Enantioselective synthesis of N-Cbz-protected 6-amino-6-deoxymannose, -talose, and -gulose

Article abstract of DOI:10.1021/ol016743m

equation presented The enantioselective synthesis of three 6-amino-6-deoxy sugars has been achieved in six to eight steps from furfural. A sequence of diastereoselective oxidation and reduction reactions produced Cbz-protected 6-aminomannose from furfuryl alcohol 3. The incorporation of a Mitsunobu reaction into the reaction sequence allows for the selective synthesis of both N-Cbz-protected 6-aminotalose and 6-aminogulose. The overall procedure allows for the synthesis of either enantiomer of these three aminosugars.

Full text of DOI:10.1021/ol016743m

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3899-3902
Enantioselective Synthesis of
N-Cbz-Protected
6-Amino-6-deoxymannose, -talose, and
-gulose
Michael H. Haukaas and George A. O’Doherty*
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
odoherty@chem.umn.edu
Received September 11, 2001
ABSTRACT
The enantioselective synthesis of three 6-amino-6-deoxy sugars has been achieved in six to eight steps from furfural. A sequence of
diastereoselective oxidation and reduction reactions produced Cbz-protected 6-aminomannose from furfuryl alcohol 3. The incorporation of a
Mitsunobu reaction into the reaction sequence allows for the selective synthesis of both N-Cbz-protected 6-aminotalose and 6-aminogulose.
The overall procedure allows for the synthesis of either enantiomer of these three aminosugars.
Since their identification in the 1950s, the aminoglycosides
have been an important class of antibiotics in the fight against
infections.1 The aminoglycosides consist of a large class of
mono- and bis-glycosidated diaminocyclitols such as kana-
mycins A-C2 (Scheme 1) and others.3 These compounds
belong to a class of broad spectrum antibacterial compounds
that are currently used to treat various Gram-negative and
Gram-positive infections, as well as tuberculosis.3 Although
these antibiotics have high toxicity (nephrotoxicity and
ototoxicity)4 associated with their use, they are still admin-
istered because there are no alternatives.5 Along with their
continued use as antibiotics, aminoglycosides are being
screened as potential anti-HIV compounds.6
The increased incidence of bacterial resistance has created
a great need for new antibacterial compounds.5 The rapid
escalation of the incidence of multiple-antibiotic-resistant
pathogens is now raising very serious concerns worldwide.7,8
The synthesis and evaluation of new aminoglycoside ana-
Scheme 1
(1) Goodman-Gilman, A.; Goodman, L. S.; Rall, T. W.; Murad, F.
Goodman and Gilman’s The Pharmacological Basis of Therapeutics;
MacMillan Publishing Co: New York, 1985.
(2) For the first synthesis of kanamycin A, see: Nakajima, M. Hasegawa,
A. Kurihara, N.; Shibata, H.; Ueno, T.; Nishumura, D. Tetrahedron Lett.
1968, 9, 623-627.
(3) Hooper, I. R. The Naturally Occurring Aminoglycoside Antibiotics.
In Aminoglycoside Antibiotics; Hooper, I. R., Umezawa, H., Eds.; Springer-
Verlag: NewYork, 1982.
(4) Ruppersberg, J. P. HNO 1997, 45(3), 111-112.
(5) Brickner, S. J. Chem. Ind. 1997, 131-135.
10.1021/ol016743m CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/02/2001

iminosugars of type 7 were prepared in five-seven steps
from Cbz-protected furfurylamine 6. Both furans 4 and 6
were easily prepared as either enantiomer by the Sharpless
asymmetric dihydroxylation reaction (AD)14 and amino-
hydroxylation reaction (AA),15 respectively. Buoyed by this
success, we decided to investigate a related strategy toward
Cbz-protected 6-amino-6-deoxysugars 1 from pyran 2. Thus
we envisioned pyran 2 arising via an Achmatowicz strategy16
from furfuryl alcohol 3 (Scheme 1). Ultimately we envision
this route allowing access to unnatural C-2/C-3-dideoxy-6-
aminosugars.
