GERALD L.

LARSON
Gelest Inc., 11 East Steel Road, Morrisville, PA 19067, USA

Gerald L. Larson

The synthesis of gliflozins

KEYWORDS: Gliflozins, diabetes 2, glucose transporters, silane reductions.

Abstract Some of the general approaches to the key steps in the synthesis of gliflozins, a class of glucose
transporters, are discussed. In particular the glycosidation step for the introduction of the key aryl moiety
onto the glucose and the reduction steps are presented.

INTRODUCTION significantly reduced (3). (Figure 1b) Nevertheless, this led to

investigations of structurally similar, more hydrolytically stable
Gliflozins constitute a class of compounds that is useful derivatives of phlorizin as SGLT2 inhibitors (4,5).
as sodium glucose co-transporter-2 (SGLT2) inhibitors. The
gliflozins have shown particular expediency in the treatment
of diabetes 2. They accomplish this through blocking of
sodium glucose transport proteins, which, in turn, inhibit the
kidneys from resorbing glucose back into the blood stream.
The excess, non-resorbed glucose is then eliminated with the
urine with the net result being a dosage-regulated glucose
Figure 1b. Phloretin decomposition.
level. It has been shown that a key feature of the gliflozins
is their ability to distinguish between the inhibition of the
SGLT1 transporter, a low-capacity, high-affinity transporter Five of the gliflozins have now been approved for prescribed
that is expressed in the gut, heart and kidney, and the SGLT2 use. These are dapagliflozin 4, Farxica or Forxica, (Bristol Myers-
transporter, a high-capacity, low-affinity transporter expressed Squibb/AstraZeneca), canagliflozin 5, Invokana, (Janssen
mostly in the kidney. It is estimated that by the year 2025 Pharmaceuticals), ipragliflozin 6, Suglat, (Allesta Pharmaceuticals),
nearly 400 million people will suffer from diabetes 2 (1). Due empagliflozin 7, Jardiance, (Boehringer-Ingelheim/Eli Lilly) and
in large part to this growing population of diabetes sufferers, ertugliflozin 8, Sitaglipton, (Pfizer/Merck) (Figure 1c).
considerable efforts have been and continue to be taken
in the gliflozin approach towards addressing the diabetes
2 affliction. A significant part of these efforts has centered
on various derivatives of the gliflozin class, represented by
the general structure 1. (Figure 1a) An excellent review of
the structure activity relationship and some of the history of
this class of drugs has appeared (2). This mini-review will look
at some of the general
approaches to the
Figure 1a. synthesis of the gliflozins
General Figure 1c. Structures of five approved Gloflozins.
structure of with an emphasis on the
typical Gliflozin. glycosidation and the
key reduction steps. The general structures of the gliflozins have in common a
glucose sugar to which is attached an aromatic group in the
As early as the 19th century phlorizin 2 was isolated and shown β−position at the anomeric carbon 1. It will be noted that in
to inhibit both SGLT1 and SGLT2 and, thus, promote urinary addition to the glucose sugar moiety and the β−isomeric aryl
excretion of glucose. Unfortunately, being a hemiacetal substituent the aryl group is composed of a diarylmethylene
structure, phlorizin is subject to hydrolysis to phloretin 3 structure. The differences in the structures are not large, vis the
and glucose thus excluding it as a candidate for oral similarities in the structures of dapagliflozin, empagliflozin and
administration as the SGLT inhibitory activity of the phloretin is ertugliflozin as well as those of canagliflozin and ipragliflozin.

