β-Selective glycosylations with masked D-mycosamine precursors

Article abstract of DOI:10.1021/ol016617i

Equation presented Both an intramolecular aglycon delivery (IAD) method and an intermolecular S_N2 displacement method were examined for β-selective glycosylations of cholesterol with D-mycosamine. An anomeric sulfoxide, sulfide, selenide, and fluoride were all successfully used as glycosyl donors in IAD reactions. The α-bromo ketone 19 was synthesized from protected mycosamine and employed in an intermolecular S_N2 glycosylation reaction. Both routes were successful for the model alcohol, cholesterol.

Full text of DOI:10.1021/ol016617i

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3393-3396
â-Selective Glycosylations with Masked
D-Mycosamine Precursors
Garrick K. Packard and Scott D. Rychnovsky*
Department of Chemistry, UniVersity of California, IrVine, California, 92697-2025
srychnoV@uci.edu
Received August 20, 2001
ABSTRACT
Both an intramolecular aglycon delivery (IAD) method and an intermolecular SN2 displacement method were examined for â-selective
glycosylations of cholesterol with D-mycosamine. An anomeric sulfoxide, sulfide, selenide, and fluoride were all successfully used as glycosyl
donors in IAD reactions. The r-bromo ketone 19 was synthesized from protected mycosamine and employed in an intermolecular SN2
glycosylation reaction. Both routes were successful for the model alcohol, cholesterol.
The mycosamine residue is present in a large number of
macrolide antibiotics,1 and stereoselective glycosylation is
generally the last challenge in a macrolide total synthesis.
Mycosamine is a difficult substrate with which to form
â-glycosides because of the axial orientation of the alcohol
at C2. Nicolaou’s group solved this problem in their synthesis
of amphotericin B2 by using a mycosamine donor with an
equatorial acetate at C2 and then inverting the stereochem-
istry through deprotection, oxidation, and subsequent reduc-
tion. Although effective, the overall process required four
steps and proceeded in only 14% yield.3 In conjunction with
a macrolide total synthesis project, we sought to develop a
method that would allow us to form mycosamine glycosides
with high â-selectivity, in high yield, and under conditions
mild enough for a sensitive macrolide aglycon.
sylation with mycosamine. An intramolecular aglycon de-
livery (IAD) method developed by Stork5 looked attractive
since it requires only two steps to achieve a completely
â-selective glycosylation and has been successful even with
hindered glycosyl acceptors. An intermolecular SN2 displace-
ment method pioneered by Lichtenthaler6 also looked at-
tractive since it uses mild, basic conditions to achieve the
same overall transformation. In this paper we detail our
efforts to implement both the Stork and Lichtenthaler
methods for â-selective glycosylations with D-mycosamine.
Cholesterol was selected as the glycosyl acceptor since, as
a moderately hindered secondary alcohol, it resembles a
typical protected macrolide aglycon.
D-Mycosamine can be obtained by acidolysis7 of nystatin
A (Scheme 1). For our purposes we required the amine at
C3 protected as an azide and the hydroxyls at C2 and C4
differentially protected. Both of these requirements were met
by first converting the C3 amine to an azide with TfN3,8
hydrolyzing the mycosamine moiety, and then forming an
acetonide between the C1 and C2 hydroxyls. Next the
The synthesis of â-mannosides has been an area of active
research in recent years and has been extensively reviewed.4
Two methods immediately seemed appropriate for glyco-
(1) Schaffner, C. P. Macrolide Antibiotics: Chemistry, Biology, and
Practice; Omura, S., Ed.; Academic Press: New York, 1984.
(2) Nicolaou, K. C.; Daines, R. A.; Ogawa, Y.; Chakraborty, T. K. J.
Am. Chem. Soc. 1998, 110, 4696-4705.
(3) The first step proceeded in 40% yield on the basis of 50% recovered
aglycon.
(5) Stork, G.; La Clair, J. J. J. Am. Chem. Soc. 1996, 118, 247-248.
(6) Lichtenthaler, F. W.; Schneider-Adams, T. J. Org. Chem. 1994, 59,
6728-6734.
(7) Dutcher, J. D.; Young, M. B.; Sherman, J. H.; Hibbits, W. E.; Walters,
D. R. Antibiotics Annual, 1956-1957; Medical Encyclopedia, Inc.: New
York, 1956; p 866.
(4) Gridley, J. J.; Osborn, H. M. I. J. Chem. Soc., Perkin Trans. 1 2000,
1471-1491 and references therein.
10.1021/ol016617i CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/27/2001

