Stereoselective synthesis of D-desosamine and related glycals via tungsten-catalyzed alkynol cycloisomerization

Article abstract of DOI:10.1021/ol049630m

Stereoselective synthesis of D-desosamine diacetate ester (iii, R = Ac) was achieved from the glycal (ii) generated by tungsten carbonyl-catalyzed cycloisomerization of the corresponding amino-alkynol (i). A wide variety of N-substituents (R, R′) are compatible with the cycloisomerization, provided that at least one R or R′ is an acyl derivative.

Full text of DOI:10.1021/ol049630m

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1601-1603
Stereoselective Synthesis of
D-Desosamine and Related Glycals via
Tungsten-Catalyzed Alkynol
Cycloisomerization
Mary H. Davidson and Frank E. McDonald*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
fmcdona@emory.edu
Received February 29, 2004
ABSTRACT
Stereoselective synthesis of D-desosamine diacetate ester (iii, R ) Ac) was achieved from the glycal (ii) generated by tungsten carbonyl-
catalyzed cycloisomerization of the corresponding amino-alkynol (i). A wide variety of N-substituents (R, R′) are compatible with the
cycloisomerization, provided that at least one R or R′ is an acyl derivative.
Deoxy amino sugars occur widely in nature, exhibiting varied
biological activities.1 In particular, amino sugars have been
identified as critical recognition and selectivity elements of
many classes of carbohydrate antibiotics.2 A strong potential
for pharmaceutical use, coupled with their intrinsic stereo-
complexity, makes these molecules worthy synthetic targets.3
Since its structural elucidation by chemical degradation and
NMR studies,4 D-desosamine, the 3,4,6-trideoxy-3-dimethyl-
aminohexose component of several important macrolide
antibiotics (erythromycin, narbomycin, picromycin, olean-
domycin),5 has elicited considerable synthetic interest.6
Herein, we report preparation of D-desosamine from the
glycal generated by our simple and versatile tungsten-
catalyzed alkynol endo-cycloisomerization reaction.7
Previous work from our laboratory has applied the
tungsten-catalyzed isomerization protocol to the preparation
of 1,2-pyranose glycals from non-carbohydrate alkynol
substrates, with subsequent elaboration to 2,3,6-trideoxy-
hexose oligosaccharides.8 Iterative application of the meth-
odology provided stereoselective preparation of 2,6-dideoxy
disaccharides,9 whereas synthesis of vancosamine and sac-
charosamine glycals extended the methodology to 3-amino-
2,3,6-trideoxyhexose structures.10 In this paper a series of
differentially acylated 3-amino-3,4,6-trideoxyhexose glycal
(1) Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J. Chem.
ReV. 1996, 96, 1195.
(6) (a) Tietze, L. F.; Hartfiel, U. Tetrahedron Lett. 1990, 31, 1697. (b)
Berube, G. Luce, E.; Jankowski, K. Bull. Soc. Chim. Fr. 1983, II, 109. (c)
Redlich, H.; Roy, W. Liebigs Ann. Chem. 1981, 1215. (d) Baer, H. H.;
Chiu, C. W. Can. J. Chem. 1974, 52, 122. (e) Korte, F.; Bilow, A.; Heinz,
R. Tetrahedron 1962, 18, 657.
(7) (a) Sheng, Y.; Musaev, D. G.; Reddy, K. S.; McDonald, F. E.;
Morokuma, K. J. Am. Chem. Soc. 2002, 124, 4149. (b) McDonald, F. E.;
Reddy, K. S. J. Organomet. Chem. 2001, 617, 444.
(8) (a) McDonald, F. E.; Zhu, H. Y. H. J. Am. Chem. Soc. 1998, 120,
4246. (b) McDonald, F. E.; Zhu, H. Y. H. Tetrahedron 1997, 53, 11061.
(9) (a) McDonald, F. E.; Reddy, K. S. Angew. Chem., Int. Ed. 2001, 40,
3653. (b) McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J. Am. Chem. Soc. 2000,
122, 4304.
(2) Mallams, A. The Carbohydrate-Containing Antibiotics. In Carbo-
hydrate Chemistry, 1st ed.; Kennedy, J. F., Ed.; Clarendon Press: Oxford,
1988; pp 73-133.
(3) Otsomaa, L. A.; Koskinen, A. M. P. Prog. Chem. Org. Nat. Prod.
1998, 74, 197.
(4) (a) Newman, H. J. Org. Chem. 1964, 29, 1461. (b) Hofheinz, W.;
Grisebach, H. Tetrahedron Lett. 1962, 3, 377. (c) Woo, P. W. K.; Dion, H.
W.; Durham, L.; Mosher, H. S. Tetrahedron Lett. 1962, 3, 735. (d) Bolton,
C. H.; Foster, A. B.; Stacey, M.; Webber, J. M. J. Chem. Soc. 1961, 4831.
(e) Flynn, E. H.; Sigal, M. V.; Wiley, P. F.; Gerzon, K. J. Am. Chem. Soc.
1954, 76, 3121.
(5) Richardson, A. C. J. Chem. Soc. 1964, 5364.
(10) Cutchins, W. W.; McDonald, F. E. Org. Lett. 2002, 4, 749.
10.1021/ol049630m CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/14/2004