Monographic special issue: Oligos & Peptides - Chimica Oggi - Chemistry Today - vol. 33(2) March/April 2015 37
SYNTHESIS OF GLIFLOZINS Alternatively, a Friedel-Crafts acylation/reduction sequence
can be used as was employed in the preparation of 14 via
The synthetic approaches to the gliflozins essentially the formation and reduction of intermediate 13, in a synthesis
consist of three general steps: 1) construction of the aryl of dapagliflozin, 4. In this approach the acid chloride required
substituent, 2) introduction of the aryl moiety onto the sugar for the Friedel Crafts acylation is prepared in-situ and reacted
or glucosylation of the aryl substituent, and 3) deprotection directly with ethylphenyl ether to give the required 4-acylated
and modification of the arylated anomeric center of the derivative (11). The direct organosilane reduction of ketone
sugar to the final desired product. carbonyls, especially acetophenone derivatives, to a
methylene group is well documented (12) (Figure 2d).
Synthesis of the aryl group
The synthetic approach to the gliflozins first involves the
construction of the aryl substituent with a suitable handle
to allow its attachment to the sugar. There are two classical
entries into the diarylmethylene units, namely, reaction of
an organometallic reagent with an aldehyde to give the
diaryl carbinol or a Friedel-Crafts acylation to provide a
diaryl ketone. Both of these intermediates would then be
followed by a reduction of the functionalized carbon to the
requisite methylene. The former of these is exemplified in a
Figure 2d. Friedal-Crafts approach to aryl portion of Gliflozins.
synthetic route to 12 wherein aldehyde 9 was reacted with
the Grignard reagent 10 to form the diarylmethanol 11, which
was then reduced with triethylsilane to the diarylmethane 12 Reduction of the carbonyl functionality to the methylene
(6).It is worth noting that organosilanes have been shown to can be accomplished in a number of ways, but it has been
be excellent reagents for the reduction of benzylic alcohols to shown that the reduction of aryl ketones to the corresponding
the corresponding alkanes (7,8) (Figure 2a). methylenes can be conveniently done with an organosilane
and an acid catalyst. The reduction of benzyl alcohols
or aryl ketones to the corresponding methylene group
is a particularly efficient process due in large part to the
enhanced stability of the benzyl cationic intermediate. In
a related case triethylsilane, and with greatly improved
selectivity and the avoidance of a hazardous intermediate,
tetramethyldisiloxane, TMDS, have been used in the reduction
of an acetophenone derivative in the synthesis of the key
intermediate 15 in a synthesis of ziprasidone, a Pfizer anti-
psychotic drug (13). In this case the use of TMDS resulted
Figure 2a. Grignard approach to aryl portion of a Gloflozins. in the avoidance of the hazardous chloromethyl ketone
intermediate as well as the partially- and over-reduced by-
A similar approach was employed in procuring the aryl products. Pentamethyldisiloxane and dimethylethoxysilane
substrate in a synthesis of ipragliflozin (9) (Figure 2b). were less selective than TMDS for this process. Common
catalysts for these organosilane reductions are trifluoroacetic
acid or boron trifluoride etherate among others. The yields for
these reductions are typically high and offer a facile isolation
of the final product (Figure 3a).

Figure 2b. Lithium reagent approach to aryl portion of a Gloflozins.

In an alternate approach to the diarylcarbinol precursor to the

diarylmethane moiety Fürstner and Krause showed that the
rhodium trichloride-catalyzed coupling of an aryl boronic acid
with an aldehyde leads to the diaryl carbinol intermediates in
high yields (10). Two of the 16 examples reported involved the
preparation of an aryl bromide, indicating that the reaction can
be carried out without competing aryl-aryl, Suzuki-type cross-
coupling taking place. The resulting brominated diarylmethane
could be converted to an organometallic reagent for reaction
Figure 3a. Reduction of the benzoyl carbonyl in the synthesis of Ziprasidone.
with the gluconolide leading to a gliflozin (Figure 2c).

Addition of the aryl group to the glucose

The second aspect in the synthesis of the gliflozins is that of
glucosylation of the aryl moiety with the final stereochemistry
being that wherein the aryl group occupies a β−position. One
early approach to the gliflozins is illustrated for the synthesis of
Figure 2c. Boronic acid approach to aryl portion of Gliflozins.
17 as a general entry into the C1-aryl gluconosides.

38 Monographic special issue: Oligos & Peptides - Chimica Oggi - Chemistry Today - vol. 33(2) March/April 2015
It had been shown that the reaction of an aryllithium reagent
with gluconolactone resulted in the hemiketal, which could
in turn be reduced with triethylsilane (14). Thus, lithium-
bromine exchange of 12 and reaction of the lithium reagent
with gluconolactone 16 followed by triethylsilane reduction
provided the C1-arylated glycopyranoside 17 (9). In a similar
vein lithium reagent 19 was reacted with trimethylsilyl-protected
gluconolactone 18 and the resulting hemiketal reduced with
triethylsilane to dapagliflozin 4. The reduction step is based
on the findings of Kraus and Molina as well as those of Kishi
and coworkers, who showed that triethylsilane reduction
of glucose hemiketals leads to β−C-glycopyranosides with
high stereoselectivity (6,15). The selective reduction of ketals
and hemiketals as well as aminals and hemiaminals with the
Figure 4b. Zinc cross-coupling approach to Dapagliflozin.
weakly hydridic organosilanes is well documented and can
be attributed to the stability of the resulting α−oxygenated
carbocationic intermediate (12) (Figure 3b/4a). The tribenzyl glycal 23 was converted to the gliflozin structures in
Thus, the triethylsilane reduction of the initially formed hemiketal a couple of ways. One of these is via the corresponding epoxide
followed by deprotection provided the desired gliflozin 24, which serves to place the 3-hydroxyl group on the sugar
derivative. This reduction has been studied in a number of cases as well as provide a route for the introduction of the aryl unit
with varying degrees of stereoselectivity with triethylsilane/ (22). Reaction of 24 with 2-lithiofuran leads to the β−substituted
BF3•OEt2 giving rather poor β:α ratios and the more hindered benzyl-protected glucose 25. On the other hand reaction of the
triisopropylsilane providing a high β:α ratio (16) (Figure 4a). epoxide with the corresponding zinc reagent 26 results in the
introduction of the aryl group in the α−position. This is based on
the earlier work of Halcomb and Danishefsky (23) (Figure 5a).

Figure 3b. Llithium reagent approach to arylation of glucose derivative.

Figure 5a. Epoxide approach to arylation of glucose.

