total synthesis of diospongin A, B and their enantiomers, b) towards the enantioselective total

Transcription

1 ABSTRACT

2 Thesis title: Enantioselective total synthesis of diospongins, towards the enantioselective total synthesis of solandelactones and an expedient synthesis of eantioenriched substituted (benzofuran-yl) aryl and heteroaryl carbinols. This thesis comprises three chapters and describes in sequence a) the enantioselective total synthesis of diospongin A, B and their enantiomers, b) towards the enantioselective total synthesis of solandelactones and c) an expedient synthesis of eantioenriched substituted (benzofuran-yl) ary and heteroary carbinols. Chapter I deals with the total synthesis of diospongin A, B and their enantiomers using organo catalytic / hetero-diels-alder reactions. Chapter II deals with the development of protocol for the preparation of key intermediates of solandelactone A, B via a catalytic asymmetric cyclopropanation and catalytic asymmetric reduction. Chapter III illustrates the synthesis of eantioenriched substituted (benzofuran-yl) aryl and heteroaryl carbinols. Chapter I: A Flexible enantioselective total synthesis of diospongins A, B and their enantiomers using catalytic etero-diel-alder / Rh-catalyzed 1,4-addition and asymmetric transfer hydrogenation reactions as key steps. C-aryl glycoside natural products diospongins A (2) and B (1) which were isolated from the rhizomes of Diocorea spongiosa through a bioassay-guided fractionation show promising antiosteoporotic activity (45Ca release at 200 μm (30.5%) and 20 μm (18.2%), hence, can be considered to be a lead for the discovery of potent and novel antiosteoporotic agents. Diospongins A (2) and B (1) contain a six-membered cyclic ether structural unit with 2-aryl and 6-phenacyl substitution. Despite their structural similarity, they exhibit remarkable differences in their biological profile. Diospongin B displays potent inhibitory activity on bone resorption induced by parathyroid hormone, which is comparable to that of elcitionin, a drug used clinically for osteoporosis while diospongin A did not show any activity (Figure 1).

3 Rh-catalyzed 1,4-addition Catalytic oyori's reduction Keck hetero-diels-alder reaction 1 2 diospongin B diospongin A ent-1 ent-2 Figure 1 We envisaged a flexible route for the synthesis of the diospongins based on three catalytic steps: (a) catalytic asymmetric hetero-diels-alder reaction, (b) diastereoselective rhodium(i)- catalyzed 1,4-addition, and (c) catalytic asymmetric transfer hydrogenation (CATy) reaction and corresponding retrosynthesis is shown in Scheme 1. PMB Me Diospongin B (1) 6 7 P(Me) 2 PMB 5 Me 3 Si Me 3 4 Scheme 1 The synthesis of diospongins initiated using catalytic asymmetric hetero-diels-alder reaction between Danishefsky s diene 3 and furfuraldehyde 4 with 10 mol % of the (S)-BIL /

4 Ti(iPr) 4 derived catalyst, L 1. After work up, and purification generated dihydropyranone 8 with 96% enantiomeric excess. Further, single recrystallization of 8 from hexane:ether (2:1) solvent mixture resulted in 99.9% enantiomeric excess with 60% yield. Similarly, 10 mol % of the (R)-BIL / Ti(iPr) 4 derived catalyst, L 2 generated ent-8 under otherwise identical conditions with the same enantioselectivity and yield. The enantioselectivity and absolute configuration was assigned based on optical rotation reported in the literature and advanced further (Scheme 2) mol% L 1 C 2 Cl C, 42h 60% 8 (96%ee) (after recrstallization >99%ee) mol% L 2 C 2 Cl C, 42h 60% ent-8 (96%ee) (after recrstallization >99%ee) ipr Ti ipr Ti ipr ipr (S)-BIL/Ti(iPr)4 L 1 (R)-BIL/Ti(iPr)4 L 2 Scheme 2 With enantioenriched 8 in hand, we sought a flexible and appropriate means for introducing a C-aryl group into the pyranose ring. To this end, we have examined the rhodium(i)-catalyzed stereoselective 1,4-addition of an arylboronic acid to a cyclic enone, the reaction of 8 with