Scheme 2
Traditionally, 6-amino-6-deoxysugars are obtained from
an azide displacement of a protected C-6-halosugar followed
by reduction to the free amine.2,17,18 Because we desired
access to both enantiomers of various 6-aminosugars, we
were interested in testing the viability of an Achmatowicz
approach (2 from 3) to these aminoglycoside intermediates16
(Scheme 1), where the initial asymmetry will be derived from
furan 3. Herein we report our successful efforts at the
conversion of furfural into either enantiomer of N-Cbz-
protected â-pivaloyl-6-aminomannose 1a and the corre-
sponding talose and gulose isomers 1b and 1c.
Previously we found that N-Cbz-protected amino alcohol
3 was produced (42% yield) as the major regioisomer (2:1
ratio) from the asymmetric aminohydroxylation (AA) of
vinylfuran, however in low enantioexcess.19 Using the
(DHQ)2PHAL ligand the minor isomer (+)-9 was pro-
duced in greater than 87% enantiomeric excess,20 while the
major isomer (+)-3 was formed with 14% enantiopurity
(Scheme 3). Accordingly, the pseudoenantiomeric ligand
logues will greatly increase our understanding of how to
control bacterial infections and resistance.9
Analysis of the aminoglycosides reveals two common
structural motifs, a 2-deoxystreptamine core and variously
substituted aminosugars (Scheme 1). Wong and Mobashery
have demonstrated the importance of the 6-amino-6-deoxy-
sugar for both ribosomal RNA binding and antibiotic
activity.5,10 Previous structure-activity studies of the ami-
noglycoside antibiotics have used semisynthesis techniques
to remove hydroxyl groups from the existing aminoglyco-
sides and strategically added functional groups of interest.11
We felt a complementary approach would be to start with a
drastically simplified structure and to sequentially increase
its stereochemical and functional complexity. To implement
this strategy, we desired a flexible route to D- and L-6-amino-
6-deoxysugars that allows for the synthesis of various
stereoisomers and deoxy analogues.
Recently, our group has had success at using asymmetric
catalysis for the synthesis of D- and L-sugars and iminosugars
from the achiral vinylfuran via chiral furans 4 and 6 (Scheme
2).12,13 Four hexoses of the type 5 were derived from
monoprotected diol 4 in four-six steps. Similarly, two
Scheme 3
(6) (a) Green, M. R. AIDS Res. ReV. 1993, 3, 41-55. (b) Alper, P. B.;
Hendrix, M.; Sears, P.; Wong, C.-H. J. Am. Chem. Soc. 1998, 120, 1965-
1978.
(7) Miller, G. H.; Sabatelli, F. J.; Hare, R. S.; Glupczynski, Y.; Mackey,
P.; Shlaes, D.; Shimizu, K.; Shaw, K. J.; Bauernfeind, A.; Schweighart, S.;
Shannon, K.; Patzer, J.; Molinari, G.; Schito, G. C.; Gomezlus, R.;
Gomezlus, S.; Ferreira, H.; Sousa, J. C.; Vaz, M. J. M.; Collatz, E.; Bismuth,
R.; Lambert, T.; Courvalin, P.; Minozzi, C.; Klugman, K. Clin. Infect. Dis.
1997, 24, S 46-S 62.
(8) For instance, worldwide Streptococcus pneumoniae is responsible
for 1.2 million deaths per year in children under the age of 5, see: (a)
Bruyn G. A. W.; Zegers, B. J. M.; van Furth, R. Clin. Infect. Dis. 1992,
14, 251-262. (b) Janoff, E. N.; Rubins, J. B. Microb. Drug Resist. 1997,
3, 215-232. Even more alarming is that Mycobacterium tuberculosis is
estimated to cause 3 million deaths per year, see: (c) Swartz, M. N. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 2420-2427.
(9) Umezawa, H.; Kondo, S. Mechanisms of Resistance to Aminogly-
coside Antibiotics. In Aminoglycoside Antibiotics; Hooper, I. R., Umezawa,
H., Eds.; Springer-Verlag: New York, 1982.
(DHQD)2PHAL provided the enantiomer (-)-3 in a slightly
higher enantiomeric excess (20%) and (-)-9 in a similar
enantiomeric excess (> 87%). Although the use of
(14) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483-2547.
(15) (a) Sharpless, K. B.; Patrick, D. W.; Truesdale, L. K.; Biller, S. A.
J. Am. Chem. Soc. 1975, 97, 2305-2306. (b) Li, G.; Chang, H.-T.; Sharpless,
K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451-454.
