Highly efficient synthesis of ketoheptoses

Article abstract of DOI:10.1021/ol2012764

A reliable, facile, high overall yielding and diastereoselective synthesis of ketoheptoses was developed and applied for preparation of the two most diabetogenic ketoheptoses as well as in a modified version for the synthesis of kamusol.

Full text of DOI:10.1021/ol2012764

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3628–3631
Highly Efficient Synthesis of Ketoheptoses
Daniel Waschke, Julian Thimm, and Joachim Thiem*
University of Hamburg, Faculty of Science, Department of Chemistry,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
thiem@chemie.uni-hamburg.de
Received May 12, 2011
ABSTRACT
A reliable, facile, high overall yielding and diastereoselective synthesis of ketoheptoses was developed and applied for preparation of the two
most diabetogenic ketoheptoses as well as in a modified version for the synthesis of kamusol.
Ketoheptoses are rare seven carbon sugars with a num-
ber of interesting pharmacological properties. Previously it
was demonstrated that injection of D-manno-heptulose (1)
leads to a serious increase in blood glucose levels by
inhibition of the glucose metabolism in vitro and in vivo.1aꢀd
In a survey of eight ketoheptoses only D-manno-heptulose
(1) and D-gluco-heptulose (2) showed significant diabeto-
genic properties.2 Due to their ability to increase blood
glucose levels and inhibit glucose metabolism, they are of
particular pharmacological interest as potential therapeu-
tics for hypoglycemia3 or cancer.4,5
or iodomethyllithium.7f Synthesis of a wider range of
ketoheptoses was achieved by KilianiꢀFischer synthesis2
or aldol condensation.7g All of these multistep syntheses
resulted in the formation of diastereomeric mixtures with
yields typically below 25%.
D-manno-Heptulose (1) was first extracted and obtained
in rather low yields from avocado in 1917.6 A number
of earlier synthetic approaches focusing on the synthesis of
1 were developed. These involved the Lobryꢀde Bruyn
transformation,7a condensation of D-arabinose with 2-
nitroethanolate,7b the oxidation of volemitol,7c and a chain
elongation using a Grignard reaction,7d by Wittig reaction7e
Figure 1. Synthesized ketoheptoses 1ꢀ3.
A novel and universally applicable synthetic access to
ketoheptoses starting from the corresponding aldohexose
is reported. This synthetic route was exploited for the
preparation of the two most diabetogenic ketohep-
toses, D-manno-heptulose (1) and D-gluco-heptulose (2)
(Figure 1). Preparation involves seven synthetic steps with-
out any epimerization or time-consuming purification
(Schemes 1, 2). Using this novel method, ketoheptoses
were obtained in overall yields of 56% (1 and 2).
(1) (a) Roe, J. H.; Hudson, C. S. J. Biol. Chem. 1936, 112, 443–449. (b)
Simon, E.; Kraicer, P. F. Arch. Biochem. Biophys. 1957, 69, 592–601. (c)
Paulsen, E. P.; Richenderfer, L.; Winick, P. Nature 1967, 214, 276–277.
(d) Coore, H. G.; Randle, P. J. Biochem. J. 1964, 91, 56–59.
(2) Nelkin, W. Acta Physiol. Hung. 1970, 38, 401–404.
(3) Paulsen, E. P. Ann. N.Y. Acad. Sci. 1968, 150, 455–456.
(4) Board, M.; Colquhoun, A.; Newsholme, E. A. Cancer Res. 1995,
55, 3278–3285.
By a slight modification of this synthetic route, the
natural product kamusol (3), one of several metabolites
from Aspergillus sulphureus,8a,b was prepared and thus the
(5) Malaisse, W. J. Diabetologia 2001, 44, 393–406.
(6) La Forge, F. B. J. Biol. Chem. 1917, 28, 511–522.
(7) (a) Montgomery, E. M.; Hudson, C. S. J. Am. Chem. Soc. 1939,
61, 1654–1659. (b) Sowden, J. C. J. Am. Chem. Soc. 1950, 72, 3325. (c)
Ettel, V.; Liebster, J. Collect. Czech. Chem. Commun. 1949, 14, 80–90. (d)
Kampf, A.; Dimant, E. Carbohydr. Res. 1974, 32, 380–382. (e) Cheng, J.;
Fang, Z.; Li, S.; Zheng, B.; Jiang, Y. Carbohydr. Res. 2009, 344, 2093–
2095. (f) Bessieres, B.; Morin, C. J. Org. Chem. 2003, 68, 4100–4103. (g)
Schaffner, R.; Isbell, H. S. J. Org. Chem. 1962, 27, 3268–3270.
(8) (a) Kamal, A.; Haider, Y.; Arkhtar, R.; Qureshi, A. A. Pakistan J.
Sci. Ind. Res. 1971, 14, 63–67. (b) Kamal, A.; Haider, Y.; Qureshi, A. A.
Pakistan J. Sci. Ind. Res. 1971, 14, 68–70.
(9) Prenner, R. H.; Schmid, W. Monatsh. Chem. 1996, 127, 1045–
1050.
ꢀ
r
10.1021/ol2012764
Published on Web 06/14/2011
2011 American Chemical Society

