- Email: [email protected]
Efficient synthesis of the core structure of muraymycin and caprazamycin nucleoside antibiotics based on a stereochemically revised sulfur ylide reaction
Tetrahedron: Asymmetry 21 (2010) 763–766
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Efficient synthesis of the core structure of muraymycin and caprazamycin nucleoside antibiotics based on a stereochemically revised sulfur ylide reaction Anatol P. Spork a, Stefan Koppermann a, Birger Dittrich b, Regine Herbst-Irmer b, Christian Ducho a,* a b
Georg-August-University Göttingen, Department of Chemistry, Institute of Organic and Biomolecular Chemistry, Tammannstr. 2, 37077 Göttingen, Germany Georg-August-University Göttingen, Department of Chemistry, Institute of Inorganic Chemistry, Tammannstr. 4, 37077 Göttingen, Germany
a r t i c l e
i n f o
Article history: Received 8 March 2010 Accepted 31 March 2010 Available online 27 May 2010
a b s t r a c t The reaction of protected uridine 50 -aldehydes with sulfur ylides has been reinvestigated. Further transformation of the resulting epoxide product provided a compound of which a single crystal for X-ray diffraction was obtained. As a consequence from the elucidated structure, the stereochemical configuration of the epoxide furnished by the sulfur ylide reaction was revised. Based on these results, an efficient synthesis of the core structure of the naturally occurring muraymycin and caprazamycin nucleoside antibiotics was developed. Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Due to the emerging resistances of bacterial strains towards established antibiotics, there is a particular need for the development of novel antimicrobial agents.1 Nucleoside antibiotics represent a class of antibacterially active natural products bearing unique nucleoside core structures. These antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular stages of peptidoglycan biosynthesis.2,3 Nucleoside antibiotics should therefore be considered as attractive lead structures for drug development, thus making the facile synthesis of their structural key motifs an important objective. Muraymycin (e.g., muraymycin A1 1)4 and caprazamycin antibiotics (e.g., caprazamycin A 2)5 represent two subclasses of nucleoside antibiotics with identical (50 S,60 S)-configured nucleosidic core moieties 3 (Fig. 1). So far, only one practical synthesis of this nucleosyl amino acid scaffold based on a Sharpless aminohydroxylation strategy has been reported.6 An aldol approach for the construction of the nucleoside moiety has also been described,7 but it suffers from a lack of stereocontrol and from moderate yields. In contrast, the reaction of sulfur ylides with suitably protected uridine 50 -aldehydes was reported to occur with high diastereoselectivity and to provide epoxides leading to biologically active 50 -epi muraymycin analogues.7,8 We have recently described an improved version of this approach for the convergent synthesis of muraymycin analogues.9
The original assignment of the stereochemical configuration of the epoxides obtained by the aforementioned sulfur ylide reaction was based on a model compound and computational investigations.8,10 We reacted the protected uridine 50 -aldehyde 4a with the sulfur ylide derived from sulfonium salt 5 to give diastereomerically pure epoxide 6a as the sole epoxide product in 60% yield.9 Nucleophilic ring-opening of 6a with amine 79 provided the protected nucleosyl amino acid 8 in 52% yield (Scheme 1). As expected,8–12 the ring-opening reaction of epoxy ester 6a occurred in a perfectly regio- and diastereoselective SN2-type manner, as proven by rigorous 2D NMR analyses, and no other product was observed. In contrast to any other similar derivative we had previously synthesised via this strategy, amino alcohol 8 could be crystallised from benzene, and single crystals suitable for X-ray diffraction were obtained. However, the X-ray crystal structure of 813–16 (Fig. 2) revealed that the original stereochemical assignment of the epoxide provided by Sarabia et al. (50 S,60 R)8,10 could not be correct. In contrast, the formal stereochemistry of the epoxide moiety of 6a had to be (50 R,60 S), as shown in Scheme 1, in order to provide the ring-opening product 8 with the proven (50 S,60 R)-configuration.17 It was then investigated if the stereochemical outcome of the sulfur ylide reaction might differ depending on various structural features of the reactants. We have demonstrated before that the transformation of uridine 50 -aldehydes 4a and 4b into epoxides 6a,b and 9a,b provides identical product stereochemistry regardless of the sulfur ylide employed. The sulfur ylides derived from the tert-butyl ester sulfonium salt 5 and from Sarabia’s originally used indoline amide sulfonium salt 108,10 were tested, and further conversion of epoxides 9a,b obtained from the latter reaction into
* Corresponding author. Tel.: +49 (0)551 39 3285; fax: +49 (0)551 39 9660. E-mail address: [email protected] (C. Ducho). 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.03.037
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A. P. Spork et al. / Tetrahedron: Asymmetry 21 (2010) 763–766
O
H N
HO
O 6'
HN
N H
O HN HN
HO
O
H N
N H
N
OR 2 O
5'
O
O
O
R 3O O
OH OH
O
O
N
NH O 6'
N
O
5'
O
OR 4 O
N
OH OH
H2N
O
NH
O OH O
N
O
OH OH 3
H 2N O
R2 =
NH2
HO H 2N
2
NH 11
N
O 9
1
N H
R1 =
HOOC
NH
OR1 O
O
OH
R3 =
OH
MeO
O OMe
O
R4 = OMe
O OH
OH
Figure 1. Structures of muraymycin and caprazamycin antibiotics, exemplified by muraymycin A1 1 and caprazamycin A 2, and their common nucleoside core structure 3.