The di-tert-butylsilylene-protected dihydropyran 27 was

subjected to a Stille cross-coupling reaction with an aryl
Figure 4a. Llithium reagent - silane reduction approach to arylation of sulfonyl chloride to show that this approach will work
glucose derivative. to introduce an aryl group to the sugar. Introduction of
the requisite 3-hydroxyl group in the α−position was then
accomplished via hydroboration/oxidation to provide the β−
Finally, the tetramethyldisiloxane, TMDS, silane reducing arylated sugar derivative 29 (24) (Figure 5b).
agent has been employed in the successful reduction of a
hemiketal to the corresponding furan derivative as shown
in the reduction of the protected precursor to canagliflozin,
which is based on some earlier work by Kraus and
coworkers who demonstrated the silane reduction of sugar
hemiketals (17-20).

A highly stereoselective introduction of the aryl moiety can be

accomplished via the cross-coupling of an aryl zinc reagent,
using the well-developed organozinc chemistry of Knochel
and co-workers, with the bromo-functionalized glucose 21
(21). Thus, zinc reagent 21 was reacted with bromopyran Figure 5b. Stille cross-coupling approach to Gliflozins.
22 to introduce the aryl group in the β−position assisted by
the neighboring group participation of the pivaloyl group.
Other ester protecting groups for the hydroxyls on the sugar Gong and Gagné have shown that the reaction of arylzinc
also worked, but the pivalate protection was shown to be reagents with suitably-protected glucosyl bromides under
preferred for reasons of selectivity and yield. Deprotection led Ni(0) catalysis results in the C1-aryl glucoside with good β−
to dapagliflozin 4 (Figure 4b). selectivity (25) (Figure 5c).

Monographic special issue: Oligos & Peptides - Chimica Oggi - Chemistry Today - vol. 33(2) March/April 2015 39
 2. S. Nomura S. (2010) Curr. Top. Med. Chem. 10, 411.
3. Chan S.S., Lotspeich W.D. (1962) Am. J. Phys. Legacy Content 203, 975.
4. Mackenzie B., Loo D.D.F. (1996) J. Biol. Chem. 271, 32678.
5. Kanai Y., Lee W.S., You G., et al. (1994) J. Clin. Invest. 93, 397.
6. Lewis M.D., Cha J.C., Kishi Y. (1982) J. Am. Chem. Soc. 104, 4976.
7. Carey F.A., Tremper H.S. (1968) J. Am. Chem. Soc. 90, 2578.
Figure 5c. Organozinc cross-coupling approach to Gliflozins.
8. Adlington M.G., Orfanopoulos M., Fry J.L. (1976) Tetrahedron Lett.
17, 2955.
9. Imamura M., et al. (2012) Bioorg. Med. Chem. 20, 3263.
CONCLUSIONS
10. Fürstner A., Krause H. (2001) Adv. Synth. Catal. 343, 343.
11. Meng W., et al. (2008) J. Med. Chem. 51, 1145.
A number of gliflozins has now been approved for prescription
12. Larson G.L., Fry J.L., Denmark S.E. (2008) Ed. “Ionic and
use in the dosage control of diabetes 2. The most general and
Organometallic-Catalyzed Organosilane Reductions” Organic
flexible synthetic approaches to this class of drugs are outlined
Reactions, Wiley, New York, 71.
herein and follow a similar three-step sequence of preparation of 13. Nadkarni D., Hallissey J.F. (2008) Org. Proc. Res. Dev. 12, 1142.
the appropriate aryl substituent, attachment of the aryl moiety to 14. Czernecki S., Ville G. (1989) J. Org. Chem. 54, 610.
a protected glucose followed by deprotection and modification 15. Kraus G.A., Molina M.T. (1988) J. Org. Chem. 53, 752.
of the anomeric center of the arylated glucose. The use of the 16. Ellsworth B.A., et al. (2003) Tetrahedron: Asymmetry 14, 3243.
gluconolactone intermediate does have the disadvantage of 17. Lemair S., et al. (2012) Org. Lett. 14, 1480.
carrying out an oxidation step to the lactone and a subsequent 18. Nomura S., et al. (2010) J. Med. Chem. 53, 6355.
reduction step, usually carried out with an organosilane. 19. Lee J., et al. (2010) Bioorg. Med. Chem. 18, 2178.
20. Kraus G.A., Frazier K.A., Roth B.D., et al. (1981) J. Org. Chem. 46, 2417.
21. Lemair S., et al. (2012) Org. Lett. 14, 1480.
REFERENCES AND NOTES 22. Xue S., Han K.-Z., He L., et al. (2003) Synlett 870.
23. Halcomb R.L., Danishefsky S.J. (1989) J. Am. Chem. Soc. 111, 6661.
1. International Diabetes Federation. Diabetes Atlas, 3rd Ed.; 24. Dubbaka S.R., Steunenberg P., Vogel P. (2004) Synlett 1235.
International Diabetes Federation: Brussels, Belgium, 2006. 25. Gong H., Gagné M.R. (2008) J. Am. Chem. Soc. 130, 12177.

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