Studies towards the synthesis of ertugliflozin from L-Arabinose

Article abstract of DOI:10.1016/j.tet.2018.08.005

A new method for the diastereoselective synthesis of enantiomerically pure ertugliflozin was developed. The crucial step involves an aldol condensation between 1-(4-chloro-3-(4-ethoxybenzyl)phenyl)ethanone and (4R,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-5-((trityloxy)methyl)-1,3-dioxolane-4-carbaldehyde, which was prepared from known 2-C-trityloxymethyl-2,3-O-isopropylidene-L-erythrose (easily accessible in three steps from L-arabinose) by standard reduction/oxidation and protection/deprotection manipulations. Dihydroxylation of the aldol condensation product and further global deprotection led to the formation of the target molecule.

Full text of DOI:10.1016/j.tet.2018.08.005

Accepted Manuscript
Studies towards the synthesis of ertugliflozin from L-Arabinose
Virginia V. Triantakonstanti, Olga G. Mountanea, Kyriaki-Eleni C. Papoulidou, Thanos
Andreou, Theocharis V. Koftis, John K. Gallos
PII:
S0040-4020(18)30943-8
10.1016/j.tet.2018.08.005
TET 29724
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 April 2018
Revised Date: 1 August 2018
Accepted Date: 6 August 2018
Please cite this article as: Triantakonstanti VV, Mountanea OG, Papoulidou K-EC, Andreou T, Koftis
TV, Gallos JK, Studies towards the synthesis of ertugliflozin from L-Arabinose, Tetrahedron (2018), doi:
10.1016/j.tet.2018.08.005.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Leave this area blank for abstract info.
Studies towards the Synthesis of
Ertugliflozin from L-Arabinose
V. V. Triantakonstanti, O. G. Mountanea, K.-E. C. Papoulidou, T. Andreou, T. V. Koftis, J. K. Gallos
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece, and
Pharmathen SA – R&D API Operations, 9th km Thermi-Thessaloniki, Thessaloniki 57001, Greece
1

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Studies towards the Synthesis of Ertugliflozin from L-Arabinose
Virginia V. Triantakonstanti,a Olga G. Mountanea,a Kyriaki-Eleni C. Papoulidou,a Thanos
Andreou,b Theocharis V. Koftisb and John K. Gallosa*
a Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece. E-mail: igallos@chem.auth.gr
b Pharmathen SA – R&D API Operations, 9th km Thermi-Thessaloniki, Thessaloniki 57001, Greece
Keywords:
ertugliflozin
L-arabinose
dihydroxylation
aldol condensation
SGLT2 inhibitors
Abstract:
A new method for the diastereoselective synthesis of enantiomerically pure ertugliflozin was
developed. The crucial step involes an aldol condensation between 1-(4-chloro-3-(4-
ethoxybenzyl)phenyl)ethanone and (4R,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-5-
((trityloxy)methyl)-1,3-dioxolane-4-carbaldehyde, which was prepared from known 2-C-
trityloxymethyl-2,3-O-isopropylidene-L-erythrose (easily accessible in three steps from L-arabinose)
by standard reduction/oxidation and protection/deprotection manipulations. Dihydroxylation of the
aldol condensation product and further global deprotection led to the formation of the target molecule.
Indroduction
Diabetes is a metabolic disorder characterized by an increase in blood sugar (hyperglycaemia) and a
glucose metabolism disorder, either as a result of decreased insulin secretion or because of decreased
sensitivity of body cells to insulin.1 Diabetes has a chronic course and can cause a number of serious
complications, such as cardiovascular disease, chronic renal failure, retinal lesions, nerve damage,
erectile dysfunction, etc. Current treatments include insulin, metformin, sulfonylureas, PPARgamma
agonists, DPP-IV inhibitors and GLP-1 agonists. Although these medicines are effective in treatments,
there exists safety concern for long term treatment. Therefore, there is a substantial need to identify
new classes of treatments for diabetes.2
There is currently a fierce interest for the development of new selective sodium-glucose transporter-2
(SGLT2) inhibitors. SGLT2 inhibition lowers the renal glucose concentration and the maximum
glucose reabsorption capacity of the kidney, which results in increased urinary glucose excretion.
Using the natural product phlorizin as a lead compound, a number of C-glucosides developed and
among them dapagliflozin, canagliflozin and empagliflozin are now in the market as SGLT2
inhibitors3 (Figure 1).
Figure 1. Structures of selected gliflozins
2

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In addition, researchers at Pfizer recently disclosed a new class of such C-glucosides with a unique
dioxa-bicyclo[3.2.1]octane structure, and among them ertugliflozin is one of the most potent and
selective SGLT2 inhibitors.4 A few months ago, the US Food and Drug Administration (FDA)
approved ertugliflozin (Steglatro) for the treatment of glycemic control in patients with type 2 diabetes
as a drug taken on its own as a fixed-dose, or in combination with metformin and sitagliptin, both oral
antihyperglycemic agents.
Ertugliflozin was firstly prepared from D-glucose in 13 steps4a but in very low overall yield (0.3%)
and required HPLC separation from its C4 epimer. A more attractive synthesis of ertugliflozin was
reported from the same labs, starting from diacetone-α-D-mannofuranose.4b This research team
prepared the target compound in 5 steps and 25% overall yield, but this approach found to be
unsuitable for large scale preparations, mainly due to the lack of crystalline intermediates and the
requirement for low temperature reactions.
To overcome this problem, Pfizer’s researchers turned their attention to the use of D-glucose
derivatives as starting materials. Firstly, they started from persilylated D-gluconolactone, which was
converted to ertugliflozin in several steps involving inter alia Grignard addition, selective desilylation,
oxidation and aldol-crossed-Cannizzaro reaction.5 Although this process could be scaled up in very
good overall yields, it was found not commercially viable. Finally, the Pfizer laboratories developed a
practical and commercially acceptable process for the preparation of ertugliflozin in a 12-step
sequence, starting from 2,3,4,6-tetra-O-benzyl-D-glucose,6 which involved nucleophilic
hydroxymethylation of a ketogluconamide intermediate, and a highly efficient arylation of the
protected diol thus obtained.
Results and Discussion
Taking into account its current interest, we designed a new synthesis of ertugliflozin, depicted in
Scheme 1. According to this retrosynthetic analysis, ertugliflozin (1) could be prepared from enone 2
by a correct diastereoselective dihydroxylation and further global deprotection, which allows the
resulting polyhydroxylated ketone to be self-organized towards the desired product. Compound 2
could be prepared by a Wittig reaction between the stable ylide 4, accessible from 5-bromo-2-
chlorobenzoic acid (7) via compound 67 by standard manipulations, and aldehyde 3, which in turn
could be obtained from the known erythrose template 58 by reduction and careful protection-
deprotection manipulations.
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EtO
Cl
Cl
OEt
O
O
O
OTBS
OTr
HO
HO
OH
O
O
2
OH
1
EtO
OTBS
OTr
EtO
O
+
Cl
O
O
O
Cl
Br
3
PPh3
6
4
Br
O
OH
OH
O
L-arabinose
O
O
OTr
Cl
7
5
Scheme 1. Retrosynthetic analysis of ertugliflozin (1)
To this end, we firstly focused on the synthesis of aldehyde 3 (Scheme 2). Protected hydroxymethyl L-
erythrose 5, a known useful building block prepared in three steps from L-arabinose,8 was reduced by
NaBH4 to diol 8. In order to discern the two primary hydroxyl groups in 8, protection of the less
hindered one was attempted. Among several reagents and protecting protocols used, the pivaloylation
was more selective resulting in the formation of desired monopivaloylated product 9 along with the
byproducts 10 and 11, which as easily separable can be recycled by methanolysis with KOΗ to 8. The
free hydroxyl group in 9 was then protected with TBS-Cl, the pivaloyl group was removed by
methanolysis and the new alcohol was oxidized by pyridinium dichromate (PDC) to afford aldehyde 3,
in 26% overall yield from 5.
Scheme 2. Reagents and conditions: (i) 2,2-Dimethoxypropane, TsOH, DMF, 3 h, then NaIO4 H2O, 12 h, then
Na2CO3; (ii) HCHO, K2CO3, MeOH, 65 °C; (iii) TrCl, pyridine, 60 °C; (iv) NaBH4, MeOH, 0 °C to reflux, 2 h;
(v) PivCl, pyridine, DMAP, DCM, 0 to 20 °C, 12 h; (vi) KOH, MeOH, 20 °C, 12 h; (vii) TBSCl, imidazole,
DMAP, DCM, 0 to 20 °C, 12 h; (viii) KOH, MeOH, 20 °C, 2 h; (ix) PDC, DCM, reflux, 4 h.
We then proceeded into the next step, which was the synthesis of ylide 4. As depicted in Scheme 3, 5-
bromo-2-chlorobenzoic acid (7) was converted to its chloride and a subsequent Friedel-Crafts reaction
afforded ketone 14, which was further reduced to give compound 15, 7 in quantitative yields. Lithiation
of the latter with n-BuLi and reaction of the lithiated product with the Weinreb amide
4