their corresponding tert-butyl esters gave 6a and 6b, respectively (Scheme 2).9 Furthermore, epoxide 6a obtained without N-3-PMB protection of the uracil moiety could be transformed into epoxide 6b by alkylation with PMB chloride (75% yield). The epoxide 6b furnished from this reaction was found to be identical both spectroscopically (NMR) and chromatographically (HPLC) to the product isolated from the aforementioned sulfur ylide reaction with 5 (Scheme 2). Thus, the stereochemical course of the sulfur ylide reaction was completely independent not only of the sulfur ylide employed, but also of the presence or absence of nucleobase protection. Finally, the potential influence of the protecting groups at 20 -OH and 30 -OH of the ribose moiety was studied. Epoxide 9b was treated with tetra-n-butyl ammonium azide to give the ringopening product 11 in 68% yield. The TBDMS groups of 11 were
O O
S
O
Br
O
5 5, NaH, THF, O then 4a , CH Cl 2 2
NH N O O TBDMSO
NH O O
O
6'
60 % OTBDMS
N 5'
O
OTBDMS 6a
Cl
H N
CbzHN
O
TBDMSO
4a
NH 3
O
7
7, DIPEA, MeOH
O
O CbzHN
52 %
6'
N H
N H
NH
O
5',6 '- configuration proven by X-ray crystal structure analysis Previous configurational assignment o f 6a: [8,10]
N
OH O
5'
TBDMSO
OTBDMS 8
O NH
O O 6'
N 5'
TBDMSO
O
Corrected assignment of 6a based on the stereochemistry of 8 :
O
O
O
then cleaved under acidic conditions, providing product 12 in 90% yield; an isopropylidene group was subsequently introduced to afford derivative 13 in 37% yield (reaction not optimised). However, the corresponding material obtained from the previously described sulfur ylide reaction of uridine 50 -aldehyde 14 with 10,8 followed by ring-opening with tetra-n-butyl ammonium azide (53% yield over two steps), was found to be identical by means of rigorous NMR and HPLC analyses (Scheme 2). It was therefore concluded that the protecting group pattern at the ribose moiety had no influence on the stereochemical outcome of the sulfur ylide transformation. All epoxide products obtained from the sulfur ylide reaction displayed the stereochemical configuration proven for 6a. Hence, Sarabia’s ribose derivative originally employed for the wrong configurational assignment10 might have been an unsuitable model compound for this transformation or the assignment was otherwise flawed. With respect to the corrected stereochemistry, it was then investigated if the sulfur ylide reaction could be applied to the synthesis of nucleoside-building blocks with potential use for the preparation of muraymycins or caprazamycins. Besides the apparent potential to open the epoxide products from the sulfur ylide reaction with nitrogen nucleophiles in order to obtain (60 R)-config-
NH O
O O
O OTBDMS
O 6'
N 5'
TBDMSO
O
O OTBDMS
Scheme 1. Sulfur ylide reaction of 4a with 5, further transformation of the resulting epoxide 6a into 8 and correction of the stereochemistry of 6a.
Figure 2. X-ray crystal structure of compound 8 (ORTEP plot with 50% probability ellipsoids; one of four main molecules with identical absolute configuration in the asymmetric unit); only hydrogen atoms at stereogenic centres are displayed (green).
