Enantiodivergent strategy for the synthesis of polyhydroxylated pyrrolizidines and evaluation of their inhibitory activities against glycosidases

Tetrahedron Letters 56 (2015) 331–334

Contents lists available at ScienceDirect

Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Enantiodivergent strategy for the synthesis of polyhydroxylated pyrrolizidines and evaluation of their inhibitory activities against glycosidases Daisuke Minehira a,⇑, Takuya Okada b, Ren Iwaki a, Atsushi Kato a,⇑, Isao Adachi a, Naoki Toyooka b,c,⇑ a b c

Department of Hospital Pharmacy, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan Graduate School of Science and Technology, University of Toyama, Gofuku 3190, Toyama 930-8555, Japan Graduate School of Innovative Life Science, University of Toyama, Gofuku 3190, Toyama 930-8555, Japan

a r t i c l e

i n f o

Article history: Received 28 October 2014 Revised 12 November 2014 Accepted 18 November 2014 Available online 27 November 2014 Keywords: Imino sugar Pyrrolizidine Hyacinthacine Enantiodivergent strategy Glycosidase

a b s t r a c t The enantiodivergent synthesis of polyhydroxylated pyrrolizidines has been achieved, starting from common intermediate 1. The synthesis involved the stereoselective construction of the pyrrolizidine core unit by using intramolecular Michael cyclization reaction as the key reaction. The synthesized eight isomers were evaluated for various glycosidase inhibition effects. Compound 15 showed a moderate inhibitory activity against a-L-fucosidase and a high selectivity compared from the other glycosidases. Ó 2014 Elsevier Ltd. All rights reserved.

Introduction In 1999, new type of polyhydroxylated pyrrolizidine alkaloid hyacinthacines were isolated from the blubs of Hyacinthoides non-scripta and Scilla campanulata and named hyacinthacines B1, B2, and C1, respectively.1 We also have isolated hyacinthacines A1, A2, A3, B3, and C1 from Muscari armeniacum blubs.2 Hyacinthacines were basically characterized as 7aR-hydro-1,2-dihydroxy-3hydroxymethyl-pyrrolizidines with the methyl or hydroxymethyl group at C-5 and with hydroxyl substituents present at C-6 and/ or C-7 in some cases (Fig. 1). Furthermore, the known hyacinthacines have been classified into three groups A, B, and C on the basis of the number of hydroxyl and hydroxymethyl groups on the second ring. More recently, we have isolated hyacinthacines A4, A5, A6, A7, B3, B4, B5, and B6 from Scilla siberica bulbs,3 hyacinthacines A3, A5, B3, B4, B7, C2, C3, C4, and C5 from Scilla socialis bulbs.4 These plants are also known to produce hyacinthacine derivatives bearing a long side chain at C-5.5 The distribution of these hyacinthacines appears to be restricted to the Hyacinthaceae family examined to date and the genera Scilla is especially rich sources of them. Consequently, the search for lead compounds of this type ⇑ Corresponding authors. Tel.: +81 76 445 6859; fax: +81 76 445 6697. E-mail addresses: [email protected] (D. Minehira), [email protected]. jp (A. Kato), [email protected] (N. Toyooka). http://dx.doi.org/10.1016/j.tetlet.2014.11.087 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

from natural sources tends to be constrained compared to other type of iminosugar class. On the other hand, some of hyacinthacines have been reported to exhibit potent glycosidase inhibitory effect,1,5 nevertheless, study done thus far has remained limited to total synthesis and simply interest toward structural feature.6 In addition, none of the systematic studies of this class of compound toward the structure-activity relationship of inhibitory effects against various glycosidases has been reported. In this Letter, we wish to report the flexible and enantiodivergent synthesis of polyhydroxylated pyrrolizidines and their inhibitory effects against several glycosidases. Results and discussion We planned the synthesis of pyrrolizidine derivatives A and entA as the target compound (Fig. 1). The synthesis began with known chiral mono acetate 1,7 which was converted to silyl ether 2. Deprotection of 2 with K2CO3 in MeOH afforded the alcohol 3. After oxidation of the alcohol 3 with sulfur trioxide pyridine complex in DMSO, the resulting aldehyde was subjected to Horner–Wadsworth–Emmons (HWE) reaction to give unsaturated ester 4. To construct the dihydroxyl moiety in the stereoselective manner, first, examined the asymmetric dihydroxylation using AD-mix a. However, the reaction did not proceed smoothly, because of the bulkiness of the AD-mix reagent. Therefore, we applied the

332

D. Minehira et al. / Tetrahedron Letters 56 (2015) 331–334

m(HO)