5 phenylboronic acid in the presence of the Rh catalyst with 2.5 mol% of K (1:2 catalyst:k), the reaction proceeded smoothly to yield the required product in 98% (Scheme 3). Then, ent-8 was converted to ent-9 following the same sequence of reaction conditions mol% Rh(I)(cod) 2 BF 4 5 mol% K B() 2 Dioxane/ C, 2h 98% 9 (de = >99.9%) ent mol% Rh(I)(cod) 2 BF 4 5 mol% K B() 2 Dioxane/ C, 2h 98% Scheme 3 ent-9 (de = >99.9%) ext, we focused on the reduction of the keto group of 9. Varieties of achiral and chiral reducing agents were screened for this transformation. While oyori s catalyst i.e., R,Rdiamine-Ru catalyst A, catalysed the reaction in high enantioselectivity with stable organic hydrogen donor Et 3 :C 2. Catalyst A (0.5 mol %) with the Et 3.C 2 azeotropic mixture and heating at 50 o C for 3 h afforded the alcohol 10 in 96% isolated yield with >99.9% diastereoselectivity (Scheme 4). Similarly, the reduction of the keto group of ent-9 with R,R-diamine-Ru catalyst A (0.5 mol %), using a Et 3.C 2 azeotropic mixture, smoothly furnished the alcohol ent-10 in 98% yield. Further, the optical rotation of ent-10 was found to be approximately equal in magnitude to that of 10 but opposite in sign, indicating an enantiomeric relationship.

6 9 0.5 mol% cat. A Et 3 :C 2 (5:2) EtAc, 50 0 C, 3h 96% 10 de = >99.9% ent mol% cat. A Et 3 :C 2 (5:2) EtAc, 50 0 C, 3h 98% ent-10 (de = >99.9%) Ru Tos cat. A Scheme 4 aving prepared the two enantiomeric tetrahydropyryl alcohols 10, ent-10 we next proceeded to synthesise diospongin B 1 and its enatiomer ent-1. Proceeding further, the hydroxy group of 10 was converted to PMB ether, then, the furyl group of 5 was oxidatively cleaved to acid and the resulting acid on esterification gave methyl ester which was subjected to reduction with DIBAL- at -78 o C lead to 6 in 88% yield (after 3 steps). The aldehyde 6 was then treated with the anion derived from orner-emmons reagent 7 and subsequent hydrolysis of intermediate enol ether resulted in 11 (75%). Finally, compound 11 was exposed to DDQ furnished the target compound 1 in 92% isolated yield (Scheme 5). The chirooptical data of 1 were in full agreement with that reported in the literature ([α] 23 D 22.5, (c 0.2, CCl 3 ) {lit. ([α] 23 D 22.6, (c , CCl 3 }).

7 10 a PMBCl TF, 0 0 C to rt 6h 98% PMB 5 i) 3, 15min. DCM:Me (1:1) ii) C 2 2, Et C to rt, 1h iii) DIBAL- toluene, C, 1h PMB C 6 88% (over 3 steps) Me P(Me) 2 7 n-buli, TF C to rt, 3h Cl 3 CC 2 /acetone rt, 6h 75% PMB 11 DDQ DCM: 2 (9:1) 0 0 C to rt, 1h 92% 1 Scheme 5 The 2, 6-trans enantiomer ent-1 was synthesized in 67% yield (over 6 steps) from ent-10 following the above mentioned conditions. To evaluate the product formed from TBDPS, the C-5 hydroxyl group of diospongin B, 1 was converted as TBDPS ether 12. While subjecting deprotection of the TBDPS group of compound 12 with 10eq of TBAF in TF at ambient temperature, unexpectedly, furnished the product 2 in 86% yield (Scheme 6). Moreover, the optical data of 2 were in full agreement with that of diospongin A reported in the literature ([α] 23 D 19.2, (c 1.2, CCl 3 ) {lit. ([α] 23 D 19.6, (c , CCl 3 }). Also the 1 MR and 13 C MR data were in full accord with those reported for the natural product.