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ClCH2CON(Me)OMe led to the formation of the desired ylide precursor 16, which was then easily
converted to 4 by standard procedures.
Scheme 3. Reagents and conditions: (i) oxalyl chloride, DCM, DMF (cat.), 20 °C, 12 h, then phenetole, DCM,
AlCl3, -20 to 20 °C, 1 h; (ii) BF3ꢀOEt3, Et3SiH, ClCH2CH2Cl/MeCN, 0 to 50 °C, 3 h; (iii) n-Buli, THF, -78 °C,
45 min, then ClCH2CON(Me)OMe, THF, -78 °C, 3 h; (iv) PPh3, MeCN, reflux, 12 h, then Na2CO3, 20 °C, 3 h.
The Wittig reaction of aldehyde 3 with ylide 4 required reflux in toluene in order to reach its
completion (Scheme 4). This caused an extended epimerization of aldehyde 3, leading to an
inseparable (by column chromatography) mixture of diastereoisomers 2 and epi-2, in varying ratios,
depending on the exact reaction conditions, such as temperature and reaction time. When the Wittig
reaction was interrupted before its completion, the unreactive aldehyde 3 was isolated and its NMR
data clearly indicated that it was a mixture of epimers 3 and epi-3. HPLC/MS analysis of the Wittig
product revealed that this intermediate had an average 2/epi-2 diastereomeric ratio of ca. 3:1, with the
1
non-epimerized product 2 to be the major one, as shown by comparing the H NMR spectrum of this
mixture with that of pure 2, prepared independently (Scheme 6).
Dihydroxylation of 2 can lead to the formation of 17 and 18, whereas epi-17 and epi-18 are the
possible dihydroxylation products of epi-2. From all of these possible products, only compound 18
deprotection could afford ertugliflozin (1) by deprotection, while epi-17 leads to the formation of ent-
1, since deprotected 18 and epi-17 are enantiomers. Unfortunately, the inseparable mixture of 2/epi-2
upon dihydroxylation with OsO4 lead to the formation of two diastereoisomeric mixtures 17/epi-18
and 18/epi-17 in ratio 2:1, respectively, which were separated chromatographically and without
complete characterization were treated with TFA. Under these conditions, the minor slower moving
dihydroxylated product 18/epi-17 gave ertugliflozin with NMR data identical to those reported in the
literature for the authentic compound and with ca. 50% ee, as found from its [α]D [+4.0 (c 0.5,
25
MeOH)] compared to the [α]D value of authentic ertugliflozin4b {[a]D +8.0 (c 0.5, MeOH)}. It
also indicated that the 18/epi-17 ratio is also ca. 3:1.
5

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Scheme 4. Reagents and conditions: (i) compound 4, toluene, reflux, 12 h; (ii) OsO4, NMO, acetone/H2O (4:1),
20 °C, 12 h, (iii) TFA/H2O (9:1), 20 °C, 1 h.
Summarizing the above results, we had to solve two major problems in the way to prepare
enantimerically pure ertugliflozin: to avoid epimerization and to improve the diastereoselection in the
dihydroxylation step. To overcome the epimerization problem, we considered several alternative
pathways in order to connect the aglycon and sugar parts of ertugliflozin. In a first plan, it was likely
that a base promoted aldol reaction between hydroxyketone 20 (Scheme 5) and aldehyde 3 could
directly lead to the formation of desired product 18, along with its all possible syn-/anti-diastereomeric
adducts. The diastereoselectivity of aldol addition could then controlled by selecting the proper
catalyst. Similar diastereoselective reactions with related educts have been reported in the literature.9
Scheme 5. Reagents and conditions: (i) Mg, THF, reflux, 1 h, then (CH3CO)2O, THF, -20 to 20 °C, 3 h; (ii)
PIDA, KOH, MeOH, 0 to 20°C, 12 h.
Hydroxyketone 20 was easily prepared from 15 in two steps. Firstly, lithiation of 15 and further
reaction with acetic anhydride afforded methylketone 19, which was then oxidized with phenyliodine
diacetate (PIDA) in the presence of KOH in methanol to give 20 in 64% overall yield from 15. A
mixture of hydroxyketone 20 and aldehyde 3 was treated with a number of organic bases (Et3N,
pyridine, quinine, quinchonine, L-proline, etc.) in different reaction conditions regarding solvents and
temperature in prolonged reaction times. Always, the reaction was very slow and after several days,
more than 70% of reactants remained unchanged, and a number of products had been formed, as
shown in TLC. Since the isolation and characterization of these products was proved extremely
difficult, the mixture was treated with TFA, but no amount of 1 was identified.
At this point, we turned our attention in the preparation of enone 2 by an indirect method with the
scope of avoiding epimerization. Thus, we firstly tried a Wittig reaction of aldehyde 3 with the simple
reactive ylide Ph3P=CH2 in low temperature, in order to avoid epimerization. To our satisfaction,
product 21 was obtained in 99% yield in enantiomerically pure form, as shown by NMR. Further cross
metathesis with Weinreb acrylamide led to the desired amide 22, and its reaction with the lithiated
6