(16) An Achmatowicz reaction is the oxidative rearrangement of furfuryl
alcohols to 2-substituted 6-hydroxy-2H-pyran-3(6H)-ones. (a) Achmatowicz,
O.; Bielski, R. Carbohydr. Res. 1977, 55, 165-176. (b) Grapsas, I., K.;
Couladouros, E. A.; Georgiadis, M. P. Pol. J. Chem. 1990, 64, 823-826.
For its use in carbohydrate synthesis, see: ref 12 and the following. (c)
Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863-866. (d) Balachari,
D.; O’Doherty, G. A. Org. Lett. 2000, 2, 4033-4036.
(17) (a) Ponpipom, M. M.; Hanessian, S. Can. J. Chem. 1972, 50, 246-
252. (b) Ponpipom, M. M.; Hanessian, S. Can. J. Chem. 1972, 50, 253-
258.
(10) Roestamadji, J.; Grapsas, I.; Mobashery, S. J. Am. Chem. Soc. 1995,
117, 11060-11074.
(11) (a) Umezawaa, S.; Tsuchiya, T. Total Synthesis and Chemical
Modification of the Aminoglycoside Antibiotics. In Aminoglycoside Anti-
biotics; Hooper, I. R., Umezawa, H., Eds.; Springer-Verlag: NewYork,
1982. (b) Okuda, T. Ito, Y. Biosynthesis and Mutasynthesis of Aminogly-
coside Antibiotics. In Aminoglycoside Antibiotics; Hooper, I. R., Umezawa,
H., Eds.; Springer-Verlag: NewYork, 1982.
(12) (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.
(13) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401-404.
(18) Recently, Herscovici reported the use of this approach to structures
related to 2 by a six-step route from triacetyl-D-glucal, see: Herscovici, J.;
Egron, M. J.; Quenot, A.; Leclercq, F.; Leforestier, N.; Mignet, N.; Wetzer,
B.; Scherman, D. Org. Lett. 2001, 3, 1893-1896.
3900
Org. Lett., Vol. 3, No. 24, 2001

(DHQ)2AQN as a ligand in the AA has been reported to
achieve a reversal of regioselectivety,21 its use in the AA of
vinylfuran produced results similar to those of (DHQ)2PHAL
(1:2 ratio of regioisomers favoring the furfuryl alcohol;
furfurylamine, 74% ee; furfuryl alcohol, 14% ee).22,23
While the aminohydroxylation provided enough material
to investigate the Achmatowicz reaction sequence, we still
desired a more practical and enantioselective approach to 3.
Racemic aminoalcohol 3 was readily prepared from furfural
via a Henry reaction24/hydrogenation/Cbz-protection se-
quence (10 to (()-3, Scheme 4). This procedure routinely
furnished excellent results.28 In practice, treating a neat
admixture of Et3N/HCO2H (5:2) and ketone 11 to the Noyori
reagent system (0.5 mol % of 12 in a neat 5:2 ratio of Et3N/
HCO2H)29 gave (+)-3 in excellent yield and enantioexcess
(92% yield, >96% ee).
Employing the Achmatowicz reaction on furan 330 pro-
duced dihydropyranone 13 in an excellent yield (82%, 1.05
equiv of NBS, 1 equiv of NaOAc and 2 equiv of NaHCO3,
Scheme 5).12 Our preference is for the NBS procedure, but
Scheme 5
Scheme 4
alternative oxidants such as mCPBA also convert 3 to 13.
The anomeric hydroxyl of pyranone 13 was then protected
as the pivaloate (PivCl, Et3N, -78 °C), providing a 68%
yield of a 12:1 mixture of anomers 14R and 14â.31
With the stereochemistry set at C-1 and C-5, the other
three stereocenters were diastereoselectively added in two
remaining steps (Scheme 6). The pivaloate 14R was subjected
provided multigram quantities of racemic 3 in a 40% overall
yield and with the use of only one chromatographic purifica-
tion. While we initially investigated the use of an asymmetric
Henry reaction25 to provide 3, the reduction of the nitro group
gave significant amounts of partially reduced byproducts.
Thus, we desired a more reliable method to induce the
asymmetry.