8 1 diospongin B i) t Bu() 2 SiCl Et 3, DCM 0 0 C to rt, 6h 92% TBDPS 12 excess TBAF (10 equiv.) TF, rt 86% 2 diospongin A TBDPS ent-1 ent-12 ent-2 Scheme 6 Under identical conditions ent-12 also resulted in ent-2. The structure of ent-2 was confirmed by 1 and 13 C MR data. Furthermore, the optical rotation of ent-2 was found to be equal in magnitude to 2, but opposite in sign and hence, was considered as enantiomer to 2 (Scheme 6). The full details have been discussed elaborately along with experimental results in this chapter. In conclusion, we have accomplished the total synthesis of diospongins A, 2 and B, 1 and their enantiomers employing achiral starting materials. To the best of our knowledge, the synthesis of 2, 6-trans isomer ent-1 and 2, 6-cis isomer ent-2 are described here for the first time. All three stereocenters are introduced by means of catalytic reactions and this strategy in turn could be used to generate a library of small molecules with varying substitutions in aromatic nucleus. Chapter II: Towards the enantioselective total synthesis of solandelactones using organocatalytic cyclopropanation, and catalytic asymmetric transfer hydrogenation reactions as key steps. In 1996 solandelactones, 13a-h were isolated as oils from the hydroid Solanderia secunda of the Korean coast. Solandelactones possess trans-cyclopropane motif and differ in

9 their configuration at C-11 and by the degree of saturation found in the lactones and fatty acid chain. They show inhibition of enzyme farnesyl transferase which is responsible for proper expression of ras proteins (Figure 2) Solandelactone A, 13a Solandelactone C, Solandelactone E, Solandelactone G, 7 19, 20 4, 5 4, 5, 13c, 13e 19, 20, 13g Solandelactone B, 13b Solandelactone D, 19, 20, 13d Solandelactone F, 4, 5, 13f Solandelactone, 4, 5 19, 20, 13h Figure 2 wing to precious biological activity coupled with divergent stereogenic features within subfamilies of oxylipins, they have attracted considerable interest in the synthetic community. erein, we describe a convergent, enantioselective formal synthesis of 13a, b based on two catalytic steps to set key stereogenic canters (C 7, C 8, C 10 and C 14 ) a) organocatalytic cyclopropanation b) catalytic asymmetric transfer hydrogenation (CATy) reaction. ur retrosynthetic approach is shown in Scheme 7.

10 Catalytic Gaunt cyclopropanation Catalytic oyori's reduction ozaki-iyama-kishi coupling a I or 15 TBS Me Me 17 TBDPS Me Me 18 Br 19 TBDPS 20 Scheme 7 Synthesis of Cyclopropane Unit: ur synthesis began with the mono-tbdps protection of commercially available heptane- 1,7-diol 20 followed by oxidation provided the required aldehyde 24 in 87% yield. A freshly prepared vinyl magnesium bromide was added at 0 o C to the aldehyde 24 led to allyl alcohol 25 in 83 % yield. The oxidation of hydroxyl group of allyl alcohol 25 was carried out using

11 2-iodoxy benzoic acid in DMS:TF (1:1) at room temperature for about 3 h to furnished the vinyl ketone 19 in 89% isolated yield (Scheme 8). 20 a, TF TBDPS-Cl, cat.tbai 0 o C to rt, 12 h, 89% 23 TBDPS PCC, aac DCM, rt, 1 h 87% 24 TBDPS 2 C CMgBr 0 o C, 4 h, 83% 25 TBDPS IBX DMS:TF rt, 3 h, 89% 19 Scheme 8 The α-bromo Weinreb amide 18 was prepared by treating,-dimethylamine hydrochloride 26 with bromo acetyl bromide 27 (Scheme 9). Me.Cl Br Py, C 2 Cl 2 Me Br Me 0 o C to rt, 3 h Me 18 Br Scheme 9 aving synthesized required precursors 18 and 19, we planned to exploit the enantioselective organocatalytic cyclopropanation protocol. A solution of α-bromo Weinrebamide 18 and enone 19 in C 3 C were added to a mixture of 10 mol% of L 1 (DQD) 2 Pyr and Cs 2 C 3 in C 3 C furnished the anticipated cyclopropane product 28 in 88% isolated yield (Scheme 10). Subjecting α-bromo Weinrebamide 18 and enone 19 in the presence of 20 mol% of L 2 as ligand under identical conditions led to the product 29 gave approximately equal magnitude of rotation as 28 but opposite in sign. At this juncture, the enantioselectivity and relative configuration was assigned based upon analogy and advanced further.

