Protecting group and solvent control of stereo-and chemoselectivity in glucal 3-carbamate amidoglycosylation

Article abstract of DOI:10.1021/ol900126q

In the Rh₂(OAc)₄-catalyzed amidoglycosylation of glucal 3-carbamates, anomeric stereoselectivity and the extent of competing C3-H oxidation depend on the 4O and 6O protecting groups. Acyclic protection permits high α-anomer selectivi

Full text of DOI:10.1021/ol900126q

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1527-1530
Protecting Group and Solvent Control of
Stereo- and Chemoselectivity in Glucal
3-Carbamate Amidoglycosylation
Ritu Gupta, Kimberly M. Sogi, Sarah E. Bernard, John D. Decatur,† and
Christian M. Rojas*
Department of Chemistry, Barnard College, 3009 Broadway,
New York, New York 10027 and Department of Chemistry, Columbia UniVersity,
3000 Broadway, New York, New York 10027
crojas@barnard.edu
Received January 20, 2009
ABSTRACT
In the Rh2(OAc)4-catalyzed amidoglycosylation of glucal 3-carbamates, anomeric stereoselectivity and the extent of competing C3-H oxidation
depend on the 4O and 6O protecting groups. Acyclic protection permits high r-anomer selectivity with further improvement in less polar
solvents, while electron-withdrawing protecting groups limit C3-oxidized byproducts. Stereocontrol and bifurcation between alkene insertion
and C3-H oxidation reflect an interplay of conformational, stereoelectronic, and inductive factors.
2-Amino sugars having a 2,3-cis stereo array include N-
acetylmannosamine (ManNAc, 1), which is the biosynthetic
precursor of the sialic acids,1 and 2-allosamine, a constituent
of the potent Chitinase inhibitor allosamidin (2)2 and a useful
ligand scaffold (3)3 for asymmetric catalysis. The challenge of
stereoselective C2-N bond construction is acute in these
systems, and control of anomeric configuration in the prepara-
tion of glycoside derivatives is desirable. Synthetic methods
based on intermolecular additions to glycals typically place the
C2-N group trans to the C3-oxygen substituent.4 Gin’s
activated-sulfoxide-mediated acetamidoglycosylation5 of glucals
is an exception, producing ManNAc structures, though with
N-acetylglucosamine (GlcNAc) byproducts.5c
Figure 1. 2-Amino sugars with cis-2,3 stereochemistry.
glucal 3-carbamates9 to establish the 2,3-cis relationship. With
the 3O-carbamoyl glycals, we extended Du Bois’s C-H
amidation method10 to alkene insertion,11,12 a new reaction of
allylic carbamates.13 Mechanistic studies14 imply that these
conditions produce rhodium nitrenoids having reactivity
strikingly analogous to metal carbenoids.15 With iodosoben-
zene (PhIO)16 instead of PhI(OAc)2 as the oxidant, we
achieved in situ glycosylation of alcohols without nucleo-
As an alternative,6 we have used intramolecular nitrogen atom
delivery from allal 3-azidoformates,7 allal 3-carbamates,8 and
† Columbia University NMR Laboratory.
(1) Angata, T.; Varki, A. Chem. ReV. 2002, 102, 439–469.
(2) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. ReV. 1999, 99,
779–844.
(3) Park, H.; RajanBabu, T. V. J. Am. Chem. Soc. 2002, 124, 734–735.
