Osmium-catalyzed tethered aminohydroxylation of glycals: A stereodirected access to 2- and 3-aminosugars

Article abstract of DOI:10.1021/ol503754f

The osmium-catalyzed aminohydroxylation of glycals has been achieved with complete regio- and stereocontrol by taking advantage of the Donohoe tethering approach. Glucals and galactals showed complementary reactivity in dependence of the stage at which the reaction was performed, i.e., directly or after double-bond shift consequent to a Ferrier rearrangement (that is, on the 1,2 or 2,3-unsaturated sugar), allowing access to both classes of 2-amino (mannosamine) and 3-amino (talosamine) sugar derivatives, respectively.

Full text of DOI:10.1021/ol503754f

Letter
pubs.acs.org/OrgLett
Osmium-Catalyzed Tethered Aminohydroxylation of Glycals: A
Stereodirected Access to 2- and 3‑Aminosugars
Stefania Mirabella, Francesca Cardona,* and Andrea Goti*
̀
Dipartimento di Chimica “Ugo Schiff”, Universita di Firenze, Via della Lastruccia 3-13, I-50019 Sesto Fiorentino (FI), Italy, associated
with ICCOM-CNR, Firenze, Italy
S
* Supporting Information
ABSTRACT: The osmium-catalyzed aminohydroxylation of glycals has been achieved with complete regio- and stereocontrol
by taking advantage of the Donohoe tethering approach. Glucals and galactals showed complementary reactivity in dependence
of the stage at which the reaction was performed, i.e., directly or after double-bond shift consequent to a Ferrier rearrangement
(that is, on the 1,2 or 2,3-unsaturated sugar), allowing access to both classes of 2-amino (mannosamine) and 3-amino
(talosamine) sugar derivatives, respectively.
he importance of the 1,2-amino alcohol motif is
documented by its occurrence in a wide variety of natural
tion of glycals and 2,3-hexenopyranosides (Figure 1), taking
advantage of the tethered approach to obtain, in a stereoselective
T
products and bioactive compounds, among which aminosugars
and aminoglycosides are of particular relevance. In particular, 2-
and 3-aminosugars are found, among the glycoconjugates, in
naturally occurring antibiotics (macrolides, aminoglycosides, and
anthracyclines), and SAR studies have shown the close
relationship of this motif with the activity of the aminosugar-
containing antibiotics.1 Moreover, recent studies have shown
that simple aminosugars exhibit antifungal and antibacterial
activity.2
Extensive synthetic studies have been carried out in order to
achieve the direct oxyamination of olefins,3 following the
pioneering Sharpless asymmetric aminohydroxylation (AA)
reaction.4 In order to circumvent the drawbacks of low regio-
and stereoselectivity often observed in the oxidation of several
classes of olefins with the Sharpless methodology, Donohoe and
co-workers introduced in 2001 a variant named “tethered
aminohydroxylation” (TA).5 This procedure guarantees full
regiocontrol by tethering the nitrogen source to an allylic alcohol
moiety, affording also a high level of stereoselectivity with chiral
allylic substrates. The optimized protocol, recently applied in the
total synthesis of valuable naturally occurring amino-hydroxy-
lated scaffolds,6 employs as substrate an O-aroyloxy carbamate,
capable of directly oxidizing the used osmium(VI) catalyst to the
actual osmium(VIII) active species, obviating the need of adding
an external stoichiometric oxidant.7
Following our longstanding interest in the field of nitrogen-
containing glycomimetics, particularly in iminosugars and
iminodisaccharides synthesis,8 we turned our attention to
aminosugar derivatives and envisaged that the double bond of
glycal derivatives bearing a free OH group in allylic position
could be manipulated to this aim. Herein we report the results of
preliminary studies on the osmium-catalyzed aminohydroxyla-
Figure 1. Aim of the work: the tethered aminohydroxylation (TA) of
glycals either before or after Ferrier rearrangement.
way, suitably protected 2- and 3-aminosugars with different
configurations at the new stereogenic carbon atoms.
