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ChemComm
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DOI: 10.1039/C5CC03549J
COMMUNICATION
Journal Name
due to the enhanced electrophilic nature of the phosphorus centre
when small amino substituents are present, resulting in the
formation of the corresponding bis-alkyoxychlorophosphine 23
(observed at δ 165 ppm in the 31P NMR). This is possible via
acetylation of the amino group in favour of the phosphorus centre.
We therefore explored the possibility of synthesising 26 via the
ketophosphonate intermediate 25. We postulated that 25 would
behave as a softer electrophile in relation to acetyl chloride
therefore favouring our desired reaction pathway towards the
unsymmetrical BP 26. Gratifyingly, when phosphoramidite 22 was
reacted with ketophosphonate 25 in the presence of Py.HClO4, 26
was obtained as a diastereoisomeric mixture.
3. A. Horatscheck, S. Wagner, J. Ortwein, B. G. Kim, M. Lisureck, S.
Beligny, A. Schütz and J. Rademann, Angew. Chem. Int. Ed., 2012,
51, 9441
4. A.-L. Alanne, M. Lahtinen, M. Löfman, P. Turhanen, E.
Kolehmainen, J. Versäläinen and E. Sievänen, J. Mater. Chem. B.,
2013, 1, 6201
5. P. A. Turhanen, J. Org. Chem., 2014, 79, 6330
6. M. Fang, R. D. Toogood, A. Macova, K. Ho, F. G. Franzblau, M. R.
McNeil, D. A. R. Sanders and D. R. J. Palmer, Biochem., 2010, 49,
2672
7. W. M. Abdou and A. A. Shaddy, Arkivoc, 2009, 143
8. R. Niemi, P. Turhanen, J. Vepsäläinen, H. Taipale and T. Järvinen,
Eur. J. Pharm. Sci., 2000, 11, 173
9. M. J. Rogers, X.H. Ji, R. G. G. Russell, G. M. Blackburn, M. P.
Williamson, A. V. Bayless, F. H. Ebetino and D. J. Watts, Biochem.
J., 1994, 303, 303
13b
10. J. H. Lin, Bone, 1996, 18, 75
ꢀ78°C to r.t.
24
23
22
11. C. Schultz, Bioorg. Med. Chem., 2003, 11, 885; S. J. Hecker and M.
D. Erion, J. Med. Chem., 2008, 51, 2328
13b
12. C-H. C. Hsiao, X. Lin, R. J. Barney, R. R. Shippy, J. Li, O.
Vinogradova, D. F. Wiemer and A. J. Wiemer, Chemistry and
Biology, 2014, 21, 945; A. J. Wiemer, J. S. Yu, L. W. Shull, R. J.
Barney, B. M. Wasko, K. M. Lamb, R. J. Hohl and D. F. Wiemer,
Bioorg. Med. Chem., 2008, 16, 3652
22
Py .HClO4
DCM, room temp
ov ernight
ꢀ78°C to r.t.
25
26
(i) TMSBr
(ii) MeOH/H2O
(iii) Cꢀ18 purif ication
52 %
82 %
13. E. Migianu, E. Guénin and M. Lecouvey, Synlett, 2005, 3, 425
14. K. G. Devine, C. Mc Guigan, T. J. O’Connor, S. R. Nicholls and D,
Kichington, AIDS, 1990, 4, 371; P. D. van Poelje, Q. Dang and M.
D. Erion, Curr. Opin. Drug Discovery Dev., 2007, 10, 430; L. W.
Peterson, J.-S. Kim, P. Kijek, S. Mitchell, J. Hilfinger, J.
Breitenbach, K. Borysko, J. C. Drach, B. A. Kashemirov and C. E.
McKenna, Bioorg. Med. Chem. Lett., 2011, 21, 4045; C.
McGuigan, P. Murziani, M. Slusarczyk, B. Gonczy, J. Vande
Voorde, S. Liekens, snd J. Balzarini, J. Med. Chem., 2011, 54, 7247
27
Figure 7 Synthesis of masked BP with small amino substituent
However, 31P NMR also showed the presence of two unidentified
trivalent ‘P’ species which were inseparable from the product by
standard silica column chromatography. Nevertheless, the crude
mixture was subjected to deprotection conditions with TMSBr and
purified by careful C-18 reverse phase column chromatography to
afford the fully deprotected masked BP 27.
