A method for preparing C-glycosides related to phlorizin

Article abstract of DOI:10.1016/S0040-4039(00)01709-3

Johnson's Suzuki coupling protocol was employed to prepare C-glycoside analogs of phlorizin (1). In vitro biological evaluation of these C-glycosides indicated the anomeric oxygen is important to the SGLT inhibitory activity of phlorizin (1) and related a

Full text of DOI:10.1016/S0040-4039(00)01709-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9213–9217
A method for preparing C-glycosides related to phlorizin
J. T. Link* and Bryan K. Sorensen
Metabolic Disease Research, Abbott Laboratories, Abbott Park, IL 60064-6098, USA
Received 18 August 2000; revised 25 August 2000; accepted 28 September 2000
Abstract
Johnson’s Suzuki coupling protocol was employed to prepare C-glycoside analogs of phlorizin (1). In
vitro biological evaluation of these C-glycosides indicated the anomeric oxygen is important to the SGLT
inhibitory activity of phlorizin (1) and related agents. © 2000 Elsevier Science Ltd. All rights reserved.
Noninsulin dependent diabetes mellitus (NIDDM) is a substantial and growing international
health problem.1 Treatments of the disease are sought by the development of pharmaceuticals
which alleviate hyperglycemia.2 One potential strategy is inhibition of the Na+/glucose cotrans-
porters (SGLTs) found in the kidney.3 SGLTs mediate intestinal absorption and renal reabsorp-
tion of glucose.4 Phlorizin (1), a b-aryl glucoside, is a specific inhibitor of SGLTs (Scheme 1).5
Upon subcutaneous injection, phlorizin (1) has been demonstrated to lower blood glucose levels
in diabetic animal models by promoting urinary glucose excretion.6 One weakness of phlorizin
(1) as an agent is its inactivation via conversion to phloretin (2) by b-glucosidases in the
intestine.3,7 Phloretin (2) is a weak SGLT inhibitor with the undesired effect of inhibiting the
OH
O
OH
O
OH
O
O
HO
O
OH
HO
OH
OH
X
O
O
OH
OH
HO
RO
OH
OH
HO
HO
1 phlorizin
2 phloretin
3 X=O, R=H T-1095A
4 X=O, R=CO2Me T-1095
5 X=CH2, R=H
Scheme 1.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01709-3

9214
facilitated glucose transporters (GLUTs) which mediate the uptake of glucose into a variety of
cells, most notably muscle. Researchers at Tanabe have studied analogs of phlorizin (1) and
discovered T-1095A (3) and its prodrug T-1095 (4).8 T-1095 (4) can be administered orally, is
metabolized to T-1095A (3), and inhibits renal SGLTs, thereby inducing urinary glucose
excretion and decreasing blood glucose levels in diabetic animal models. Spurred by these
observations, we became interested in designing phlorizin (1) analogs in which the glycosidic
bond was replaced by a more stable connection. One classic method for achieving this goal is to
construct a related C-glycoside, e.g. 5.9 Such derivatives would be stable to glycosidases while
maintaining a similar structure to phlorizin (1) or T-1095A (3). A short efficient method of
synthesis amenable to analog production was required and Johnson’s Suzuki cross-coupling
protocol was selected.10
A model coupling between 2-bromoacetophenone and exo-glycal 610 was explored (Scheme
2).11 Precedented stereoselective hydroboration of exo-glycal 6 with 9-BBN in refluxing THF,
followed by Suzuki coupling of the resulting alkylborane yielded the b-C-glycoside 7 in 55%
yield. In addition, a second product was isolated and has been assigned the structure 8.
Acetylation of 8 yielded the monoacetate 9 whose COSY and ROESY spectra support its
assignment.12 Although optimization of the reaction conditions to moderate (or eliminate) the
production of 8 could be envisioned, we did not initiate such studies due to our desire to
evaluate acyclic C-glycosides as potential SGLT inhibitors.
O
O
H
(55%)
OMOM
(20%)
OMOM
OMOM
O
1. 9-BBN, THF,reflux, 5 h
OMOM
HNOE
RO
H
O
2. 2-bromoacetophenone,
Pd(dppf)·CH2Cl2, K3PO4,
H2O, DMF, rt, 18 h
MOMO
MOMO
OMOM
MOMO
MOMO
MOMO
6
OMOM
OMOM
Ac2O, Et3N,
CH2Cl2, 89%
7
8 R=H
9 R=OAc
Scheme 2.
