Since the deoxyamino sugar portion of macrolides is in general
essential for their antimicrobial activities,3 its modifications hold
promise as a valuable approach toward preparing new macrolide
antibiotics with improved and/or altered biological properties.4 In
this regard, several synthetic and biosynthetic approaches to novel
glycosylated macrolides have been reported.5 These approaches
are limited in terms of the stereochemical diversity of structures
that can be generated. In addition, the methods that use in vivo
modified biosynthetic pathways and/or in vitro enzymatic reactions
for the production of new glycosylated antibiotics6 are limited by
the availability and the lability of the sugar nucleotide glycosyl
donors. Similarly, these routes often suffer from the reduced
catalytic efficiency of the glycosyltransferases involved when
dealing with unnatural substrates.
Pd-catalyzed coupling of macrolactone III and 13a-d.7,8 The
required pyranone stereoisomers 13a-d can be stereoselec-
tively prepared from the achiral acetyl furan 14 via our de
novo asymmetric synthesis approach.9
Accordingly, our synthetic effort began with the isolation of
4
d
10-deoxymethynolide III and preparation of the required D/L-
and R/ꢀ-Boc-pyranones 13a-d for coupling.8 As previously
described, the Pd-glycosyl donors 13a-d were synthesized from
the achiral acetyl furan 14 by a very practical three-step
sequence, employing an enantioselective Noyori reduction (14
to 15/ent-15), an Achmatowicz oxidation, and a stereodivergent
tert-butyl carbonate formation (see Scheme 2).10
To address these concerns, we envisioned the development of
a highly diastereoselective, yet stereodivergent, route that would
allow for the mild installation of the sugar moieties onto complex
antibiotic aglycons using simple achiral starting material. It is in
this, as well as other, contexts that we developed a de novo
asymmetric approach to carbohydrates, which we hoped would
allow for the facile synthesis of various methymycin analogues
for carbohydrate SAR-type studies (Figure 1). Herein, we report
our successful efforts at the use of this approach for the synthesis
of stereochemically (L/D- and R/ꢀ-) diverse glycosylated 8,9-
dihydro-10-deoxymethymycin analogues.
Scheme 2. Synthesis of D/L- and R/ꢀ-Boc-Pyranones 13a-d
Our basic retrosynthetic analysis for the preparation of the
stereochemically diverse methymycin analogues is shown in
Scheme 1. The plan was that various amino- and/or deoxy-
4
d
The double bond of 10-deoxymethynolide III was then
selectively reduced by treatment with excess diimide (NBSH,
Et3N)11 to give the desired 8,9-dihydro-10-deoxymethynolide (16)
in 95% yield (Scheme 3). The resulting macrolactone 16 was
subjected to the diastereoselective Pd-catalyzed glycosylation with
R-L-Boc-pyranone 13a, producing R-L-glycoside 12 as a single
diastereomer in good yield (86%). A NaBH4 reduction12 of enone
12 gave the equatorial allylic alcohol 17 in 82% yield. Diimide
reduction of 17 with an excess triethylamine and O-nitrophenyl-
sulfonyl hydrazide led to the 2,3-dideoxy analogue 1 in excellent
yield (90%). Preparation of the rhamno-sugar analogue 2 was
accomplished by diastereoselective dihydroxylation of 17 under
Upjohn conditions13 (OsO4/NMO) in 85% yield.
Scheme 1. Retrosynthetic Analysis of Methymycin Analogues
(5) (a) Velvadapu, V.; Andrade, R. B. Carbohydr. Res. 2008, 343, 145–
150. (b) Packard, G. K.; Scott, D.; Rychnovsky, S. D. Org. Lett. 2001, 3,
sugar glycosylated macrolide analogues could be prepared from
macrolides like 12 with the desired pyranone stereochemistry.
The macrolides 12, in turn, could be prepared by a stereospecific
3393–3396
.
(6) (a) Mendez, C.; Salas, J. A. Trends Biotechnol. 2001, 19, 449–456.
