B. A. Aleiwi et al. / Tetrahedron Letters 54 (2013) 2077–2081
2081
Synthesis 1992, 1058; (v) Chancellor, T.; Morton, C. Synthesis 1994, 1023; (w)
Giard, T.; Be’nard, D.; Plaquevent, J. C. Synthesis 1998, 297; (x) Meinnel, T.;
Patiny, L.; Ragusa, S.; Blanquet, S. Biochemistry 1999, 38, 4287; (y) Reddy, P. G.;
Kumar, G. D. K.; Baskaran, S. Tetrahedron Lett. 2000, 41, 9149; (z) Hill, D. R.;
Hsiao, C.-N.; Kurukulasuriya, R.; Wittenberger, S. J. Org. Lett. 2002, 4, 111; (aa)
Cochet, T.; Bellosta, V.; Greiner, A.; Roche, D.; Cossy, J. Synlett 2011, 1920. see
Ref. 2.
the reactions were performed in water or in water-containing sol-
vents (see Scheme 1).
We have applied these formylation reaction conditions to sev-
eral antibacterial natural products. Selective N-formylation of
kanamycin A could be achieved at the primary amine, yielding
the 60-formylated kanamycin A in 30% isolation yield (65% yield
based on LC–MS) (entry 20 in Table 1).7 Formylation of spectino-
mycin in H2O at rt furnished the mono-formylated product in
50% yield (entry 21).8 Daptomycin is a cyclic lipopeptide antibiotic
used in the treatment of certain community-associated methicillin
resistant Staphylococcus aureus (CA-MRSA) and healthcare-
associated-MRSA (HA-MRSA) infections.9 Daptomycin possesses
stereoelectronically different three free amines, four carboxylic
acids, a free alcohol in the molecule, however, shows limited water
solubility. Selective N-formylation of daptomycin was achieved at
the primary amine of the lysine residue in DMF–H2O (2/1) to pro-
vide the expected N-formylation product in 65% isolation yield
after a reverse HPLC purification (90% yield based on analysis of
the crude product via 1H NMR and LC–MS) (Scheme 2).10
2. (a) Jung, S. H.; Ahn, J. H.; Park, S. K.; Choi, J.-K. Bull. Korean Chem. Soc. 2002, 23,
149; (b) Mihara, M.; Ishino, Y.; Minakata, S.; Komatsu, M. Synthesis 2003, 2317;
(c) De Luca, L.; Giacomelli, G.; Porcheddu, A.; Salaris, M. Synlett 2004, 2570; (d)
Iranpoor, N.; Firouzabadi, H.; Jamalian, A. Tetrahedron Lett. 2005, 46, 7963; (e)
Bose, A. K.; Ganguly, S. N.; Manhas, M. G.; Guha, A.; Pombo-Villars, E.
Tetrahedron Lett. 2006, 47, 4605; (f) Hosseini-Sarvari, M.; Shargi, H. J. Org. Chem.
2006, 71, 6652; (g) Das, B.; Krishnaiah, M.; Balasubramanyam, P.;
Veeranjaneyulu, B.; Kumar, D. N. Tetrahedron Lett. 2008, 49, 2225; (h)
Chandra Shekhar, A.; Ravi Kumar, A.; Sathaiah, G.; Luke Paul, V.; Sridhar, M.;
Shanthan Rao, P. Tetrahedron Lett. 2009, 50, 7099; (i) Saidi, O.; Bamford, M. J.;
Blacker, A. J.; Lynch, J.; Marsden, S. P.; Plucinski, P.; Watson, R. J.; Willimas, J. M.