A concise preparation of an aglycone related to T-1095 (4) was also developed (Scheme 3).
2,6-Dihydroxy acetophenone 10 was monoprotected with MOMCl and condensed with aldehyde
1213 under basic aldol conditions to yield enone 13 in good yield. Standard hydrogenation
conditions (H2, Pd/C) reduced the alkene, dibenzofuran, and the benzylic ketone, so the milder
Wilkinson’s catalyst was employed and delivered the ketone 14 in moderate yield. Incomplete
OHC
O
H2 (4 atm),
Rh(PPh3)3Cl,
MOMO
O
MOMO
O
OR
O
12
PhH, 80 °C
50%
KOH, EtOH, rt,
82%
O
O
OH
OR
OH
13
PhNTf2, i-Pr2NEt,
CH2Cl2, rt, 96%
10 R=H
11 R=MOM
NaH, DMF, rt;
MOMCl, rt, 60%
14 R=H
15 R=Tf
Scheme 3.

9215
conversion and ketone reduction accounted for the remainder of the material. Triflation of 14
then provided aglycone 15 suitable for Suzuki cross coupling.
Aryl bromide 1614 and aryl triflate 15 behaved similarly to 2-bromoacetophenone in the
Suzuki coupling reaction (Scheme 4). Coupling of bromide 16 with the hydroboration products
of exo-glycal 6 provided the protected C-glycoside 17 and its acyclic relative 19. The assignment
of the structure of 19 was supported by the formation of monoacetate 20 under acetylation
conditions. The MOM protecting groups were cleanly removed from 17 and 19 to yield
C-glycoside 18 and the pentaol 21. Triflate 15 also underwent Suzuki coupling to provide 22 and
24. In this case, deprotection also unmasked a phenol which has been shown to be critical to
phlorizin’s (1) in vivo activity.15
O
O
O
O
O
OMe
OMe
(18%)
O
a
O
OR1
OR1
R2O
OR1
(51%)
Br
OMe
R1O
R1O
R1O
OR1
OR1
17 R1=MOM
18 R1=H
19 R1=MOM, R2=H
20 R1=MOM, R2=Ac
21 R1=H, R2=H
16
c
b
b
R1O
O
R1O
O
MOMO
O
O
O
a
O
OR1
OR1
(50%)
HO
(17%)
OR1
O
OTf
R1O
R1O
R1O
OR1
OR1
22 R1=MOM
23 R1=H
24 R1=MOM, R2=H
15
b
Scheme 4. (a) 6, Pd(dppf)·CH2Cl2, K3PO4, H2O, DMF, rt, 18 h; (b) HCl, MeOH, H2O, 91–95%; (c) Ac2O, Et3N,
CH2Cl2, 85%
In vitro examination of C-glycosides 18 and 23 in several assays indicated these compounds
were much weaker inhibitors of SGLT than phlorizin (1), indicating the importance of the
glycosidic oxygen in this family of SGLT inhibitors.16
Acknowledgements
The help rendered by Dr T. S. Pagano and Dr L. Seif in NMR studies and in high pressure
hydrogenation experiments, respectively, is greatly appreciated. Dr C. Lin, Dr B. Dayton, and
Dr B. Cool are acknowledged for their determination of the biological activity of analogs. Dr
B. Szczepankiewicz is thanked for thoughtful discussions.

9216
References
1. Edelman, S. V. Adv. Intern. Med. 1998, 43, 449–500.
2. Cobb, J.; Dukes, I. Ann. Rep. Med. Chem. 1998, 33, 213–222.
3. Tsujihara, K.; Hongu, M.; Saito, K.; Inamasu, M.; Arakawa, K.; Oku, A.; Matsumoto, M. Chem. Pharm. Bull.
1996, 44, 1174–1180.
4. Hediger, M. A.; Rhoads, D. B. Physiol. Rev. 1994, 74, 993–1026.
5. (a) McKee, F. W.; Hawkins, W. B. Physiol. Rev. 1945, 25, 255–280. (b) Alvarado, F.; Crane, R. K. Biochim.
Biophys. Acta 1962, 56, 170–172. (c) Alvarado, F.; Crane, R. K. Biochim. Biophys. Acta 1964, 93, 116–135. (d)
Toggenburger, G.; Kessler, M.; Semenza, G. Biochim. Biophys. Acta 1982, 688, 557–571.