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A. P. Spork et al. / Tetrahedron: Asymmetry 21 (2010) 763–766
O O N N O
R
O
N
O
O
OTBDMS PMB-Cl, KHMDS, DMF S
NP MB
O
N O
Cl
OTBDMS
O
N
R
O 13
Me2CH(O Me )2, acetone, B SA
9b, B u4NN 3, amberlyst 15, acetone
O
O
6b: R = PMB
O TB DMSO
O
14
75 %
N
OH O
53 % (over 2 steps)
O
NPMB
O
37 %
O N
O
N N3
O
N
O
4 steps
10
O
O
1) 10, NaOH, CH 2Cl2, H2 O 2) Bu 4NN3, amberlyst 15, acetone
O
6a: R = H
O N
R
O TBDMSO
4a: R = H 4b: R = PMB 10, NaO H, CH 2Cl2, H 2O
O N
5, NaH, THF, then 4, CH2Cl2
O
O
5
O
TBDMSO
Br
S
O
N
68 % OTBDMS
NPMB
O OH O
N3
O
TBDMSO
9a: R = H 9b: R = PMB
N
O
N AcCl, MeOH
N
OH O
N3
90 %
NPMB
O
OTBDMS
O
OH O H
11
12
Scheme 2. Syntheses to investigate the influence of structural features of the reactants on the stereochemical outcome of the sulfur ylide reaction.
O
O NPMB O
N
O
N
O
N
OH O
85 % OTBDMS
NPMB
O
Br
O TBDMSO
NaBr , amberlyst 15, acetone
TBDMSO
9b LevOH, DIC, DMAP , CH 2Cl2
Br
N
O
Bu 4NN 3, various solvents
N
OH O
N3 OTBDMS
NPMB
O
TBDMSO
15
N
O +
11
OTBDMS 17
82 % O
O N
O
O OLe v O
TBDMSO
NPMB 1) Bu NN , DMF 4 3 2) N2 H 4 HOA c, N O DMF, MeOH
OTBDMS
93 % (one-pot)
N
NPMB
O
N3
OH O
TBDMSO
16
O
N
O
H 2 (1bar), 10 % Pd/C, MeOH 92 %
OTBDMS 17
N H2 N
NPMB
O OH O
TBDMSO
N
O
OTBDMS 18
Scheme 3. Conversion of epoxide 9b obtained via the sulfur ylide approach into the protected nucleoside-building block 18.
ured muraymycin or caprazamycin analogues, it was also desired to conceive a synthesis of the natural product-like nucleoside unit via this route. Epoxide 9b was therefore reacted with sodium bromide in the presence of amberlyst™ 158 to give bromohydrin 15 in 85% yield (Scheme 3). It was envisaged to convert 15 into the corresponding azide by simple SN2 nucleophilic displacement at C-60 . However, this reaction was non-trivial due to the apparent reformation of epoxide 9b under the reaction conditions, giving rise to significant amounts of 11 as a by-product. Several attempts to overcome this limitation, particularly by changing the solvent, were unsuccessful. Hence, a protecting group was introduced at the 50 -hydroxy moiety in order to avoid epoxide reformation. Levulinyl (Lev) protection furnished 16 in 82% yield. Employing a convenient one-pot sequence of treatment with tetra-n-butyl ammonium azide and levulinyl deprotection using hydrazine ace-
tate, the desired product 17 could then be obtained in 93% yield. The subsequent reduction of the azide moiety furnished amine 18 in 92% yield (Scheme 3). The protected nucleosyl amino acid 18 is a suitable building block for the synthesis of muraymycins, caprazamycins and analogues thereof as the aminoacylated alkyl side chain can be easily introduced via reductive amination.7
3. Conclusion In conclusion, we have reinvestigated and revised the stereochemical outcome of the previously described reaction of uridine 50 -aldehydes with sulfur ylides.8–10 It was reported before to employ this transformation to synthesise biologically active 50 -epi analogues of muraymycin nucleoside antibiotics, which is not fea-
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sible with respect to the corrected stereochemistry of the epoxide products obtained from the sulfur ylide reaction. In contrast, we developed an efficient synthesis of the nucleoside core structure of both muraymycin and caprazamycin antibiotics based on the sulfur ylide-epoxide strategy (60% overall yield over five steps from protected uridine 50 -aldehyde 4b). Although this novel route is slightly longer than the previously described Sharpless aminohydroxylation approach,6 it is completely stereocontrolled, and avoids the use of toxic heavy metals and expensive chiral ligands, thus potentially enabling the synthesis of the protected nucleosidebuilding block on a multi-gram scale. Acknowledgements We thank the Deutsche Forschungsgemeinschaft (DFG, SFB 803 ‘Functionality controlled by organization in and between membranes’) and the Fonds der Chemischen Industrie (FCI) for financial support. Donation of laboratory equipment by the BASF SE is gratefully acknowledged. References 1. Taubes, G. Science 2008, 321, 356–361. 