J. Tetrahedron Lett. 2010, 51, 5804; (j) Kim, J.-G.; Jang, D. O. Synlett 2010, 1231;
(k) Chen, F. M. F.; Benoiton, N. L. Synthesis 1979, 709; (l) Brahmachari, G.;
Laskar, S. Tetrahedron Lett. 2010, 51, 2319; (m) Lei, M.; Ma, L.; Hu, L. Tetrahedron
Lett. 2010, 51, 4186; (n) Shastri, L. A.; Shastri, S. L.; Bathula, C. D.; Basanagouda,
M.; Kulkarni, M. V. Synth. Commun. 2011, 41, 476; (o) Krishnakumar, B.;
´
Swaminathan, M. J. Mol. Catal. A: Chem. 2011, 334, 98; (p) SuchY, M.; Elmehriki,
A. A. H.; Hudson, R. H. E. Org. Lett. 2011, 13, 3952.
3. (a) Wang, Y.; Aleiwi, B. A.; Wang, Q.; Kurosu, M. Org. Lett. 2012, 14, 4910; (b)
Wang, Q.; Wang, Y.; Kurosu, M. Org. Lett. 2012, 14, 3372.
In summary, we have demonstrated selective N-formylation
reactions using HCO2H, Oxyma 1 or glyceroacetonide-Oxyma 2,
EDCI, and NaHCO3 in DMF–H2O system or in H2O.11 The N-formy-
lation reaction conditions described here do not require strict
anhydrous conditions necessary for ordinal formylation reac-
tions.1,2 To the best of our knowledge, N-formylation reactions of
4. (a) Khattab, S. N. Bull. Chem. Soc. Jpn. 2010, 83, 1374; (b) El-Faham, A.; Subiros-
Funosas, R.; Albericio, F. Chem. Eur. J. 2010, 19, 3641; (c) Subiros-Funosas, R.;
Prohens, R.; Barbas, R.; El-Faham, A.; Albericio, F. Chem. Eur. J. 2009, 15, 9394.
5. We have demonstrated that Oxyma 1 and glyceroacetonide-Oxyma 2 exist as
their Na salts in aq NaHCO3 solution.
6. Poor reactivity of 2-aminobenzoic acid and 2-aminophenol in these
formylations is probably due to the strong formation of intramolecular
hydrogen bonding between the NH2 and COOH or OH groups.
7. Difference in reactivity of the nitrogen atoms in kanamycin and amikacin, see:
(a) Hanessian, S.; Kornienkoa, A.; Swayze, E. E. Tetrahedron 2003, 59, 995; (b)
Bera, S.; Zhanel, G. G.; Schweizer, F. J. Med. Chem. 2010, 53, 3626; (c)
Kawaguchi, H.; Naito, T.; Nakagawa, S.; Fujisawa, K. Antibiotics 1972, 25, 695;
(d) Mingeot-Leclercq, M. P.; Glupczynski, Y.; Tulkens, P. M. Antimicrob. Agents
Chemother. 1999, 43, 727; (e) Mingeot-Leclercq, M. P.; Tulkens, P. M.
Antimicrob. Agents Chemother. 1999, 43, 1003.
8. (a) Andre, B. Antimicrob. Agents Chemother. 2005, 470; (b) Peeters, M.
Antimicrob. Agents Chemother. 1984, 26, 608; (c) Sanson-Lepors, M.
Antimicrob. Agents Chemother. 1986, 30, 512.
a
-amino acids have never been achieved efficiently without a suit-
able C-protection. We demonstrated that high yielding N-formyla-
tions of -amino acids could readily be accomplished with the
a
described conditions. Glyceroacetonide-Oxyma 2 displays remark-
able physico-chemical properties as an additive of N-formylation
reactions with EDCI in water media. Importantly, simple aqueous
work-up procedures can remove all reagents utilized in the reac-
tions to afford N-formylation products in high yield with excellent
purity.
9. Debono, M.; Barnhart, M.; Carrell, C. B.; Hoffmann, J. A.; Occolowitz, J. L.;
Abbott, B. J.; Fukuda, D. S.; Hamill, R. L.; Biemann, K.; Herlihy, W. C. J. Antibiot.
1987, 40, 761.
Acknowledgments
10.