6. (a) Rossetti, L.; Smith, D.; Shulman, G. I.; Papachristou, D.; DeFronzo, R. A. J. Clin. Invest. 1987, 79,
1510–1515. (b) Blondel, O.; Bailbe, D.; Portha, B. Metabolism 1990, 39, 787–797.
7. (a) Rosenberg, T.; Wilbrandt, W. Helv. Physiol. Acta 1957, 15, 168–176. (b) Kotyk, A.; Kolinsha˜, J.; Veres, K.;
Szammer, J. Biochem. Z. 1965, 342, 129–138.
8. (a) Oku, A.; Ueta, K.; Arakawa, K.; Ishihara, T.; Nawano, M.; Kuronuma, Y.; Matsumoto, M.; Saito, A.;
Tsujihara, K.; Anai, M.; Asano, T.; Kanai, Y.; Endou, H. Diabetes 1999, 48, 1794–1800. (b) Tsujihara, K.;
Hongu, M.; Saito, K.; Kawanishi, H.; Kuriyama, K.; Matsumoto, M.; Oku, A.; Ueta, K.; Tsuda, M.; Saito, A.
J. Med. Chem. 1999, 42, 5311–5324.
9. Jaramillo, C.; Knapp, S. Synthesis 1994, 1–20.
10. (a) Johns, B. A.; Pan, Y. T.; Elbein, A. D.; Johnson, C. R. J. Am. Chem. Soc. 1997, 119, 4856–4865. (b) Johnson,
C. R.; Johns, B. A. Synlett 1997, 1406–1408.
1
11. Characterization data. (7) H NMR (300 MHz, CDCl3) l 7.62 (d, J=7.5 Hz, 1H), 7.36 (m, 2H), 7.27 (m, 1H),
4.97 (d, J=6.5 Hz, 1H), 4.87 (d, J=6.1 Hz, 1H), 4.85 (d, J=6.1 Hz, 1H), 4.82 (d, J=6.4 Hz, 1H), 4.78 (d, J=6.8
Hz, 1H), 4.71 (d, J=6.4 Hz, 1H), 4.54 (d, J=6.4 Hz, 1H), 4.50 (d, J=6.4 Hz, 1H), 3.50–3.72 (m, 4H), 3.49 (s,
3H), 3.46 (m, 1H), 3.45 (s, 3H), 3.39 (s, 3H), 3.36 (m, 2H), 3.26 (s, 3H), 3.21 (m, 1H), 2.84 (dd, J=14.2, 9.8 Hz,
1
1H), 2.58 (s, 3H); MS (APCI) (M+H2O)+ at m/z 490. (8) H NMR (300 MHz, CDCl3) l 7.66 (dd, J=7.1, 1.4
Hz, 1H), 7.40 (m, 1H), 7.24–7.31 (m, 2H), 4.88 (d, J=6.5 Hz, 1H), 4.66–4.84 (m, 7H), 3.77–4.01 (m, 6H), 3.66
(dd, J=10.5, 5.8 Hz, 1H), 3.46 (s, 3H), 3.44 (s, 3H), 3.41 (s, 3H), 3.39 (s, 3H), 3.03 (m, 1H), 2.87 (m, 1H), 2.57
1
(s, 3H), 1.87 (m, 2H); MS (APCI) (M+Cl)− at m/z 509. (9) H NMR (300 MHz, CDCl3) l 7.64 (dd, J=7.8, 1.4
Hz, 1H), 7.40 (m, 1H), 7.32 (m, 1H), 7.26 (m, 1H), 5.24 (m, 1H), 4.80 (d, J=6.8 Hz, 1H), 4.75 (s, 2H), 4.72 (m,
3H), 4.64 (d, J=6.4 Hz, 1H), 4.60 (d, J=6.4 Hz, 1H), 4.00 (dd, J=6.1, 4.1 Hz, 1H), 3.90 (dd, J=11.2, 3.4 Hz,
1H), 3.86 (m, 1H), 3.76 (m, 2H), 3.45 (s, 3H), 3.41 (s, 3H), 3.36 (s, 3H), 3.35 (s, 3H), 3.35 (s, 3H), 3.07 (m, 1H),
1
2.88 (m, 1H), 2.58 (s, 3H), 2.09 (s, 3H), 1.99 (m, 2H); MS (APCI) (M+H2O)+ at m/z 534. (13) H NMR (300
MHz, CDCl3) l 12.91 (s, 1H), 7.92 (m, 2H), 7.84 (d, J=1.3 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.61 (dd, J=8.8,