10.1021/ol900126q CCC: $40.75
Published on Web 03/02/2009
2009 American Chemical Society

philic competition from acetate, an overall amidoglycosy-
lation process.8,9,17
Table 1. Protecting Group and Solvent Effects on Stereo- and
Chemoselectivity of Glucal 3-Carbamate Amidoglycosylation
Allal frameworks (e.g., 4, Scheme 1) provided high 1,2-trans
selectivity, offering a concise route to ꢀ-linked 2-amidoallopy-
Scheme 1. ꢀ-Selective Allal 3-Carbamate Amidoglycosylation
ranosides as found in allosamidin.7,8 However, in the C3-
epimeric series, our one-pot amidoglycosylation process
applied to glucal 3-carbamates 6a and 6b, having 4O,6O
acetonide or di-tert-butylsilylene protection, gave anomeric
mixtures only slighly favoring the 1,2-trans products 7-r and
also generated dihydropyranone byproducts 8a and 8b via
oxidation at the C3-H bond (Table 1, entries 1 and 5).9
Using 4-penten-1-ol as the acceptor, we were able to
stereoconvergently advance either anomer of n-pentenyl
(4) (a) Bongat, A. F. G.; Demchenko, A. V. Carbohydr. Res. 2007, 342,
374–406. (b) Griffith, D. A.; Danishefsky, S. J. J. Am. Chem. Soc. 1990,
112, 5811–5819. (c) Dahl, R.; Finney, N. S. J. Am. Chem. Soc. 2004, 126,
8356–8357. (d) Leblanc, Y.; Fitzsimmons, B. J.; Springer, J. P.; Rokach, J.
J. Am. Chem. Soc. 1989, 111, 2995–3000. (e) Lemieux, R. U.; Ratcliffe,
R. M. Can. J. Chem. 1979, 57, 1244–1251. (f) Lafont, D.; Guilloux, P.;
Descotes, G. Carbohydr. Res. 1989, 193, 61–73. (g) Du Bois, J.; Tomooka,
C. S.; Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 3179–3180.
(h) Guthikonda, K.; Wehn, P. M.; Caliando, B. J.; Du Bois, J. Tetrahedron
2006, 62, 11331–11342.
a In Hz, CDCl3 unless otherwise noted. b From 1H and 13C NMR of the
crude reaction mixture. c Isolated yield of the R anomer. d Data from ref 9.
e In DMSO-d6. f NMR yield of the R anomer vs mesitylene as an internal
standard. g In C6D6. h In acetone-d6. i Calcd from the total yield (54%) of
inseparable anomeric mixture.
glycoside18 7a, but the lack of amidoglycosylation selectivity
stymied direct access to R-linked ManNAc derivatives.9
Herein we report that proper choice of 4O and 6O protecting
groups and solvent enables high levels of stereocontrol and
chemoselectivity in amidoglycosylation of glucal 3-carbamates.
Our studies also illuminate electronic and conformational
aspects of both amidoglycosylation and the competing C3-H
oxidation.
For comparison, we began by treating benzylidene-protected
allal 3-carbamate 48 under our standard conditions with
4-penten-1-ol as the acceptor (Scheme 1). As in our previous
study with other acceptors,8 only ꢀ product 5, unaccompanied
by dihydropyranone, was observed. The outcome was compa-
rable in the three solvents tested.
(5) (a) Liu, J.; Gin, D. Y. J. Am. Chem. Soc. 2002, 124, 9789–9797. (b)
Di Bussolo, V.; Liu, J.; Huffman, L. G., Jr.; Gin, D. Y. Angew. Chem., Int.
Ed. 2000, 39, 204–207. (c) Liu, J.; Di Bussolo, V.; Gin, D. Y. Tetrahedron
Lett. 2003, 44, 4015–4018.
(6) For a strategy of internally directed glycal aminohydroxylation, see:
(a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Vega, J. A. Angew. Chem.,
Int. Ed. 2000, 39, 2525–2529. (b) Nicolaou, K. C.; Baran, P. S.; Zhong,
Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J. Am. Chem.
Soc. 2002, 124, 2233–2244.
(7) (a) Kan, C.; Long, C. M.; Paul, M.; Ring, C. M.; Tully, S. E.; Rojas,
C. M. Org. Lett. 2001, 3, 381–384. (b) Churchill, D. G.; Rojas, C. M.
Tetrahedron Lett. 2002, 43, 7225–7228.
(8) Levites-Agababa, E.; Menhaji, E.; Perlson, L. N.; Rojas, C. M. Org.
Lett. 2002, 4, 863–865.