7

H N

H OH

N

H

TBDPSO

7

OH

H A

c

ent-A

TBDPSO

R = alkyl, OH

10

H

a OAc

TBDPSO

H

H

b OAc

N

Boc

Boc 2

reported (1)

H

H

c-d

OH

TBDPSO

H

H

N

N

Boc

Boc

3

11

CO2Et

H

H

EtO 2C

EtO2C

OBn

H H Hb

OBn

OBn

H

7.8% 13

12

f

Scheme 3. Reagents and conditions: (a) LiBH4, THF (94%); (b) DMP, CH2Cl2 (97%); (c) NaH, (EtO)2P(O)CH2CO2Et, THF (97%); (d) TFA, CH2Cl2; (e) K2CO3, CH2Cl2 (12:77%, 13:23%, 2 steps); (f) TBDPSCl, imidazole CH2Cl2 (95%).

HO

a

H

H OBn

N

13

b

HO

H

H OH

N

OBn

H

H

HO

OH

HO 15

14

Scheme 4. Reagents and conditions: (a) LiAlH4, THF (88%); (b) BCl3, CH2Cl2 (100%).

To test the inhibitory activity against several glycosidase, we synthesized other types of alkylated derivatives. Half-reduction of the ester moiety in 12 with diisobutylaluminum hydride, Wittig olefination of the resulting aldehyde, followed by hydrogenation of the corresponding olefin and treatment with TBAF furnished 17a–17c. Finally, deprotection of the benzyl group afforded triol 18a–18c (Scheme 5). The enantiomers ent-15, and ent-18a-18c were also synthesized starting from 1 via ent-3 in the enantiodivergent manner as shown in Scheme 6. The IC50 values of 18a, 18b, 18c, and 15 and their enantiomers toward various glycosidases are shown in Table 1. Most of the compounds tested showed no inhibitory activity against a-L-fucosidase from bovine kidney, only 15 showed a moderate

H

H

OH CO 2Et

TBDPSO

H

H

OH CO2Et

N

Boc OH

Boc OH

5

6

a-b

TBDPSO

H

OBn

N Boc OBn 7

b-c

TBDPSO

H

12

OBn

H

H

c-d

HO

H

H OBn

N

OBn R

H

OBn

R 16a (R = H, 73%) 16b (R = Et, 80%) 16c (R = n-Bu, 75%)

e

H

H N

HO

6.0%

TBDPSO

H N

Ha

Scheme 1. Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2 (100%); (b) K2CO3, MeOH (97%); (c) SO3-Py, Et3N, DMSO; (d) NaH, (EtO)2P(O)CH2CO2Et, THF (95%, 2 steps); (e) OsO4, NMO, Acetone/H2O (8: 1) (5:58%, 6:30%).

a

H

HO

OBn

N

4

N

5

d-e CO 2Et

Boc OBn

N

TBDPSO

OBn

H N

dihydroxylation under the normal conditions with substrate control to provide the diols 5 and 6, which were able to separate easily in 88% combined yield with moderate diastereoselectivity (Scheme 1). To confirm the newly formed stereochemistry in 5, the major diol 5 was transformed into corresponding lactam 8 via the dibenzyl ether 7 as shown in Scheme 2. In difference NOE experiments, NOE enhancement (ca. 6.0%) was observed on the Ha proton by irradiation of the Hb proton indicating the S,S configuration for the major diol 5. Next, we investigated the synthesis of key pyrrolizidine intermediate 12. Reduction of dibenzyl ether 7 with LiBH4 followed by Dess–Martin oxidation of the alcohol 9 and HWE reaction of the resulting aldehyde 10 afforded unsaturated ester 11 in excellent yield. The key pyrrolizidine skeleton was constructed by the intramolecular Michael-type cyclizaiton.8 Deprotection of the Boc group in the presence of TFA, followed by treatment of K2CO3 gave rise to 12 (77%) along with alcohol 13 (23%), which was transformed into 12. The newly formed stereochemistry of 12 was determined as shown in Scheme 3 based on NOE experiments. In different NOE experiments, NOE enhancement (ca. 7.8%) was observed on the Ha proton by irradiation of the Hb proton indicating the S configuration for the pyrrolizidine 12 (Scheme 3). The alcohol 13 was converted to tetraol 15 via diol 14 in 2 steps as shown in Scheme 4.

e

O

Boc OBn

9

TBDPSO

TBDPSO

OBn

N

Figure 1. General structure of hyacinthacine alkaloids and target compounds.