(b) Griffith, B. R.; Langenhan, J. M.; Thorson, J. S. Curr. Opin. Biotechnol.
2005, 16, 622–630. (c) Melanc¸on, C. E.; Thibodeaux, C.; Liu, H.-w. ACS
Chem. Biol. 2006, 1, 499–504. (d) Mendez, C.; Luzhetskyy, A.; Bechthold,
A.; Salas, J. A. Curr. Top. Med. Chem. 2008, 8, 710–724. (e) Williams,
G. J.; Gantt, R. W.; Thorson, J. S. Curr. Opin. Chem. Biol. 2008, 12, 556–
(1) (a) Rawlings, B. J. Nat. Prod. Rep. 2001, 18, 190–227. (b) Rawlings,
B. J. Nat. Prod. Rep. 2001, 18, 231–281. (c) Staunton, J.; Weissman, K. J.
Nat. Prod. Rep. 2001, 18, 380–416. (d) Walsh, C. Antibiotics: Actions,
Origins, Resistance; ASM Press: Washington, D.C., 2003. (e) Weissman,
K. J. Philos. Trans. R. Soc. London, Ser. A 2004, 362, 2671–2690.
(2) (a) Donin, M. N.; Pagano, J.; Dutcher, J. D.; McKee, C. M. Antibiot.
Annu. 1953-19541, 179–185. (b) Djerassi, C.; Zderic, J. A. J. Am. Chem.
Soc. 1956, 78, 6390–6395. (c) Xue, Y.; Zhao, L.; Liu, H.-w.; Sherman,
D. H. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 12111–12116.
564
.
(7) (a) Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125,
12406–12407. (b) Comely, A. C.; Eelkema, R.; Minnaard, A. J.; Feringa,
B. L. J. Am. Chem. Soc. 2003, 125, 8714–8715. (c) Kim, H.; Men, H.;
Lee, C. J. Am. Chem. Soc. 2004, 126, 1336–1337. (d) Babu, R. S.; Zhou,
M.; O’Doherty, G. A. J. Am. Chem. Soc. 2004, 126, 3428–3429
.
(8) (a) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem.
1999, 64, 2982–2983. (b) Harris, J. M.; Keranen, M. D.; Nguyen, H.; Young,
V. G.; O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17–36. For its use in
oligosaccharide synthesis, see: (c) Guo, H.; O’Doherty, G. A. Angew. Chem.,
Int. Ed. 2007, 46, 5206–5208. (d) Zhou, M.; O’Doherty, G. A. Org. Lett.
(3) (a) Weymouth-Wilson, A. C. Nat. Prod. Rep. 1997, 14, 99–110. (b)
Thorson, J. S.; Hosted, J.; Jiang, J.; Biggins, J. B.; Ahlert, J. Curr. Org.
Chem. 2001, 5, 139–167. (c) Kren, V.; Martinkova, L. Curr. Med. Chem.
2001, 8, 1303–1328.
(4) (a) He, X. M.; Liu, H.-w. Annu. ReV. Biochem. 2002, 71, 701–754.
(b) Thibodeaux, C. J.; Melancon, C. E., III; Liu, H.-w. Nature 2007, 446,
1008–1016. (c) Thibodeaux, C. J.; Melancon, C. E., III; Liu, H.-w. Angew.
Chem., Int. Ed. 2008, 47, 9814–9859. (d) Borisova, S. A.; Zhao, L.;
Sherman, D. H.; Liu, H.-w. Org. Lett. 1999, 1, 133–136.
2008, 10, 2283–2286.
(9) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 2521–2522. (b) Li, M.; Scott, J. G.;
O’Doherty, G. A. Tetrahedron Lett. 2004, 45, 1005–1009. (c) Li, M.;
O’Doherty, G. A. Tetrahedron Lett. 2004, 45, 6407–6411.
Org. Lett., Vol. 12, No. 22, 2010
5151