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Multi-chelation approach towards natural product-like skeletons: one-pot access to a nitrogen-containing tetracyclic framework from AlaAla dipeptidewz Kasipandi Vellaisamy, John Victor Napoleon, Ramkumar Venkatachalam and Muraleedharan Kannoth Manheri* Received 19th August 2010, Accepted 7th October 2010 DOI: 10.1039/c0cc03355c Reductive transformation of the dipeptide BocAlaAlaOMe to a complex, internally charge-stabilized, natural product-like skeleton in one synthetic step is discussed. Stepwise replacement of the B–H bonds in borane by B–N or B–O resulted in incorporation of three boron atoms in a tetracyclic framework whereby one is stereogenic! Conformational preferences through intramolecular secondary interactions or steric discrimination are the key design principles in functionally important bio-molecules and the related foldamers.1,2 The idea of using an internal tether to create discrete molecular surfaces with potential application in therapy however has not received significant attention thus far. In this report, we delineate such a strategy through the preparation of a complex, tetracyclic, natural product-like framework in just one synthetic operation starting from readily accessible BocAlaAlaOMe dipeptide under the reducing conditions of borane. The experimental protocol involved refluxing a solution of BocAlaAlaOMe in THF with sodium borohydride/I2 system3 for 48 h, quenching the excess borane with methanol followed by basic work-up and chromatographic purification (Scheme 1). The 1H NMR spectrum of the product showed doublets respectively at 1.07, 1.12, 1.17 and 1.36 ppm corresponding to four alanine–CH3 groups—suggestive of two dipeptide derived fragments constituting the framework. The 13C NMR spectrum showed the presence of fourteen carbon atoms of which four CH, four CH2 and five CH3 groups were distinguished based on DEPT analysis. The peak at 161.8 ppm in the 13C NMR spectrum corresponded to a carbonyl group which gave absorption at 1570 cm1 in its IR spectrum. Structure assignment of fragment I started by taking this carbonyl carbon as the reference. In HMBC, it showed correlations with C9–H, C11–H and C12–H (Fig. 1). Continuous two- and three-bond correlations, starting from the relatively down-shifted methylene carbon at 63.6 ppm corresponding to C8 could then be identified which supported the structure I. The singlet at 2.15 ppm in 1H NMR that correlated to the methyl carbon
Department of Chemistry, Indian Institute of Technology Madras, Chennai-600 036, India. E-mail:
[email protected]; Fax: (+91)-44 2257 4202; Tel: (+91)-44 2257 4233 w Electronic supplementary information (ESI) available: Experimental details, NMR spectra, mass analysis and crystallographic summaries. CCDC 766965. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c0cc03355c z Respectfully dedicated to Professor M. V. George on the occasion of his 82nd birthday.
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at 34.2 ppm in HSQC was assigned as a N–CH3 group based on literature precedents.4 Taking this as the reference, a continuous correlation of signals corresponding to the fragment II could be established using a combination of COSY, HSQC and HMBC experiments. The 11B NMR spectrum of 2 showed the presence of three types of boron atoms: a singlet at 9.0 ppm, a broad triplet at 10.5 ppm and a broad quartet at 16.6 ppm corresponding to tetra-coordinated –B, –BH2 and –BH3 units respectively. The lack of direct connectivity between fragments I and II in 2D-NMR indicated that one or more boron atoms are likely bridging the framework. HRMS (ESI) of the compound showed a fragmentation peak at 337.2757 corresponding to the [M+ H] ion from the boron adduct with the formula C14H33B3N4O3. Crystals of 2 with a melting range of 155–157 1C were obtained from ethyl acetate solution and X-ray diffraction analysis confirmed the tetracyclic, alkaloid-type skeleton shown in Fig. 2. Mechanistically, compound 2 can be considered as arising from a boron–carbamato complex of type I (Fig. 3). TLC examination of the reaction mixture at various intervals has shown the presence of at least three intermediates en route to 2. Although these compounds were not stable enough for detailed characterization, we could isolate and crystallize one compound from ethyl acetate solution, and perform X-ray diffraction analysis. Its structure shown in Fig. 4 suggests that both ester and amide functionalities undergo reduction prior to the Boc-carbamate linkage and is a possible precursor to the intermediate I proposed in Fig. 3. Tri- or tetra-coordinated boron atoms complexed to nitrogen or oxygen atoms from the backbone are likely involved in the process and a general outline is given here. Reduction at the NIQCI bond followed by chelation to another molecule through NI possibly leads to the adduct II. Two more reduction cycles at NIQCI assisted by chelation involving internal nitrogen and oxygen atoms could generate the intermediates III and IV, which is followed
Scheme 1 Preparation of 2 from Boc(Ala)2OMe.
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Fig. 1 HMBC correlations are indicated on the structures of fragments I and II; carbon atoms are numbered arbitrarily. Fig. 4 Pov-ray diagram (CCDC number 778722) of the intermediate A en route to compound 2.
Fig. 2 Pov-ray diagram of compound 2 (CCDC number 766965).