Scheme 1. Synthesis of Ketoheptoses 1 and 2
Scheme 2. Alternative Route to D-manno-Heptulose (1)
Scheme 3. Synthesis of Kamusol (3)
only existing synthetic access9 (reported 10%) to 3 signifi-
cantly improved [42% in a five step synthesis (Scheme 3)].
The key step of the synthetic route is the methylenation
of a sugar lactone to an exocyclic enol ether using the
Petasis reagent (4).10,11a,11b Compared to alternative
(10) Example reaction protocol: Under argon and exclusion of light,
compound 13 (5.28 mmol) was dissolved in anhydrous toluene (80 mL)
and compound 4 (11.1 mmol) was added. The reaction mixture was
heated to 60 °C and stirred for 3 d in the dark. Then the solvent was
removed in vacuum, and the crude product was purified by column
chromatography (petroleum ether/ethyl acetate 15:1) to obtain 15
(4.66 mmol, 88%) as a slightly yellow oil.
(11) (a) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
6392–6394. (b) Csuk, R.; Glanzer, B. I. Tetrahedron 1991, 47, 1655–
1664.
€
(12) Clauss, K.; Bestian, H. Liebigs Ann. 1962, 654, 8–19.
ꢀ
(13) (a) Zemplen, G. Ber. Dtsch. Chem. Ges. 1926, 59B, 1254–1266.
ꢀ
(b) Zemplen, G.; Pacsu, E. Ber. Dtsch. Chem. Ges. 1929, 62B, 1613–1614.
Org. Lett., Vol. 13, No. 14, 2011
3629