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compound 15 (Scheme 3) afforded enone 2. However, long reaction times and moderate overall yields
led us to search for a more convenient method. Better results were obtained by an aldol condensation
of aldehyde 3 and ketone 19 using LDA as a base at low temperature to afford desired enone 2 in 58%
yield.
Scheme 6. Reagents and conditions: (i) Ph3PCH3Br, THF, addition of n-BuLi at -78 °C, stirring at -60 °C, 1 h,
then addition of 3 at -78 °C and stirring, 2 h, then stirring at 20 °C, 12 h; (ii) CH2=CHCON(Me)OMe, Grubbs
2nd generation catalyst, THF, reflux, 4 days; (iii) compound 15, n-BuLi, -78 °C, 45 min, 1 h, then 20 °C, 2 days;
(iv) compound 19, LDA, THF, -78 °C to 20 °C, 12 h; (v) OsO4, NMO, citric acid, acetone/H2O (4:1), 20 °C, 12
h; (vi) TFA/H2O (9:1), 20 °C, 1 h.
We then turned our attention in an attempt to improve the diastereoselectivity in the dihydroxylation
step. A plethora of conditions in the dihydroxylation reaction were tried, regarding reagent (OsO4,
K2OsO4, NaIO4, KMnO4, AgOAc + I2), co-oxidant [NMO, Κ3Fe(CN)6], additives (citric acid, methane
sulfonamide, L(+)-tartaric acid, K2CO3), temperature, solvent and catalyst ratio, including the classic
mixtures [Κ3Fe(CN)6, K2CO3, (DHQ)2PHAL, OsO4, methane sulfonamide] and [Κ3Fe(CN)6, K2CO3,
(DHQ)2AQΝ, OsO4, methane sulfonamide] and also the commercial AD-mix α and AD-mix β, but
always the undesired faster moving product 17 was the major one. The best 17:18 ratio obtained was
2:1 when the dihydroxylation proceeded with OsO4, NMO, citric acid, in acetone/H2O (4:1), 20 °C, 12
h, with 90% total yield, favoring unfortunately the undesired diastereoisimer 17. Finally, compound 18
was converted to 1 in 85% yield, by treatment with TFA with spectral and physical data identical to
those reported for 1.
It is worthy to mention that there was no appreciable difference in the diastereoselection when each of
AD-mix α and AD-mix β was used as catalysts in the dihydroxylation of 2, both of them favoring
exclusively the formation of the undesired diastereoisimer 18. This observation led us in the
conclusion that the intrinsic substrate-driven induction selectivity is superior to the selectivity induced
by the catalyst. It is likely that each one of the bulky AD-mix α and AD-mix β catalysts are strongly
hindered to approach the desired side of the double bond because of the substrate bias, much stronger
than OsO4 itself. Attempted removing of the TBS protecting group in order to reduce the substrate
bias led, unfortunately, to an intramolecular 1,4-addition reaction.
3. Conclusion
The following Scheme 7 summarizes the achieved steroselective synthesis of ertugliflozin (1). It was
synthesized in eight steps with 4% overall yield from known trityloxymethyl L-erythrose 5, which in
our hands was prepared from cheap commercial L-arabinose, in three steps and 60% overall yield.
Reduction of 5 with NaBH4 and a further protection-deprotection sequence lead to the formation of
key-aldehyde 3, in 26% overall yield from 5. This yield is practically higher, since undesired products
10 and 11 (Scheme 2) can be recycled. The carbon skeleton of the target molecule was constructed by
7

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an aldol condensation of 3 with the aromatic methylketone 19, whereas dihydroxylation of the
resulting double bond and further global deprotection afforded ertugliflozin (1) in 15% from 3.
Scheme 7. Overall synthetic scheme for ertugliflozin (1)
All above steps involve simple experimental manipulation and utilize cheap materials and reagents.
Unfortunately, the undesired reverse stereoselectivity in the dihydroxylation step is a drawback of our
approach which lacks the existing synthesis methods. Possibly, replacing the acetonide by a more
flexible protecting group in the erythrose backbone could allow the correct diastereoselection in the
dihydroxylation step by selecting the proper catalyst. Studies towards this direction are in progress.
4. Experimental section
4.1. General
All reagents are commercially available and were used without further purification. Solvents were
dried by standard methods. The progress of reactions was checked by thin layer chromatography
(TLC) on Merck silica gel 60F254 glass plates (0.25 mm). The spots were visualised by heat staining
with anisaldehyde in ethanol/sulfuric acid. Column chromatography was performed with Merck silica
gel 60 (0.063-0.200 mm). Melting points were determined with a Kofler hot-stage microscope. 1H and
1
13C NMR spectra were recorded at 300 or 500 MHz and 75 or 126 MHz, respectively. H NMR
chemical shifts (δ) are reported in ppm relative to tetramethylsilane (δ = 0.0 ppm), using the residual
solvent signal as an internal standard (δ = 7.26, singlet, for CDCl3), or using tetramethylsilane itself.
The proton resonances are annotated as: chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br., broad), coupling constant (J [Hz]), and integration. 13C NMR chemical shifts
are reported in ppm, and spectra were calibrated using the central line of the triplet at δ = 77.0 ppm for
CDCl3. IR spectra were recorded with an FTIR instrument as indicated. High-resolution mass spectra
(HRMS) were obtained using the electrospray technique, positive mode.
4.2 2,3-O-Isopropylidene-L-erythrose
L-Arabinose (5.0 g, 33.3 mmol), p-toluenesulphonic acid (127 mg, 0,67 mmol) and 2,2-
dimethoxypropane (12.3 mL, 100 mmol) were stirred in DMF (34 mL) for 3 h. After neutralization,
with solid Na2CO3 (70mg, 0,67mmol), solids were filtered off and washed with DCM and volatiles
were removed under reduced pressure. The residue was dissolved in water (80 mL) and solid NaIO4
(17.8 g, 83,3 mmol) was added in portions under vigorous stirring to the aqueous layer and the mixture
stirred for 12 h, when solid Na2CO3 was added carefully until pH=7. Solids were filtered off and
washed with DCM. Aqueous layer was extracted with ethyl acetate (4x120 mL), the combined organic
layers were dried over Na2SO4 and the solvent was evaporated off. The residue was purified by
column chromatography, with hexane/ethyl acetate (3:1) as eluent, to give 2,3-O-isopropylidcne-L-
erythrose (5.40 g, 77%) as an α/β (1:10) mixture of anomers with spectral and physical data in
agreement to those reported in the literature.8a
4.3 2,3-O-Isopropylidene-2-hydroxymethyl-L-erythrose
8