Fig. 3 Plausible complexation and reduction sequence which lead to 2. B* could be either tri- or tetra-coordinated boron.
by complexation of the terminal hydroxyl group to BII and a final closure of the carbonyl oxygen to form the tetracyclic fused ring structure in 2. Participation of the carbonyl oxygen in chelation and ring formation is evident from the tetrahedral nature of BII. While the observed CQO bond length (1.295 A˚) in this six-membered ring is comparable to literature values, that of B–O is slightly shorter (1.483 A˚).5,6 The sequence of events depicted in Fig. 3 is largely notional and multiple boron complexation/de-complexations, assisted by species such as I2 or I in the reaction mixture, could be driving the cyclizations. Interestingly, use of BH3/THF instead of NaBH4/I2 system did not lead to the tetracycle 2. This journal is
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Compound 2 showed remarkable stability in neutral and alkaline solutions but was found unstable to acids. Thermogravimetric analysis under nitrogen atmosphere showed that no weight loss happens up to 181 1C! An early onset of weight loss (172 1C) was seen when the analysis was performed under aerial conditions (ESIw). A two-stage process, centred approximately at 217 1C and 291 1C with maximum weight loss rates of 32 and 5% per 1C respectively was observed in this case. Clearly, the structure 2 permits significant charge relay between atoms located at different positions in the skeleton. Studies on charge distribution in such systems having interlinked bonding patterns such as N–B–N–B–N–B, N–CQO–B–N–B and N–B–N–B–O could give valuable information on the stability and reactivity profiles of boron-rich compounds which are being considered for diverse applications including hydrogen storage.7 A small number of boron-containing natural products, examples being boromycin, aplasmomycin and tartrolones with antibiotic, cytotoxic or anti-HIV activities are known.8–11 Compounds with stereogenic boron atoms, although less common due to their labile nature, are parallely gaining attention because of their potential application in synthesis.12,13 Unique shapes, charge distributions, and affinity for electrons in trivalent form suggest that boron-compounds could offer a lot of promise in drug discovery arena. Synthetic compounds such as 1,2-dihydro-1,2-azaborines reported by Liu et al. with good binding affinity towards the non-polar cavity in T4 lysozyme,14 Velcades—a synthetic boron-containing dipeptide useful against multiple myeloma,15,16 and a more recent report on the use of peptidyl bis(boroxoles) as oligosaccharide receptors in aqueous medium,17 are examples showing the potential of boron to become an integral part of future biomedical research. The work depicted here, which gives access to an alkaloid-type of framework in one synthetic step, therefore opens up a new window of opportunity to design natural product-like frameworks from peptides or their hybrids with other chemical groups. To summarise, a one-pot method which involve multiple reductions, N-methylation and boron complexation that lead to a highly functionalized, tetracyclic, alkaloid type of skeleton from BocAlaAlaOMe dipeptide under the reducing condition of sodium borohydride/iodine system is demonstrated. Apart from its extraordinary resemblance with natural products and potential biological properties, such a compound would Chem. Commun., 2010, 46, 9212–9214
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be useful in examining the charge relay in molecular frameworks with extended B–N–B–N–B–N bonds. Financial support of this work by the Department of Science and Technology (DST), INDIA (Grants SR/S1/ OC-13/2007) is gratefully acknowledged. KP thanks UGC and JV thanks CSIR for research fellowships. We thank Mr Narayanan, IITM for TGA analysis.
Notes and references 1 D. J. Hill, M. J. Mio, R. B. Prince, T. S. Hughes and J. S. Moore, Chem. Rev., 2001, 101, 3893–4011. 2 A. Hetenyi, Z. Szakonyi, M. Mandity Istvan, E. Szolnoki, K. Toth Gabor, A. Martinek Tamas and F. Fulop, Chem. Commun., 2009, 177–179. 3 M. J. McKennon, A. I. Meyers, K. Drauz and M. Schwarm, J. Org. Chem., 1993, 58, 3568–3571. 4 A. Nefzi, J. M. Ostresh, J.-P. Meyer and R. A. Houghten, Tetrahedron Lett., 1997, 38, 931–934. 5 V. A. Dorokhov, O. G. Boldyreva, B. M. Mikhailov, Z. A. Starikova and I. A. Teslya, Izv. Akad. Nauk SSSR, Ser. Khim., 1985, 431–435.
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6 M. P. Hughes and B. D. Smith, J. Org. Chem., 1997, 62, 4492–4499. 7 M. E. Bluhm, M. G. Bradley, R. Butterick, III, U. Kusari and L. G. Sneddon, J. Am. Chem. Soc., 2006, 128, 7748–7749. 8 J. Kohno, T. Kawahata, T. Otake, M. Morimoto, H. Mori, N. Ueba, M. Nishio, A. Kinumaki, S. Komatsubara and K. Kawashima, Biosci., Biotechnol., Biochem., 1996, 60, 1036–1037. 9 T. S. S. Chen, C.-j. Chang and H. G. Floss, J. Am. Chem. Soc., 1979, 101, 5826–5827. 10 M. Pe´rez, C. Crespo, C. Schleissner, P. Rodrı´ guez, P. Zu¨n˜iga and F. Reyes, J. Nat. Prod., 2009, 72, 2192–2194. 11 J. Mulzer and M. Berger, J. Org. Chem., 2004, 69, 891–898. 12 E. Vedejs, S. C. Fields, R. Hayashi, S. R. Hitchcock, D. R. Powell and M. R. Schrimpf, J. Am. Chem. Soc., 1999, 121, 2460–2470. 13 P. F. Kaiser, J. M. White and C. A. Hutton, J. Am. Chem. Soc., 2008, 130, 16450–16451. 14 L. Liu, A. J. V. Marwitz, B. W. Matthews and S.-Y. Liu, Angew. Chem., Int. Ed., 2009, 48, 6817–6819. 15 Y.-Q. Zhu, M. Lei, A.-J. Lu, X. Zhao, X.-J. Yin and Q.-Z. Gao, Eur. J. Med. Chem., 2009, 44, 1486–1499. 16 S. J. Baker, C. Z. Ding, T. Akama, Y.-K. Zhang, V. Hernandez and Y. Xia, Future Med. Chem., 2009, 1, 1275–1288. 17 A. Pal, M. Berube and D. G. Hall, Angew. Chem., Int. Ed., 2010, 49, 1492–1495.
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