Glycals offer a viable choice for accessing aminosugars.9−11
However, these compounds present inherent challenges
associated with specific carbohydrate features. Several proce-
dures for the introduction of an amino group at C-2 of glycals
have been reported. Among the metal-free procedures, Lemieux
and co-workers were able to introduce an oxime12 or an azido13
group at C-2 of galactal, and Danishefsky proposed a
sulfonamidoglycosylation of glycals,14 while a direct [4 + 2]
cycloaddition of dibenzyl azodicarboxylate with glycals allowed
the preparation of 2-amino-2-deoxycarbohydrates and more
complex aminoglycosides.15 A one-pot acetamidoglycosylation
with glycal donors was also described.16 Carreira proposed a
direct transition-metal-promoted amination of glycals using
Received: December 30, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503754f
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
manganese nitrido complexes which afforded N-trifluoroaceta-
mido derivatives.17 Intramolecular nitrogen atom delivery
strategies, either metal-free or promoted by Rh(II) and copper
salts, were also described by Rojas and co-workers.18 These
reactions, efficient on allal derivatives, were not completely
chemoselective with glucals, resulting in lower yields. In contrast,
only a few synthetic efforts have been documented for obtaining
3-aminosugars from unsaturated carbohydrates, and these often
require lengthy and not very efficient synthetic routes.19
Nicolaou and co-workers employed a tethered reaction for the
introduction of a N-phenylamino functionality at C-2 or C-3 of
glucal derivatives with IBX.20 Recently, a direct tandem
hydroamination−glycosylation of glycals was described.21
We initially investigated the TA reaction on the benzylidene-
protected glucal 1, synthesized from 3,4,6-tri-O-acetyl-D-glucal
according to the literature.22 The required precursor 3 was
prepared by reaction of allyl alcohol 1 with N,N′-carbon-
yldiimidazole (CDI) followed by hydroxylamine hydrochloride
in pyridine, which afforded 2 (58%) followed by aroylation with
p-chlorobenzoyl chloride (Scheme 1). The TA reaction was then
which was converted into the corresponding p-chlorobenzoyl
derivative 8a in 81% yield. Compound 8a was reacted under the
standard TA conditions (t-BuOH/H2O = 3/1) with a reduced
amount of catalyst (1 mol %) and selectively provided an
anomeric mixture (α/β = 2:1) of the desired oxazolidinone 9 in
31% yield (36% based on converted 8a) after acetylation of the
crude reaction mixture. To our delight, the silylene 8a had
undergone a clean TA exclusively, albeit leading only to a
moderately increased yield. Encouraged by these preliminary
results, the hydroxycarbamate 7 was reacted with a different acid
chloride, namely pentafluorobenzoyl chloride, reported as a
superior reoxidant for the TA reaction (Scheme 1).7
Unfortunately, no improvement was achieved, since the TA
conditions (1 mol % catalyst), applied to the O-aroyl
hydroxycarbamate 8b, obtained as above, provided the desired
oxazolidinone 9 (as a 2:1 α/β anomeric mixture) in 30% yield,
again with complete chemoselectivity.
In order to extend the study of the scope and limitations of the
TA reaction to other glycals, the same protocol was applied to
3,4,6-tri-O-acetyl-D-galactal. The di-tert-butylsilylene galactal 10
was prepared in two steps as reported.25 The required O-aroyloxy
carbamate 12 was readily accessed in 57% overall yield by
sequential reaction of 10 with CDI and hydroxylamine
hydrochloride and subsequent aroylation (Scheme 2). Com-
Scheme 1. TA Reaction on Glucals
Scheme 2. TA Reaction on Galactal
pound 12, when subjected to the TA conditions (5 mol %
catalyst) followed by acetylation, failed to cyclize to the desired
oxazolidinone. Instead, on purification by FCC over silica gel, the
carbamate 13 and the acetyl acetyloxy carbamate 14 were
recovered in 40% and 20% yield, respectively.
Rationalization of the substrate dependent behavior (glucal vs
galactal) in the above TA reactions relies on the mechanism
proposed by Donohoe.5 On this basis, the intermediate
trioxoimido osmium(VIII) complex A in the glucal series
(from 3 or 8a,b) is well suited for the intramolecular [3 + 2]
4
performed on the O-aroyloxy carbamate 3 with 5 mol % of
K2OsO2(OH)4 for 5 days.23 Direct acetylation of the crude
reaction mixture with an excess of acetic anhydride in pyridine
gave a mixture of two compounds, that were identified as
carbamate 5 (36%) and an anomeric mixture (α/β = 0.8:1, as
cycloaddition in its preferred half-chair H5 conformation to
generate the cyclic oxazolidinone 4 or 9 after hydrolysis and
acetylation (Figure 2a). With galactal 12, the opposite
configuration at C-4 places the silyloxy group in the axial
position in complex B, thus hampering the cyclization.