2. Kimura, K.-I.; Bugg, T. D. H. Nat. Prod. Rep. 2003, 20, 252–273. 3. Winn, M.; Goss, R. J. M.; Kimura, K-I.; Bugg, T. D. H. Nat. Prod. Rep. 2010, 27, 279–304. 4. McDonald, L. A.; Barbieri, L. R.; Carter, G. T.; Lenoy, E.; Lotvin, J.; Petersen, P. J.; Siegel, M. M.; Singh, G.; Williamson, R. T. J. Am. Chem. Soc. 2002, 124, 10260– 10261. 5. Igarashi, M.; Nakagawa, N.; Doi, S.; Hattori, N.; Naganawa, H.; Hamada, M. J. Antibiot. 2003, 56, 580–583. 6. Hirano, S.; Ichikawa, S.; Matsuda, A. Angew. Chem. 2005, 117, 1888–1890; Angew. Chem., Int. Ed. 2005, 44, 1854–1856.
7. Yamashita, A.; Norton, E.; Petersen, P. J.; Rasmussen, B. A.; Singh, G.; Yang, Y.; Mansour, T. S.; Ho, D. M. Bioorg. Med. Chem. Lett. 2003, 13, 3345–3350. 8. Sarabia, F.; Martín-Ortiz, L. Tetrahedron 2005, 61, 11850–11865. 9. Spork, A. P.; Koppermann, S.; Ducho, C. Synlett 2009, 2503–2507. 10. Sarabia, F.; Martín-Ortiz, L.; López-Herrera, F. J. Org. Lett. 2003, 5, 3927–3930. 11. Valpuesta, M.; Durante, P.; López-Herrera, F. J. Tetrahedron Lett. 1995, 36, 4681– 4684. 12. Azzena, F.; Crotti, P.; Favero, L.; Pineschi, M. Tetrahedron 1995, 51, 13409– 13422. 13. The crystal structure determination of 8 was not without challenges. Although sufficiently large and transparent rectangular crystals could be grown by solvent evaporation with ease, the fact that the co-crystallising solvent led to crystal decay within seconds required low-temperature crystal-mounting conditions. Furthermore, the crystals investigated by us were composed of twin domains, so that for data integration two orientation matrices were required (Bruker (2001). SAINT. Bruker AXS Inc., Madison, WI). The crystal lattice appeared to be of higher metric symmetry than was the case (orthorhombic rather than monoclinic) leading to additional twinning by pseudo-merohedry. There were four domains of potentially overlapping reflections. A more detailed description of the twinning in connection with the determination of the Flack-parameter will be given elsewhere. In spite of the twinning, determination of the Flack-parameter (0.04 ± 0.02),14 which was crucial for arriving at the conclusions reported, was possible. Full crystallographic data for this structure have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 770311. These data can be obtained free of charge on application to CCDC, 12, Union Road, Cambridge, CB2 1EZ; fax +44 (1223)336033; or email: [email protected]. 14. Flack, H. D.; Bernardinelli, G. J. Appl. Cryst. 2000, 33, 1143–1148. 15. SHELXL (Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112–122) was used for structure refinement. 16. Structure solution was achieved with the program SHELXD (Uson, I.; Sheldrick, G. M.; de la Fortelle, E.; Bricogne, G.; Di Marco, S.; Priestle, J. P.; Grüttler, M. G.; Mittl, P. R. E. Structure 1999, 7, 55–63). The asymmetric unit consists of four main molecules with identical absolute configuration, which are accompanied by further seven benzene solvent molecules to give eleven independent molecules. 17. It should be noted that the descriptor of the stereocenter at C-50 formally changes from (R) to (S) upon reaction with the nitrogen nucleophile at C-60 due to altered priorities.
