First total synthesis of seimatopolide B

Abstract

The first enantioselective total synthesis of seimatopolide B has been achieved, using ring-closing metathesis and DCC (N,N′-dicyclohexylcarbodiimide) coupling as key steps. The stereogenic centres were generated by means of iterative hydrolytic kinetic resolution (HKR) of racemic epoxides.

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Introduction

Seimatopolides A and B, two polyhydroxylated 10-membered macrolides, were recently isolated by Jang and Lee et al.¹ from an ethyl acetate extract of Seimatosporium discosioides culture medium, along with three known compounds: monosporascone, arthrinone and 3a,9a-deoxy-3a-hydroxy-1-dehydroxyarthrinone. Seimatopolides belong to a novel class of 10-membered lactones, as well as members of the deacarestrictine,² microcarpalide³ and pinolidoxin⁴ families etc. (Fig. 1). These compounds are structurally related to each other based on their physico-chemical properties. Owing to their interesting biological properties, including inhibition of cholesterol biosynthesis,⁵ antimalarial and antibacterial activities,⁶ and microfilament formation,³ these compounds have attracted a great deal of interest among synthetic organic chemists worldwide as attractive synthetic targets towards developing new therapeutic agents. Seimatopolides exhibited significant activity in a reporter gene assay for activation of peroxisome proliferator-activated receptor γ (PPAR-γ)^7a with EC₅₀ values of 11.05 μM, which shows therapeutic potential in the treatment of type 2 diabetes, inflammatory disease and certain cancers.^7b

Fig. 1 Some selected examples of 10-membered lactones.

As a part of our research programme aimed at developing enantioselective syntheses of biologically active natural products⁸ based on hydrolytic kinetic resolution (HKR),⁹ we became interested in the design of a simple and concise route to seimatopolide B. Herein we report our successful endeavours towards the first total synthesis of seimatopolide B employing HKR, DCC coupling and ring-closing metathesis (RCM)¹⁰ as the key steps.

Results and discussion

In continuation of our ongoing interest in exploiting the HKR method to install the stereocentres and ring-closing metathesis for making cyclic compounds viz. 10-membered lactone rings based upon protecting group directed ring-closing metathesis protocol¹¹ and generalizing its substrate based selectivity, we planned to synthesize seimatopolide B.

Our retrosynthetic analysis for seimatopolide B is based on the convergent approach as outlined in Scheme 1. We envisioned that the natural product 1 could be obtained by ring-closing metathesis of diene precursor 2, which in turn could be prepared by intermolecular DCC coupling of acid 3 and alcohol 4. Acid 3 could be obtained from 3-butene-1-ol (5) while the alcohol fragment could be prepared from rac-epichlorohydrin (6) via iterative HKR.

Scheme 1 Retrosynthetic route to seimatopolide B.

As depicted in Scheme 2, synthesis of acid fragment 3 commenced from commercially available 3-butene-1-ol (5). This, upon hydroxy group protection with TBSCl followed by oxidation using mCPBA, gave epoxide 7 in 90% yield. The rac-epoxide 7 was subjected to Jacobsen's HKR⁹ using (R,R)-salen-Co^III(OAc) catalyst to give the enantiopure epoxide^12a (R)-7a in 46% yield along with diol 7b in 45% yield, which were separated by silica gel column chromatography.

Scheme 2 Synthesis of the acid fragment 3. Reagents and conditions: (a) TBDMSCl, imidazole, CH₂Cl₂, 0 °C to rt, 4h, 88%; (b) m-CPBA, CH₂Cl₂, 0 °C to rt, 1h, 90%; (c) R,R-salen-Co-(OAc) (0.5 mol %), dist. H₂O (0.55 equiv), isopropyl alcohol, 0 °C, 24h, (46% for 7a, 45% for 7b); (d) (CH₃)₃SI, n-BuLi, THF, 4h, 86%; (e) MEMCl, DIPEA, CH₂Cl₂, 16h, 87%; (f) TBAF, THF, 1h, 88%; (g) TEMPO, NaH₂PO₄, NaOCl, NaClO₂, CH₃CN, overnight, 95%.

