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Concise diastereoselective synthesis of calcaripeptide C via asymmetric transfer hydrogenation/Pd-induced chiral allenylzinc as a key reaction† Gullapalli Kumaraswamy,* Vykunthapu Narayanarao and Ragam Raju Synthesis of the natural product calcaripeptide C derived from the fungal metabolite mycelium KF525 of Calcarisporium sp. has been achieved. This complementary approach avoids the use of a stoichiometric
Received 9th June 2015, Accepted 30th June 2015
amount of chiral auxiliary reagents as commonly used to generate enantioenriched advanced precursors.
DOI: 10.1039/c5ob01164g
The enantioselective synthesis of calcaripeptide C is remarkable in that using catalytic reactions sets the two stereogenic centers efficiently with good levels of enantioselectivity. Further diversification of the cal-
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caripeptide C structures is possible by employing a complementary catalytic enantioenriched Ru-catalyst.
Introduction Macrocyclic structures composed of a polypeptide and a polyketide motif, such as cyclodepsipeptide, have attracted attention owing to their broad range of bioactivity that offers possible leads for natural product-derived drugs.1 A recent addition to this class include novel, macrocyclic structurally related calcaripeptides A (1), B (2) and C (3)2 as derived from the marine fungal metabolite mycelium KF525 of Calcarisporium sp. (Fig. 1). NMR spectroscopic data and chemical derivatization coupled with X-ray crystallography structural elucidation confirm that the calcaripeptides A–C possess a structurally varied poly ketide carbon-chain which includes methyl stereogenic centers connected to a cyclic (L-proline), acyclic amino acid (L-phenylalanine) dipeptide residue with the cis-orientation of the amide bonds. Interestingly, the calcaripeptides A–C were tested for broad panel of 43 assays; however, antibacterial, antifungal, and cytotoxic properties were not detected nor was there an inhibition of the enzyme targets. This biological observation is contrary to observations of cyclic depsipeptides and their derivatives, which exhibit a diverse spectrum of biological activities, including insecticidal, antiviral, antimicrobial, antitumor, tumor-promotive, antiinflammatory and immunosuppressive actions.3 This provides an opportunity to undertake systematic SAR monitoring of the macrocyclic structures of calcaripeptides A–C and their relative
Fig. 1
Marine cyclodepsipeptide of calcaripeptides A–C.
stereogenic centers, which influence the biological and pharmaceutical activity levels. Furthermore, variations in the configuration of the stereogenic centers are expected to lead to good activity. Thus, they show noteworthy differences in their biological profiles.4
Results and discussion Organic & Biomolecular Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 607, India. E-mail: [email protected]; Fax: +91-40-27193275; Tel: +91-40-27193154 † Electronic supplementary information (ESI) available: Copies of 1H and NMR spectra. See DOI: 10.1039/c5ob01164g
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13
C
Recently, a flexible total synthesis of calcaripeptides A–C was pioneered based on a set of aldol reactions, in this case Evans alkylation, Crimmins syn-aldol and Crimmins acetate aldol to install the 2S, 4R, and 7R methyl stereogenic centers that are
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embedded in sub-structures.5 We previously demonstrated that the catalytic asymmetric transfer hydrogenation is the genesis of chirality, thus accessing functionalized chiral building blocks which have the option of potential stereogenic variation by switching a complementary ligand with a low level of loading.6 In relation to this, we envisioned utilizing catalytic asymmetric transfer hydrogenation to install stereogenic centers with the highest degree of diastereo- and enantioselectivity required for calcaripeptide C, 3. From a structural viewpoint, calcaripeptide C is highlighted by the presence of 14-membered macrocyclic structures with L-proline-L-phenylalanine dipeptide residue connected to a sub-structure possessing 2S, 4R and 7R methyl stereogenic centers. At the outset, we planned to execute a synthetic strategy for the non-peptidic part 5 of calcaripeptide C, which is a smaller cyclic member of the family. The stereogenic center 7R in the critical synthons 5 is established by the catalytic asymmetric transfer hydrogenation of a prochiral keto of 6, which in turn would be accessed by Marshall’s allenylation protocol7 using a (S)-propargyl mesylate 8 and an aldehyde