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Efficient synthesis of the core structure of muraymycin and caprazamycin nucleoside antibiotics based on a stereochemically revised sulfur ylide reaction Anatol P. Spork a, Stefan Koppermann a, Birger Dittrich b, Regine Herbst-Irmer b, Christian Ducho a,* a b
Georg-August-University Göttingen, Department of Chemistry, Institute of Organic and Biomolecular Chemistry, Tammannstr. 2, 37077 Göttingen, Germany Georg-August-University Göttingen, Department of Chemistry, Institute of Inorganic Chemistry, Tammannstr. 4, 37077 Göttingen, Germany
a r t i c l e
i n f o
Article history: Received 8 March 2010 Accepted 31 March 2010 Available online 27 May 2010
a b s t r a c t The reaction of protected uridine 50 -aldehydes with sulfur ylides has been reinvestigated. Further transformation of the resulting epoxide product provided a compound of which a single crystal for X-ray diffraction was obtained. As a consequence from the elucidated structure, the stereochemical configuration of the epoxide furnished by the sulfur ylide reaction was revised. Based on these results, an efficient synthesis of the core structure of the naturally occurring muraymycin and caprazamycin nucleoside antibiotics was developed. Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Due to the emerging resistances of bacterial strains towards established antibiotics, there is a particular need for the development of novel antimicrobial agents.1 Nucleoside antibiotics represent a class of antibacterially active natural products bearing unique nucleoside core structures. These antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular stages of peptidoglycan biosynthesis.2,3 Nucleoside antibiotics should therefore be considered as attractive lead structures for drug development, thus making the facile synthesis of their structural key motifs an important objective. Muraymycin (e.g., muraymycin A1 1)4 and caprazamycin antibiotics (e.g., caprazamycin A 2)5 represent two subclasses of nucleoside antibiotics with identical (50 S,60 S)-configured nucleosidic core moieties 3 (Fig. 1). So far, only one practical synthesis of this nucleosyl amino acid scaffold based on a Sharpless aminohydroxylation strategy has been reported.6 An aldol approach for the construction of the nucleoside moiety has also been described,7 but it suffers from a lack of stereocontrol and from moderate yields. In contrast, the reaction of sulfur ylides with suitably protected uridine 50 -aldehydes was reported to occur with high diastereoselectivity and to provide epoxides leading to biologically active 50 -epi muraymycin analogues.7,8 We have recently described an improved version of this approach for the convergent synthesis of muraymycin analogues.9
The original assignment of the stereochemical configuration of the epoxides obtained by the aforementioned sulfur ylide reaction was based on a model compound and computational investigations.8,10 We reacted the protected uridine 50 -aldehyde 4a with the sulfur ylide derived from sulfonium salt 5 to give diastereomerically pure epoxide 6a as the sole epoxide product in 60% yield.9 Nucleophilic ring-opening of 6a with amine 79 provided the protected nucleosyl amino acid 8 in 52% yield (Scheme 1). As expected,8–12 the ring-opening reaction of epoxy ester 6a occurred in a perfectly regio- and diastereoselective SN2-type manner, as proven by rigorous 2D NMR analyses, and no other product was observed. In contrast to any other similar derivative we had previously synthesised via this strategy, amino alcohol 8 could be crystallised from benzene, and single crystals suitable for X-ray diffraction were obtained. However, the X-ray crystal structure of 813–16 (Fig. 2) revealed that the original stereochemical assignment of the epoxide provided by Sarabia et al. (50 S,60 R)8,10 could not be correct. In contrast, the formal stereochemistry of the epoxide moiety of 6a had to be (50 R,60 S), as shown in Scheme 1, in order to provide the ring-opening product 8 with the proven (50 S,60 R)-configuration.17 It was then investigated if the stereochemical outcome of the sulfur ylide reaction might differ depending on various structural features of the reactants. We have demonstrated before that the transformation of uridine 50 -aldehydes 4a and 4b into epoxides 6a,b and 9a,b provides identical product stereochemistry regardless of the sulfur ylide employed. The sulfur ylides derived from the tert-butyl ester sulfonium salt 5 and from Sarabia’s originally used indoline amide sulfonium salt 108,10 were tested, and further conversion of epoxides 9a,b obtained from the latter reaction into
* Corresponding author. Tel.: +49 (0)551 39 3285; fax: +49 (0)551 39 9660. E-mail address: [email protected] (C. Ducho). 0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2010.03.037
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A. P. Spork et al. / Tetrahedron: Asymmetry 21 (2010) 763–766
O
H N
HO
O 6'
HN
N H
O HN HN
HO
O
H N
N H
N
OR 2 O
5'
O
O
O
R 3O O
OH OH
O
O
N
NH O 6'
N
O
5'
O
OR 4 O
N
OH OH
H2N
O
NH
O OH O
N
O
OH OH 3
H 2N O
R2 =
NH2
HO H 2N
2
NH 11
N
O 9
1
N H
R1 =
HOOC
NH
OR1 O
O
OH
R3 =
OH
MeO
O OMe
O
R4 = OMe
O OH
OH
Figure 1. Structures of muraymycin and caprazamycin antibiotics, exemplified by muraymycin A1 1 and caprazamycin A 2, and their common nucleoside core structure 3.