Epoxide (R)-7a, on ring opening with dimethylsulfonium methylide,¹³ afforded one-carbon homologated allylic alcohol 8 in 86% yield, which was protected as the MEM ether using MEMCl and DIPEA followed by removal of the TBS group to furnish alcohol 10 in 88% yield. TEMPO-catalysed oxidation of the alcohol with NaOCl resulted in the formation of acid 3 in excellent yield.

As illustrated in Scheme 3, synthesis of alcohol fragment 4 started from commercially available (±) epichlorohydrin 6, which was converted to epoxide 12 by a known procedure.^8m The racemic epoxide 12 was resolved using (S,S)-salen Co^III-OAc to give enantiopure epoxide^12b12a in 45% yield. The epoxide 12a was opened with allylmagnesium bromide, followed by epoxidation and hydroxy group protection as TBS to give the epoxide 14 as mixture of syn and anti compounds (syn : anti, 1 : 1.15).¹⁴ In order to obtain the diastereomerically pure epoxide, the epoxide 14 was resolved using (S,S)-salen Co^III-OAc and water in THF to give the diastereomerically pure epoxide 14a in 48% yield. As the HKR method provided the desired epoxide 14a along with unwanted diol 14b, we thought it appropriate to convert diol 14b into the required epoxide 14avia internal nucleophilic substitution of the secondary mesylate.¹⁵ Accordingly, chemoselective pivalation of diol 14b with pivaloyl chloride was followed by mesylation of the secondary hydroxy group. Treatment of the crude mesylate with potassium carbonate in methanol led to deprotection of the pivaloyl ester and concomitant ring closure via intramolecular S_N2 displacement of the mesyl group to furnish epoxide 14a in 68% overall yield.

Scheme 3 Synthesis of the alcohol fragment 4. Reagents and conditions: (a) Octylmagnesium bromide, THF, CuI, −40 °C, 12 h; (b) KOH, CH₂Cl₂, rt, 14h; (c) S,S-salen-Co-(OAc) (0.5 mol %), dist. H₂O (0.55 equiv), isopropyl alcohol, 0 °C, 14h, (45% for 12a, 43% for 12b); (d) Allylmagnesium bromide, ether, CuI, −20 °C, 2h, 89%; (e) (i) TBDMSCl, imidazole, CH₂Cl₂, 0 °C to rt, 16h, 90%; (ii) m-CPBA, CH₂Cl₂, 0 °C to rt, 1h, 80%; (f) S,S-salen-Co-(OAc) (0.5 mol %), dist. H₂O (0.55 equiv), isopropyl alcohol, 0 °C, 16h, (48% for 14a, 39% for 14b); (g) (i) PivCl, Et₃N, cat. DMAP, rt, 2h; (ii) MsCl, Et₃N, DMAP, 0 °C to rt, 1h; (iii) K₂CO₃, MeOH, rt, overnight (68% for three steps); (h) (CH₃)₃SI, n-BuLi, THF, 4h, 81%; (i) MEMCl, DIPEA, CH₂Cl₂, 14h, 80%; (j) TBAF, THF, 3h, 81%.

With substantial amounts of epoxide 14a in hand we further proceeded towards the synthesis of alcohol fragment 4 by ring opening of the epoxide with dimethylsulfonium methylide to obtain the allylic alcohol 15 in excellent yield. Subsequent hydroxyl group protection as its MEM ether followed by TBS removal furnished the alcohol fragment 4 in 81% yield (Scheme 3).