methylenating agents such as Tebbe’s reagent and Grubbs’
titanacyclobutanes, the Petasis reagent (4) has a number of
advantages. Easily accessible from titanocene dichloride12
and much easier to handle due to lower sensitivity to
moisture and air, it also tolerates higher reaction tempera-
tures and this results in enhanced yields.
Typically, the synthetic route starts from an aldohexose
to reach the corresponding ketoheptose within seven steps.
D-Glucose (6) and D-mannose (5) were peracetylated and
glycosylated in a one-pot procedure to give phenyl 2,3,4,6-
tetra-O-acetyl-1-thio-R-D-mannopyranoside (7, 80%) and
phenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside
(8, 85%), and both were purified by crystallization. Fol-
13a,b
ꢀ
lowing deacetylation under Zemplen conditions
by
subsequent perbenzylation, phenyl 2,3,4,6-tetra-O-benzyl-
1-thio-R-D-mannopyranoside (9, 97%) and phenyl 2,3,4,6-
tetra-O-benzyl-1-thio-β-D-glucopyranoside (10, 95%) were
obtained (full synthetic scheme in the Supporting
Information). Then, thioglycosides 9 and 10 were hy-
drolyzed using NIS in water/acetone to give the hemi-
acetals 2,3,4,6-tetra-O-benzyl-D-mannopyranose (11,
98%) and 2,3,4,6-tetra-O-benzyl-D-glucopyranose (12,
97%).14 Afterward these were oxidized to the related
lactones 2,3,4,6-tetra-O-benzyl-D-mannono-1,5-lac-
tone (13, 96%) and 2,3,4,6-tetra-O-benzyl-D-glucono-
1,5-lactone (14, 94%).15 Starting from 5 and 6 the
lactones could be obtained in four steps with overall
yields of 73% (13) and 77% (14).
By methylenation of 13 and 14 using the Petasis reagent
4 the exocyclic enol ethers 2,6-anhydro-3,4,5,7-tetra-O-
benzyl-1-deoxy-D-mannohept-1-enitol (15, 88%) and 2,
6-anhydro-3,4,5,7-tetra-O-benzyl-1-deoxy-D-glucohept-1-
enitol 16 (81%) could be obtained.
The following Sharpless dihydroxylation gave 3,4,5,
7-tetra-O-benzyl-R-D-glycero-D-lyxo-hept-2-ulopyranose
(17, 94%) and 3,4,5,7-tetra-O-benzyl-R-D-glycero-D-xylo-
hept-2-ulopyranose (18, 94%).16aꢀc Interestingly only the
R-configured products (confirmed by NOESY experi-
ments) were isolated from the reaction mixture in both
cases. As known from literature neither 1 nor 2 shows
mutarotation,2 and a corresponding effect seems to be true
for 17 and 18.
Figure 2. X-ray structure of 1; red (O); blue (C); white (H).
By application of this synthetic route, the ketoheptoses 1
and 2 were obtained in total yields of 56% (1) and 56% (2)
starting from 5 and 6. As none of the reaction steps in-
volves epimerization or the formation of significant amounts
of byproducts, workup and purification are usually easy
and done by crystallization or flash chromatography. All
reactions could be performed in scale up to 10 g and gave
reproducibly good yields.
Since D-mannose (5) can form a suitable diisopropyli-
dene derivative, an alternative route for the preparation
of 1 was developed. After preparation of 2,3:5,6-di-O-
isopropylidene-R-D-mannofuranose (19, 95%)17 only the
R-anomer was isolated, purified by crystallization. The
R-configuration was also confirmed by X-ray struc-
ture. The following oxidation gave 2,3:5,6-di-O-iso-
propylidene-R-D-mannono-1,4-lactone (20, 83%) after
crystallization.
By methylenation of 20, 2,5-anhydro-1-deoxy-3,4:6,
7-di-O-isopropylidene-D-mannohept-1-enitol (21, 80%)
was obtained in good yield.
This compound was dihydroxylated to give 3,4:6,7-di-
O-isopropylidene-R-D-glycero-D-lyxo-hept-2-ulofuranose
(22, 95%), and again only the R-anomer (NOESY experi-
ments) was isolated. Cleavage of the acetals was per-
formed in aqueous solution using Amberlite IR-120 Hþ
to give 1 (98%).
In comparison to the first method (Scheme 1), this
furanose route is shorter and the workup is less elaborate,
since the first two compounds can be easily crystallized
even in large scale, and this results in a higher overall yield
of 1 (59%).
The presented synthetic route was modified for the
preparation of the natural product kamusol (3), which
was isolated as one of several metabolites from the
fungus Aspergillus sulphureus.8a,b Starting with 3,4,6-
tri-O-benzyl-D-glucal (23), which in turn is easily pre-
pared from 6 (Scheme 3), first the preparation of 3,4,6-
In the final step, 17 and 18 were hydrogenated to give the
desired ketoheptoses 1 (93%) and 2 (97%). Again only the
R-anomers were isolated after chromatography in both
cases. NMR spectra recorded in aqueous solution showed
the presence of a single diastereomer for 1 and 2, and no
traces of furanoses were detected. Additionally, the optical
rotation in aqueous solution remained constant for two
days. The R-configuration of 1 was also confirmed by
X-ray structure (Figure 2).
(14) Motawia, M. S.; Marcussen, J.; Møller, B. L. J. Carbohydr.
Chem. 1995, 14, 1279–1294.
(15) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1965, 87, 4214–
4216.
(16) (a) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroeder, G.;
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968–1970. (b) Kolb,
H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
2483–2547. (c) Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990,
55, 766–768.
(17) Schmidt, O. T. Methods Carbohydr. Chem. 1963, 2, 318–325.
(18) Costantino, V.; Imperatore, C.; Fattorusso, E.; Mangoni, A.
Tetrahedron Lett. 2000, 41, 9177–9180.
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Org. Lett., Vol. 13, No. 14, 2011