12 L 1 (10 mol%) Cs 2 C 3, C 3 C slow addition, 80 o C, 24 h 88% Me Me 28 TBDPS L 2 (20 mol%) Cs 2 C 3, C 3 C slow addition, 80 o C, 24 h 85% Me Me 29 TBDPS Me Me Me Bn (DQD) 2 Pyr L 1 Quinine 9--Benzylether, L 2 Scheme 10 Synthesis of Cyclopropyl alcohols: The reduction of compounds keto group of 28 and 29 was achieved by oyori s catalytic asymmetric transfer hydrogenation reaction. The enantiomeric ratio was assigned to be 9.5:0.5 by chiral PLC (D column, 20% isopropanol in hexane, flow rate 0.5 ml/min) (Scheme 11). The major diastereomer 17 was isolated in 85% isolated yield by column chromatography. Similarly, in the case of compound 29, using the ligand L 3 under similar conditions, the product 30 was obtained with good facial selectivity (9.6:0.4) in 88% isolated yield (Scheme 11).

13 28 L 3 (1mol%) K 2 C 3, IPA 80 o C, 6 h 85% Me Me 17 TBDPS 29 L 3 (1mol%) K 2 C 3, IPA 80 o C, 6 h 88% Me Me 30 TBDPS Ts Ru L 3 Scheme 11 Synthesis of Cyclopropyl δ-lactone Aldehydes: aving prepared the required two diastereomeric cyclopropyl alcohols 17 and 30, we next proceeded to convert them into their respective cyclopropyl δ-lactone aldehydes 14 and 15 by applying the same synthetic protocol to each diastereomer. The secondary hydroxyl group of cyclopropyl alcohol 17, was protected as TES-ether 31, and the reduction of amide group of 31 with DIBAL- at -78 o C resulted in the crude aldehyde, which was further subjected to reduction using ab 4 in Me at 0 o C gave the product 32 in 78% isolated yield over two steps (Scheme 12). The alcohol protected as trityl ether to give 33 in 92% isolated yield. Further treatment of compound 33 using 1M solution of TBAF in TF led to the deprotection of TES and TBDPS ether to furnish diol 34 in 90% yield.

14 17 TESTf 2, 6-lutidine DCM, 0 o C 45 min, 92% Me Me 31 TES TBDPS i) DIBAL- DCM, -78 o C, 2 h ii) ab 4, Me 0 o C, 1 h 78% over 2 steps 32 TES TBDPS TrCl, Et 3 DCM, TBAI 0 o C to rt, 3 h 92% Tr 33 TES TBDPS TBAF, TF 0 o C to rt, 1 h 90% Tr 34 Scheme 12 ext approach was to convert this diol 34 to cyclopropyl δ-lactone aldehyde by Yamaguchi protocol. Initially, the diol 37 was oxidized to aldehyde 35 in 95% yield. n further oxidation of 35 using acl 2 and 20% aq. a 2 P 4 in t-bu provided cleanly the mono-hydroxy acid 36 in 93% and subsequent cyclization under Yamaguchi conditions afforded the eight membered lactone 37 in 94% yield (Scheme 13). Deprotection of trityl group and resulting alcohol 38 upon further oxidation using Ley conditions gave cyclopropyl δ-lactone aldehyde 14 in 79% yield. Similarly, the aldehyde 15 was also synthesized from diastereomer 30. Thus both the cyclopropyl δ-lactone aldehydes were synthesized and fully characterized.