which would be expected to arise from 7. The commercially available Roche ester envisions providing a lone 2S stereogenic center. Preceding studies5 suggested that the L-proline-L-phenylalanine dipeptide can be connected via a macrolactamization and macrolactonization strategy. Also, 8 could be readily prepared from enantioenriched propargyl alcohol7d which in turn necessitates the employment of an ATH procedure. The probable retrosynthetic plan of calcaripeptide C is shown in Scheme 1. Accordingly, the synthesis of 5 began with PMB protection of the primary alcohol of commercially available (R)-Roche ester 9 and the subsequent reduction of the ester to provide alcohol8 7 at a yield of 87% (over two steps). The Dess–Martin periodinane9 oxidation of 7 furnished the crude aldehyde, which was then directly subjected to a Pd-catalyzed-Znmediated addition of a (S)-propargyl mesylate 8. The expected syn–anti stereotriad 10 was isolated at a yield of 84% with an excellent diastereomeric ratio (96 : 4) as an inseparable mixture
Scheme 1
(Scheme 2). The diastereomeric ratio was determined by 1H NMR. The selectivity of this addition is considerably higher than that in the previously examined7b PMB-protected (R)-aldehyde and (R)-propargyl mesylate under similar reaction conditions.10 The secondary alcohol of 10 gave TBS-ether at a yield of 91% by means of TBSOTf in DCM. The prochiral keto was then introduced by a reaction of Weinreb–Nahm ketone synthesis11 employing the Weinreb
Scheme 2
Synthesis of prochiral keto compound 6.
Retro-synthetic analysis of calcaripeptides C.
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amide and pre-performed Li-acetylide generated from n-BuLi and 11 (Scheme 2). With the prochiral keto 6 in hand, we sought to realize ATH reduction conditions in order to generate enantioenriched advanced intermediate 12. An array of chiral-reducing agents was screened for this transformation. These results are shown in Table 1. The reaction of 6 with 1 mol% of the 18-electron precursor RuCl[(1R,2R)N-p-toluenesulfonyl-1,2-diphenylethanediamine](η6-pcymene), Cat. A and a formic acid/triethylamine azeotropic mixture as a hydrogen source, while stirring at an ambient temperature, resulted in the desired alcohol 12 at a yield of 40% (Table 1, entry 1). The same reaction in DCM with Cat. B
Table 1 Catalytic asymmetric transfer hydrogenation of prochiral ketone 6a
Entry
Conditions
Yieldb (%)
drc
1
1 mol% Cat. A HCO2H : Et3N (5 : 2) DCM, rt, 24 h 1 mol% Cat. B HCO2H : Et3N (5 : 2) DCM, rt, 24 h 1 mol% Cat. B 10 mol% K2CO3 2-Propanol, rt, 24 h 0.5 mol% Cat. B 10 mol% K2CO3 2-Propanol, rt, 24 h
40
—
81
—
96
96 : 4
75
96 : 4
2 3 4
a
All reactions were carried out on a scale of 1.0 mmol. b Isolated yields but not optimized. c The dr ratio was determined by 1H NMR.
Scheme 3
led to 12 at a yield of 81% (Table 1, entry 2). On the other hand, employing 1 mol% of the chiral 16-electron Ru complexes, Cat. B with 2-propanol as a hydrogen source, the prochiral ketone 6 was reduced to enantiomerically enriched alcohol 12 at a yield of 96% by 96 : 4 dr with a substrate-to-catalyst (S/C) ratio of 100 (Table 1, entry 3). The diastereomeric ratio was determined by 1H NMR and the stereochemistry of the newly formed hydroxyl group was assigned based on Noyori’s protocol.12 The optimum catalyst loading was found to be 1 mol%, while reducing it to 0.5 mol% led to a significant drop in the yield of product 12 (Table 1, entry 4). At this stage, we propose to protect the secondary alcohol as acetate for prospective synthetic convenience. Consequently, saponification would provide carboxylic acid derived from the corresponding proline ester and alcohol eventually intended for macrolactonization. Thus, the secondary alcohol in 12 was converted to acetate (Ac2O/Et3N/DMAP) and oxidative cleavage (DDQ, DCM : H2O) of the PMB group was undertaken, led by 13 at a yield of 85% (over two steps). Then, hydrogenation under a balloon pressure over 10% Pd/C on activated charcoal failed to reduce the triple bond, with a recovery of only the starting material. Also, replacing 10% Pd/C with 10% palladium dihydroxide on activated charcoal did not cause the reaction; however, employing 10 mol% of 20 wt% of palladium dihydroxide on carbon under otherwise identical conditions successfully reduced the internal acetylene to afford 14 at a 90% isolated yield. The primary alcohol of 14 was oxidized by Dess–Martin periodinane9 and the resulting aldehyde was exposed to Pinnick oxidation13 to obtain carboxylic acid 15 at a yield of 86% (over two steps), which is set for macrolactamiza-
Synthesis of calcaripeptides C (3).