tography. Sulfide 8 is the product of simple reduction of
sulfoxide 6. Desilylation of 7 and 8 using HF‚pyridine gave
glycosylated product 9 as one diastereomer. Both axial and
equatorial sulfoxides 6 gave similar results, with a 31-39%
yield of 9 from cholesterol. The stereochemistry and con-
nectivity of coupled product 9 were proven by NOE analysis.
A significant amount of sulfoxide 6 was converted to
sulfide 8 during the glycosylation reaction. This unexpected
side reaction led us to examine other glycosyl donors:
anomeric sulfides, selenides, and fluorides.
Scheme 1. Preparation of Mycosamine Donorsa
We began by examining sulfide 2 (Scheme 3). Silylation
followed by addition of cholesterol gave tethered product
a (a) i. TfN3, DMAP, CuSO4 (cat.), DMSO; ii. H2SO4, wet
acetone; iii. 2,2-dimethoxy propane, 56% overall; (b) Ac2O,
pyridine, DMAP, CH2Cl2; (c) PhSH, BF3‚OEt2, CH2Cl2, 88%, (3.2:
1, equatorial to axial sulfide); (d) OXONE, MeOH, pH 7 buffer,
21% of axial sulfoxide, 64% of equatorial, 12% starting material;
(e) PhSeH, BF3‚OEt2, CH2Cl2, 85%, (3:1, equatorial to axial
selenide); (f) DMTSF, 4 Å molecular sieves, THF, (38%).
Scheme 3. Sulfide Glycosylationsa
hydroxyl at C4 was protected as an acetate.9 Reaction with
thiophenol and BF3‚OEt2 gave sulfide 2 as an inseparable
mixture of diastereomers. Similarly, treatment of 1 with
phenylselenol and BF3‚OEt2 gave selenide 4 as a mixture of
diastereomers. Oxidation of 2 with buffered Oxone gave
sulfoxide 3 while reaction of 2 with DMTSF10 gave fluoride
5.
a (a) Me2SiCl2, imidazole, DMAP, DMF, then cholesterol, 76%;
(b) MeOTf, 2,6-di-tert-butylpyridine, 4 Å molecular sieves, CH2Cl2;
(c) PPTS, wet MeOH, CH2Cl2, 61% from 8.
Investigation of the IAD method began with sulfoxide 3
(Scheme 2). Silylation followed by addition of cholesterol
8.11 Several reagents were evaluated as intramolecular
glycosylation promoters. Treatment of 8 with DMTSF12 gave
cholesterol as the only identifiable product. Reaction with
dimethyl sulfate gave back recovered starting material, but
treatment with the more reactive methyl triflate gave coupled
products 7 and 10 in good yield. Desilylation was then
effected with PPTS in MeOH to give 9 as one diastereomer
in 46% overall yield from cholesterol.
Scheme 2. Sulfoxide Glycosylationsa
Although the dimethylsilyl tether had served our purposes
thus far, we found that forming a diisopropylsilyl tether
proceeded in higher yield and gave cleaner tethered products.
Both tethers gave similar results in IAD reactions.
Anomeric selenides are reportedly activated under very
mild conditions.13 Silylation of selenide 4 (Scheme 4) with
(i-Pr)2Si(OTf)2 followed by addition of cholesterol gave 11
in excellent yield. Although AgOTf proved to be an
ineffective glycosylation promoter, reaction of 11 with
MeOTf gave an excellent yield of coupled product 12. This
material was then desilylated to give 9 as one diastereomer
in 75-83% overall yield from cholesterol.
a (a) Me2SiCl2, imidazole, DMAP, DMF, then cholesterol, 60%
for axial sulfoxide, 84% for equatorial; (b) Tf2O, 2,6-di-tert-
butylpyridine, 4 Å molecular sieves, CH2Cl2; (c) HF‚pyr, pyridine,
THF, 51% from 6 for axial sulfoxide, 46% from 6 for equatorial.
Anomeric fluorides also are good glycosylation substrates
since they are activated under a variety of reaction condi-
gave tethered product 6. Treatment of 6 with Tf2O in CH2Cl2
gave 7 and 8, which were inseparable by column chroma-
(8) Cavender, C. J.; Shiner, V. J. J. Org. Chem. 1972, 37, 3567-3569.
Vasella, A.; Witzig, C.; Chiara, J.-L.; Martin-Lomas, M. HelV. Chem. Acta
1991, 74, 2073-2076. Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron
Lett. 1996, 37, 6029-6032.
(9) A TBS protecting group was not robust enough for the chemistry to
follow.
(10) Blomberg, L.; Norberg, T. J. Carbohydr. Chem. 1992, 11, 751-
760. Meerwein, H.; Zenner, K.-F.; Gipp, R. Liebigs Ann. Chem. 1965, 688,
67-77.
(11) The axial isomer could not be separated from impurities.
(12) Padwa, A.; Waterson, A. G. J. Org. Chem. 2000, 65, 235-244.
(13) Mehta, S.; Pinto, B. M. J. Org. Chem. 1993, 58, 3269-3276.
3394
Org. Lett., Vol. 3, No. 21, 2001