15 34 TEMP, BIAB DCM, rt, 1 h Tr 35 a 2 P 4, acl 2 t-bu, 20 o C, 1 h Tr 36 i) 2,4,6-trichloro benzoyl chloride Et 3, DMAP TF, 1 h ii) toluene, reflux 4 h Tr 37 1M BCl 3, DCM -30 o C, 30 min 38 TPAP, M 4A o MS DCM, rt, 20min. Scheme The synthesis of compound 21 started from commercially available cis-3-nonenol 22. The Dess-Martin oxidation of compound 22 to give aldehyde and this was immediately subjected to addition with TMS-acetylene in presence of 1.2eq of n-buli in TF led to the acetylene attached alcohol compound (±)-39 in 95% yield over two steps. The recemic compound (±)- 39 was oxidized and subjected to oyori reduction in presence of (S,S)-Ru catalyst L 5 using Et 3 :C as a hydrogen donor furnished the desired alcohol (-)-39 in 95% yield over two steps (Scheme 14). ext, the secondary alcohol of (-)-39 was protected as its TBS ether and the TMS group of TBS ether compound was removed under basic conditions to generated the acetylene compound 21 in 92% yield. The chiroptical data of 21 was in full agreement with the reported one ([α] D (c 0.5, CCl 4 ) {lit. [α] D 28.5 (c 0.02, CCl 4 ) for opposite isomer}. The iododiene 16 can be prepared from acetylene compound 21 by following reported procedures (Scheme 14).

16 22 i) DMP, C 2 Cl 2 0 o C to rt 1h ii) n-buli, TMS -78 o C, 2h 95% over 2 steps (±)-39 SiMe 3 i) DMP, C 2 Cl 2 0 o C to rt 1h ii) Cat L 4 (1 mol%) Et 3 :C (5:2) EtAc, rt, 3h 95% over 2 steps SiMe 3 i) TBSTf, 2,6-lutidine C 2 Cl 2, 0 o C, 2h TBS ii) K 2 C 3, Me rt, 12h (-) I Ts 16 Ru L 4 Scheme 14 Previously, White and Pietruszka et. al. independently reported the coupling of iododiene 16 and aldehyde 14 leading to the formation of solandelactone A and B 2a & 2b in 3.5:1 ratio with 41% yield. Analogous way, the coupling of iododiene 16 and aldehyde 15 could furnish the congeners of solandelactone A and B 2a &2b (Scheme 15). The complete discussion along with supporting analytical data is placed in this chapter.

17 a 2b 3.5:1, 41% 2a' b' Scheme 15 In conclusion, we have succeeded in developing a catalytic enantioselective unified strategy for towards the synthesis of the oxylipin class of natural products. The salient features of this protocol are i) the genesis of chirality through an organocatalytic reaction. ii) the cyclopropanes can be produced as either enantiomer employing catalytic quantity of quinine or quinidine based alkaloids. iii) application of oyori s CATy reaction that could lead synthesis of C(5) epimeric alcohols which in turn would facilitate the synthesis of every representative member of oxylipin family. Chapter 3: An expedient synthesis of enantioenriched substituted (benzofuran- yl)-aryl and heteroaryl carbinols via Rap-Stoermer reaction / asymmetric transfer hydrogenation. Benzofuran structural moiety is present in numerous biologically active natural products. These privileged pharmacophore containing molecules exhibit therapeutical properties over wide range of targets. wing to their prevalence in natural products as well as pharmaceuticals has stimulated significant interest in the synthesis of benzofuran containing heterocycles. A flurry of synthetic methods has been appeared in the literature for the

