De novo enantioselective syntheses of galacto-sugars and deoxy sugars via the iterative dihydroxylation of dienoate

Article abstract of DOI:10.1021/ol050044i

(Chemical Equation Presented) An efficient route to various sugar lactones has been developed. Key to the overall transformation is the sequential osmium-catalyzed dihydroxylation of 2,4-dienoates. The simplest (one-step/racemic) example of this reaction occurs when the dihydroxylation is performed with aqueous NMO in MeOH. When the first dihydroxylation is performed using the AD-mix procedure, an enantioselective variant results. When a matched AD-mix procedure is used for the second dihydroxylation, an exceedingly diastereo- and enantioselective synthesis of galacto-1,4-lactone results.

Full text of DOI:10.1021/ol050044i

ORGANIC
LETTERS
2005
Vol. 7, No. 4
745-748
De Novo Enantioselective Syntheses of
Galacto-Sugars and Deoxy Sugars via
the Iterative Dihydroxylation of Dienoate
Md. Moinuddin Ahmed, Bryan P. Berry, Thomas J. Hunter, Dennis J. Tomcik, and
George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
george.odoherty@mail.wVu.edu
Received January 10, 2005
ABSTRACT
An efficient route to various sugar lactones has been developed. Key to the overall transformation is the sequential osmium-catalyzed
dihydroxylation of 2,4-dienoates. The simplest (one-step/racemic) example of this reaction occurs when the dihydroxylation is performed with
aqueous NMO in MeOH. When the first dihydroxylation is performed using the AD-mix procedure, an enantioselective variant results. When
a matched AD-mix procedure is used for the second dihydroxylation, an exceedingly diastereo- and enantioselective synthesis of galacto-
1,4-lactone results.
There has been a tremendous growth in our understanding
of the important role carbohydrates play in biology.1 While
this new understanding certainly has and will continue to
have a great impact on medicine, unfortunately this effect is
limited by the medicinal chemist’s inability to prepare
unnatural sugar analogues and hence to do thorough structure
activity relationship studies. This need is exemplified by the
fact that of the 16 possible stereoisomers of the hexoses,
only three are readily available from natural sources (D-
glucose, D-mannose, and D-galactose).
Since the seminal work of Sharpless and Masamune,2 the
de novo enantioselective synthesis of the hexoses stands as
a challenge to asymmetric catalysis.3 Recently, McMillan
reported a short iterative aldol strategy toward this goal.4
Despite substantial efforts over the years,3,5 there still does
not exist a general and truly practical route to all the hexoses.
As part of our program aimed at the use of catalysis for the
synthesis of natural6 and unnatural carbohydrates7 and
oligosaccharides,8 we were interested in finding a highly
diastereo- and enantioselective synthesis of a simple hexose,
which could serve as a useful starting material for oligo-
saccharide assembly. Herein, we present our discovery of
an expeditious route to either enantiomer of galacto-1,4-
lactone using the Sharpless dihydroxylation for enantio-
control. These studies resulted in a three-step synthesis of
enantiopure galacto-1,4-lactone, a one-step variant to racemic
material, as well as a five-step synthesis of C-4 deoxy sugars.
All routes are amenable to various C-6 substituents.
(4) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752-
1755.
(1) (a) Ernst, B.; Hart, G. W.; Sinay, P., Eds. Carbohydrates in Chemistry
and Biology; Wiley-VCH: New York, 2000. (b) Wong, P. G.; Bertozzi, C.
P., Eds. Glycochemistry. Principles, Synthesis and Applications; Marcel
Dekker Inc.: New York, 2001. (c) Vogel, P. In Glycoscience; Fraser-Reid,
B. O., Tatsuta, K., Thiem, J., Eds.; Springer: Berlin, Germany, 2001; Vol.
2, pp 1023-1174.
(5) (a) Taniguchi, T.; Nakamura, K.; Ogasawara, K. Synlett 1999, 341-
354. (b) Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-H. Chem. ReV.