SN2 reaction of an aglycon with an R-bromo ketone followed
by diastereoselective reduction to give the required axial
alcohol at C2. Lichtenthaler has published several routes to
R-ulosyl bromides.16 None of these methods could be
successfully applied to mycosamine; therefore we were
forced to develop our own route.
Scheme 4. Selenide Glycosylationsa
Sulfide 2 was converted in four steps to TBS ether 16 in
85% overall yield (Scheme 6).17 Oxidation of alcohol 16 gave
Scheme 6. Synthesis of Bromide 19a
a (a) (i-Pr)2Si(OTf)2, pyridine, DMF, then cholesterol, 96%; (b)
MeOTf, 2,6-di-tert-butylpyridine, 4 Å molecular sieves, CH2Cl2,
75% for axial selenide, 83% for equatorial; (c) TBAF, THF,
quantitative.
tions14 but, unlike bromides or chlorides, are stable and
isolable intermediates. Fluoride 13 was prepared from 5 in
98% yield using the procedure described for selenide 11
(Scheme 5). Treatment of 13 with Ce(ClO4)3 gave coupled
a (a) Ethyl vinyl ether, PPTS, CH2Cl2; (b) NaOH, MeOH, H2O;
(c) TBSOTf, 2,6-lutidine, CH2Cl2; (d) HCl, MeOH, H2O, 91% from
2; (e) TFAA, DMSO, tetramethylurea, Et3N, CH2Cl2, 59% of 17
and 18% of 18; (f) IBr, 4 Å mol. sieves, CH2Cl2, quant.
Scheme 5. Fluoride Glycosylationsa
ketone 17 as the major product along with varying amounts
of the epimerized product 18, which could be separated by
careful chromatography. Treatment of sulfide 17 with IBr
resulted in quantitative conversion to bromide 19.18
With bromide 19 in hand, we examined the Lichtenthaler
glycosylation protocol. Initial glycosylation attempts resulted
in complex mixtures of products that appeared to be mixtures
of diastereomers. Independent synthesis of ketones 21 and
23 revealed why (Scheme 7). Oxidation of alcohol 20 gave
a (a) Ce(ClO4)3, K2CO3, 4 Å molecular sieves, Et2O, 71%; (b)
Cp2ZrCl2, AgClO4, 4 Å molecular sieves, toluene, 73%; (c) TBAF,
THF, quantitative.
product 12 while reaction with Cp2ZrCl2/AgClO4, gave
fluoride 14. This transformation can also be achieved using
AgOTf in place of AgClO4 although it requires much longer
reaction times. The use of AgOTf alone, Yb(OTf), and SnCl2/
AgClO4 all gave back recovered starting material. Fluoride
14 was desilylated to give 9 as one diastereomer in 72%
overall yield from cholesterol.
Scheme 7. â-ketones Epimerize and Form Hydratesa
Although several methods were developed to glycosylate
mycosamine by the IAD method, none proved to be useful
for our total synthesis project due to the extreme acid lability
of our macrolide aglycon. Therefore, we turned our attention
to the Lichtenthaler15 methodology for the synthesis of
â-mannosides. This methodology involves intermolecular
a (a) TFAA, DMSO, tetramethylurea, Et3N, CH2Cl2, 97% of 21
and 100% of 23.
an excellent yield of ketone 21 as one diastereomer.
Oxidation of alcohol 22, however, gave four different
products identified as C3 epimers of ketone and ketone
hydrate 23.
(14) (a) Hosono, S.; Kim, W.; Sasai, H.; Shibasaki, M. J. Org. Chem.
1995, 60, 4-5. (b) Nicolaou, K. C.; Dolle, R. E.; Papahatjis, D. P.; Randall,
J. L. J. Am. Chem. Soc. 1984, 106, 4189-4192. (c) Matsumoto, T.; Maeta,
H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron Lett. 1988, 29, 3567-3570.
(d) Hosono, S.; Kim, W.; Sasai, H.; Shibasaki, M. Tetrahedron Lett, 1995,
36, 4443-4446. (e) Kim, W.; Sasai, H.; Shibasaki, M. Tetrahedron Lett.
1996, 37, 7797-7800. (f) Barrena, I.; Echarri, R.; Castillon, S. Synlett 1996,
675-676.
(15) Lichtenthaler, F. W.; Schneider-Adams, T. J. Org. Chem. 1994, 59,
6728-6734.
Org. Lett., Vol. 3, No. 21, 2001
3395