tri-O-benzyl-2-deoxy-R-D-glucose (24, 97%) in a simple
one-pot procedure was performed.18 The standard
oxidation procedure using Ac2O and DMSO was un-
suitable for the preparation of 3,4,6-tri-O-benzyl-2-
deoxy-D-glucono-1,5-lactone (25) since the acetate an-
ion formed during the reaction progress acts as a base
and promotes deprotonation of the CꢀH acidic pro-
tons at C-2 leading to the formation of significant
amounts of the R,β-unsaturated lactone. As a conse-
quence the less basic PCC was used for oxidation of 24
to give 25 in a 75% yield.
Methylenation of 25 with 4 led to 2,6-anhydro-1,3-
dideoxy-4,5,7-tri-O-benzyl-D-glucohept-1-enitol (26, 79%).
Further, the exocyclic enol ether 26 was dihydroxylated to
give 3-deoxy-4,5,7-tri-O-benzyl-R-D-glycero-D-xylo-hept-
2-ulo-pyranose (27) in 90% yield. Once more only the
R-anomer of 27 was isolated as confirmed by NOESY
experiments. In the final step compound 27 was hydro-
genated to give 3 in 81% yield.
corresponding ketoheptose can be reached within seven
steps usually with high yields for the individual steps. The
utility of this method was tested by the preparation of D-
manno-heptulose (1) and D-gluco-heptulose (2) from D-
mannose (5) and D-glucose (6). Overall yields for the
preparation of 1 and 2 (both 56%) were much higher than
those reported in previous work.7aꢀf Another advantage of
the reported method is the versatility. In contrast to earlier
studies, which focused mainly on the synthesis of 1, a
variety of ketoheptoses can be prepared.
Furthermore the synthetic route was modified for the
synthesis of the natural product kamusol (3), and the
reported synthesis9 of 3 improved in terms of stereoselec-
tivity and yield, enhancing the previously reported overall
yield of 10% in a five step synthesis to 42%.
The presented synthetic route additionally allows access
to novel ketoheptose derivatives. Further derivatization of
1, 2, and 3 as well as future applications are under study
and will be reported in due course.
This method allowed the preparation of 3 starting from
23 in a total of five steps and an overall yield of 42%. The
previously reported synthesis of 3 started from 2,3-di-O-
formyl-D-erythrose and also required five steps;9 however,
in only 10% yield overall yield a diastereomeric mixture
could be prepared.
Acknowledgment. We thank the EU Programme FP7-
NMP-228933-VIBRANT for financial support.
Supporting Information Available. General experimen-
tal procedure for preparation of 1, 2, and 3 with full
spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, a versatile synthetic access to ketohep-
toses was established. Starting from an aldohexose, the
Org. Lett., Vol. 13, No. 14, 2011
3631