(9) Bodner, R.; Marcellino, B. K.; Severino, A.; Smenton, A. L.; Rojas,
C. M. J. Org. Chem. 2005, 70, 3988–3996.
(10) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598–
600.
(11) (a) Padwa, A.; Stengel, T. Org. Lett. 2002, 4, 2137–2139. (b) Padwa,
A.; Flick, A. C.; Leverett, C. A.; Stengel, T. J. Org. Chem. 2004, 69, 6377–
6386.
By analogy with our earlier results7,8 and Padwa’s studies,11
we attribute high 1,2-trans selectivity to nucleophilic opening
of a glycosyl aziridine.4c,17,19 In the glucal series, low
anomeric stereocontrol might be due to glycosylation via an
oxocarbenium intermediate. Padwa has invoked aziridine-
opened zwitterions in reactions of indolyl and benzofuranyl
carbamates.11
(12) Related aziridinations: (a) Wehn, P. M.; Lee, J.; Du Bois, J. 2003,
5, 4823–4826. (b) Guthikonda, K.; Du Bois, J. J. Am. Chem. Soc. 2002,
124, 13672–13673. (c) Duran, F.; Leman, L.; Ghini, A.; Burton, G.; Dauban,
P.; Dodd, R. H. Org. Lett. 2002, 4, 2481–2483. (d) Liang, J.-L.; Yuan,
S.-X.; Chan, P. W. H.; Che, C.-M. Tetrahedron Lett. 2003, 44, 5917–5920.
(13) (a) Knapp, S.; Yu, Y. Org. Lett. 2007, 9, 1359–1362. (b) Donohoe,
T. J.; Johnson, P. D.; Cowley, A.; Keenan, M. J. Am. Chem. Soc. 2002,
124, 12934–12935. (c) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc.
2005, 127, 14198–14199.
(14) Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 562–568.
(15) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley: New York, 1998.
(16) Dauban, P.; Sanie`re, L.; Tarrade, A.; Dodd, R. H. J. Am. Chem.
Soc. 2001, 123, 7707–7708.
(17) Another Rh-nitrenoid approach to 2-amino glycosides, using glucal
sulfamates: Lorpitthaya, R.; Xie, Z.-Z.; Kuo, J.-L.; Liu, X.-W. Chem. Eur.
J. 2008, 14, 1561–1570.
(18) Fraser-Reid, B.; Madsen, R. In PreparatiVe Carbohydrate Chem-
istry; Hanessian, S., Ed.; Marcel Dekker: New York, 1997; pp 339-356.
1528
Org. Lett., Vol. 11, No. 7, 2009

We evaluated the effect of solvent polarity on anomeric
stereoselectivity, beginning with acetonide- and di-tert-butyl-
silylene-protected glucal 3-carbamates 6a and 6b (Table 1,
entries 1-7). There was a modest trend toward higher R
selectivity in less polar solvents, which we reasoned favored
assistance from the C2 nitrogen versus an oxocarbenium donor.
However, with the cyclic 4O,6O protection in 6a and 6b,
maintaining N-anomeric contact in the donor entails significant
strain.
to the rhodium acyl carbenoid.22,23 Another possible path to
byproduct 8, involving initial reaction of the enol ether π
bond with the hypervalent iodine oxidant, is not consistent
with our control experiments.24
The extent of the unwanted oxidation should depend on the
electronic characteristics of the C3-H bond. As was found with
rhodium carbenoids,25 C-H insertion of rhodium nitrenoids is
most favorable for electron-rich C-H bonds.14 Insertion R to
oxygen is facile,26 and Parker’s group has described activation
of allylic C-H bonds vinylogously R to the ring oxygen of
glycal substrates.27 Compain suggested that an anomeric C-H
bond is more reactive toward nitrenoid insertion in an axial
rather than equatorial position,28 an effect recognized in
carbenoid reactions.29 In our glucal 3-carbamate systems, a
vinylogous anomeric effect30 may activate the pseudoaxial
C3-H bond for insertion (Af8). By contrast, in allal 3-car-
bamate 4 (Scheme 1) or in glucal conformer A′ the C3-H bond
has the pseudoequatorial orientation.