1996, 96, 443-474. (c) Davies, S. G.; Nicholson, R. L.; Smith, A. D. Synlett
2002, 1637-1640. (d) Bataille, C.; Begin, G.; Guillam, A.; Lemiegre, L.;
Lys, C.; Maddaluno, J.; Toupet, L. J. Org. Chem. 2002, 67, 8054-8062.
(6) Harris, J. M.; Kera¨nen, M. D.; Nguyen, H.; Young V. G.; O’Doherty,
G. A. Carbohydr. Res. 2000, 328, 17-36.
(2) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K.
B. Science 1983, 220, 949-951.
(7) Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125, 12406-
12407.
(3) For a review of other approaches to hexoses, see: Hudlicky, T.;
Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J. Chem. ReV. 1996, 96, 1195-
1220. For related work published since 1996, see ref 5.
(8) Babu, R. S.; Zhou, M.; O’Doherty, G. A. J. Am. Chem. Soc. 2004,
126, 3428-3429.
10.1021/ol050044i CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/22/2005

We have targeted galacto-1,4-lactones 4a/b9,10 or the more
easily isolated peracetates 5a/b because they lacked an
anomeric stereocenter and are common starting material in
carbohydrate synthesis.11,12 The ideal synthesis should also
start from a commercially available starting material, and
as such, we chose 2,4-dienoate esters, which are easily
prepared13 or commercially available. Thus our strategy,
outlined below, is an iterative and highly stereocontrolled
oxidation of both double bonds in dienoates 1a/b to establish
all four stereocenters in galacto-lactone (Scheme 1).
(2% OsO4/2.1% (DHQ)2PHAL, 3 equiv of K3Fe(CN)6/
K2CO3, 1 equiv of MeSO2NH2) to give diols 2a/b in good
yields (80% and 89%) and enantiomeric excess (80% ee and
90% ee).20 While the double bond selectivity can easily be
explained in terms of electron density of the π-system (i.e.,
the most electron-rich double bond reacts first), there is an
underlying stereocontrol element to this reaction. The second
double bond does not react under the reaction conditions
because of conflicting diastereo-controlling issues (mis-
matching reagent and substrate control).
This substrate/reagent mismatch effect can be seen in the
case when the ligand ((DHQ)2PHAL) was removed from the
AD-mix reaction condition (Scheme 1). Thus, when diols
2a/b were exposed to the typical Upjohn procedure (OsO4/
NMO in t-BuOH/acetone), they reacted with achiral OsO4
to afford tetrol products with good conversion, which could
be isolated as their corresponding tetraacetates 3a/b (55%
for 3a; 60% for 3b). While these tetrol and tetraacetate
products were difficult to isolate, it was determined that they
were formed in about a 5:1 ratio of stereoisomers (galacto
to ido).
Scheme 1. Two-Step Enantioselective Synthesis of Ethyl
Galactonate Sugars
We found it easier to isolate the dihydroxylation product
as a lactone 4b (Scheme 2). This less polar triol 4b was
Scheme 2. Two-Step Enantioselective Synthesis of
galacto-γ-Lactone
While conceptually a bis-dihydroxylation reaction appears
ideal for an efficient carbohydrate synthesis, there were issues
associated with regioselectivity (which double bond reacts
first), enantioselectivity (the facial selectivity of the first
dihydroxylation), and double diastereoselectivity (a balance
between substrate and catalyst stereocontrol).14,15 The solution
to these problems emerged from our continuing study of the
Sharpless dihydroxylation of di- and tri-enoates,16 which we
have used in natural product synthesis.17
To accomplish this goal we chose to start with dienoates
1a/b (Scheme 1). Previously, Sharpless had demonstrated
that the initial dihydroxylation could be controlled in terms
of regio- and enantioselectivity (e.g. ethyl sorbate 1a reacted
with the AD-mix reagent to afford diol 2a with good
enantioselectivity).18,19 Similarly, we found that dienoates
1a/b reacted under the typical Sharpless AD-mix procedure
formed by acid-catalyzed lactonization (Py‚TsOH in MeOH/
benzene) and isolated in a 53% yield. In general, we found
that the triacetates 5a/b had clearer 1H NMR spectra, which
facilitated spectroscopic comparison to known materials.9
Thus, the galacto-triacetates 5a and 5b were prepared in 97%
and 96% yields, respectively.