H

H

R

X = H, OH m, n, o = 0, 1

H

H

TBDPSO

N

OH

H

R

Hyacinthacine alkaloids

HO

b OH

Boc OBn

OH

H

OBn

H

1

3 HO

H OH HO

OH

N

o

H

HO

H

5

X

a

(OH)n

H

17a (R = H, 88%) 17b (R = Et, 87%) 17c (R = n-Bu, 94%)

H OH

N

Ha N

CO 2Et

O

OBn R Hb OBn

8

Scheme 2. Reagents and conditions: (a) NaH, BnBr, DMF (68%); (b) TFA, CH2Cl2; (c) AlMe3, CH2Cl2, reflux (48%, 2 steps).

H

OH

18a (R = H, 100%) 18b (R = Et, 100%) 18c (R = n-Bu, 97%)

Scheme 5. Reagents and conditions: (a) DIBAL-H, CH2Cl2, 78 °C; (b) Wittig reagent, t-BuOK, THF; (c) H2, Pd/C, EtOAc; (d) TBAF, THF; (e) BCl3, CH2Cl2.

333

D. Minehira et al. / Tetrahedron Letters 56 (2015) 331–334 a-d

H

TBDPSO

1

e-f

H

OH

H

TBDPSO

Boc

Boc

TBDPSO

H

H

OBn

i

CO 2Et

H

l-m

Boc OBn

n

HO

j OH

H

H OBn

N

HO

o

N

CO2Et

H

H

OBn

k O

OBn HO

H

H OBn

N

EtO 2C

OBn

H ent-13

H

H

OBn

H

OH

ent-10

OBn

H

OH

N

OH

H

HO

HO ent-15

ent-14

TBDPSO

TBDPSO

Boc OBn

ent-12

ent-13

p-q

OBn

N

H

EtO2C

ent-11

H

ent-6

N

N

CO 2Et

N

H

Boc OH

Boc OBn

H

TBDPSO

CO2Et

N

ent-9

OBn

TBDPSO

ent-5

H

ent-7

OH

Boc OH

H

TBDPSO

Boc OBn

H

H

ent-4

N

TBDPSO

H

TBDPSO

CO 2Et

N

ent-3 h

g

H

N

H

H OBn

N

ent-12

H

r-s

HO

H

H OBn

N

OBn

H

R

t

HO

H

H OH

N

OBn

H

R

OH

R ent-16a (R = H, 77%) ent-16b (R = Et, 78%) ent-16c (R = n-Bu, 64%)

ent-18a (R = H, 100%) ent-18b (R = Et, 100%) ent-18c (R = n-Bu, 88%)

ent-17a (R = H, 96%) ent-17b (R = Et, 87%) ent-17c (R = n-Bu, 73%)

Scheme 6. Reagents and conditions: (a) TBSCl, imidazole, CH2Cl2; (b) K2CO3, MeOH; (c) TBDPSCl, imidazole, CH2Cl2; (d) AcCl, EtOH (60%, 4 steps); (e) SO3-Py, Et3N, DMSO; (f) NaH, (EtO)2P(O)CH2CO2Et, THF (67%, 2 steps); (g) OsO4, NMO, Acetone/H2O (8: 1) (ent-6:60%, ent-7:34%); (h) NaH, BnBr, DMF (82%); (i) LiBH4, THF (95%); (j) DMP, CH2Cl2 (98%); (k) NaH, (EtO)2P(O)CH2CO2Et, THF (98%); (l) TFA, CH2Cl2; (m) K2CO3, CH2Cl2 (ent-12:72%, ent-13:26%, 2 steps); (n) LiAlH4, THF (71%); (o) BCl3, CH2Cl2 (69%); (p) DIBALH, CH2Cl2, 78 °C; (q) Wittig reagent, t-BuOK, THF; (r) H2, Pd/C, EtOAc; (s) TBAF, THF; (t) BCl3, CH2Cl2.

Table 1 Concentration of 18a, 18b, 18c, 15, and their enantiomers giving 50% inhibition of various glycosidases IC50 (lM)

Enzyme 18a

18b

18c

15

ent-18a

ent-18b

ent-18c

ent-15

0%

7.6%

10.2%

10.6%

0%

6.5%

3.9%

9.0%

5.3%

0.9%

0.2%

0%

7.1%

3.6%

2.1%

7.7%

3.1%

9.2%

7.2%

1.1%

0%

0%

0%

3.9%

49.7%

48.7%

49.0%

23.6%

47.7%

970

587

792

Jack beans

1.7%

0%

0%

5.0%

0%

0%

0%

0%

b-Mannosidase Snail

0%

0%

0%

0.6%

0%

0%

0%

4.5%

0%

3.0%

2.0%

34

0%

0%

0%

0%

a-Glucosidase Rat intestinal maltase b-Glucosidase Almond

a-Galactosidase Coffee beans b-Galactosidase Bovine liver

a-Mannosidase

a-L-fucosidase Bovine kidney

Bold face indicates the value of half maximal inhibitory concentration. Other values mean inhibition % at 1000 lM.

