac Scheme 2: Bicyclic Dihydroxydione 12 as a Dienophile

7 7 4. Naphthazarin Glucoside Dienophile Ac Ac Ac Ac Ac Ac Ac + SiMe 3 C 2 Cl 2, r.t. Ac SiMe 3 Me Me predominant product Scheme 3: Naphthazarin Glucoside 14 as a Dienophile Utilising the D-glucose chiral auxiliary on the dienophile as an alternative stereodirecting moiety was investigated in attempted anthracyclinone syntheses 5 (Scheme 3). Thus, naphthazarin glucoside (14) reacted with Danishefsky s Diene (15) to give predominantly the cycloadduct (16) in 77% yield (a small amount of isomerisation of the double bond on the ring-a also occurred); no other diastereomers were reported in the thesis. 5. References 1. K. Friedrichs, F. ölzel and F. Jänicke, "Combination of taxanes and anthracyclines in first-line chemotherapy of metastatic breast cancer: an interim report", European Journal of Cancer, 2002, 38(13), I. Fleming, Frontier rbitals and rganic Chemical Reactions, John Wiley & Sons, Chichester, 1976, p ISBN R. C. Gupta, D. S. Larsen and R. J. Stoodley, A. M. Z. Slawin and D. J. Williams, Asymmetric Diels Alder reactions. Part 2. A model to account for the diastereofacial reactivity of (E)-1-(2,3,4,6-tetra--acetyl- -Dglucopyranosyloxy)-3-trimethylsiloxybuta-1,3-diene and its 2-methyl derivative. X-Ray molecular structure of (E)-1-(2,3,4,6-tetra--acetyl- -Dglucopyranosyloxy)-3-trimethylsiloxybuta-1,3-diene and of (1R,6R,9R,10S)-9- methyl-10-(2,3,4,6-tetra--acetyl- -D-glucopyranosyloxy)bicyclo[4.4.0]dec-3- ene-2,5,8-trione, J. Chem. Soc., Perkin Trans. 1, 1989, R. C. Gupta, P. A. arland and R. J. Stoodley, An efficient enantiocontrolled synthesis of (+)-4-demethoxydaunomycinone, Tetrahedron, 1984, 40,

8 8 5. J. P. Miller and R. J. Stoodley, Asymmetric Synthesis of Anticancer Anthracyclines, PhD Thesis, University of Manchester, Dr Jonathan Miller