(9) Although it is a rare sugar, L-galacto-1,4-lactone is a naturally
occurring metabolite produced in plants as an intermediate in the biosyn-
thesis of vitamin C, see: Smirnoff, N. Nat. Biotechnol. 2003, 21, 134-
136.
(10) It has been suggested that the level of the important antioxidant
ascorbic acid can be increased by treatment with L-galacto-1,4-lactone,
see: Smirnoff, N. Philos. Trans. R. Soc. London 2001, 335, 1455-1464.
(11) Binch, H.; Stangier, K.; Thiem, J. Carbohydr. Res. 1998, 306, 409-
419.
An improved and simplified procedure resulted from
performing the second dihydroxylation reactions (OsO4/
NMO) in MeOH (2a/b to 4a/b, Scheme 2), whichsdue to
the basic reaction conditionssprovides the lactones 4a/b in
one step (65% for 4a; 70% for 4b). Despite the solvent
change, the diastereoselectivity for these dihydroxylations
was found to be the same as before (6:1 for 4a and 5:1 for
(12) Zaliz, C. L. R.; Varela, O. Tetrahedron: Asymmetry 2003, 14, 2579-
2586.
(13) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 1049-1052.
(14) Masamune, S.; Choy, W.; Petersen, J.; Sita, L. R. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 1-76.
(18) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992,
114, 7570-7571.
(19) Becker, H.; Soler, M. A.; Sharpless, K. B. Tetrahedron 1995, 51,
1345-1376.
(15) Morikawa, K.; Sharpless, K. B. Tetrahedron Lett. 1993, 34, 5575-
5578.
(20) All enantioexcesses were determined by examining the 1H NMR
and/or 19F NMR of a corresponding Mosher ester, see: Sullivan, G. R.;
Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143-2147.
(16) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2002, 4, 4447-4450.
(17) Smith, C. M.; O’Doherty, G. A. Org. Lett. 2003, 5, 1959-1962.
746
Org. Lett., Vol. 7, No. 4, 2005

4b). In the case of 5a, the minor diastereomer was removed
by silica gel chromatography, whereas for 5b the minor
isomer was removed by a selective crystallization of the
major isomer from EtOAc/hexanes.
A highly efficient one-step protocol for the synthesis of
racemic galacto-γ-lactone (()-4a/b was easily achieved by
subjecting the dienoates 1a/b to the dihydroxylation/lacton-
ization procedure (OsO4/NMO in MeOH) (Scheme 3). Thus,
on an acetonide protected form of diols 2a/b, which were
dihydroxylated with the pseudo-enantiomeric reagent AD-
â* (2% OsO4/2.1% (DHQD)2PHAL, 3 equiv of K3Fe(CN)6,
3 equiv of K2CO3, and 1 equiv of MeSO2NH2) to give good
yields of diols 6a/b (79% for 6a and 65% for 6b) with
improved diastereocontrol (dr ) 10:1/9:1), once again with
the galacto-stereoisomer prevailing. For both 6a and 6b, the
minor isomers were easily removed by silica gel chroma-
tography and the diasteromerically pure products 6a/b were
deprotected and lactonized to give 4a/b (65% for 4a and
55% for 4b). As before, the triols 4a/b were peracylated and
the triacetates formed proved to be identical with the
previously prepared 5a/b. Because the enantiomeric impurity
in 2a/b is converted into the minor diastereomer during the
second asymmetric dihydroxylation, the galacto-lactones
4a/b formed by this procedure are essentially enantiomeri-
cally pure.