18 synthesis of benzofurans and their derivatives. Among them, Rap-Stoermer reaction is appears to be a versatile straightforward approach for the synthesis of functionally varied benzofuran scaffolds. It was observed that the racemic substituted (benzofuran-yl)- phenylcarbinols and related compounds reduced blood lipids in both laboratory animals and patients. This prompted us to initiate a programme for the synthesis of enantioenriched substituted (benzofuran-yl)-phenylcarbinols in substantial amount. Initially, we have evaluated base mediated reaction of salicylaldehyde 40a with α-haloacyl -methoxy--methylketone 41a employing solvent, solvent-free and microwave-assisted conditions. The desired product (benzofuran-yl)--methoxy--methyketone 42a was obtained in poor yield. In Rap-Stoermer reaction, the choice of base and solvent was found to be critical; hence we screened a number of bases (aac, KAc, K 2 C 3, K 3 P 4, Cs. 2, Cs 2 C 3 ) and solvents (toluene, C 2 Cl 2, CCl 3, DMF, EtAc, C 3 C), but found that only Cs 2 C 3 and acetonitrile gave the desired product 42a in 95% yield (Scheme 16). The Cs 2 C 3 and EtAc system also resulted in the product 42a but slightly less yield (90%). Br Me Me 40a, (1equiv.) 41a, (1equiv.) Cs 2 C 3 (1 equiv.) C 3 C rt, 6h Me Me 42a, 95%yield Scheme 16 The generality and scope of this protocol were evaluated using above optimized conditions and the results are shown in Scheme 17.

19 40a Br 41b Cs 2 C 3 C 3 C rt, 6h 42b, 95% Y 40a Br 41c Boc Cs 2 C 3 C 3 C rt, 6h 42c, 93% Y Boc S 40b 41a Cs 2 C 3 C 3 C rt, 6h Me S Me 42d, 92% Y 40a Br 41d Et Cs 2 C 3 C 3 C rt, 6h Et 42e, 95%Y Scheme 17 aving realized optimum conditions for synthesis of benzofuryl derivative; further, we envisaged to generate optically active carbinols via a Rap-Stoermer reaction / catalytic asymmetric transfer hydrogenation (AT). At the outset, we have selected salicylaldehyde 40a and 41e as test substrates and carried out the reaction under standard protocol. After considerable experimentation, using 1 mol% of R,R-diamine-Rh catalyst B employing EtAc as solvent in both reactions (i.e. Rap-Stoermer reaction and AT reaction) furnished the desired product 43a in 93% yield with 99%ee (Scheme 18). The enantiomeric excess was analyzed by PLC on chiral column D- and the absolute configuration of new stereogenic center was assigned as R by comparison of sign of rotation {[α] 23 D = -7.9 o (c = 3.0, CCl 3 ); lit. [α] 23 D = 3.5 o (c = 0.041, CCl 3 for the opposite isomer}.

20 a) Cs 2 C 3 (1 equiv.) Br EtAc, rt, 6h b) 1 mol% cat. B Et 3 :C 2 (5:2) 40a 41e rt, 3h (R)-43a Yield = 93% ee = 99% Cat. A Ru Cl Tos Cat. B Rh Cl Tos Scheme 18 To test the generality and efficiency of this methodology, we subjected various substituted salicylaldehydes with α-bromoaryl and heteroaryl kotones and our results are shown in Scheme 19.

21 C Br a) Cs 2 C 3 (1 equiv.) EtAc, rt, 6h b) 1 mol% cat. B Et 3 :C 2 (5:2) 40c 41e rt, 3h (R)-43b Yield = 90% ee = 99% 40a Me 40d Br 41f 41f S a) Cs 2 C 3 (1 equiv.) EtAc, rt, 6h b) 1 mol% cat. B Et 3 :C 2 (5:2) rt, 3h a) Cs 2 C 3 (1 equiv.) EtAc, rt, 6h b) 1 mol% cat. B Et 3 :C 2 (5:2) rt, 3h Me (R)-43c Yield = 92% ee = 94% (R)-43d Yield = 87% ee = 99% S S 40a Br 41g a) Cs 2 C 3 (1 equiv.) EtAc, rt, 6h b) 1 mol% cat. B Et 3 :C 2 (5:2) rt, 3h (R)-43e Yield = 85% ee = 87% Scheme 19 The full details with discussion along with duly characterized compound data is given in this chapter. In conclusion, we have developed an expedient synthesis of enantioenriched substituted (benzofuran-yl)-aryl and heteroaryl carbinols with high optical and chemical yields. A key feature of this protocol is synthesis of functionally varied benzofuran scaffolds via a Rap-Stoermer reaction / catalytic asymmetric transfer hydrogenation (AT) using substituted salicylaldehyde and α-haloaryl ketones.