their corresponding tert-butyl esters gave 6a and 6b, respectively (Scheme 2).9 Furthermore, epoxide 6a obtained without N-3-PMB protection of the uracil moiety could be transformed into epoxide 6b by alkylation with PMB chloride (75% yield). The epoxide 6b furnished from this reaction was found to be identical both spectroscopically (NMR) and chromatographically (HPLC) to the product isolated from the aforementioned sulfur ylide reaction with 5 (Scheme 2). Thus, the stereochemical course of the sulfur ylide reaction was completely independent not only of the sulfur ylide employed, but also of the presence or absence of nucleobase protection. Finally, the potential influence of the protecting groups at 20 -OH and 30 -OH of the ribose moiety was studied. Epoxide 9b was treated with tetra-n-butyl ammonium azide to give the ringopening product 11 in 68% yield. The TBDMS groups of 11 were
O O
S
O
Br
O
5 5, NaH, THF, O then 4a , CH Cl 2 2
NH N O O TBDMSO
NH O O
O
6'
60 % OTBDMS
N 5'
O
OTBDMS 6a
Cl
H N
CbzHN
O
TBDMSO
4a
NH 3
O
7
7, DIPEA, MeOH
O
O CbzHN
52 %
6'
N H
N H
NH
O
5',6 '- configuration proven by X-ray crystal structure analysis Previous configurational assignment o f 6a: [8,10]
N
OH O
5'
TBDMSO
OTBDMS 8
O NH
O O 6'
N 5'
TBDMSO
O
Corrected assignment of 6a based on the stereochemistry of 8 :
O
O
O
then cleaved under acidic conditions, providing product 12 in 90% yield; an isopropylidene group was subsequently introduced to afford derivative 13 in 37% yield (reaction not optimised). However, the corresponding material obtained from the previously described sulfur ylide reaction of uridine 50 -aldehyde 14 with 10,8 followed by ring-opening with tetra-n-butyl ammonium azide (53% yield over two steps), was found to be identical by means of rigorous NMR and HPLC analyses (Scheme 2). It was therefore concluded that the protecting group pattern at the ribose moiety had no influence on the stereochemical outcome of the sulfur ylide transformation. All epoxide products obtained from the sulfur ylide reaction displayed the stereochemical configuration proven for 6a. Hence, Sarabia’s ribose derivative originally employed for the wrong configurational assignment10 might have been an unsuitable model compound for this transformation or the assignment was otherwise flawed. With respect to the corrected stereochemistry, it was then investigated if the sulfur ylide reaction could be applied to the synthesis of nucleoside-building blocks with potential use for the preparation of muraymycins or caprazamycins. Besides the apparent potential to open the epoxide products from the sulfur ylide reaction with nitrogen nucleophiles in order to obtain (60 R)-config-
NH O
O O
O OTBDMS
O 6'
N 5'
TBDMSO
O
O OTBDMS
Scheme 1. Sulfur ylide reaction of 4a with 5, further transformation of the resulting epoxide 6a into 8 and correction of the stereochemistry of 6a.
Figure 2. X-ray crystal structure of compound 8 (ORTEP plot with 50% probability ellipsoids; one of four main molecules with identical absolute configuration in the asymmetric unit); only hydrogen atoms at stereogenic centres are displayed (green).