Scheme 3. One-Step Racemic Synthesis of galacto-γ-Lactone
Our fully optimized procedure allows for a three-step
conversion of achiral 1b to optically pure 4b (Scheme 4).
The need for the inclusion of a protection step was finally
eliminated when we realized that there was a competing
hydrolysis reaction occurring during the dihydroxylation of
2b, thus reducing the yield of 4b. This competing reaction
was easily overcome by simply increasing the catalyst
loading from 2% OsO4 to 10% OsO4 and the ligand from
2.1% to 12%. Thus, exposing 2b to the pseudo-enantiomeric
reagent AD-â** (10% OsO4/12% (DHQD)2PHAL, 6 equiv
of K3Fe(CN)6, 3 equiv of NaHCO3, 3 equiv of K2CO3, and
1 equiv of MeSO2NH2) provides, after lactonization with Py‚
TsOH, the galacto-γ-lactone 4b in good yield (57%). The
triol 4b formed by this latter procedure was, for all practical
purposes, both enantiomerically and diasteromerically pure
(>96% ee and de).
Due to the fact that the substrate 2b and the catalyst (OsO4/
(DHQD)2PHAL) were synergistically directing the stereo-
chemical course of the reaction, once again the product
enantiopurity (>96% ee) was even greater than that of the
original starting material (90% ee). This presumably resulted
from the fact that the minor enantiomer (ent-2b) did not react
with the mismatched OsO4/(DHQD)2PHAL catalyst system.
Finally, this procedure also produced the enantiomer of 4b
(D-galacto-γ-lactone) equally well, by simply using the AD-
mix reagent systems in reverse. That is to say, using OsO4/
(DHQD)2PHAL for the conversion of 1b to ent-2b and then
OsO4/(DHQ)2PHAL for the conversion of ent-2b to ent-4b.
Thus, our final optimized procedure also produced ent-4b
in good yield (63% from ent-2b) and with virtually complete
stereocontrol (>96% ee and de).
exposing dienoates 1a/b to a catalytic amount of OsO4 with
excess NMO in methanol provided racemic galacto-γ-lactone
(()-4a/b in 70% and 73% yields, respectively. The lactones
(()-4a/b were converted to the peracetates (()-5a/b and
shown to be identical with the previously prepared material
in all ways except optical rotation. Evidence that the initial
dihydroxylations occurred to give diols 2a/b before subse-
quent dihydroxylation/lactonization was suggested by the
identical diastereoselectivities for this one-step procedure as
for the two-step procedure (Scheme 2).
While these procedures (Schemes 2 and 3) are highly
efficient in terms of yields and steps, they do suffer a
drawback associated with less than perfect diastereocontrol.
This issue of diastereoselectivity was easily resolved when
the second dihydroxylation was performed in a diastereo-
merically matched sense between substrate and catalyst
(Scheme 4). For isolation purposes, this was first carried out
Scheme 4. Three- or Four-Step Highly Enantio- and
Diastereoselective Synthesis of galacto-γ-Lactone
Further insights into the origins of the substrate stereo-
control in the dihydroxylation of diols 2a/b were gained from
the application of this methodology for the preparation of
C-4 deoxy-sugar lactones (Schemes 6 and 7). In particular,
we found that the substrate control essentially disappeared
when the C-4 hydroxy group is removed as in the δ-
hydroxyenoate 8a/b.