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tion. Following a similar protocol, the coupling of 414 with 15 in DMF and EDCI, HOBt, DIPEA under stirring for 13 h at an ambient temperature gave 16 at a yield of 87% (Scheme 3). As anticipated, saponification15 under basic conditions liberated peptide-carboxylic acid and C7-alcohol successfully and the crude residue was subjected to MNBA-mediated macrolactonization16 conditions. The protected cyclodepsipeptide 17 was isolated at a yield of 50% over two steps. In the end, the fluoride-induced deprotection of the TBS group delivered the expected secondary chiral alcohol, which upon oxidation with Dess–Martin periodinane led to the anticipated target compound calcaripeptide C (3) at a yield of 88% (over two steps) (Scheme 3). The physical data for the synthesized compound were in full agreement with those reported for natural calcaripeptide C (3) and a comparison of the sign of 2 23 rotation ([α]23 D = −75.8 (c 0.2, MeOH) {lit. [α]D = −79.0 (c 0.2, MeOH)}) helped to assign the relative configuration of the new and existing stereogenic centers as 2S, 4R and 7R.
Conclusion In conclusion, we have developed a concise synthesis for cyclodepsipeptide calcaripeptide C in which two stereogenic centers were installed by efficient catalytic asymmetric transfer hydrogenation (ATH) together with Marshall’s allenylation. This process is significant in how it demonstrated that a single Ru-asymmetric catalyst is the basis for the synthesis of two variant intermediates with high diastereo- and enantioselectivity. Further, a set of diastereo-divergent congeners of this family can be realized by employing a complementary catalyst. In general, its high catalytic competence, enantioselectivity and operational expediency can make this process adoptable for analogous biologically active natural molecules. Further optimization and application of this strategy for the diastereo-divergent congeners of calcaripeptide C in particular and in general cyclodepsipeptide family members are at present under investigation in our lab.
Experimental General information All reactions were conducted under an inert atmosphere. The apparatus used for reactions were oven dried. THF was distilled over sodium benzophenone ketyl before use and DCM was distilled over calcium hydride. (S)-But-3-yn-2-yl methanesulfonate was prepared according to the reported procedure.7d All other chemicals used were commercially available. Progress of the reactions was monitored by TLC on pre-coated silica gel 60 F-254. Evaporation of solvents was performed at reduced pressure on a rotary evaporator. Column chromatography was carried out with silica gel grade 60–120 and 100–200 mesh. 1H NMR spectra were recorded at 300 & 500 MHz and 13C NMR at 75 MHz in CDCl3. Chemical shifts (δ) are reported in ppm. Tetramethylsilane (δ = 0.00 ppm for 1H) and CDCl3 (δ =