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A mixture of 2,3-O-Isopropylidene-L-erythrose (4.07 g, 25.6 mmol), MeOH (115 mL) and aqueous
methanolic solution formaldehyde (17.6 mL, 256 mmol) was heated with stirring to boiling point,
whereupon potassium carbonate was added in small portions (about 500mg) every 20 minutes as the
previous dose was almost dissolved. The end of the reaction was indicative at the point where the
dissolution of the potassium carbonate was much slower, whereas the color of the reaction started to
darken. After cooling the mixture to ambient temperature, the solid suspended particles were removed
by filtration and the filtrate was transferred to an extraction funnel along with DCM (120 mL) and
aqueous NaCl (sat.) (90 mL). The organic layer was separated and the aqueous was washed several
times with EA (9x200 mL) until all of the product was transferred to the organic solvent. The organic
layers were combined, dried (Na2SO4) and concentrated under reduced pressure. The residue was
purified by column chromatography with hexane/ethyl acetate (2:1) as eluent, to give a mixture of
anomers of 2,3-O-isopropylidene-2-hydroxymethyl-L-erythrose (4.14 g, 86%, ratio of α/β ca. 1:2) as a
colorless oil with spectral and physical data in agreement to those reported in the literature.8b
4.4 2,3-O-Isopropylidene-2-trityloxymethyl-L-erythrose (5)
2,3-O-Isopropylidene-2-hydroxymethyl-L-erythrose (4.07 g, 21.4 mmol) was dissolved in 45 ml of
dry pyridine, and 6.6 g (23.6 mmol) of TrCl were added in one portion. The reaction mixture was
heated at 60 °C for 36 hours under argon atmosphere, then was allowed to return to room temperature,
diluted with 100 ml of toluene and washed with aq. NaCl (sat.) (3x100 mL). The organic layer was
dried (Na2SO4), the solvent was evaporated off under reduced pressure and the residue was
chromatographed (EtOAc/hexanes 1:5) to give a mixture of anomers 5 (8.14 g, 90%, ratio of α/β ca.
2:1) as a thick oil with spectral and physical data in agreement to those reported in the literature.8b
4.5 ((4S,5S)-2,2-Dimethyl-4-((trityloxy)methyl)-1,3-dioxolane-4,5-diyl)dimethanol (8)
To a solution of compound 58b (1.2 g, 2.76 mmol) in MeOH (40 mL), NaBH4 (261 mg, 6.9 mmol) was
added with stirring in portions to avoid foaming at 0 °C and then, the reaction mixture was refluxed
for about 2 h where TLC showed consumption of the starting material. The mixture was brought to
ambient temperature, H2O (100 mL) and AcOH were added to adjust the pH to 5. The resulting
mixture was extracted with EtOAc (3x200 mL) and the organic layer was dried over Na2SO4, the
solvent was evaporated off under reduced pressure and the residue was chromatographed on a silica
25
gel column (hexane/ethyl acetate 3:1) to give product 8 (970 mg, 81%) as a viscous white oil. [a]D
+11.8 (c 7.0, CHCl3). FTIR (neat film) 3444, 3058, 2986, 2934, 1637, 1448 cm-1. 1H NMR (500 MHz,
CDCl3) δ 7.47 (m, 6H), 7.33-7.23 (m, 9H), 3.95 (t, J = 5.3 Hz, 1H), 3.85 (dd, J = 11.9, 5.3 Hz, 1H),
3.80 (dd, J = 11.9, 5.3 Hz, 1H), 3.77 (d, J = 11.9 Hz, 1H), 3.70 (d, J = 11.9 Hz, 1H), 3.46 (d, J = 9.7
13
Hz, 1H), 3.15 (d, J = 9.7 Hz, 1H), 2.30 (br s, 2H), 1.47 (s, 3H), 1.32 (s, 3H). C NMR (126 MHz,
CDCl3) δ 143.4, 128.6, 127.9, 127.2, 108.5, 87.2, 83.2, 79.9, 65.7, 62.6, 60.4, 28.2, 26.2. LC-MS (ESI
positive) m/z: 435 [M+H]+ HRMS m/e: C27H31O5 [(M+H)+] calcd: 435.2166, found: 435.2169.
4.6 ((4S,5S)-5-(Hydroxymethyl)-2,2-dimethyl-5-((trityloxy)methyl)-1,3-dioxolan-4-yl)methyl pivalate
(9)
Dry pyridine (0.16 mL), pivaloyl chloride (198 mg, 0.2 mL) and DMAP (5 mg) were successively
added to a stirred solution of diol 8 (600 mg, 1.38 mmol) in dry DCM (12 mL) under argon
atmosphere at 0 °C. The mixture was stirred for 1 h at 0 °C and then allowed to stir at ambient
temperature for 12 h where TLC showed consumption of the starting material. The reaction was
quenched by addition of saturated aqueous NaHCO3 (50 mL) and the mixture was extracted with
DCM (3x100 mL). The combined organic layers were dried over Na2SO4, the solvent was evaporated
off under reduced pressure and the residue was chromatographed on a silica gel column (hexane/ethyl
acetate 8:1) to give firstly compound 10 as a white foam (280 mg, 35%), followed by product 9 (365
25
mg, 52%) as a colorless viscous oil and finally compound 11 (38 mg, 8%). For compound 9, [a]D
-
9.1 (c 0.44, CHCl3). FTIR (neat film) 3451, 2978, 1732, 1635, 1480 cm-1. 1H NMR (500 MHz, CDCl3)
δ 7.48 (m, 6H), 7.31–7.21 (m, 9H), 4.35 (dd, J = 11.7, 4.9 Hz, 1H), 4.24 (dd, J = 11.5, 6.6 Hz, 1H),
9