To better enable an R-selective aziridine donor (C, Figure
2), we removed the stricture of cyclic 4O,6O protection.
Dibenzyl-protected 6c20 provided high to complete R selectivity,
depending on solvent (Table 1, entries 8-11). In benzene, we
detected only the R anomer, but the yield was lowered and we
noted chloroform-insoluble material in the crude product that
was not present when the reaction solvent was CH2Cl2. Mixed
solvents with a less polar component increased R selectivity
while better maintaining yields relative to CH2Cl2 alone.
Our analysis prompted two substrate-controlled31 approaches
for minimizing C3-H oxidation. First, electron-withdrawing
4O and 6O protecting groups might inductively deactivate the
C3-H bond toward nitrenoid insertion. Second, shifting the
conformational equilibrium from all-equatorial 4H5 (A) toward
Unfortunately, the dibenzyl protection in 6c did not remedy
the chemoselectivity problem. Our mechanistic model (Figure
2) is that amidoglycosylation and C3 oxidation both occur via
rhodium nitrenoid conformers A/A′. Du Bois has reported
5
inverted H4 (A′) would diminish stereoelectronic priming of
the C3-H bond. The conformational preference in glucals is
sensitive to hydroxyl protection,32 and the 4H5/5H4 distribution
can affect the stereoselectivity of addition reactions at the glycal
alkene.32b Electron-withdrawing substituents at C6, including
Br and OTs, along with 3O-ester protection, favor the inverted
5H4 conformation.32 This raised the possibility of simultaneous
inductive and conformational deactivation of the C3-H bond,
diminishing the formation of byproduct 8. These effects could
also improve stereocontrol by stabilizing aziridine donor C
relative to B/B′ (half-chair conformers lacking the stereocon-
trolling element of covalent33 N-C1 attachment) and by
(23) Clark, J. S.; Dossetter, A. G.; Wong, Y.-S.; Townsend, R. J.;
Whittingham, W. G.; Russell, C. A. J. Org. Chem. 2004, 69, 3886–3898
.
(24) No reaction of 6b occurred in the absence of Rh(II) catalyst, and
non-redox-active Lewis acid catalysts Sm(OTf)3, Ln(OTf)3, or Zn(OTf)2
did not produce byproduct 8b (or any 7b) from 6b. We also noted earlier
(ref 8) that tri-O-acetyl-D-glucal does not react under our conditions, though
it is a substrate for Kirschning-type oxidation: (a) Kirschning, A. Eur. J.
Org. Chem. 1998, 2267–2274. Compare: (b) Cochran, B. M.; Michael, F. E.
Org. Lett. 2008, 10, 5039–5042.
Figure 2. Model for factors affecting anomeric stereoselectivity
and extent of C3-H oxidation.
(25) Wang, P.; Adams, J. J. Am. Chem. Soc. 1994, 116, 3296–3305.
(26) Fiori, K. W.; Fleming, J. J.; Du Bois, J. Angew. Chem., Int. Ed.
2004, 43, 4349–4352.
ketone formation in reactions of secondary-alcohol-derived
carbamates and tentatively ascribed them to C-H insertion at
the R position, followed by fragmentation of the resulting four-
membered-ring carbamate.21 In the carbenoid field, Doyle found
that the diazoacetate ester of 1-indanol provides 1-indanone and
ketene upon treatment with dirhodium(II) catalysts.22 The
proposed mechanism involves intramolecular hydride transfer
(27) Parker, K. A.; Chang, W. Org. Lett. 2005, 7, 1785–1788.
(28) (a) Toumieux, S.; Compain, P.; Martin, O. R. Tetrahedron Lett.
2005, 46, 4731–4735. (b) Toumieux, S.; Compain, P.; Martin, O. R.; Selkti,
M. Org. Lett. 2006, 8, 4493–4496.
(29) (a) Sulikowski, G. A.; Lee, S. Tetrahedron Lett. 1999, 40, 8035–
8038. (b) Wardrop, D. J.; Zhang, W.; Fritz, J. Org. Lett. 2002, 4, 489–492.