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77.00 ppm for 13C) were used as the internal standards. Scalar coupling constants ( J) are reported in hertz (Hz). The following abbreviations are used to designate the multiplicities: s = singlet, d = doublet, t = triplet, dd = doublet of doublets, ddd = doublet of doublet of doublets, m = multiplet, br.s = broad singlet. Mass spectral data were compiled using MS (ESI), and high resolution mass spectra (HRMS) were recorded by using the ESI probe in positive mode using an ORBITRAP analyzer. Optical rotations were recorded on a high sensitive polarimeter with a 1 mL cell. (2R,3R,4R)-1-((4-Methoxybenzyl)oxy)-2,4-dimethylhex-5-yn3-ol (10). A DCM (30 mL) solution of 7 (1.5 g, 7.14 mmol) was treated with NaHCO3 (1.8 g, 21.42 mmol) and Dess–Martin periodinane (6.05 g, 14.29 mmol) at 0 °C, and the resulting reaction mixture was allowed to stir for 1 h at the same temperature. Then, the reaction mixture was quenched by the sequential addition of satd. aqueous Na2S2O3 (15 mL) and satd. aqueous NaHCO3 (15 mL) and extracted with DCM (2 × 30 ml). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford an aldehyde as a pale yellow oil, which was taken onto the next step without purification. To a stirring solution of Pd(OAc)2 (75.38 mg, 0.34 mmol) in THF (20 mL) at −78 °C was added PPh3 (88.10 mg, 0.34 mmol), aldehyde (1.40 g, 6.73 mmol), and mesylate (S)-8 (1.49 g, 10.10 mmol) in the same order. To this reaction mixture, diethylzinc (20.2 mL, 1 M in hexane) was added over a period of 10 min, and stirring was maintained for 15 min. Then, the mixture was warmed to −20 °C and stirred overnight at the same temperature. The reaction mixture was quenched with NH4Cl : Et2O (1 : 1), and the layers were separated. The aqueous layer was extracted with Et2O (2 × 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the residue which was purified by silica gel column chromatography using hexane/ethyl acetate as the eluent to give 10 (1.48 g, 84%) as an inseparable mixture of isomers 1 (dr = 96 : 4, based on nmr). [α]35 D = −7.12 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 7.25 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.44 (s, 2H), 3.81 (s, 3H), 3.60–3.41 (m, 3H), 2.73–2.60 (m, 1H), 2.13 (d, J = 2.5 Hz, 1H), 2.10–1.87 (m, 2H), 1.20 (d, J = 7.0 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H). 13C NMR (75 MHz): 159.1, 130.2, 129.1, 113.7, 86.2, 75.6, 73.5, 72.8, 70.4, 55.2, 36.1, 30.4, 17.7, 10.9. IR (KBr): 3424, 2935, 2865, 1639, 1378, 1095, 982, 916, 742 cm−1. MS (ESI) m/z: 285 (M + Na)+. tert-Butyl(((2R,3R,4R)-1-((4-methoxybenzyl)oxy)-2,4-dimethylhex-5-yn-3-yl)oxy)dimethylsilane (11). To a solution of 10 (1.2 g, 4.58 mmol) in CH2Cl2 (15 mL) were added 2,6-lutidine (0.64 mL, 5.50 mmol) and TBSOTf (1.2 mL, 5.04 mmol) at 0 °C. After being stirred at 0 °C for 30 min, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (2 × 30 mL). The organic layer was washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic contents were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, followed by
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purification by silica gel column chromatography using hexane/ethyl acetate as the eluent to afford the protected alcohol 11 (1.56 g, 94%) as a colourless oil. [α]34 D = −1.6 (c = 1.2, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.25 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.3 Hz, 2H), 4.42 (s, 2H), 3.81 (s, 3H), 3.79–3.75 (m, 1H), 3.48–3.40 (m, 1H), 3.32–3.24 (m, 1H), 2.67–2.56 (m, 1H), 2.14–2.05 (m, 1H), 2.03 (d, J = 3 Hz, 1H), 1.18 (d, J = 7.5 Hz, 3H), 0.95–0.84 (m, 13H), 0.09 (s, 3H), 0.04 (s, 3H). 