ACCEPTED MANUSCRIPT
4.13 (dd, J = 6.6, 4.9 Hz, 1H), 3.73 (d, J = 11.5 Hz, 1H), 3.70 (d, J = 11.5 Hz, 1H), 3.41 (d, J = 9.7 Hz,
1H), 3.22 (d, J = 9.7 Hz, 1H), 1.49 (s, 3H), 1.35 (s, 3H), 1.12 (s, 9H). 13C NMR (126 MHz, CDCl3) δ
177.9, 143.4, 128.7, 127.9, 127.2, 108.9, 87.1, 83.4, 77.7, 65.3, 62.6, 62.1, 38.6, 28.3, 27.1, 26.3. LC-
MS (ESI positive) m/z: 541 [M+Na]+ HRMS m/e: C32H38NaO6 [(M+Na)+] calcd: 541.2561, found:
541.2572.
4.7 Recycling of (2R,3S)-2,3-O-Isopropylidene-2,3-dihydroxy-2-((trityloxy)methyl)butane-1,4-diyl
bis(2,2-dimethylpropanoate) (10) and ((4R,5S)-5-(Hydroxymethyl)-2,2-dimethyl-4-((trityloxy)methyl)-
1,3-dioxolan-4-yl)methyl pivalate (11)
The above prepared compound 10 (750 mg, 1.9 mmol) was dissolved in MeOH (20 mL) and then
solid KOH (160 mg, 2.84 mmol) was added. The mixture was stirred for 12 h where consumption of
the starting material was observed. Then, H2O (15 mL) was added and the mixture was extracted with
DCM (3x30 mL). The combined organic layers were dried with (Na2SO4) and the solvent was
removed under reduced pressure. The residue was chromatographed (hexane/ethyl acetate 5:1),
whereby 640 mg of viscous white product 8 (89%) was obtained. Similarly, compound 11 was
converted to 8, approximately with the same yield.
4.8 ((4S,5R)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-5-((trityloxy)methyl)-1,3-dioxolan-
4-yl)methyl pivalate (12)
Imidazole (85.3 mg, 1.25 mmol), TBSCl (215 mg, 1.42 mmol) and DMAP (7 mg) were successively
added to a stirred solution of compound 9 (300 mg, 0.57 mmol) in dry DCM (8 mL) under argon
atmosphere at 0 °C. The mixture was stirred for 1 h at 0 °C and then allowed to stir for 12 h at ambient
temperature. Saturated aqueous NaHCO3 (20 mL) was then added and then the mixture was extracted
with DCM (2x10 mL). The combined organic layers were dried over Na2SO4, the solvent was
removed under reduced pressure and the residue was chromatographed on a silica gel column
25
(hexane/ethyl acetate 10:1) to give product 12 (335 mg, 93%) as a white viscous oil. [a]D -5.0 (c
1.44, CHCl3). FTIR (neat film) 2956, 2930, 2857, 1732, 1635, 1463 cm-1. (500 MHz, CDCl3) δ 7.49
(m, 6H), 7.31–7.19 (m, 9H), 4.27 (dd, J =11.1, 2.6 Hz, 1H), 4.18 (m, 2H), 3.66 (d, J = 10.1 Hz, 1H),
3.59 (d, J = 10.1 Hz, 1H), 3.32 (d, J = 9.8 Hz, 1H), 3.21 (d, J = 9.8 Hz, 1H), 1.47 (s, 3H), 1.39 (s, 3H),
1.15 (s, 9H), 0.78 (s, 9H), 0.01 (s, 3H), -0.07 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 178.1, 143.8,
128.8, 127.7, 126.9, 108.3, 86.7, 83.3, 77.3, 64.4, 63.0, 62.5, 38.6, 28.5, 27.2, 26.4, 25.8, 18.0, -5.6, -
5.7. LC-MS (ESI positive) m/z: 655 [M+Na]+ HRMS m/e: C38H52NaO6Si [(M+Na)+] calcd: 655.3425,
found: 655.3431.
4.9 ((4S,5R)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-5-((trityloxy)methyl)-1,3-dioxolan-
4-yl)methanol (13)
Solid KOH (80 mg, 1.42 mmol) was added to a solution of compound 12 (300 mg, 0.47 mmol) in
methanol (10 mL) and mixture was stirred at ambient temperature for about 2 h where consumption of
the starting material was observed by TLC. Water (10 mL) was then added and the mixture was
extracted with DCM (3x100 mL). The combined organic layers were dried over Na2SO4, the solvent
was removed under reduced pressure and the residue was chromatographed on a silica gel column
(hexane/ethyl acetate 10:1) to give product 13 (175 mg, 67%) as a white viscous foam, [a]D25 -11.7 (c
9.2, CHCl3). FTIR (neat film) 3459, 2928, 1635, 1448 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.50 (m,
6H), 7.28-7.22 (m, 9H), 4.13 (t, J = 6.3 Hz, 1H), 3.75 (m as br s, 2H), 3.68 (d, J = 10.0 Hz, 1H), 3.66
(d, J = 10.0 Hz, 1H), 3.30 (d, J = 10.0 Hz, 1H), 3.18 (d, J = 10.0 Hz, 1H), 2.70 (br s, 1H), 1.47 (s, 3H),
1.43 (s, 3H), 0.77 (s, 9H), 0.03 (s, 3H), -0.08 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 143.8, 128.8,
127.7, 127.0, 108.1, 86.8, 83.7, 78.6, 65.2, 62.4, 60.7, 28.5, 26.3, 25.7, 18.0, -5.7, -5. 9. LC-MS (ESI
positive) m/z: 571 [M+Na]+ HRMS m/e: C33H44NaO5Si [(M+Na)+] calcd: 571.2850, found: 571.2845.
4.10 (4R,5R)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-5-((trityloxy)methyl)-1,3-
dioxolane-4-carbaldehyde (3)
10

ACCEPTED MANUSCRIPT
PDC (220 mg, 0.58 mmol) was added to a solution of alcohol 13 (160 mg, 0.29 mmol) in 10 ml dry
DCM (10 mL) and the mixture was refluxed for 4 h where consumption of the starting material was
observed by TLC. The solvent was then evaporated off and the residue was chromatographed on a
silica gel column (dichloromethane) to give aldehyde 3 (155 mg, 98%), which was used in the next
steps without further purification. 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1H), 7.47 (m, 6H), 7.22-7.30
(m, 9H), 4.45 (s, 1H), 3.64 (d, J = 10.4, 2H), 3.53 (d, J = 10.4, 2H), 3.35 (d, J = 10.0, 2H), 3.30 (d, J =
10.0, 2H), 1.56 (s, 3H), 1.43 (s, 3H), 0.77 (s, 9H), -0.08 (s, 3H), -0,13 (s, 3H).
4.11 (5-Bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone (14)
Oxalyl chloride (1.9 mL, 21.3 mmol) and DMF (30 ꢁL) were added to a solution of 5-bromo-2-
chlorobenzoic acid (5.0 g, 21.3 mmol) in dry DCM (10 mL) and the mixture was stirred at room
temperature for 12 h. Volatiles were then evaporated off under reduced pressure and the crude 5-
bromo-2-chlorobenzoyl chloride was dissolved in dry DCM (10 mL). The resulting solution was
cooled at -5 °C and phenetole (2.6 g, 21.3 mmol) was added. Then, the mixture was further cooled at -
20 °C, whereupon AlCl3 (2.8 g, 21.3 mmol) was gradually added. After 1 h of stirring at room
temperature, the reaction mixture was placed in an ice bath and water (40 mL) was added in portions.
The resulting mixture was extracted with DCM (3x 80 mL) and the combined organic layers were
washed with 1N HCl (2x50 mL), H2O, 1N NaOH (2x50 mL) and brine before dried over Na2SO4.
Concentration and column column chromatography on silica gel (hexane/ethyl acetate 10:1) afforded
compound 14 as a white solid (6.86 g, 95%) with spectral and physical data identical to those reported
in the literature, m.p. 68-70 °C (lit. m.p. 60 °C7a and 68-72 °C7c). 1H NMR (500 MHz, CDCl3) δ 7.76
(d, J = 8.8, 2H), 7.53 (dd, J = 2.2, 8.4, 1H), 7.48 (d, J = 2.2, 1H), 7.32 (d, J = 8.4, 1H), 6.93 (d, J = 8.8,
2H), 4.11 (q, J = 7.0, 2H), 1.45 (t, J = 7.0, 3H). 13C NMR (126 MHz, CDCl3) 192.0, 163.9, 140.7,
133.7, 132.6, 131.5, 131.4, 130.1, 128.6, 120.5, 114.5, 63.9, 14.6. LC-MS (ESI positive) m/z: 340
[M+H]+.
4.12 4-Bromo-1-chloro-2-(4-ethoxybenzyl)benzene (15)
Et3SiH (6.76 mL, 42.34 mmol) was added to a solution of compound 14 (6.0 g, 17.8 mmol) in 1:2
mixture of dry 1,2-dichloroethane/acetonitrile (2:1, 60 mL) and the mixture was cooled in an ice bath.
BF3·OEt2 (2.53 mL, 20.51 mmol) was added and the mixture was heated at 50 °C for 3 h and then
cooled at room temperature. Aqueous 7N KOH (30 mL) was added and the aqueous layer was
extracted with dichloromethane (2x100 mL). The combined organic layers were washed with 2N KOH
(2x) and brine and dried over Na2SO4. The solvent was removed under reduced pressure and the
residue was chromatographed on a silica gel column (hexane/ethyl acetate 15:1) to give product 15
(5.6 g, 97%) as colorless crystals, with spectral and physical data identical to those reported in the
literature,7 m.p. 40-42 °C (lit. m.p. 37 °C7a and 40-41 °C7b). 1H NMR (400 MHz, CDCl3) 7.20-7.28 (m,
3H), 7.08 (d, J = 8.8, 2H), 6.83 (d, J =8.8, 2H), 4.00 (q, J = 7.0, 2H), 3.96 (s, 2H), 1.40 (t, J = 7.0, 3H);
13C NMR (125 MHz, CDCl3) 157.6, 141.3, 133.5, 133.1, 130.9, 130.5, 130.4, 130.0, 120.4, 114.6,
63.4, 38.2, 14.9. LC-MS (ESI positive) m/z: 325 [M+H]+.
4.13 2-Chloro-1-(4-chloro-3-(4-ethoxybenzyl)phenyl)ethanone (16)
To a cold solution (-78 °C) of compound 15 (470 mg, 1.45 mmol) in dry THF (3 mL) 1.6 N solution
of n-BuLi in hexanes (0.13 mL) was added dropwise. The mixture was stirred at this temperature for
45 min and to this mixtute a solution of 2-chloro-N-methoxy-N-methylacetamide (200 mg, 1.45 mmol)
in dry THF (2 mL) was added dropwise at -78 °C. Stirring was continued for 3 h at this temperature
where the consumption of the starting material was checked by TLC. Saturated aqueous solution of
NH4Cl (5 mL) was then added, followed by extraction with of DCM (3x8 mL). The combined organic
layers ware dried over Na2SO4, the solvent was removed under reduced pressure and the residue was
chromatographed on a silica gel column (hexane/ethyl acetate 12:1) to give product 16 (455 mg, 98%)
as a colorless oil. FTIR (neat film) 3033, 1702, 1629 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J =
2.0 Hz, 1H), 7.72 (dd, J = 8.3, 2.0 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.83 (d,
11