765
A. P. Spork et al. / Tetrahedron: Asymmetry 21 (2010) 763–766
O O N N O
R
O
N
O
O
OTBDMS PMB-Cl, KHMDS, DMF S
NP MB
O
N O
Cl
OTBDMS
O
N
R
O 13
Me2CH(O Me )2, acetone, B SA
9b, B u4NN 3, amberlyst 15, acetone
O
O
6b: R = PMB
O TB DMSO
O
14
75 %
N
OH O
53 % (over 2 steps)
O
NPMB
O
37 %
O N
O
N N3
O
N
O
4 steps
10
O
O
1) 10, NaOH, CH 2Cl2, H2 O 2) Bu 4NN3, amberlyst 15, acetone
O
6a: R = H
O N
R
O TBDMSO
4a: R = H 4b: R = PMB 10, NaO H, CH 2Cl2, H 2O
O N
5, NaH, THF, then 4, CH2Cl2
O
O
5
O
TBDMSO
Br
S
O
N
68 % OTBDMS
NPMB
O OH O
N3
O
TBDMSO
9a: R = H 9b: R = PMB
N
O
N AcCl, MeOH
N
OH O
N3
90 %
NPMB
O
OTBDMS
O
OH O H
11
12
Scheme 2. Syntheses to investigate the influence of structural features of the reactants on the stereochemical outcome of the sulfur ylide reaction.
O
O NPMB O
N
O
N
O
N
OH O
85 % OTBDMS
NPMB
O
Br
O TBDMSO
NaBr , amberlyst 15, acetone
TBDMSO
9b LevOH, DIC, DMAP , CH 2Cl2
Br
N
O
Bu 4NN 3, various solvents
N
OH O
N3 OTBDMS
NPMB
O
TBDMSO
15
N
O +
11
OTBDMS 17
82 % O
O N
O
O OLe v O
TBDMSO
NPMB 1) Bu NN , DMF 4 3 2) N2 H 4 HOA c, N O DMF, MeOH
OTBDMS
93 % (one-pot)
N
NPMB
O
N3
OH O
TBDMSO
16
O
N
O
H 2 (1bar), 10 % Pd/C, MeOH 92 %
OTBDMS 17
N H2 N
NPMB
O OH O
TBDMSO
N
O
OTBDMS 18
Scheme 3. Conversion of epoxide 9b obtained via the sulfur ylide approach into the protected nucleoside-building block 18.
ured muraymycin or caprazamycin analogues, it was also desired to conceive a synthesis of the natural product-like nucleoside unit via this route. Epoxide 9b was therefore reacted with sodium bromide in the presence of amberlyst™ 158 to give bromohydrin 15 in 85% yield (Scheme 3). It was envisaged to convert 15 into the corresponding azide by simple SN2 nucleophilic displacement at C-60 . However, this reaction was non-trivial due to the apparent reformation of epoxide 9b under the reaction conditions, giving rise to significant amounts of 11 as a by-product. Several attempts to overcome this limitation, particularly by changing the solvent, were unsuccessful. Hence, a protecting group was introduced at the 50 -hydroxy moiety in order to avoid epoxide reformation. Levulinyl (Lev) protection furnished 16 in 82% yield. Employing a convenient one-pot sequence of treatment with tetra-n-butyl ammonium azide and levulinyl deprotection using hydrazine ace-
tate, the desired product 17 could then be obtained in 93% yield. The subsequent reduction of the azide moiety furnished amine 18 in 92% yield (Scheme 3). The protected nucleosyl amino acid 18 is a suitable building block for the synthesis of muraymycins, caprazamycins and analogues thereof as the aminoacylated alkyl side chain can be easily introduced via reductive amination.7
3. Conclusion In conclusion, we have reinvestigated and revised the stereochemical outcome of the previously described reaction of uridine 50 -aldehydes with sulfur ylides.8–10 It was reported before to employ this transformation to synthesise biologically active 50 -epi analogues of muraymycin nucleoside antibiotics, which is not fea-
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sible with respect to the corrected stereochemistry of the epoxide products obtained from the sulfur ylide reaction. In contrast, we developed an efficient synthesis of the nucleoside core structure of both muraymycin and caprazamycin antibiotics based on the sulfur ylide-epoxide strategy (60% overall yield over five steps from protected uridine 50 -aldehyde 4b). Although this novel route is slightly longer than the previously described Sharpless aminohydroxylation approach,6 it is completely stereocontrolled, and avoids the use of toxic heavy metals and expensive chiral ligands, thus potentially enabling the synthesis of the protected nucleosidebuilding block on a multi-gram scale. Acknowledgements We thank the Deutsche Forschungsgemeinschaft (DFG, SFB 803 ‘Functionality controlled by organization in and between membranes’) and the Fonds der Chemischen Industrie (FCI) for financial support. Donation of laboratory equipment by the BASF SE is gratefully acknowledged. References 1. Taubes, G. Science 2008, 321, 356–361. 