13C NMR (75 MHz): 159.1, 130.7, 129.2, 113.7, 87.3, 74.4, 73.1, 72.4, 70.0, 55.2, 36.9, 31.6, 26.1, 17.5, 12.1, −3.9, −4.2. IR (KBr): 2955, 2931, 2857, 2208, 1613, 1513, 1462, 1361, 1085, 835, 632 cm−1. MS (ESI) m/z: 399 (M + Na)+. HRMS: calculated for C22H36O3NaSi [M + Na]+, 399.2326, found 399.2344. (5R,6R,7R)-6-((tert-Butyldimethylsilyl)oxy)-8-((4-methoxybenzyl)oxy)-5,7-dimethyloct-3-yn-2-one (6). TBS protected alcohol 11 (1.5 g, 3.99 mmol) was dissolved in THF (15 mL) under argon and cooled to −78 °C. Then, a 2.5 M solution of n-butyllithium in hexane (1.9 mL, 4.79 mmol) was added and warmed to −30 °C, and stirred for 30 min at this temperature. Again the reaction mixture was cooled to −78 °C, then Nmethoxy-N-methylacetamide (616 mg, 5.98 mmol) in THF (2 mL) was added. The resulting reaction mixture was stirred at −30 °C (3 h), followed by quenching by addition of saturated NH4C1 solution (20 mL). The aqueous layer was extracted with EtOAc (2 × 30 mL), washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure resulting in a crude residue which was purified by silica gel column chromatography using hexane/ethyl acetate as the eluent and gave keto compound 6 (1.19 g, 71%) as a colourless oil. [α]34 D = +6.48 (c = 1.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.25 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 4.41 (s, 2H), 3.81 (s, 3H), 3.8 (t, J = 4 Hz, 1H), 3.45–3.40 (m, 1H), 3.30–3.25 (m, 1H), 2.80–2.75 (m, 1H), 2.28 (s, 3H), 2.08–1.98 (m, 1H), 1.22 (d, J = 7.17 Hz, 3H), 0.93 (d, J = 6.86 Hz, 3H), 0.91 (s, 9H), 0.1 (s, 3H), 0.05 (s, 3H). 13C NMR (75 MHz): 184.7, 159.1, 130.5, 129.2, 113.7, 96.5, 82.8, 74.5, 72.54, 72.52, 55.2, 37.8, 32.7, 32.0, 26.0, 18.3, 17.3, 12.2, −4.1. IR (KBr): 2955, 2931, 2857, 2212, 1752, 1677, 1613, 1513, 1462, 1359, 1249, 1085, 836, 775 cm−1. MS (ESI) m/z: 441 (M + Na)+. HRMS: calculated for C24H38O4NaSi [M + Na]+, 441.2432, found 441.2447. (2R,5R,6R,7R)-6-((tert-Butyldimethylsilyl)oxy)-8-((4-methoxybenzyl)oxy)-5,7-dimethyloct-3-yn-2-ol (12). To a solution of 6 (1.0 g, 2.39 mmol) in isopropanol (10.0 mL) was added pre-dissolved ruthenium catalyst B6a [14.8 mg, 0.024 mmol in DCM (2.0 mL)] and K2CO3 (33.0 mg, 0.24 mmol) successively under argon. The resulting reaction mixture was stirred for 12 h at room temperature, and then the solvent was evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography using EtOAc in hexane as the eluent resulting in alcohol 12 (965 mg, 96% yield). [α]34 D = +13.4 (c = 1.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.26 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.68 Hz, 2H), 4.42 (s, 2H), 3.81 (s, 3H), 3.77–3.72 (m, 1H), 3.47–3.38 (m, 1H), 3.32–3.23 (m, 1H), 2.68–2.55 (m, 1H), 2.14–2.02 (m, 1H), 1.69 (br.s, 1H), 1.38 (d, J = 6.42 Hz, 3H), 1.15 (d, J = 7.17 Hz, 3H), 0.94–0.86 (m, 13H), 0.08 (s, 3H), 0.03 (s, 3H). 13C NMR (75 MHz): 159.1, 130.7,