Thus, there are two problems with the Lichtenthaler
procedure as it pertains to â-selective glycosylations with
mycosamine: (1) the product ketones readily form hydrates
and (2) the product ketones are very prone to epimerization.
We reasoned that if the SN2 displacement and NaBH4
reduction could be run sequentially in one pot in the absence
of water, these problems would be avoided. Initial one-pot
procedures (Scheme 8) using CH2Cl2 as solvent were
AgOAc, and AgOTs) were ineffective promoters that showed
no conversion of starting materials.
Turning to deprotection (Scheme 9), the azide group of
24 was reduced to the corresponding amine and acetylated
Scheme 9. Deprotectiona
Scheme 8. Intermolecular Glycosylationa
a (a) Propanedithiol, Et3N, MeOH; (b) Ac2O, MeOH, 79% from
24; (c) TBAF, THF, 80%; (d) i. propanedithiol, Et3N, MeOH, 40
°C; ii. Ac2O, MeOH, 90%.
a (a) Cholesterol, Ag2CO3, 3 Å molecular sieves, THF, then
MeOH, NaBH4, 82%, (14:1, 24:25); (b) cholesterol, Ag2CO3,
AgOTf, 3 Å molecular sieves, then DMAP, MeOH, NaBH4, 95%,
(7:1, 24:25).
to aid in purification, and then the TBS protecting group
was cleaved with TBAF to give 26 in 63% overall yield.
Azide 9 was reduced in a similar fashion and then acetylated
to give 26 in 90% overall yield.
In summary, two methods have been developed for the
â-selective glycosylation of cholesterol with D-mycosamine.
These methods are an extension of previous methods used
for formation of â-mannosides and should allow the attach-
ment of â-D-mycosamine to a wide range of alcohols.
successful but proceeded very slowly and gave only an
∼30% yield of coupled product 24. Changing the solvent to
THF resulted in a more rapid reaction, and coupled products
24 and 25 were obtained in 82% yield as a 14:1 mixture of
diastereomers favoring 24. AgOTf proved to be a very
effective promoter of this reaction, resulting in rapid conver-
sion even under dilute conditions at -78 °C although with
only a 7:1 diastereoselectivity. Other silver salts (AgSiO4,
Acknowledgment. Financial support from the National
Institutes of Health (GM 43854) is gratefully acknowledged.
(16) Lichtenthaler, F. W.; Klares, U.; Szurmai, Z.; Werner, B. Carbohydr.
Res. 1998, 305, 293-303. Lichtenthaler, F. W.; Metz, T. W. Tetrahedron
Lett. 1997, 38, 5477-5480. Lichtenthaler, F. W.; Jarglis, P.; Hempe, W.
Liebigs Ann. Chem. 1983, 1959-1972.
Supporting Information Available: Experimental pro-
cedures and characterization data for all numbered com-
pounds except 7, 10, and 20-23). This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) The TBS protecting group is necessary since both C4 acetates and
benzoates are eliminated upon oxidation of the C2 alcohol.
(18) This product decomposes upon exposure to SiO2; therefore, fol-
lowing an aqueous workup, it is used directly in the next step.
OL016617I
3396
Org. Lett., Vol. 3, No. 21, 2001