Acylation of amines 3a,b followed by removal of silyl ether
and silyl alkyne protective groups provided amido alkynol
cycloisomerization substrates 4-8, while application of a
Mitsunobu protocol12 to protected 2a,b provided the bis-BOC
carbamate-substituted substrates 9a,b after sequential removal
of silyl ether and silyl alkyne protective groups.
Scheme 1. Preparation of Aminoalkyne Substrates 4-9a
The tungsten-catalyzed cyclizations were conducted with
both diastereomers of the alkynol substrates 4-9 and in all
cases required only relatively low (5-15 mol %) catalytic
loading, proceeding with nearly universal endo selectivity
and resulting in good to excellent yields of the glycal
cycloisomerization product (Table 1).
Stereoselective synthesis of D-desosamine could be ac-
complished beginning with application of the Carreira
protocol13 for zinc-mediated addition of TMS-acetylene to
(R)-3-tert-butyldimethylsiloxybutanal (1).11 Although the
overall yield for our substrate was somewhat lower than the
yields reported by Carreira for simpler substrates, the
stereoselectivity was nearly 100%. None of the undesired
diastereomer was recovered during purification by column
chromatography. Methylation and LAH reduction of the Boc-
protected nitrogen of glycal (10b) quickly established the
dimethylamine functionality required for desosamine. An
acidic protocol for dihydroxylation of problematic olefins
substituted with trialkylamines recently described by the
Sharpless laboratory14 proved to be effective when applied
to dimethylamino glycal (16) and generated the C2 hydroxyl
group anti to the tertiary amine group at C3 as well as the R
anomeric hydroxyl group at C1. Finally, D-desosamine (17)
was treated with acetic anhydride to facilitate characterization
Scheme 2. Stereoselective Synthesis of D-Desosaminea
a Conditions: (a) TMS-acetylene, n-BuLi, THF, -78 °C; then
chromatographic separation. (b) ClSO2Me, Et3N, CH2Cl2. (c) NaN3,
15-C-5, DMF. (d) LiAlH4, THF, 0 °C. (e) (RCO)2O, Et3N, CH2Cl2.
(f) HCO2H, DCC, CH2Cl2. (g) TBAF, THF, 0 °C. (h) NaH, CH3I,
DMF. (i) PPh3, Boc2NH, Et3N, DEAD, THF. (j) HF-py, THF, 0
°C.
analogues has been prepared in conjunction with the target
amino sugar, expanding our repertoire and the scope of
tungsten-mediated deoxyhexose precursors to include C4
methylene structures.
Preparation of amido-alkynol cycloisomerization substrates
(4-9) began with addition of TMS-acetylene to the known
TBS-protected aldehyde 1,11 and incorporation of amine
functionality by addition of sodium azide to the mesylate
followed by LiAlH4 reduction (Scheme 1). Although this
reaction was not stereoselective, the alcohol diastereomers
2a,b could be separated by careful silica gel chromatography
and permitted our exploration of each diastereomeric pattern.
a Conditions: (a) Zn(OTf)2, Et3N, (+)-N-methylephedrine, TMS-
acetylene, toluene, 23 °C, 18 h (60% yield). (b) ClSO2CH3, Et3N,
CH2Cl2. (c) NaN3, 15-C-5, DMF. (d) LAH, THF, 0 °C. (e) Boc2O,
Et3N, CH2Cl2. (f) TBAF, THF, 0 °C (60% yield, five steps). (g)
5% W(CO)6, THF, DABCO, hν, 55 °C (90% yield). (h) NaH, MeI,
DMF, 23 °C. (i) LAH, THF, 0 °C (90% yield, two steps). (j) 10%
OsO4, citric acid, Me3NO/H2O, BuOH/H2O. (k) Ac2O, DMAP,
Et3N, CH2Cl2 (46% yield, two steps).
(11) Ohta, K.; Miyagawa, O.; Tsutsui, H.; Mitsunobu, O. Bull. Chem.
Soc. Jpn. 1993, 66, 523.
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Org. Lett., Vol. 6, No. 10, 2004

Table 1. 3-Nitrogen-Substituted Glycals from W(CO)6-Catalyzed Alkynol Cycloisomerization
a Also 8% exo isomer found.
1
as the diacetate (18, Scheme 2). The H NMR data for the
diacetate 18 is identical with that reported for the natural
product-derived D-desosamine diacetate.4b
Wipf and Graham for certain diastereomers of alkynol
substrates with propargylic oxygen substituents.15 This
suggests possible stabilization of the vinylidene-W(CO)5
intermediate by propargylic nitrogen substituents.
In conclusion, we have demonstrated the generality of our
tungsten-catalyzed alkynol endo-cycloisomerization reaction
for a broad spectrum of N-protective groups. The nearly
exclusive endo-cycloisomerization observed herein for alkynol
substrates with propargylic nitrogen substituents regardless
of relative stereochemistry is notable, especially when
compared to the lower regioselectivity recently reported by
Acknowledgment. We thank the National Institutes of
Health (CA 59703) for support of this research. M.H.D. was
a Clare Boothe Luce Graduate Fellow (2000-2002). We also
acknowledge the use of shared instrumentation (NMR
spectroscopy, mass spectroscopy) provided by grants from
the National Institutes of Health, National Science Founda-
tion, and the Georgia Research Alliance.
(12) (a) Hughes, D. L.; Reamer, R. A. J. Org. Chem. 1996, 61, 2967.
(b) Koppel, I.; Koppel, J.; Degerbeck, F.; Grehn, L.; Ragnarsson, U. J.
Org. Chem. 1991, 56, 7172. (c) Hughes, D. L.; Reamer, R. A.; Bergan, J.
J.; Grabowski, E. J. J. J. Am. Chem. Soc. 1988, 110, 6487.
(13) (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687. (b) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806. (c) Carreira, E. M. Acc. Chem. Res. 2000, 33, 373.
(14) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K.
B. AdV. Synth. Catal. 2002, 344, 421.
Supporting Information Available: Experimental details
and procedures for compounds 2-18. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL049630M
(15) Wipf, P.; Graham, T. H. J. Org. Chem. 2003, 68, 8798.
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