ACCEPTED MANUSCRIPT
J = 8.6 Hz, 2H), 4.58 (s, 2H), 4.07 (s, 2H), 4.00 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H). 13C NMR
(126 MHz, CDCl3) δ 190.2, 157.7, 140.4, 140.2, 132.8, 130.8, 130.2, 130.1, 129.9, 127.5, 114.7, 63.4,
45.8, 38.3, 14.7. LC-MS (ESI positive) m/z: 361 [M+K]+ HRMS m/e: C17H16KO2 [(M+K)+] calcd:
361.0159, found: 361.0156.
4.14 1-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-(triphenylphosphoranylidene)ethanone (4)
Triphenylphosphine (330 mg, 1.25 mmol,) was added to a solution of compound 16 (400 mg, 1.25
mmol,) in dry acetonitrile (12 mL) and the mixture was refluxed for 12 h. Aqueous solution of Na2CO3
(130 mg) in water (5 mL) was then added and the mixture was stirred for 3 h, followed by extraction
with DCM (3x20 ml). The combined organic layers were dried over Na2SO4, the solvent was removed
under reduced pressure and the residue was chromatographed on a silica gel column (hexane/ethyl
1
acetate 7:1) to give product 4 (480 mg, 72%) as colorless crystals, m.p. 193-197 °C. H NMR (500
MHz, CDCl3) δ 7.86 (s, 1H), 7.75 (d, J = 7.9, 1H), 7.70 (m, 6H), 7.55 (m, 3H), 7.47 (m, 6H), 7.32 (d, J
= 7.9, 1H), 4.35 (d, J = 16.6, 1H), 4.05 (s, 2H), 3.98 (q, J = 7.9, 2H), 1.37 (t, J = 7.9, 3H). LC-MS
(ESI positive) m/z: 549 [M+H]+ HRMS m/e: C35H3135ClO2P [(M+H)+] calcd: 549.1745, found:
549.1755.
4.15 Ertugliflozin (1) via the Wittig reaction
A solution of aldehyde 3 (510 mg, 0.95 mmol) and ylide 4 (580 mg, 1.05 mmol) in toluene (10 mL)
was reflux for 12 h. Then, the solvent was evaporated off and the residue was chromatographed on a
silica gel column (hexane/ethyl acetate 10:1) to give a c.a. 3:1 inseparable mixture of 2/epi-2 (507 mg,
65%) as a colorless oil. This mixture (50 mg, 0.061 mmol) was dissolved in acetone/water (4:1) (4
mL), then NMO (7 ꢁL, 0.07 mmol, 1.2 eq.) and a catalytic amount of OsO4 solution 4% in water (22
ꢁL) were added and the resulting mixture was stirred for about 12 h at ambient temperature, where
TLC showed the consumption of the starting material and the formation of two products. A solution of
NaHSO3 (180 mg) in H2O (5 mL) was then added and the resulting mixture was stirred for 0.5 h.
Solids were filtered off and the solution was extracted with EA (3x30 mL). The organic layers were
dried over Na2SO4, the solvent was removed under reduce pressure and the residue was
chromatographed on a silica gel column (hexane/ethyl acetate 7:1) to give firstly a mixture of 17/epi-
18 (39.5 mg, 76%), followed by 18/epi-17 (13 mg, 23%). The slower moving 18/epi-17 was dissolved
in a mixture of TFA/H2O (9:1) (2.1 mL). The mixture was stirred at ambient temperature for 1 h and
then the solvent was removed under reduced pressure. The residue was dissolved in EA and washed
with water, 1M aqueous NaOH and brine. The organic layer was dried with Na2SO4, the solvent was
removed under reduced pressure and the residue was chromatographed on a silica gel column (20%
MeOH in CH2Cl2) to give ertugliflozin (1) (12 mg, 92%), with NMR spectra identical to those
reported in the literature.4b [α]D25 +4.0 (c 0.5, MeOH).
4.16 1-(4-Chloro-3-(4-ethoxybenzyl)phenyl)ethanone (19)
Activated magnesium (744 mg, 31 mmol) was added to dry THF (30 mL) and a few drops of a
solution of compound 15 (0.5 g, 1.55 mmol) in dry THF (5 mL) were initially added to this mixture.
To initiate the reaction a drop of CH3I is added, if necessary. Then, the rest of solution of compound
15 was added and the mixture was refluxed for 1 h. The mixture was subsequently cooled at -20 °C, a
solution of acetic anhydride (633 mg, 6.2 mmol) in dry THF (4 mL) was added dropwise and the
resulting solution was left to stir at room temperature for 3 h. Water (5 mL) was then added to the
mixture followed by careful addition of about 0.8 ml of a 50% aqueous NaOH solution to adjust the
pH to 8. The mixture was extracted wit DCM (3x20 mL), the combined organic layers were dried over
Na2SO4, the solvent was removed under reduced pressure and the residue was chromatographed on a
silica gel column (hexane/ethyl acetate 7:1) to give compound 19 (380 mg, 84%) as white crystals,
1
m.p. 50-52 °C. FTIR (neat film) 3048, 2979, 1682, 1630, 1583 cm-1. H NMR (500 MHz, CDCl3) δ
7.76 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 8.2, 2.1 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 8.6 Hz,
2H), 6.83 (d, J = 8.6 Hz, 1H), 4.09 (s, 2H), 4.01 (q, J = 7.0 Hz, 2H), 2.52 (s, 3H), 1.40 (t, J = 7.0 Hz
12

