An efficient synthesis of protected (2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic acid, a constituent of callipeltins A and D

Article abstract of DOI:10.1016/S0040-4039(03)01368-6

An efficient and stereoselective synthesis of protected (2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic acid, a constituent of the depsipeptides, callipeltins A and D, from D-ribose is described.

Full text of DOI:10.1016/S0040-4039(03)01368-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5645–5647
An efficient synthesis of protected
(2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic acid, a
constituent of callipeltins A and Dꢀ
A. Ravi Kumar and B. Venkateswara Rao*
Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 29 April 2003; revised 23 May 2003; accepted 30 May 2003
Abstract—An efficient and stereoselective synthesis of protected (2R,3R,4S)-4,7-diamino-2,3-dihydroxyheptanoic acid, a con-
stituent of the depsipeptides, callipeltins A and D, from
© 2003 Elsevier Ltd. All rights reserved.
D-ribose is described.
Cyclic depsipeptides have emerged as very important
classes of bioactive compounds in marine natural prod-
ucts.1 Among these cyclic depsipeptides, callipeltin A
shows anti-HIV, antifungal and cytotoxic activities
against selected human carcinoma cell lines.2 The isola-
tion of callipeltins 1 and 2 was reported by Minale et al.
in 1996 from a shallow water sponge of the Callipelta
species3 and later by D’Auria and co-workers from
Latruncula sp.4 They show marked activity in cytotoxic
assays against KB and P388 cells and recently it was
found that callipeltin A is a selective and powerful
inhibitor of Na/Ca cardiac exchange and a positive
inotropic agent in guinea pig left atria.5 Callipeltin A
contains a number of novel amino acid residues:
methoxy-tyrosine, (2R,3R,4S)-4-amino-7-guanidino-
2,3-dihydroxyheptanoic acid (AGDHE) and (3S,4R)-
3,4-dimethyl- -glutamine.
L
Recent reports have revealed that the side-chain
attached to the macrocycle in callipeltin A is essential
for anti-HIV activity and it is also present in callipeltin
D.4 The key residue in the side-chain is the novel amino
acid (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxy-
heptanoic acid (AGDHE) 3. Two syntheses have been
reported for this fragment to date and one of these was
from our laboratory starting from
D
-glucose.6 Recently
Keywords: Wittig olefination; SN2 displacement; selective primary O-Boc ester; AGDHE fragment; depsipeptides; callipeltins A and D.
ꢀ IICT Communication Number: 030415.
* Corresponding author. Fax: +91-40-27160512; e-mail: venky@iict.ap.nic.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01368-6

5646
A. Ra6i Kumar, B. Venkateswara Rao / Tetrahedron Letters 44 (2003) 5645–5647
Lipton et al. reported this fragment from protected
-ornithine.7 In this paper we report an efficient synthe-
sis of the AGDHE fragment 3 starting from readily
available -ribose.
L
D
D
-Ribose was converted into compound 4 via a
reported procedure in one step.8 Compound 4 under-
went Swern oxidation and Wittig olefination to afford
5, whose NMR spectral data were in agreement with
the literature.8 Reduction of 5 using LAH gave com-
pound 6, which was subsequently converted to azide 7.
Under acidic conditions compound 7 underwent iso-
propylidene cleavage to give diol 8, which was pro-
tected as the dibenzyl ether 9. Hydrolysis of the
O-glycosidic bond of 9 afforded the corresponding
lactol 10. Compound 10 was treated with LAH, result-
ing in opening of the lactol and reduction of the azide
to the corresponding amine. The reaction was quenched
with 15% NaOH solution and immediately (Boc)2O was
added to convert the amine into the N-Boc derivative.
Interestingly, it was found that the primary hydroxy
was also protected as its Boc ester 11, selectively, in
good yield. Compound 11 was converted into azide 12
in 90% yield by SN2 displacement of the intermediate
mesylate. In comparison to our earlier synthesis6 con-
version of the secondary hydroxyl to azide is efficient in
the presence of O-Boc. Compound 12 was N-benzyl-
ated using NaH/BnBr in DMF. Under these conditions
concomitant cleavage of the O-Boc ester occurred to
give 13. Azido alcohol 13 was reduced to the corre-
sponding amine using TPP/benzene–H2O and was
immediately protected as the Boc derivative 14, [h]2D5=
−14.2 (c 0.8, CHCl3), [lit.6 [h]D25=−14.8 (c 0.7, CHCl3)],
whose NMR spectral data were in agreement with the
literature.6 Compound 14 is known to give methyl ester
15 in one step.6
will also help in making different analogues. The selec-
tive protection of the primary hydroxyl as the O-Boc
derivative during the LAH reduction of 10 and its
removal during benzylation of 12, minimized the num-
ber of transformations required in reaching the target
(Scheme 1).
Acknowledgements
One of the authors (A.R.K) thanks the CSIR, New
Delhi for a research fellowship (SRF). We also thank
Dr. J. S. Yadav and Dr. G. V. M. Sharma for their
support and encouragement.
In conclusion we have developed a short strategy for
the synthesis of 15, which is useful in making reason-
able quantities for the total synthesis of callipeltins and
Scheme 1. Reagents and conditions: (a) (i) (COCl)2, DMSO, −78°C, 30 min, then 4, Et3N, −78°C to rt, 1 h; (ii) Ph3PꢀCHCOOEt,
DCM, rt, 1 h, 79%; (b) LAH, THF, 0°C to rt, 6 h, 87%; (c) (i) TsCl, DCM, Et3N, 0°C to rt, 6 h; (ii) NaN3, DMF, 90°C, 8 h,
74%; (d) MeOH, conc. HCl (cat.), 60°C, 4 h, 86%; (e) BnBr, NaH, DMF, 0°C to rt, 2 h, 92%; (f) 60% AcOH–H2O, HCl (cat.),
60°C, 2 h, 76%; (g) LAH, THF, 0°C, 30 min, 15% NaOH, H2O, (Boc)2O, 12 h, 93%; (h) (i) MsCl, Et3N, DCM, 0°C to rt, 6 h;
(ii) NaN3, DMF, 90°C, 12 h, 93%; (i) NaH, BnBr, DMF, 0°C to rt, 6 h, 79%; (j) (i) PPH3, H2O, benzene, 11 h; (ii) Et3N, (Boc)O2,
12 h, 81%.

A. Ra6i Kumar, B. Venkateswara Rao / Tetrahedron Letters 44 (2003) 5645–5647
5647
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