A highly practical procedure was finally found when we
decided to induce the asymmetry in 3 via an asymmetric
reduction of ketone 11. Exposing racemic 3 to Dess-Martin
reagent (1.1 equiv in CH2Cl2) gave an 88% yield of ketone
11. While we had only modest success with the oxazaboro-
lidine-catalyzed asymmetric borane reduction26 of ketone 11
(68% yield and 78% ee with 1 equiv of catalyst at room
temperature),27 we found that a Noyori reduction of 11
Scheme 6
(19) This is an improved procedure and yield from our previously
published results, see: Bushey, M. L.; Haukaas, M. H.; O’Doherty, G. A
J. Org. Chem. 1999, 64, 2984-2985.
(20) At a smaller scale, the level of enantio-induction has been as high
as 94%, as determined by Mosher ester analysis. (a) Sullivan, G. R.; Dale,
J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143-2147. (b) Yamaguchi,
S.; Yasuhara, F.; Kabuto, K. T. Tetrahedron 1976, 32, 1363-1367.
(21) Tao, B.; Schlingloff, G.; Sharpless, K. B. Tetrahedron Lett. 1998,
39, 2507-2510.
(22) The absolute stereochemistry and the level of enantioexcesses of 3
and 6 were determined by the method of Mosher, see ref 20a.
(23) Our optimized variation from the typical Sharpless procedure was
to the use the sodium salt of N-chlorobenzylcarbamate as the limiting
reagent, providing a good yield of a mixture of regioisomers (74%). Thus,
the volatile and inexpensively produced vinylfuran in 30% excess allowed
for more efficient use of the more costly catalyst and chiral ligand. This
procedure routinely provided a ∼40% yield of the furfuryl alcohol 3 and a
21% yield of the TBS-protected regioisomer, see ref 19.
to Luche reduction conditions (NaBH4, CeCl3, -78 °C) to
give the allylic alcohol 2 (82% yield) with complete
stereocontrol.12,32 Diastereoselective osmium-catalyzed di-
hydroxylation of olefin 2 (5% OsO4, NMO(aq), in CH2Cl2)
occurred from the less hindered face to afford the manno-
triol 1a in a 98% yield. The relative stereochemistry of 1a
(27) In our hands, the TON (turn over numbers) for the catalytic (10%)
use of the oxazaborolidine was too low for practical use.
(28) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 2521-2522. For catalyst preparation, see:
(b) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 285-288.
(29) For good conversions on large scale, a 0.5 M CH2Cl2 solution of
ketone 11 was reduced with 12 and 2 equiv of Et3N and 5 equiv of HCO2H
at elevated temperatures (50 °C) with no reduction in enantiopurity and
yield, see: Cossy, J.; Eustache, F.; Dalko, P. I. Tetrahedron Lett. 2001, 42,
5005-5007.
(24) Youn, S. W.; Kim, Y. H. Synlett 2000, 880-882.
(25) (a) Iseki, K.; Oishi, S.; Sasai, H.; Shibasaki, M. Tetrahedron Lett.
1996, 37, 9081-9084. (b) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki,
T.; Itoh, N.; Shibasaki, M. J. Org. Chem. 1995, 60, 7388-7389.
(26) (a) Yadav, J. S.; Reddy, P. T.; Hashim, S. R. Synlett 2000, 1049-
1051. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-
2012.
Org. Lett., Vol. 3, No. 24, 2001
3901

was confirmed by examination of the appropriate coupling
constants and comparison to a similarly protected mannose
sugar.12 Data that were particularly indicative of the manno-
stereochemistry were the trans-diequatorial coupling constant
between H1-H2 (J ) 1.5 Hz), the cis-equatorial/axial
coupling constant between H2-H3 (J ) 3.0 Hz), and the
two trans-diaxial coupling constant between H3-H4 and
H4-H5 (J ) 9.5 and 9.5 Hz) (see Supporting Information).
With the successful synthesis of the mannose sugar 1a,
we next explored the viability of this approach to the talose
and gulose sugars 1b and 1c, respectively. As with our
conversion of furan diol 4 to gulose/talose sugars 5 (Scheme
2), we envisioned that access to pyran 15 would be required.
From these previous studies, we expected the gulose sugar
1c to result from a facial selective dihydroxylation reaction
of pyran 15. Similarly, the talose sugar 1b should be
produced from a hydroxy-directed dihydroxylation of pyran
15.