ACCEPTED MANUSCRIPT
2H). 13C NMR (126 MHz, CDCl3) δ 197.1, 157.6, 139.7, 139.4, 135.7, 130.7, 130.6, 129.8, 129.8,
127.4, 114.6, 63.4, 38.4, 26.6, 14.8. LC-MS (ESI positive) m/z: 259 [M-CH2CH3]+ HRMS m/e:
C15H1235ClO2 [(M-CH2CH3)+] calcd: 259.0520, found: 259.0528.
4.17 1-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-2-hydroxyethanone (20)
KOH (1.07 mg, 19 mmol) and PIDA (1.2 g, 3.73 mmol) were added to a stirred solution of ketone 19
(1.0 g, 3.5 mmol) in methanol (8.5 mL) at 0 °C and the mixture was allowed to stir overnight at
ambient temperature. The mixture was then extracted with DCM (20 mL) and with ethyl acetate (2x20
mL). The combined organic layers were dried Na2SO4, then filtered and concentrated. Methanol (0.1
mL) and aqueous 2M HCl (0.1 mL) were added to the residue and the resulting mixture was stirred for
1 h. The solvent was removed under reduced pressure and the residue was chromatographed on a silica
gel column (hexane/ethyl acetate 6:1) to give firstly the PhI byproduct, followed by compound 20 (810
1
mg, 76%) as white crystals, m.p. 55-57 °C. H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 2.1 Hz, 1H),
7.74 (dd, J = 8.2, 2.1 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz,
1H), 4.09 (s, 2H), 4.01 (q, J = 7.0 Hz, 2H), 3.55 (s, 2H), 1.40 (t, J = 7 Hz 2H), 0.67 (s, 1H); 13C NMR
(126 MHz, CDCl3) δ 197.1, 157.6, 139.7, 139.4, 135.7, 130.7, 130.6, 129.8, 129.8, 127.4, 114.6, 63.4,
38.4, 26.6, 14.8. LC-MS (ESI positive) m/z: 327 [M+Na]+ HRMS m/e: C17H1735ClNaO3 [(M+Na)+]
calcd: 327.0758, found: 327.0755.
4.18 tert-Butyl(((4R,5S)-2,2-dimethyl-4-((trityloxy)methyl)-5-vinyl-1,3-dioxolan-4-
yl)methoxy)dimethylsilane (21)
A solution of 1.6 M n-BuLi in hexanes (0.42 mL, 0.682 mmol) was added dropwise at -78 °C to a
stirred solution of Ph3PCH3Br (210 mg, 0.6 mmol) in dry THF (1 mL) containing catalytic amount of
12-crown-4 (10 mg). The mixture was then stirred at -40 °C for 1 h, before cooled again to -78 °C,
where a solution of aldehyde 3 (110 mg, 0.2 mmol) in dry THF (1 mL) was added dropwise. The
resulting mixture was agitated for 2 h at temperatures below -60 °C and then left to stir for 12 hours at
ambient temperature. Then, the mixture was cooled in an ice bath, a saturated aqueous solution of
NH4Cl (3 mL) was added and the mixture was extracted with DCM (3x5 mL). The combined organic
layers were dried over Na2SO4, the solvent was removed under reduced pressure and the residue was
chromatographed on a silica gel column (hexane/ethyl acetate 6:1) to give product 21 (110 mg, 99%)
as a colorless oil, [a]D25 -2.45 (c 0.75, CHCl3). FTIR (neat film) 3061, 2929, 1638, 1618, 1491 cm-1. 1H
NMR (500 MHz, CDCl3) δ 7.49 (m, 6H), 7.30-7.22 (m, 9H), 5.87 (m, 1H), 5.30 (d, J = 17.2 Hz, 1H),
5.15 (d, J = 10.5 Hz, 1H), 4.55 (d, J = 6.3 Hz, 1H), 3.69 (d, J = 10.5 Hz, 1H), 3.49 (d, J = 10.5 Hz,
1H), 3.37 (d, J = 9.5 Hz, 1H), 3.17 (d, J = 9.5 Hz, 1H), 1.49 (s, 3H), 1.40 (s, 3H), 0.79 (s, 9H), -0.01
(s, 3H), -0.04 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 144.0, 132.8, 128.8, 127.7, 126.9, 117.2, 108.2,
86.7, 84.1, 80.4, 64.1, 63.3, 28.6, 26.6, 25.8, 18.1, -5.6; LC-MS (ESI positive) m/z: 567 [M+Na]+
HRMS m/e: C34H44NaO4Si [(M+Na)+] calcd: 567.2901, found: 567.2912.
4.19 (E)-3-((4S,5R)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-5-((trityloxy)methyl)-1,3-
dioxolan-4-yl)-N-methoxy-N-methylacrylamide (22)
Compound 21 (118 mg, 0.22 mmol) was dissolved in dry THF (2 mL) and then a solution of N-
methoxy-N-methylacrylamide (126.5 mg, 1.1 mmol) in dry THF (2 mL) and Grubbs 2nd generation
catalyst (9.64 mg, 0.015 mmol, 7 mol%) were added. The mixture was refluxed for 4 days and then
filtered through a Celite pad, the solvent was evaporated off and the residue was chromatographed on
a silica gel column (hexane/ethyl acetate 12:1) to give product 22 (105 mg, 76%) as a yellowish oil,
[a]D25 -2.85 (c 0.75, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.50 (m, 6H), 7.28-7.22 (m, 9H), 6.90 (dd,
J = 15.4, 4.9 Hz, 1H), 6.62 (d, J = 15.4 Hz, 1H), 4.75 (dd, J = 4.9, 1.5 Hz, 1H), 3.63 (s, 3H), 3.61 (d, J
= 10.1 Hz, 1H), 3.47 (d, J = 10.1 Hz, 1H), 3.41 (d, J = 9.7 Hz, 1H), 3.23 (d, J = 9.7 Hz, 1H), 3.22 (s,
3H), 1.51 (s, 3H), 1.43 (s, 3H), 0.75 (s, 9H), -0.05 (s, 3H), -0.07(s, 3H). 13C NMR (126 MHz, CDCl3)
δ 166.0, 143.8, 140.6, 128.8, 127.8, 127.0, 119.0, 108.8, 86.8, 84.8, 78.8, 64.1, 63.2, 61.6, 28.6, 26.9,
13