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129.2, 87.3, 83.9, 74.5, 73.2, 72.5, 58.5, 55.3, 37.0, 31.8, 26.0, 24.5, 18.3, 17.3, 12.3, −4.1, −4.3. IR (KBr): 3424, 2955, 2931, 2855, 2225, 1733, 1612, 1513, 1462, 1371, 1249, 1084, 836, 774 cm−1. MS (ESI) m/z: 443 (M + Na)+. HRMS: calculated for C24H40O4NaSi [M + Na]+, 443.2588, found 443.2598. (2R,5R,6R,7R)-6-((tert-Butyldimethylsilyl)oxy)-8-((4-methoxybenzyl)oxy)-5,7-dimethyloct-3-yn-2-yl acetate (12a). To a DCM (10.0 mL) solution of propargyl alcohol 12 (900 mg, 2.14 mmol) were added triethylamine (0.5 mL, 3.21 mmol), and acetic anhydride (0.3 ml, 2.79 mmol) and a catalytic amount of 4-dimethylaminopyridine (10.0 mg) was added to the mixture and the resulting contents were stirred at ambient temperature for 12 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (2 × 30 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography over silica gel using hexane/ethyl acetate as the eluent affording protected alcohol 12a (886 mg, 90%) as a colourless oil. [α]34 D = +49.7 (c = 1.2, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.26 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 5.50–5.39 (m, 1H), 4.42 (s, 2H), 3.81 (s, 3H), 3.72 (t, J = 4.5, 8.3, 1H), 3.49–3.40 (m, 1H), 3.32–3.21 (m, 1H), 2.69–2.56 (m, 1H), 2.10–1.99 (m, 4H), 1.42 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.8 Hz, 3H), 0.96–0.86 (m, 13H), 0.08 (s, 3H), 0.04 (s, 3H). 13C NMR (75 MHz): 169.9, 159.0, 130.1, 129.1, 113.7, 88.1, 80.1, 74.6, 73.0, 72.4, 60.8, 55.3, 37.3, 31.6, 26.0, 21.7, 21.1, 18.3, 17.8, 12.2, −4.1, −4.2. IR (KBr): 2956, 2932, 2856, 2246, 1743, 1612, 1513, 1462, 1370, 1242, 1052, 836, 774 cm−1. MS (ESI) m/z: 485 (M + Na)+. HRMS: calculated for C26H42O5NaSi [M + Na]+, 485.2694, found 485.2705. (2R,5R,6R,7R)-6-((tert-Butyldimethylsilyl)oxy)-8-hydroxy5,7-dimethyloct-3-yn-2-yl acetate (13). To a stirred and cooled (0 °C) solution of 12a (800 mg, 1.73 mmol) in DCM/H2O (20 : 1, 10 mL) was added DDQ (472 mg, 2.08 mmol). The resulting reaction mixture was stirred for 45 min, and quenched with saturated aqueous NaHCO3 (10 mL), the aqueous layer was extracted with DCM (2 × 20 mL), and the combined organic layers were washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane/ ethyl acetate as the eluent to afford alcohol 13 (556 mg, 94%) 1 as a colourless oil. [α]34 D = +49.58 (c = 1.2, CHCl3). H NMR (500 MHz, CDCl3): δ 5.43–5.38 (m, 1H), 3.71–3.66 (m, 2H), 3.60–3.56 (m, 1H), 2.70–2.64 (m, 1H), 2.05 (s, 3H), 2.0–1.87 (m, 2H), 1.45 (d, J = 6.7 Hz, 3H), 1.18 (d, J = 7.0 Hz, 3H), 0.91 (s, 9H), 0.88 (d, J = 7.0 Hz, 3H), 0.08 (d, J = 3.2 Hz, 6H). 13C NMR (75 MHz): 170.2, 87.5, 80.5, 76.0, 65.5, 60.8, 39.6, 30.4, 25.9, 21.5, 21.1, 18.2, 17.7, 12.9, −4.2, −4.5. IR (KBr): 3462, 2856, 2929, 2856, 2241, 1742, 1460, 1372, 1242, 1038, 837, 774 cm−1. MS (ESI) m/z: 365 (M + Na)+. HRMS: calculated for C18H34O4NaSi [M + Na]+, 365.2119, found 365.2126. (2R,5R,6R,7R)-6-((tert-Butyldimethylsilyl)oxy)-8-hydroxy-5,7dimethyloctan-2-yl acetate (14). Compound 13 (500 mg, 1.46 mmol) was dissolved in MeOH (5.0 mL) and 20% Pd(OH)2/C (20% w/w; 50 mg) catalyst was added. The reaction
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flask was purged with H2 three times and the solution was left stirring under an atmosphere of H2 for 10 h. The solution was then filtered through a pad of celite and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane/ ethyl acetate as the eluent to afford compound 14 (457 mg, 1 90%) as a colourless oil. [α]34 D = −8.5 (c = 1.2, CHCl3). H NMR (500 MHz, CDCl3): δ 4.89–4.82 (m, 1H), 3.62–3.59 (m, 1H), 3.58–3.53 (m, 1H), 3.49–3.44 (m, 1H), 2.03 (s, 3H), 1.91–1.83 (m, 2H), 1.70 (br.s, 1H), 1.63–1.48 (m, 4H), 1.21 (d, J = 6.4 Hz, 3H), 0.92–0.88 (m, 13H), 0.86 (d, J = 6.9 Hz, 3H), 0.07 (s, 3H), 0.05 (s, 3H). 