With substantial amounts of both the fragments in hand the coupling of acid 3 and alcohol 4 was achieved by using intermolecular DCC coupling to afford the diene ester 2 in 91% yield, which was subjected to deprotection of MEM groups using PPTS in t-BuOH to give the naked diol ester 17. Subsequent ring-closing metathesis using Grubbs’ 2nd generation catalyst in CH₂Cl₂ resulted in the unnatural isomer, Z-seimatopolide B 1 exclusively in 74% yield (Scheme 4). Z-Seimatopolide B 1 was well characterized by physical and spectroscopic methods (see the ESI†). With an aim to synthesize the natural isomer E-seimatopolide B 1, we extended our studies to explore the protecting group directed ring-closing metathesis (RCM).¹¹ We envisaged that protecting groups around the reacting centers might act as temporary constraints to adequately shape the dienes and simultaneously confer selectivity upon the stereochemistry of the newly formed double bond. With this view in mind, the suitably protected diene ester 2 was then subjected to ring-closing metathesis conditions using Grubbs’ 2nd generation catalyst in CH₂Cl₂ under reflux conditions. To our delight, the reaction led to the formation of cyclized product 18, albeit in only 50% yield. Subsequent deprotection of MEM ethers using TFA in CH₂Cl₂ afforded the natural product, seimotopolide B 1 exclusively as the trans-isomer. E-Seimatopolide B 1 was well characterized by ¹H & ¹³C NMR, mass and IR spectral data. In ¹H NMR the coupling constant between H4 and H5 clearly demonstrated the trans nature of the double bond (Scheme 4).

Scheme 4 Synthesis of E-seimatopolide and Z-seimatopolide. Reagents and conditions: a) DCC, cat. DMAP, CH₂Cl₂, 6h, rt, 91% ; (b) Grubbs’ 2nd generation catalyst, CH₂Cl₂, reflux, 16h, 50% ;(c) PPTS, t-BuOH, reflux, 16h, 82%; (d) TFA, CH₂Cl₂, rt, 16h, 70% ; (e) Grubbs’ 2nd generation catalyst, CH₂Cl₂, reflux, 16h, 74%.

The physical and spectroscopic data of E-seimatopolide B 1 was in full agreement with that of the natural product reported in literature¹ (Fig. 2, Table 1).

Fig. 2 ¹H NMR spectra of E-seimatopolide B 1 (500 MHz, pyridine-d₅): Natural (top) and synthetic (bottom).

Table 1 Comparison of ¹H and ¹³C NMR data of both natural and synthetic E-seimatopolide B

E-Seimatopolide B (natural) spectroscopic data (500 MHz, pyridine-d5)		E-Seimatopolide B (synthetic) spectroscopic data (500 MHz, pyridine-d5)
^1H NMR (J in Hz)	^13C NMR	^1H NMR (J in Hz)	^13C NMR
6.56, dd (8.5, 16.0)	170.5	6.56, dd (8.54, 16.17)	170.6
5.98, dd (3.0, 16.0)	133.4	5.98, dd (3.05, 16.17)	133.4
5.06, ddd (7.0, 7.0, 13.0)	133.4	5.09, m	133.4
4.96, m	76.5	4.99, m	76.5
4.62, dd (7.5, 7.5)	74.9	4.64, m	74.9
2.89, dd (3.0, 11.5)	67.8	2.90, dd (3.4, 11.6)	67.8
2.72, dd (3.0, 11.5)	45.7	2.74, dd (3.9, 11.6)	45.8
2.30, m	38.5	2.32, m	38.6
2.00, m	36.3	2.00, m	36.4
2.00, m	32.4	2.00, m	32.4
1.72, m	31.0	1.72, m	31.2
1.62, m	30.2	1.63, m	30.3
1.51, m	30.2	1.51, m	30.2
1.22, m	30.1	1.23 (brs)	30.1
1.22, m	29.9	0.88, t (7.0)	29.9
1.22, m	26.0		26.1
1.22, m	23.2		23.3
1.22, m	14.6		14.6
1.22, m
1.22, m
0.86, dd (7.0, 7.0)

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Conclusion

In conclusion, a convergent and efficient first total synthesis of seimatopolide B, both natural (E-isomer) and unnatural (Z-isomer) has been accomplished with high enantioselectivity, in which the stereocentres were generated by means of iterative Jacobsen's hydrolytic kinetic resolution, and cyclization was achieved by ring-closing metathesis. This approach could be used for the synthesis of other members of this class of macrolides for structure–activity relationship studies. Work in this direction is currently in progress.