ACCEPTED MANUSCRIPT
26.6, 25.8, 18.1, -5.6, -5.7. LC-MS (ESI positive) m/z: 632 [M+H]+ HRMS m/e: C37H50NO6Si
[(M+H)+] calcd: 632.3402, found: 632.3397.
4.20 (E)-3-((4S,5R)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyl-5-((trityloxy)methyl)-1,3-
dioxolan-4-yl)-1-(4-chloro-3-(4-(ethoxymethyl)benzyl)phenyl)prop-2-en-1-one (2)
Method A: A solution of 1.6 M n-BuLi in hexanes (0.1 mL, 0.158 mmol) was added dropwise at -78
°C to a stirred solution of compound 15 (50 mg, 0.158 mmol) in dry THF (2.5 mL) and the mixture
was stirred at this temperature for 45 min. Then, a solution of amide 22 (100 mg, 0.158 mmol, 1 eqiv.)
in THF (1 mL) was added dropwise to this mixture at the same temperature, the resulting mixture was
stirred at this temperature for another 1 h, and then left at ambient temperature for 2 days. Then, the
mixture was cooled in an ice bath, a saturated aqueous solution of NH4Cl (3 mL) was added and the
mixture was extracted with DCM (3x5 mL). The combined organic layers were dried over Na2SO4, the
solvent was removed under reduced pressure and the residue was chromatographed on a silica gel
column (hexane/ethyl acetate 10:1) to give product 2 (45 mg, 35%) as a colorless oil.
Method B: An LDA solution in THF was prepared by adding dropwise at -78 °C a solution of 1.6 M
n-BuLi in hexanes (0.28 mL, 0.45 mmol) to a solution of dry DIPA (0.07 mL, 0.5 mmol), in dry THF
(5 mL). The solution was stirred for 15 minutes at 0 °C and then the temperature was again brought to
-78 °C, whereupon a solution of compound 19 (120 mg, 0.41 mmol) in dry THF (1 mL) was added
dropwise, followed by stirring for another 15 min. Then, aldehyde 3 (261 mg, 0.49 mmol) was added
dropwise at -78 °C and the resulting mixture was stired for 15 min at this temperature and furthermore
for 1 h at 0 °C and for 12 h at ambient temperature. A saturated aqueous solution of NH4Cl (10 mL)
was then added and the mixture was extracted with DCM (3x15 mL). The combined organic layers
were dried over Na2SO4, the solvent was removed under reduced pressure and the residue was
chromatographed on a silica gel column (hexane/ethyl acetate 25:1) to give product 2 (195 mg, 58%)
25
as a colorless oil, [a]D -18.1 (c 12, CHCl3). FTIR (neat film) 3060, 3033, 1674, 1627, 1591, 1591,
1491 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.74 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.51 (m, 6H),
7.44 (d, J = 8.4 Hz, 1H), 7.28-7.22 (m, 9H), 7.08 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 15.4 Hz,
1H), 6.97 (dd, J = 15.4 Hz, 4.1 Hz, 1H), 6.83 (d, J = 8.3 Hz, 2H), 4.84 (d, J = 4.1 Hz, 1H),
4.08 (s, 2H), 4.00 (q, J = 6.9 Hz, 2H), 3.56 (d, J = 9.8 Hz, 1H), 3.45 (d, J = 9.9 Hz, 2H), 3.28
(d, J = 9.9 Hz, 1H), 1.52 (s, 3H), 1.45 (s, 3H), 1.39 (t, J = 6.9 Hz, 3H), 0.68 (s, 9H), -0.14 (s,
13
3H).-0.15 (s, 3H); C NMR (126 MHz, CDCl3) δ 188.7, 157.6, 143.8, 142.7, 139.6, 139.1,
136.4, 131.0, 130.6, 129.8, 129.7, 128.7, 127.8, 127.7, 127.1, 124.1, 114.5, 108.9, 86.9, 84.9,
78.5, 64.0, 63.3, 63.1, 38.4, 28.6, 26.6, 25.7, 18.0, 14.8, -5.7, -5.8; LC-MS (ESI positive) m/z:
839 [M+Na]+ HRMS m/e: C50H5735ClNaO6Si [(M+Na)+] calcd: 839.3505, found: 839.3510.
4.21 Ertugliflozin (1) via the aldol condensation reaction
Compound 2 (50 mg, 0.061 mmol) was dissolved in acetone/water (4:1, 4 mL), and NMO (7
ꢁL, 0.070 mmol) and OsO4 solution 4% in H2O (22 ꢁL) were subsequently added. The mixture was
stirred for 12 h at ambient temperature, where TLC showed consumption of the starting
material and the formation of two products. A solution of NaHSO3 (180 mg) in H2O (5 mL) was
then added and the resulting mixture was stirred for 0.5 h. Solids were filtered off and the solution was
extracted with EA (3x30 mL). The organic layers were dried over Na2SO4, the solvent was removed
under reduce pressure and the residue was chromatographed on a silica gel column (hexane/ethyl
acetate 7:1) to give firstly compound 17 (32 mg, 60%), followed by compound 18 (16 mg, 30%). The
slower moving product (18) was dissolved in a mixture of TFA/H2O (9:1) (2.1 mL). The mixture was
stirred at ambient temperature for 1 h and then the solvent was removed under reduced pressure. The
residue was dissolved in EA and washed with water, 1M aqueous NaOH and brine. The organic layer
was dried with Na2SO4, the solvent was removed under reduced pressure and the residue was
chromatographed on a silica gel column (20% MeOH in CH2Cl2) to give ertugliflozin (1) as an
amorphous solid (7 mg, 85%), with spectral and analytical data identical to those reported in the
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literature.4b [a]D +8.0 (c 0.5, MeOH) {lit.4b [a]D +8.0 (c 0.5, MeOH)}. 1H NMR (500 MHz,
MeOD) δ 7.44 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 8.3, 1.6 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.08
(d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 4.14 (d, J = 7.5 Hz, 1H), 4.02 (s, 2H), 3.98 (q, J
= 7.0 Hz, 2H), 3.82 (d, J = 12.5 Hz, 1H), 3.77 (d, J = 8.3 Hz, 1H), 3.67 (d, J = 12.5 Hz, 1H),
3.64 (d, J = 8.3 Hz, 1H), 3.58 (d, J = 7.5 Hz, 1H), 3.54 (d, J = 7.5 Hz, 1H), 1.35 (t, J = 7.0 Hz,
13
3H). C NMR (126 MHz, MeOD) δ 157.4, 138.3, 137.1, 133.6, 131.4, 129.4, 129.1, 128.4,
125.7, 114.0, 108.2, 84.8, 77.9, 76.3, 71.7, 66.5, 63.0, 60.5, 37.8, 13.8. LC-MS (ESI positive)
m/z: 437 [M+H]+ HRMS m/e: C22H2635ClO7 [(M+H)+] calcd: 437.1361, found: 437.1368.
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