and selective inhibitory activity against a-L-fucosidase, with IC50 value of 34 lM. Although the inhibitory activity is moderate, it is very rare that the pyrrolizidine system exhibited the inhibitory effect for a-L-fucosidase.2,4 Comparison of the inhibitory effects of 15 (IC50 34 lM) and ent-15 (no inhibition) against

a-L-fucosidase revealed that the absolute stereochemistry on the pyrrolizidine core is very important for the inhibition of this enzyme. We have previously reported that hyacinthacine derivatives bearing a long side chain at C-5 showed a potent inhibition activity toward Almond b-glucosidase but they did not have

334

D. Minehira et al. / Tetrahedron Letters 56 (2015) 331–334

inhibition potency against bovine liver b-galactosidase.5 In contrast, this study revealed that our designing compounds showed selective bovine liver b-galactosidase inhibition, although the inhibitory effects are not so high. In conclusion, a highly-stereocontrolled and feasible synthetic route to four polyhydroxylated pyrrolizidine derivatives and their enantiomers starting from a common intermediate 1 in the enantiodivergent manner is described. Among the compounds obtained, 15 possessed moderate inhibitory activity and high selectivity against a-L-fucosidase. Further synthetic studies based upon the structure of 15 to improve the inhibitory effect against a-L-fucosidase are now in progress in our laboratory. Acknowledgement This work was supported in part by a Grant-in-Aid for Scientific Research (C) (N.T. & A.K.) from Japan Society for the Promotion of Science (JSPS). Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.11. 087.

References and notes 1. Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda, K.; Komae, T.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Wormald, M. R.; Fleet, G. W. J.; Asano, N. Carbohydr. Res. 1999, 316, 95. 2. Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1. 3. Yamashita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J.; Asano, N. J. Nat. Prod. 2002, 65, 1875. 4. Kato, A.; Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G. W. J.; Kuriyama, C.; Ikeda, K.; Asano, N.; Nash, R. J. J. Nat. Prod. 2007, 70, 993. 5. Asano, N.; Ikeda, K.; Kasahara, M.; Arai, Y.; Kiku, H. J. Nat. Prod. 2004, 67, 846. 6. (a) Desvergnes, S.; Py, S.; Vallee, Y. J. Org. Chem. 2005, 70, 1459; (b) Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett. 2005, 7, 2587; (c) Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem. 2005, 74, 7297; (d) Reddy, P. V.; Veyron, A.; Koos, P.; Bayle, A.; Greene, A. E.; Delair, P. Org. Biomol. Chem. 2008, 6, 1170; (e) Chandrasekhar, S.; Parida, B. B.; Rambabu, C. J. Org. Chem. 2008, 73, 7826; (f) Au, C. W.; Nash, R. J.; Pyne, S. G. Chem. Commun. 2010, 713; (g) Liu, W. J.; Ye, J. L.; Huang, P. Q. Org. Biomol. Chem. 2010, 8, 2085; (h) Liu, X. K.; Qiu, S.; Xiang, Y. G.; Ruan, Y. P.; Zheng, X.; Huang, P. Q. J. Org. Chem. 2011, 76, 4952; (i) Kondo, Y.; Suzuki, N.; Takahashi, M.; Kumamoto, T.; Masu, H.; Ishikawa, T. J. Org. Chem. 2012, 77, 7988; (j) Brock, E. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Biomol. Chem. 2013, 11, 3187; (k) Savaspun, K.; Au, C. W.; Pyne, S. G. J. Org. Chem. 2014, 79, 4569; (l) D’Adamio, G.; Parmeggiani, C.; Goti, A.; MorenoVargas, A. J.; Moreno-Clavijo, E.; Robina, I.; Cardona, F. Org. Biomol. Chem. 2014, 12, 6250. 7. Robert, C.; Frederic, J.; Pascall, G.; Mohammed, D. Tetrahedron: Asymmetry 2008, 19, 2008. 8. Toyooka, N.; Zhou, D.; Nemoto, H.; Tezuka, Y.; Kadota, S.; Andriamaharavo, N. R.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. J. Org. Chem. 2009, 74, 6784.