15. M. R. Webster, M. Zhao, M. A. Rudek, C. L. Hann and C. L. F.
Meyers, J. Med. Chem., 2011, 54, 6647
16. A. A. Prishchenko, M. V. Livantsov, O. P. Novikova, L. I. Livantsova
and V. S. Petrosyan, Hetero. Chem., 2012, 23, 32
17. B. Kaboudin and R. Nazari, Synth. Commun., 2001, 31, 2245
18. H. Firouzabadi, N. Iranpoor, S. Sobhani and A.-R. Sardarian, Tet.
Lett., 2001, 42, 4369
Conclusions
Herein, it has been demonstrated that phosphorus reagents of the
type P(OR)(NR’2)2 and in particular P(OR)2(NR’2), are extremely
useful reagents for the rapid production of acyl phosphonamidates
from a range of acid chlorides. We have demonstrated that the
phosphonamidates are highly stable and valuable intermediates for
the preparation of the BP prodrug analogues 1 and 27. They display
significant advantages over their phosphonate counterparts in that
the incorporation of bulky amino moieties into these structures
limits the possibility for BP rearrangement whilst imparting reagent
stability. Finally, the acyl phosphonamidates synthesised herein
would allow for access to functionalisable bisphosphonate
analogues via P-N bond activation.
19. J. M. Benech, M. Coindet, D. El MAnouni and Y. Leroux,
Phosphorus, Sulfur Silicon Relat. Elem., 1997, 123, 377
20. E. Breuer, H. Zaher, Z. Tashma, and D. Gibson, Hetero. Chem.
1996, 7, 515.
21. T. K. Gazizov and L. K. Sal’keev, J. Gen. Chem. USSR. (Engl.
Transl.), 1990, 1940
22. L. K. Sal’keeva, M. Y. Nurmaganbetova, E. V. Minaeva and B. Z.
Kokzhalova, Russ. J. Gen. Chem., 2006, 76, 1397; T. Erker and N.
Handler, Synthesis, 2004, 5, 668; P. A. Turhanen, R. Niemi, M.
Peräkylä, T. Järvinen and J. J. Vepsälänen, Org. Biomol. Chem.,
2003, 1, 3223
23. K. Crossey, C. Hardacre, M. E. Migaud and S. E. Norman, RSC
Advances, 2012, 2, 2988; K. Crossey, C. Hardacre and M. E.
Migaud, Chem. Commun., 2012, 48, 11969
Acknowledgements
This work was supported by the BBSRC BB/L01792X/1.
24. P. I. Alimov and L. A. Antokhina, Bull. Aca. Sci. USSR, 1966, 8,
1486; T. Kh. Gazizov, L. K. Sal’keeva, E. K. Gafurov and A. V.
Kazantsev, J. Gen. Chem. USSR, 1988, 58, 1027
25. A. O. Kolodyazhnaya, O. O. Kolodyazhnaya and O. I. Kolodyazhnyi,
Russ. J. Gen. Chem., 2010, 80, 709; O. I. Kolodyazhnyi and O. O.
Kolodiazhna, Synthetic Commun., 2012, 42, 1637
Notes and references
1. K. Afarinkia, A. J. Twist and H-W. Yu, J. Org. Chem., 2004, 69,
6500; C. V. Stevens and B. Vanderhoydonck, Tetrahedron, 2001,
57, 4793 and references therein
26. V. V. Nesterov and O. I Kolodyazhnyi, Tetrahedron, 2007, 63,
6720; S. Polat-Cakir and A. S. Demir, Tetrahedron, 2011, 67, 2396
2. A. Whitehead, S. R. Sieck, S. Mukherjee and P. R. Hanson, Science
27. Y. B. Kiran, C. Devendranath Reddy, D. Gunasekar, C. S. Reddy, A.
of
Synthesis:
Houben-Weyl
methods
of
molecular
Leon and L. C. A. Barbosa, Eur. J. Med. Chem., 2008, 43, 885
transformations, 2000, 21, 907
28. R. Niemi, P. Turhanen, J. Vepsalainen, H. Taipale and T. Jarvinen,
Eur. J. Pharm. Sci., 2000, 11, 173
4 | J. Name., 2012, 00, 1-3
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