13C NMR (75 MHz): 170.8, 76.4, 71.5, 66.4, 38.6, 37.5, 34.0, 28.9, 26.0, 21.4, 19.9, 18.3, 16.5, 11.7, −3.9, −4.3. IR (KBr): 3451, 2956, 2927, 2855, 1737, 1462, 1374, 1249, 1099, 836, 773 cm−1. MS (ESI) m/z: 369 (M + Na)+. HRMS: calculated for C18H38O4NaSi [M + Na]+, 369.2432, found 369.2449. (2S,3R,4R,7R)-7-Acetoxy-3-((tert-butyldimethylsilyl)oxy)-2,4dimethyloctanoic acid (15). A solution of 14 (400 mg, 1.16 mmol) in dry DCM (10 mL) was treated with NaHCO3 (292 mg, 3.47 mmol) and Dess–Martin periodinane (980 mg, 2.31 mmol) at 0 °C, and the resulting reaction mixture was allowed to stir at the same temperature until completion as indicated by TLC analysis (∼1 h). Then, the reaction mixture was quenched by the sequential addition of satd. aqueous Na2S2O3 (8.0 mL) and satd. aqueous NaHCO3 (8.0 mL). The aqueous layer extracted with DCM (2 × 30 mL) and the combined organic contents were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford the crude aldehyde as a pale yellow oil, which was taken to the next step without purification. The above aldehyde (380 mg, 1.11 mmol), 2-methyl2-butene (0.6 mL, 5.55 mmol), and NaH2PO4 (147 mg, 1.22 mmol) were dissolved in t-BuOH/H2O (4 : 1, v/v, 6 mL) and the resulting suspension was cooled to 0 °C. Then, NaClO2 (360 mg, 3.60 mmol) was added and the resultant mixture was stirred at room temperature for 50 min. The reaction mixture was diluted with H2O, cooled to 0 °C, and acidified with 0.5 M aqueous HCl. The resultant mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane/ethyl acetate as the eluent to afford compound 15 (360 mg, 86% over two steps) as a colourless oil. [α]34 D = +5.8. 1H NMR (500 MHz, CDCl3): δ 4.89–4.81 (m, 1H), 3.88 (t, J = 5.1, 10.1, 1H), 2.66–2.60 (m, 1H), 2.02 (s, 3H), 1.61–1.45 (m, 4H), 1.20 (d, J = 6.3 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H), 0.92–0.85 (m, 13H), 0.06 (s, 3H), 0.02 (s, 3H). 13C NMR (75 MHz): 180.9, 170.9, 76.9, 71.3, 42.6, 38.1, 33.9, 29.8, 27.9, 25.9, 21.4, 19.9, 18.3, 16.0, 11.7, −4.2, −4.3. IR (KBr): 2938, 2855, 1718, 1462, 1374, 1249, 1099, 836, 773 cm−1. MS (ESI) m/z: 383 (M + Na)+. HRMS: calculated for C18H36O5SiNa [M + Na]+, 383.2224, found 383.2238. (S)-Methyl 1-((S)-2-((2S,3R,4R,7R)-7-acetoxy-3-((tert-butyldimethylsilyl)oxy)-2,4-dimethyloctanamido)-3-phenylpropanoyl)pyrrolidine-2-carboxylate (16). A solution of dipeptide 4 (251 mg, 0.67 mmol) in DCM (4.0 mL) was treated with TFA
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(1.0 mL) and stirred at rt. Then, the solvent was evaporated under reduced pressure to get the corresponding Boc deprotected compound. The crude Boc deprotected residue was dissolved in anhydrous DMF (3.0 mL) under argon and cooled to 0 °C. DIPEA (0.20 mL, 1.11 mmol) was added, and the mixture was stirred for 15 min at 0 °C. Acid 15 (200 mg, 0.56 mmol) dissolved in anhydrous DMF (2 mL) and HOBt (91 mg, 0.67 mmol) was then added, successively. Stirring was continued further at the same temperature for 15 min before addition of EDCI (104 mg, 0.67 mmol). The combined reaction contents were warmed slowly to room temperature and stirred further overnight. DMF was removed under reduced pressure, and the resultant residue was extracted with EtOAc. The organic layers were washed with saturated NH4Cl solution, water, and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane/ethyl acetate as the eluent to afford compound 16 (303 mg, 87%) as a colourless liquid (mixture of rotamers). 