1.7 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.35 (t, J=8.5 Hz, 1H), 6.81 (dd, J=2.4, 0.8 Hz, 1H), 6.68 (dd, J=8.4, 0.8
1
Hz, 1H), 6.62 (dd, J=8.4, 0.8 Hz, 1H), 5.32 (s, 2H), 3.54 (s, 3H); MS (ESI) (M+H)+ at m/z 325. (14) H NMR
(300 MHz, CDCl3) l 13.03 (s, 1H), 7.60 (d, J=2.4 Hz, 2H), 7.46 (m, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.31 (t, J=8.5
Hz, 1H), 7.17 (dd, J=8.5, 1.7 Hz, 1H), 6.72 (m, 1H), 6.61 (m, 2H), 5.25 (s, 2H), 3.47 (t, J=7.4 Hz, 2H), 3.46
(s, 3H), 3.13 (t, J=7.4 Hz, 2H); MS (ESI) (M+H)+ at m/z 327. (15) 1H NMR (300 MHz, CDCl3) l 7.59 (d,
J=2.4 Hz, 1H), 7.35–7.45 (m, 3H), 7.18 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 6.71 (m, 1H), 5.07 (s, 2H), 3.36 (s, 3H),
1
3.19 (m, 4H); MS (ESI) (M+H2O)+ at m/z 476. (16) H NMR (300 MHz, CDCl3) l 7.64 (m, 1H), 7.32–7.47 (m,
1
3H), 6.84 (m, 4H), 5.09 (s, 2H), 3.76 (s, 3H); MS (APCI) (M)+ at m/z 321. (17) H NMR (300 MHz, CDCl3) l
7.54 (dd, J=7.9, 1.0 Hz, 1H), 7.39 (m, 2H), 7.28 (m, 1H), 6.88 (d, J=9.5 Hz, 2H), 6.81 (d, J=9.5 Hz, 2H), 5.11
(s, 2H), 4.92 (d, J=6.4 Hz, 1H), 4.84 (s, 2H), 4.81 (d, J=6.4 Hz, 1H), 4.74 (d, J=6.4 Hz, 1H), 4.69 (d, J=6.4
Hz, 1H), 4.48 (d, J=6.6 Hz, 1H), 4.45 (d, J=6.6 Hz, 1H), 3.76 (s, 3H), 3.47–3.70 (m, 4H), 3.44 (s, 6H), 3.39–3.43
(m, 1H), 3.38 (s, 3H), 3.26–3.35 (m, 3H), 3.20 (s, 3H), 2.92 (dd, J=14.1, 9.7 Hz, 1H); MS (APCI) (M+H2O)+ at
1
m/z 612. (18) H NMR (300 MHz, DMSO-d6) l 7.67 (d, J=7.2 Hz, 1H), 7.43 (m, 2H), 7.31 (dt, J=7.6, 1.7, 1H),
6.93 (d, J=9.3 Hz, 2H), 6.84 (d, J=9.3 Hz, 2H), 5.33 (d, J=18.2 Hz, 2H), 5.27 (d, J=18.2 Hz, 1H), 3.72 (s, 3H),
3.58 (dd, J=11.4, 1.7 Hz, 1H), 2.70–3.34 (m, 8H); 13C NMR (75 MHz, DMSO-d6) l 201.0, 153.5, 151.9, 138.3,
137.6, 131.1, 130.6, 126.8, 125.7, 115.5, 114.4, 80.7, 80.2, 78.0, 73.6, 72.1, 70.5, 61.3, 55.3, 33.7; HRMS (FAB) m/e
418.1620 (418.1628 calcd for C22H26O8). Anal. calcd for C22H26O8(H2O)0.05(CF3CO2H)0.55: C, 57.56; H, 5.57;
1
Found: C, 57.53; H, 5.58. (19) H NMR (300 MHz, CDCl3) d 7.64 (dd, J=7.8, 1.0 Hz, 1H), 7.45 (dt, J=7.5, 1.8
Hz, 1H), 7.35 (dd, J=7.5, 1.0 Hz, 1H), 7.30 (dd, J=7.5, 1.0 Hz, 1H), 6.82 (m, 4H), 4.63–4.86 (m, 10H), 3.76 (s,
3H), 3.34–4.00 (m, 6H), 3.44 (s, 3H), 3.42 (s, 3H), 3.39 (s, 3H), 3.36 (s, 3H), 2.98 (m, 1H), 2.84 (m, 1H), 1.98 (m,

9217
1
1H), 1.86 (m, 1H); MS (APCI) (M+H2O)+ at m/z 614. (21) H NMR (300 MHz, DMSO-d6) l 7.35 (dd, J=7.5,
1.7 Hz, 1H), 7.09–7.25 (m, 3H), 6.95 (d, J=9.5 Hz, 2H), 6.86 (d, J=9.5 Hz, 2H), 4.72 (m, 1H), 4.55 (d, J=10.0,