(30) Curran, D. P.; Suh, Y.-G. Carbohydr. Res. 1987, 171, 161–191.
(31) An alternative would be catalyst-controlled chemoselectivity. In
our systems, of various Rh(II) carboxylates examined, only Rh2(OAc)4 and
Du Bois’s Rh2(esp)2 provided complete conversion, and neither catalyst
was satisfactory in limiting C3-H oxidation. Catalyst control of chemose-
lectivity in rhodium nitrenoid and carbenoid insertions, respectively: (a)
Hayes, C. J.; Beavis, P. W.; Humphries, L. A. Chem. Commun. 2006, 4501–
4502. (b) Davies, H. M. L.; Coleman, M. G.; Ventura, D. L. Org. Lett.
2007, 9, 4971–4974.
(19) Kozlowska-Gramsz, E.; Descotes, G. Tetrahedron Lett. 1981, 22,
563–566.
(20) See Supporting Information for carbamate syntheses.
(21) (a) Espino, C. G.; Du Bois, J. In Modern Rhodium-Catalyzed
Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; pp
379-416. See also footnote 17 of. (b) Kim, M.; Mulcahy, J. V.; Espino,
C. G.; Du Bois, J. Org. Lett. 2006, 8, 1073–1076.
(32) (a) Thiem, J.; Ossowski, P. J. Carbohydr. Chem. 1984, 3, 287–
313. (b) Roush, W. R.; Sebesta, D. P.; Bennett, C. E. Tetrahedron 1997,
53, 8825–8836.
(22) Doyle, M. P.; Dyatkin, A. B.; Autry, C. L. J. Chem. Soc., Perkin
Trans. 1 1995, 619–622.
(33) Crich, D.; Vinogradova, O. J. Am. Chem. Soc. 2007, 129, 11756–
11765.
Org. Lett., Vol. 11, No. 7, 2009
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favoring the conformation required for forming the aziridine
directly (A′fC) without intervention of zwitterion B/B′.
To probe these influences, we synthesized a range of glucal
3-carbamates 6d-i20 for comparison with 6a-c. Analysis of the
Table 2. Amidoglycosylation with Various Acceptor Alcohols
1
crude reaction mixtures by H and 13C NMR determined
anomeric stereoselectivity in products 7 and the proportion of
byproducts 8 (see Table 1).34 To estimate conformational effects
on the reactivity of the derived rhodium nitrenoids (A/A′), we
determined JH4,H5 for each glucal 3-carbamate 6. In various
1
instances, second-order behavior in the H NMR spectra (up
to 500 MHz) required coupled HSQC techniques for determin-
ing JH4,H5.
35 Decreasing values of JH4,H5 indicate an increasing
proportion of conformationally inverted A′, having the equato-
rial-equatorial H4-H5 relationship.32
With 4,6-di-O-acetyl-protected 6d and 4-O-acetyl-6-O-tosyl
derivative 6e (Table 1, entries 12 and 13), much less of the
C3-H-oxidized byproducts formed, compared to dibenzyl-
protected 6c. In addition, we detected only the R anomers of
7d and 7e from reactions in CH2Cl2. From the JH4,H5 values,
6d and 6e are both weighted more toward the 5H4 conformation
than the dibenzyl-protected 6c.
To better understand conformational and inductive contribu-
tions to stereo- and chemoselectivity, we used 6f, having the
cyclic-carbonate-locked 4H5 conformation (Table 1, entry 14).
Despite the electron-withdrawing character of the 4,6-O-
carbonate protection, 6f led to considerable byproduct 8f and a
mixture of anomers, supporting conformational flexibility as a
requirement for high chemo- and stereoselection.