The enoates 8a/b were easily prepared from cyclic
carbonate 7a/b by a Pd-catalyzed π-allyl reduction reaction
with formic acid (hydride source). Exposure of diols 2a/b
Org. Lett., Vol. 7, No. 4, 2005
747

to triphosgene ((Cl3CO)2CO/Py) gave good yields (∼90%)
of carbonates 7a/b. Treatment of 7a/b with a catalytic amount
of palladium(0) source and triphenylphosphine (1 mol % of
Pd(0)/PPh3) and a mild hydride source (3 equiv of Et3N/
HCO2H) gave the reduced alcohol 8a/b in good yields (80
to 90%) and with no loss of enantiomeric excess.21
alcohols 8a/b to the pseudo-enantiomeric Sharpless reagent
system (2% OsO4 and 4% (DHQ)2PHAL) provided triols
11a/b in similarly excellent yields, diastereomeric ratios,23
and enantiomeric excesses (>96% ee). Finally, triols 11a/b
were lactonized by treatment with 5% Py‚TsOH/C6H6. The
desired lactones 12a/b were isolated in excellent yields (83-
95%). As with 4-deoxy-gluco-lactone 10a/b, the 4-deoxy-
altro-pyranone stereochemistry of 12a/b was easily assigned
1
from analysis of the relevant H-1H coupling constants.
Scheme 5. Palladium-Catalyzed Reduction at C-4
Scheme 7. Enantioselective Synthesis of
L-4-Deoxy-altro-δ-lactone
The alcohols 8a/b were subjected to Sharpless asymmetric
dihydroxylation conditions (2% OsO4 and 4% (DHQD)2-
PHAL) and gave triols 9a/b in approximately 80% yield and
>96% ee. The strong substrate diastereocontrol associated
with the second dihydroxylation reaction is diminished with
the removal of the C-4 hydroxyl group.22 Thus, triols 9a/b
were formed with a minor diastereomer (ent-11a/b), where
the formation of ent-11a/b comes primarily from the minor
enantiomer present in 8a/b (ent-8a/b). Once this minor
diastereomer was removed by silica gel chromatography,
triols 9a/b were obtained in both diastereo- and enantio-
merically pure form. As before, the stereochemistry of the
triols was most easily assigned after lactonization (9a/b to
10a/b). Treating triols 9a/b with 5% Py‚TsOH/C6H6 provided
the desired deoxy-gluco-pyranones 10a/b in excellent yields
(80 to 95% yield) (Scheme 6).
In summary, our strategy for the synthesis of either
enantiomer of galacto-sugars provides rapid and practical
access to an important sugar, which should be of use for
further oligosaccharide synthesis. Thus in only one step,
racemic 4a/b was produced in excellent yield from achiral
1a/b. Similarly, optically pure 4a was prepared in four steps
from 1a (41%, overall yield) and optically pure 4b was
prepared in three steps from 1b (51%, overall yield). In
addition, a highly enantio- and diastereoselective procedure
for the preparation of various sugar δ-lactones has been
developed resulting in the syntheses of C-4 deoxysugars.
Finally, by selecting the order in which the Sharpless reagents
were used, both D- and L-sugars were produced. This second
reagent choice in the C-4 deoxy series also determines which
sugar diastereomer is formed (gluco vs altro). This approach
serves as an excellent complement to the recently reported
enantioselective aldol approach to hexoses,4 because it
provides a related and important stereoisomer.
Scheme 6. Enantioselective Synthesis of
L-4-Deoxy-gluco-δ-lactone
Acknowledgment. We are grateful to NIH (GM63150)
and NSF (CHE-0415469) for the support of our research
program and NSF-EPSCoR (0314742) for a 600 MHz NMR
at WVU.
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL050044I
(22) This decrease in substrate control can be seen in that when 8a/b
were exposed to the achiral UpJohn conditions approximately 1:1 mixtures
of 9a/b to 11a/b were formed.
(23) It is worth noting that because (DHQ)2PHAL is a diastereomer of
(DHQD)2PHAL and not an enantiomer, the diastereomeric ratios for the
conversion of 8a/b to 9a/b should be slightly different than the ratio for
the conversion of 8a/b to 11a/b.
This same procedure (Scheme 6) can be used for the
formation of 12a/b (the C-2/C-3 bis-epimer of 10a/b, Scheme
7), because 8a/b has no strong facial bias.22 Thus, exposing
(21) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 1049-1052.
748
Org. Lett., Vol. 7, No. 4, 2005