Accordingly, the formation of 13 may be ascribed to hydrolysis
of this intermediate (Figure 2b).26
Following these observations, it was expected that 2,3-
hexenopyranosides, obtained upon Ferrier rearrangement,27
would undergo a TA process to give 3-aminosugars. One such
derivative, the gluco O-aroyloxy carbamate 17, was prepared in
good yield from the 6-O-protected α-methyl glucoside 15,
obtained from 3,4,6-tri-O-acetyl-D-glucal in three steps and 74%
1
determined by H NMR integration) of the desired oxazolidi-
none 4 (27%), acetylated at both the anomeric oxygen and at the
oxazolidinone nitrogen. The scarce chemoselectivity obtained in
the aminohydroxylation of 3 prompted us to consider a
differently protected glucal. The di-tert-butylsilylene glucal 6,
obtained from 3,4,6-tri-O-acetyl-D-glucal as previously re-
ported,24 was reacted with CDI followed by the addition of
hydroxylamine to afford the hydroxycarbamate 7 (69%),18e
B
DOI: 10.1021/ol503754f
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notably, when the reaction was repeated with p-chlorobenzoyl
carbamate 21b, synthesized in even higher yield (81%) from 20,
and with portionwise addition of the catalyst (5 mol %) over 3
days, the yield of 22 increased to a remarkable 65% (Scheme 4).
As discussed before, the observed substrate selectivity in the
aminohydroxylation reaction on substrates 17 and 21a,b may be
rationalized according to the intermediates depicted in Figure 3.
Figure 2. Likely intermediates in the TA reaction with glucal and galactal
derivatives.
overall yield as previously described.28 However, when reacted
under TA conditions with 5 mol % of catalyst, 17 failed to
undergo cyclization (Scheme 3), and the carbamate 18 was
isolated as the major product (35%), together with minor
amounts of 15 (7%) and 16 (10%), probably formed on
hydrolysis of 17.
Figure 3. Likely intermediates in the TA reaction with D-gluco- and D-
galacto-2,3-hexenopyranosides.
Scheme 3. TA Reaction on D-Gluco-2,3-hexenopyranoside
Thus, the [3 + 2] cycloaddition of the gluco complex C is
hampered by the anomeric methoxy group, with consequent
failure of cyclization and reductive cleavage to give the carbamate
18 (Figure 3a). In contrast, the cycloaddition of galacto complex
D meets with success, allowing formation of the desired
oxazolidinone 22 (Figure 3b).
Finally, the conversion of the product oxazolidinones into the
free aminosugars was demonstrated by hydrolysis of 22 to the
corresponding 3-aminotaloside 24 (Scheme 5) with LiOH in
H2O at 50 °C overnight. This also caused concomitant
deprotection of the TBDMS group, affording methyl-3-amino-
3-deoxy-α-D-talopyranoside (24)30 in excellent yield.
Scheme 5. Synthesis of Methyl 3-Amino-3-deoxy-α-D-
The same synthetic strategy was then attempted with 3,4,5-tri-
talopyranoside (24)
O-acetyl-D-galactal (Scheme 4). The required unsaturated
Scheme 4. TA Reaction on D-Galacto-2,3-hexenopyranoside
In summary, straightforward access to 2- and 3-aminosugar
derivatives by means of the osmium-catalyzed tethered amino-
hydroxylation (TA) reaction on 1,2- or 2,3-hexenopyranosides
showed complementary substrate selectivity in the gluco and
galacto series, with glucals yielding the desired 2-aminosugars
while galactals failed. By way of contrast, D-galacto 2,3-
enopyranosides afforded 3-aminosugars. Work is underway in
our laboratory to expand the scope of the reaction and exploit
this strategy for the synthesis of relevant aminosugar targets.
galacto derivative 19 was prepared in 60% overall yield by
Ferrier rearrangement of 3,4,5-tri-O-acetyl-D-galactal followed by
acetyl deprotection and TBDMS protection at the primary
alcohol as reported.29 Application of a synthetic sequence similar
to that reported above for 15 but using pentafluorobenzoyl
chloride provided the pentafluoroaroyl carbamate 21a (Scheme
4). To our delight, the TA reaction on 21a using 3 mol % of Os
catalyst provided the desired oxazolidinone 22 in 33% yield.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
C
DOI: 10.1021/ol503754f
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(16) Di Bussolo, V.; Liu, J.; Huffman, L. G., Jr.; Gin, D. Y. Angew.