Experimental section

Z-Seimatopolide B 1

To a stirred solution of 17 (0.030 g, 0.088 mmol, 0.001 M) in freshly distilled degassed anhydrous CH₂Cl₂ (90 ml) was added Grubbs’ second generation catalyst (0.015 g, 0.017 mmol) and heated under reflux for 16 h under an argon atmosphere until the complete consumption of the starting material (monitored by TLC). The solvent was evaporated to a brown residue, which was purified by silica gel column chromatography using petroleum ether : EtOAc (53 : 47) to afford Z-seimatopolide B 1 (0.020 g, 74%) as a white amorphous solid. [α]²⁵_D: −118.53 (c 0.049, MeOH). IR (neat, cm⁻¹): ν_max 3243, 2911, 2852, 1722; ¹H NMR (400 MHz, pyridine-d₅): δ 7.02 (brs, 1H), 6.58 (brs, 1H), 5.94 (dd, J = 10.55, 9.78 Hz, 1H), 5.74 (dd, J = 10.29, 11.04 Hz, 1H), 5.51 (m, 1H), 5.33 (m, 1H), 5.12 (m, 1H), 3.36 (dd, J = 14.05, 6.02 Hz, 1H), 2.78 (m, 1H), 2.35–2.44 (m, 1H), 2.02–2.12 (m, 1H), 1.70–1.82 (m, 2H), 1.50–1.59 (m, 2H), 1.23 (brs, 14H), 0.88 (t, J = 7.03 Hz, 3H); ¹³C NMR (100 MHz, pyridine-d₅): δ 170.6, 135.2, 133.9, 74.8, 66.6, 65.1, 44.6, 33.2, 32.6, 31.6, 30.3, 30.2, 30.1, 28.4, 26.8, 23.5, 14.8, 30.5; LC–MS: m/z = 335.17 [M + Na]⁺ HRMS (ESI) for C₁₈H₃₂O₄Na (M + Na)⁺ found 335.2187, calcd 335.2193.

E-Seimatopolide B 1

To a solution of compound 18 (0.040 g, 0.082 mmol) in CH₂Cl₂, was added TFA (0.062 mL, 0.82 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was quenched with a saturated aqueous solution of NaHCO₃, extracted with EtOAc and the organic layer was separated, washed with brine, dried over Na₂SO₄, concentrated under reduced pressure and purified by column chromatography using EtOAc : petroleum ether (1 : 1) as eluent to afford E-seimatopolide B 1 (0.018 g, 70%) as a white amorphous solid. [α]²⁵_D: −212.60 (c 0.035, MeOH).{lit¹. [α]²⁵_D −125.3 (c 0.03, MeOH)}; IR (neat, cm⁻¹): ν_max 3242, 2912, 2853, 1721; ¹H NMR (500 MHz, pyridine-d₅): δ 6.56 (dd, J = 8.54, 16.17 Hz 1H), 5.98 (dd, J = 3.05, 16.17 Hz 1H), 5.09 (m, 2H), 4.99 (m, 1H), 4.64 (m, 1H), 2.90 (dd, J = 3.36, 11.60 Hz, 1H), 2.74 (dd, J = 3.97, 11.60 Hz, 1H), 2.32 (m, 1H), 2.00 (m, 2H), 1.72 (m, 1H), 1.63 (m, 1H), 1.51 (m, 1H), 1.23 (m, 14H), 0.88 (t, J = 7.02 Hz, 3H); ¹³C NMR (125 MHz, pyridine-d₅): δ 170.6, 133.4, 76.5, 74.9, 67.8, 45.8, 38.6, 36.4, 32.4, 31.2, 30.3, 30.2, 30.1, 29.9, 26.1, 23.3, 14.6; LC–MS: m/z = 335.17 [M + Na]⁺. HRMS (ESI) for C₁₈H₃₂O₄ (M + Na)⁺ found 335.2187, calcd 335.2193.

Acknowledgements

UN and AH thank UGC New Delhi and AD and BMS thank CSIR New Delhi for research fellowships. Financial support from DST, New Delhi (grant No. SR/S1/OC-44/2009) is gratefully acknowledged.

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Footnote

† Electronic Supplementary Information (ESI) available: ¹H NMR, ¹³C NMR spectra of compounds 7a, 8, 9, 10, 3, 12a, 13, 14, 14a, 15, 4, 16, 2, 17, 18, Exp. See DOI: 10.1039/c2ra21838k

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