Just one electron-withdrawing group at either 4O or 6O, as
in 6g and 6h (Table 1, entries 15 and 16), gave better
chemoselectivity than either the dibenzyl- or the disilyl-protected
carbamates 6c or 6i (cf. entries 8 and 17). The 4O-acetyl group
in 6g engendered a higher 5H4 proportion and excellent anomeric
selectivity, but was comparable to the 6O-tosyl of 6h in
enforcing chemoselection.36 The large silyl groups in 6i (Table
1, entry 17) led to decreased anomeric selectivity relative to
the dibenzyl-protected 6c.
Using stereo- and chemoselective substrates 6d and 6e, we
have begun studying reactions with various acceptor alcohols
(Table 2). Reducing the amount of acceptor posed a challenge
since reactions became sluggish and yields were lower (cf.
entries 1 and 2). Reasoning that excess alcohol might be needed
to activate CH2Cl2-insoluble iodosobenzene,37 we tested hexaflu-
oroisopropanol (HFIP), a useful solvent in reactions of hyper-
valent iodine oxidants,38 as an additive (entries 3 and 8).
Although yields did not improve much, consumption of starting
material was considerably faster with HFIP added, and the
weakly nucleophilic additive did not compete as the acceptor.
Increasing the concentration of substrate 6 was also helpful,
a 1,1,1,3,3,3-Hexafluoroisopropanol. b Isolated yield of the R anomer,
corrected in entries 1-6 for small amounts of chromatographically
inseparable C1-C2 oxidative cleavage byproduct (see Supporting Informa-
c
tion for details). From H NMR of the crude reaction mixture. d Starting
1
carbamate 6e (15%) remained. e ꢀ Anomer was not detected.
although 0.2 M is close to the upper limit for this initially
heterogeneous reaction.
Stereo- and chemoselectivity in the amidoglycosylation
of glucal 3-carbamates reflects a confluence of inductive,
conformational, and stereoelectronic effects. Acyclic 4O,6O
protection enables high anomeric stereocontrol. Electron-
withdrawing, 5H4-favoring 4O and 6O groups suppress
C3-H oxidation and further enhance stereoselectivity. The
net result is direct access to variably protected 2N,3O
mannosamine oxazolidinones from glucal 3-carbamates.
Studies with other glycal stereoisomers and optimization with
a range of acceptors are underway.
Acknowledgment. Dedicated to Prof. Les Lessinger (Bar-
nard College) on the occasion of his retirement and Prof. David
R. Williams (Indiana University) on his 60th birthday. We thank
the NIH (R15 GM081889-03) for funding and the Undergradu-
ate Science Education Program of HHMI for fellowships.
Jessica Anand and Victoria Baranov (Barnard College) did early
solvent screens. Simran Buttar and Yetta Levine (Barnard
College) prepared several intermediates. We thank Dr. Yasuhiro
Itakagi (Columbia University) for mass spectrometric analyses.
(34) Since dihydropyranones 8 are Michael acceptors for alcohols under
basic or acidic conditions (for example: Mann, B.; Pitts, D.; Koviach, J.
J. Carbohydr. Chem 2005, 24, 161–168. ), we verified their stability under
the reaction conditions. See Supporting Information for details.
(35) Simova, S. Magn. Reson. Chem. 1998, 36, 505–510. See Supporting
Supporting Information Available: Experimental details
and compound characterization, including preparation of
carbamates 6, determination of JH3,H4 values, and copies of
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
Informationfor details of JH4, determinations.
H5
(36) van Roeckel, C. A. A.; Beetz, T.; van Aelst, S. F. Tetrahedron
1984, 40, 4097–4107.
(37) Liang, C.; Collet, F.; Robert-Peillard, F.; Mu¨ller, P.; Dodd, R. H.;
Dauban, P. J. Am. Chem. Soc. 2008, 130, 343–350.
(38) (a) Kita, Y.; Takada, T.; Gyoten, M.; Tohma, H.; Zenk, M. H.;
Eichhorn, J. J. Org. Chem. 1996, 61, 5857–5864. (b) Huang, X.; Shao, N.;
Palani, A.; Aslanian, R. Tetrahedron Lett. 2007, 48, 1967–1971.
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