Chem., Int. Ed. 2000, 39, 204−207.
AUTHOR INFORMATION
■
Corresponding Authors
(17) Du Bois, J.; Tomooka, C. S.; Hong, J.; Carreira, E. M. J. Am. Chem.
Soc. 1997, 119, 3179−3180.
*E-mail: francesca.cardona@unifi.it.
*E-mail: andrea.goti@unifi.it.
(18) (a) Kan, C.; Long, C. M.; Paul, M.; Ring, C. M.; Tully, S. E.; Rojas,
C. M. Org. Lett. 2001, 3, 381−384. (b) Levites-Agababa, E.; Menhaji, E.;
Perlson, L. N.; Rojas, C. M. Org. Lett. 2002, 4, 863−865. (c) Bodner, R.;
Marcellino, B. K.; Severino, A.; Smenton, A. L.; Rojas, C. M. J. Org.
Chem. 2005, 70, 3988−3996. (d) Gupta, R.; Sogi, K. M.; Bernard, S. E.;
Decatur, J. D.; Rojas, C. M. Org. Lett. 2009, 11, 1527−1530.
(e) Hurlocker, B.; Abascal, N. C.; Repka, L. M.; Santizo-Deleon, E.;
Smenton, A. L.; Baranov, V.; Gupta, R.; Bernard, S. E.; Chowdhury, S.;
Rojas, C. M. J. Org. Chem. 2011, 76, 2240−2244.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank MIUR-Italy (PRIN 2010−2011, 2010L9SH3K 006)
and Ministero della Salute/Regione Toscana (Ricerca Final-
izzata, RF-2011-02347694) for financial support. We also thank
Premio di Laurea Stefano Marcaccini 2013 for awarding S.M.
with a grant for her M.Sc. Thesis.
(19) For selected direct syntheses of 3-aminodeoxysugars from glycal
derivatives: (a) Matthew, T. M.; Peng, T.; Christopher, M. H.; Robert, S.
C.; Lowary, T. L. J. Org. Chem. 2006, 71, 8059−8070. (b) Parker, K. A.;
Chang, W. Org. Lett. 2005, 7, 1785−1788. (c) Parker, K. A.; Chang, W.
Org. Lett. 2003, 5, 3891−3893.
(20) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Vega, J. A. Angew.
Chem., Int. Ed. 2000, 39, 2525−2529.
REFERENCES
■
(1) Rai, R.; McAlexander, I.; Chang, C.-W. Org. Prep. Proced. Int. 2005,
37, 337−375.
(21) Ding, F.; William, R.; Wang, S.; Gorityala, B. K.; Liu, X.-W. Org.
Biomol. Chem. 2011, 9, 3929−3939.
(2) (a) Muhizi, T.; Coma, V.; Grelier, S. Carbohydr. Res. 2008, 343,
2369−2375. (b) Muhizi, T.; Grelier, S.; Coma, V. J. Agric. Food Chem.
2009, 57, 8770−8775. (c) Muhizi, T.; Coma, V.; Grelier, S. Pest Manage.
Sci. 2011, 67, 287−293. (d) Coleman, R. S.; Lowary, T. L. Org. Biomol.
Chem. 2009, 7, 3709−3722. (e) Shi, W.; Marcus, S. L.; Lowary, T. L.
Carbohydr. Res. 2010, 345, 10−22.
(22) Shanmugasunduram, B.; Varghese, B.; Balasubramanian, K.
Carbohydr. Res. 2002, 337, 1523−1527.
(23) We employed a 6/1 t-BuOH/H2O mixture in place of the usual 3/
1 one to overcome the solubility problem of substrate 3.
(24) Hoberg, J. O. Carbohydr. Res. 1997, 300, 365−367.
(25) Chi-Li, C.; Namba, K.; Kishi, Y. Org. Lett. 2009, 11, 409−412.
(26) Formation of 14 as a byproduct can be explained by acetylation of
unreacted 12 after hydrolysis.
(3) For a review, see: Donohoe, T. J.; Callens, C. K. A.; Flores, A.; Lacy,
A. R.; Rathi, A. H. Chem.Eur. J. 2011, 17, 58−76.
(4) Sharpless, K. B.; Chong, A. O.; Oshima, K. J. Org. Chem. 1976, 41,
177−179.