½
a 2D3
ꢀ
= +30° (c 0.1, CHCl3); IR (neat) 3302, 3063, 2928, 2856, 1723, 1717, 1657,
1545, 1536, 1503, 1454, 1408, 1203, 1142, 1024, 828, 742 cmꢁ1 1H NMR
;
The authors thank the National Institutes of Health (NIAID
Grant AI084411-02) and The University of Tennessee for generous
financial supports. NMR data were obtained on instruments sup-
ported by the NIH Shared Instrumentation Grant.
(400 MHz, DMSO-d6) d 12.31 (s, 4H), 10.80 (d, J = 2.4 Hz, 1H), 8.51–8.43 (m,
2H), 8.37 (d, J = 7.6 Hz, 3H), 8.26 (t, J = 6.1 Hz, 1H), 8.16 (d, J = 7.4 Hz, 3H), 8.07
(d, J = 5.7 Hz, 1H), 8.03 (d, J = 6.3 Hz, 1H), 8.02 (d, J = 1.7 Hz, 1H), 7.96–7.91 (m,
1H), 7.77 (t, J = 9.1 Hz, 2H), 7.69–7.57 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.30–7.25
(m, 1H), 7.18 (dd, J = 26.7, 24.4 Hz, 2H), 7.10–7.05 (m, 1H), 7.01–6.97 (m, 1H),
6.92 (s, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.56 (t, J = 7.6 Hz, 1H), 5.12–5.04 (m, 1H),
4.92–4.84 (m, 1H), 4.70–4.47 (m, 8H), 4.46–4.40 (m, 1H), 4.31–4.24 (m, 1H),
4.18–4.08 (m, 2H), 3.87 (d, J = 13.9 Hz, 1H), 3.49–3.42 (m, 2H), 3.21 (s, 1H),
3.15–3.04 (m, 3H), 2.94 (dd, J = 14.8, 9.0 Hz, 1H), 2.80 (ddd, J = 27.9, 16.7,
5.6 Hz, 2H), 2.68–2.57 (m, 2H), 2.51–2.39 (m, 4H), 2.37 (p, J = 1.9 Hz, 1H), 2.35–
2.26 (m, 2H), 2.06 (t, J = 7.3 Hz, 2H), 1.94 (dd, J = 15.6, 10.2 Hz, 1H), 1.78–1.66
(m, 1H), 1.61–1.44 (m, 3H), 1.43–1.34 (m, 2H), 1.30–1.21 (m, 10H), 1.21–1.14
(m, 5H), 1.11 (d, J = 6.4 Hz, 6H), 0.87 (q, J = 6.9 Hz, 6H); HRMS (EI) calcd for
References and notes
1. (a) Blicke, F. F.; Lu, C.-J. J. Am. Chem. Soc. 1952, 74, 3933; (b) Sheehan, J. C.; Yang,
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95; (e) Yale, H. L. J. Org. Chem. 1971, 36, 3238; (f) Kraus, M. A. Synthesis 1973,
361; (g) Effenberger, F.; Muck, A. O.; Bessey, E. Chem. Ber. 1980, 113, 2086; (h)
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1980, 113, 2110; (k) Gramain, J. C.; Rémuson, R. Synthesis 1982, 264; (l)
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C
73H102N17O27 (M+H+): 1648.7131, found: 1648.7135.
11. General procedure for N-formylations: To a solution of amine (1 equiv), formic
acid (5 equiv), sodium bicarbonate (10 equiv), and glyceroacetonide-Oxyma 1
(2 equiv) in H2O (0.2–0.3 M) solution was added EDCI (2 equiv) The reaction
mixture was stirred for 3 h and quenched with 1% aq HCl. The aqueous phase
was extracted with EtOAc (or CHCl3 or CHCl3–MeOH (10/1). The combined
organic extracts were dried over Na2SO4 and evaporated in vacuo. Purification
by
a silica gel chromatography (or sephadex LH20) afforded the desired
compound (yields were given in Table 1). Similarly, N-formylations were
performed with Oxyma 1 in DMF–H2O (9/1).