2. Kimura, K.-I.; Bugg, T. D. H. Nat. Prod. Rep. 2003, 20, 252–273. 3. Winn, M.; Goss, R. J. M.; Kimura, K-I.; Bugg, T. D. H. Nat. Prod. Rep. 2010, 27, 279–304. 4. McDonald, L. A.; Barbieri, L. R.; Carter, G. T.; Lenoy, E.; Lotvin, J.; Petersen, P. J.; Siegel, M. M.; Singh, G.; Williamson, R. T. J. Am. Chem. Soc. 2002, 124, 10260– 10261. 5. Igarashi, M.; Nakagawa, N.; Doi, S.; Hattori, N.; Naganawa, H.; Hamada, M. J. Antibiot. 2003, 56, 580–583. 6. Hirano, S.; Ichikawa, S.; Matsuda, A. Angew. Chem. 2005, 117, 1888–1890; Angew. Chem., Int. Ed. 2005, 44, 1854–1856.
7. Yamashita, A.; Norton, E.; Petersen, P. J.; Rasmussen, B. A.; Singh, G.; Yang, Y.; Mansour, T. S.; Ho, D. M. Bioorg. Med. Chem. Lett. 2003, 13, 3345–3350. 8. Sarabia, F.; Martín-Ortiz, L. Tetrahedron 2005, 61, 11850–11865. 9. Spork, A. P.; Koppermann, S.; Ducho, C. Synlett 2009, 2503–2507. 10. Sarabia, F.; Martín-Ortiz, L.; López-Herrera, F. J. Org. Lett. 2003, 5, 3927–3930. 11. Valpuesta, M.; Durante, P.; López-Herrera, F. J. Tetrahedron Lett. 1995, 36, 4681– 4684. 12. Azzena, F.; Crotti, P.; Favero, L.; Pineschi, M. Tetrahedron 1995, 51, 13409– 13422. 13. The crystal structure determination of 8 was not without challenges. Although sufficiently large and transparent rectangular crystals could be grown by solvent evaporation with ease, the fact that the co-crystallising solvent led to crystal decay within seconds required low-temperature crystal-mounting conditions. Furthermore, the crystals investigated by us were composed of twin domains, so that for data integration two orientation matrices were required (Bruker (2001). SAINT. Bruker AXS Inc., Madison, WI). The crystal lattice appeared to be of higher metric symmetry than was the case (orthorhombic rather than monoclinic) leading to additional twinning by pseudo-merohedry. There were four domains of potentially overlapping reflections. A more detailed description of the twinning in connection with the determination of the Flack-parameter will be given elsewhere. In spite of the twinning, determination of the Flack-parameter (0.04 ± 0.02),14 which was crucial for arriving at the conclusions reported, was possible. Full crystallographic data for this structure have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 770311. These data can be obtained free of charge on application to CCDC, 12, Union Road, Cambridge, CB2 1EZ; fax +44 (1223)336033; or email: [email protected]. 14. Flack, H. D.; Bernardinelli, G. J. Appl. Cryst. 2000, 33, 1143–1148. 15. SHELXL (Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112–122) was used for structure refinement. 16. Structure solution was achieved with the program SHELXD (Uson, I.; Sheldrick, G. M.; de la Fortelle, E.; Bricogne, G.; Di Marco, S.; Priestle, J. P.; Grüttler, M. G.; Mittl, P. R. E. Structure 1999, 7, 55–63). The asymmetric unit consists of four main molecules with identical absolute configuration, which are accompanied by further seven benzene solvent molecules to give eleven independent molecules. 17. It should be noted that the descriptor of the stereocenter at C-50 formally changes from (R) to (S) upon reaction with the nitrogen nucleophile at C-60 due to altered priorities.