(27) (a) Ferrier, R. J.; Zubkov, O. A. Org. React. 2003, 569−736.
(b) Gom
2013, 32, 7221−7262.
́ ́
ez, A. M.; Lobo, F.; Uriel, C.; Lopez, J. C. Eur. J. Org. Chem.
(5) (a) Donohoe, T. J.; Johnson, P. D.; Helliwell, M.; Keenan, M.
Chem. Commun. 2001, 2078−2079. (b) Donohoe, T. J.; Callens, C. K.
A.; Lacy, A. R.; Winter, C. Eur. J. Org. Chem. 2012, 655−663.
(6) (a) Carrol, C. L.; Chamberlin, A. R. Tetrahedron Lett. 2011, 52,
3995−3997. (b) Pullin, R. D. C.; Rathi, A. H.; Melikhova, E. Y.; Winter,
C.; Thompson, A. L.; Donohoe, T. J. Org. Lett. 2013, 15, 5492−5495.
(7) Donohoe, T. J.; Bataille, C. J. R.; Gattrell, W.; Kloesges, J.;
Rossignol, E. Org. Lett. 2007, 9, 1725−1728.
(28) (a) Saeeng, R.; Sirion, U.; Sirichan, Y.; Trakulsujaritchok, T.;
Sahakitpichan, P. Heterocycles 2010, 81, 2569−2580. (b) Marco-
Contelles, J. J. Org. Chem. 1996, 61, 7666−7670.
(29) Linde, R. G.; Egbertson, M.; Coleman, R. S.; Jones, A. B.;
Danishefsky, S. J. J. Org. Chem. 1990, 55, 2771−2776.
(30) Baer, H. H. J. Am. Chem. Soc. 1962, 84, 83−89.
(8) See, for example: (a) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero,
F. M.; Goti, A. Chem.Eur. J. 2009, 15, 7808−7821. (b) Cardona, F.;
Lalli, D.; Faggi, C.; Goti, A.; Brandi, A. J. Org. Chem. 2008, 73, 1999−
2002. (c) Matassini, C.; Mirabella, S.; Ferhati, X.; Faggi, C.; Robina, I.;
Goti, A.; Moreno-Clavijo, E.; Moreno-Vargas, A. J.; Cardona, F. Eur. J.
Org. Chem. 2014, 5419−5432.
(9) For a review on the synthesis of aminosugars, see: Sugai, T.
Kajimoto, T. Synthesis of Biologically Relevant Monosaccharides.
Glycoscience. Chemistry and Chemical Biology; Fraser-Reid, B., Tatsuta,
K., Thieme, J., Eds.; Springer-Verlag: Berlin, 2001.
(10) For recent examples of approaches to aminosugars not involving
the use of glycals, see: (a) Pfrengle, F.; Reissig, H.-U. Chem. Soc. Rev.
2010, 39, 549−557. (b) Adibekian, A.; Timmer, M. S. M.; Stallforth, P.;
van Rijn, J.; Werz, D. B.; Seeberger, P. H. Chem. Commun. 2008, 3549−
3551. (c) Albler, C.; Hollaus, R.; Kahlig, H.; Schmid, W. Beilstein J. Org.
̈
Chem. 2014, 10, 2230−2234.
(11) For an example of glycals employed in the synthesis of
iminosugars, see: Cardona, F.; Valenza, S.; Goti, A.; Brandi, A. Eur. J.
Org. Chem. 1999, 1319−1323.
(12) Lemieux, R. U.; Nagabhushan, T. L. Can. J. Chem. 1968, 46, 401−
403.
(13) Lemieux, R. U.; Ratcliffe, R. M. Can. J. Chem. 1979, 57, 1244−
1251.
(14) Griffith, A.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 5811−
5819.
(15) (a) Fitzsimmons, B. J.; Leblanc, Y.; Rokach, J. J. Am. Chem. Soc.
1987, 109, 285−286. (b) Fitzsimmons, B. J.; Leblanc, Y.; Chan, N.;
Rokach, J. J. Am. Chem. Soc. 1988, 110, 5229−5231. (c) Leblanc, Y.;
Fitzsimmons, B. J.; Springer, J. P.; Rokach, J. J. Am. Chem. Soc. 1989, 111,
2995−3000.
D
DOI: 10.1021/ol503754f
Org. Lett. XXXX, XXX, XXX−XXX