1H), 4.42 (d, J=10.0 Hz, 1H), 4.36 (m, 1H), 3.71 (s, 3H), 3.62 (m, 2H), 2.80 (m, 2H), 1.88 (m, 2H); MS (ESI)
1
(M)+ at m/z 420. (22) H NMR (300 MHz, CDCl3) l 7.61 (m, 1H), 7.47 (br s, 1H), 7.45 (m, 1H), 7.19 (m, 2H),
6.96 (m, 2H), 6.71 (m, 1H), 4.99 (s, 2H), 4.84 (m, 4H), 4.69 (m, 2H), 4.43 (s, 2H), 3.68 (m, 1H), 3.57 (m, 2H),
3.44 (s, 3H), 3.41 (s, 3H), 3.39 (s, 3H), 3.32 (s, 3H), 3.21 (s, 3H), 3.14 (m, 4H), 2.48 (m, 1H), 1.28 (m, 2H); MS
1
(APCI) (M+H2O)+ at m/z 680. (23) H NMR (300 MHz, CDCl3, DMSO-d6) l 9.31 (br s, 1H), 7.62 (d, J=2.2
Hz, 1H), 7.46 (d, J=1.1, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.17 (dd, J=8.4, 1.6 Hz, 1H), 7.08 (t, J=7.6 Hz, 1H),
6.84 (d, J=7.3 Hz, 1H), 6.73 (m, 2H), 3.54–3.85 (m, 2H), 3.22–3.38 (m, 5H), 3.00–3.18 (m, 5H), 2.51 (m, 1H);
13C NMR (75 MHz, CDCl3, DMSO-d6) l 207.3, 153.1, 152.4, 144.2, 135.9, 135.0, 129.3, 128.7, 126.4, 124.0,
120.6, 119.62, 112.7, 109.9, 105.54, 79.3, 78.5, 77.5, 77.4, 72.7, 70.23, 61.6, 45.5, 33.6, 28.5; HRMS (FAB)
1
(M+H)+ m/e 443.1701 (443.1706 calcd for C22H26O8). (24) H NMR (300 MHz, CDCl3) l 7.59 (m, 1H), 7.45 (m,
1H), 7.38 (m, 1H), 7.21 (m, 1H), 7.17 (m, 1H), 6.96 (m, 1H), 6.89 (m, 1H), 6.71 (m, 1H), 5.01 (s, 2H), 4.56–4.85
(m, 8H), 3.60–4.10 (m, 6H), 3.32–3.47 (m, 12H), 3.14 (s, 3H), 1.50–2.51 (m, 8H); MS (APCI) (M+H2O)+ at m/z
682.
12. An NOE signal in the ROESY spectrum between the marked aryl and benzylic protons allowed their assignment
(Scheme 2). The COSY spectrum lead to the assignment of the remainder of the signals including the
homobenzylic protons (l 1.98 ppm).
13. Tasker, A. S.; Sorensen, B. K.; Jae, H.-S.; Winn, M. W.; von Geldern, T. W.; Dixon, D. B.; Chiou, W. J.;
Dayton, B. D.; Calzadilla, S.; Hernandez, L.; Marsh, K. C.; WuWong, J. R.; Opgenorth, T. J. J. Med. Chem.
1997, 40, 322–330.
14. Aryl bromide 16 was prepared by converting 2-bromo-acetophenone to the corresponding a-bromoketone
followed by reaction with 4-methoxyphenoxide.
O
O
O
4-methoxyphenol,
K2CO3,
O
Br
PhMe3NBr3
THF
DMF, 80 °C
Br
OMe
Br
Br
16
15. Hongu, M.; Tanaka, T.; Funami, N.; Saito, K.; Arakawa, K.; Matsumoto, M.; Tsujihara, K. Chem. Pharm. Bull.
1998, 46, 22–33.
16. C-glycosides 18 and 23 were greater than tenfold weaker than phlorizin (1) in their ability to displace
[3H]-phlorizin from pig kidney membrane preparations and in their capacity to inhibit uptake of [14C]-a-methyl-
D
-glucose into rat brush-border membrane vesicles.
.
.