Scheme 7
Exposure of 2 to the Mitsunobu reaction conditions (PPh3,
DEAD, p-nitrobenzoic acid (PNBOH))33 yielded a p-ni-
trobenzoate ester34 (91%), which was selectively hydrolyzed
with Et3N in MeOH to yield the axial alcohol 15 (95%,
Scheme 7). Surprisingly, treatment of pyran 15 to conditions
identical to those for the conversion of pyran 2 to the manno-
triol 1a (5 mol % of OsO4, 50% NMOaq/CH2Cl2; Scheme 7,
condition a) afforded a 6:1 ratio of sugars 1b/1c with the
all-syn talo-triol 1b being the predominant isomer isolated
in a 60% yield along with the recovery of 22% starting
material 15. These stereochemical assignments were con-
firmed by comparison with the results of the hydroxy-
directed dihydroxylation. Exposure of allylic alcohol 15 to
Donohoe’s conditions35 (TMEDA‚OsO4, CH2Cl2; Scheme 7,
condition b) exclusively afforded the expected all-syn triol
1b (47% yield).
triols 1c/1b in a low isolated yield (33%; Scheme 7, condition
d), with the gulo-triol being the major isomer. This switch
in selectivity was further increased upon the use of the polar/
hydrogen donating solvent t-BuOH (Scheme 7, condition c).
Treatment of 15 with 5% OsO4/NMOaq in t-BuOH afforded
a 58% yield of a 6:1 mixture of the gulo- (50%) and talo-
triols (8%), respectively. The relative configurations of 1b
and 1c were determined by examining relevant coupling
constants and NOE’s from a series of H NMR, H,1H-
COSY, and HMQC experiments. Particularly diagnostic of
the stereochemistry was the larger coupling constants
between H1-H2 (J ) 4.0 Hz) for the gulo-sugar 1c than
that for the talo-sugar 1b (J ) 1.5 Hz) and the W-coupling
between H2 and H4 (J ) 1.5 Hz) of talose triol 1b.
In summary, we have developed a practical five-step
synthesis of both D- and L-6-amino-6-deoxymannose from
furfural (14% overall yield, 45% from 3). This route is
amenable to multigram scale preparation. Similarly we have
also extended this methodology to D- and L-talose and gulose
in comparable yields (23% and 19% from 3). We feel this
new route to L-sugars will be very beneficial for the synthesis
of unnatural aminoglycosides.
1
1
The facial selectivity for dihydroxylation in CH2Cl2
probably can be attributed to solvent effects on conformation.
This was evident from the dihydroxylation of 15 in more
polar solvents (acetone and t-BuOH). Substituting the more
polar solvent acetone for CH2Cl2 gave of a 3:2 mixtures of
(30) The preceding reaction sequences have been preformed on both
(+)-3 and (-)-3; for simplicity reasons we are only drawing the results for
(+)-3.
(31) By performing the reaction at higher temperatures (0 °C), the minor
isomer pivaloate 14â could also be obtained in higher yields as part of a
3:2 ratio, still favoring of the R-anomer 14R. At this point the anomers
were separated by medium-pressure liquid chromatography (MPLC, 20%
EtOAc/hexanes, UV detection) which produced baseline separation.
(32) A simpler purification procedure resulted by carrying the ∼8%
impurity of the minor diastereoisomer through to the reduction step. The
â-anomer 14â presumably hydrolyzed when subjected to the Luche
conditions; thus when samples of 14R were reduced with small amounts of
the â-anomer present, only diastereomerically pure samples of 2 were
detected after silica gel chromatography.
(33) (a) Martin, S. P.; Dodge, J. A.Tetrahedron Lett. 1991, 32, 3017-
3020. (b) Grynkiewicz, G. Pol. J. Chem. 1979, 53, 2501. (c) Mitsunobu,
O. Compr. Org. Synth. 1991, 6, 1-32.
(34) The relative stereochemistry of the p-nitrobenzoate ester was
confirmed by single-crystal X-ray analysis, see Supporting Information.
(35) Donohoe, T. J.; Moore, P. R.; Waring, M. J.; Newcombe, N. J.
Tetrahedron Lett. 1997, 38, 5027-5030.
Acknowledgment. We thank the Arnold and Mabel
Beckman Foundation for their generous support of our
program. We would also like to thank William W. Brennessel
(University of Minnesota X-ray Crystallographic Laboratory)
for help with X-ray structural determination.
Supporting Information Available: Complete experi-
mental procedures and spectral data (MP, IR, 1H NMR, 13
C
NMR, HRMS, and/or EA) for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL016743M
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Org. Lett., Vol. 3, No. 24, 2001