1 [α]34 H NMR D = −21.5 (c = 1.2, CHCl3). Major rotamer: (500 MHz, CDCl3): δ 7.31–7.20 (m, 5H), 6.44 (d, J = 7.9 Hz, 1H), 4.97–4.91 (m, 1H), 4.78–4.73 (m, 1H), 4.50–4.45 (m, 1H), 3.80–3.73 (m, 4H), 3.70–3.64 (m, 1H), 3.20–3.09 (m, 2H), 2.95 (dd, J = 13.7, 6.3 Hz, 1H), 2.38–2.31 (m, 1H), 2.22–2.14 (m, 1H), 2.0 (s, 3H), 1.97–1.88 (m, 3H), 1.55–1.39 (m, 5H), 1.15 (d, J = 6.3 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H), 0.91–0.82 (m, 12H); 0.03 (s, 3H), −0.01 (s, 3H). 13C NMR (75 MHz): 174.6, 172.2, 170.7, 170.4, 136.1, 129.7, 128.3, 126.8, 77.1, 71.3, 59.0, 52.2, 51.6, 46.9, 44.2, 38.5, 38.2, 33.9, 29.0, 27.5, 26.0, 24.9, 22.7, 21.4, 19.7, 18.3, 16.0, 14.6, −4.1, −4.2. IR (KBr): ν = 2948, 2793, 1749, 1642, 1443, 1327, 1097, 852, 779 cm−1. MS (ESI) m/z: 641 (M + Na)+. HRMS: calculated for C33H54O7N2NaSi [M + Na]+, 641.3593, found 641.3610. (3R,6R,7R,8S,11S,16aS)-11-Benzyl-7-((tert-butyldimethylsilyl)oxy)-3,6,8-trimethyldodecahydro-1H-pyrrolo[2,1-c][1,4,7]oxadiazacyclotetradecine-1,9,12-trione (17). To a solution of compound 16 (100 mg, 0.16 mmol) in THF : H2O (3 : 1, 4 mL) was added LiOH·H2O (40.3 mg, 0.96 mmol) and the resulting contents were stirred for 5 h at room temperature. The solvent was removed under reduced pressure, and the resultant residue was extracted with EtOAc. The organic layers were dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude residue of the corresponding hydroxy acid (85 mg) which was then subjected to the next reaction without purification. To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (83 mg, 0.24 mmol) and DMAP (45.7 mg, 0.38 mmol) in anhydrous DCM (80 mL) under argon was added dropwise a solution of the above crude residue of hydroxy acid (85 mg, 0.15 mmol) dissolved in anhydrous DCM (45 mL). The resulting reaction mixture was stirred for 16 h at ambient temperature and quenched with saturated NaHCO3 (10 ml) solution. The organic layer was separated and washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the residue which was purified by silica gel column chromatography using hexane/ethyl acetate
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as the eluent to afford the desired compound 17 (43 mg, 50% over two steps) as a colourless liquid. [α]34 D = −56.2 (c = 1.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.31–7.20 (m, 5H), 6.52 (d, J = 7.2 Hz, 1H), 5.20–5.11 (m, 1H), 4.76–4.68 (m, 1H), 3.71 (d, J = 5.2, 1H), 3.53 (d, J = 7.3 Hz, 1H), 3.44–3.32 (m, 2H), 3.23 (dd, J = 12.4, 4.4 Hz, 1H), 2.87–2.81 (m, 1H), 2.38–2.32 (m, 1H), 2.07–1.96 (m, 1H), 1.85–1.56 (m, 5H), 1.44–1.36 (m, 1H), 1.27–1.34 (m, 1H), 1.22 (d, J = 6.1 Hz, 3H), 1.11 (d, J = 7.0 Hz, 3H), 0.93–0.79 (m, 13H); 0.14 (s, 3H), 0.06 (s, 3H). 13C NMR (75 MHz): 173.3, 170.7, 170.1, 136.8, 129.4, 128.6, 126.9, 74.0, 58.7, 53.2, 45.4, 44.5, 41.1, 35.0, 32.0, 29.4, 29.3, 28.5, 25.9, 22.0, 20.9, 18.1, 15.3, 14.1, −4.2, −4.8. IR (KBr): 2938, 2853, 1735, 1642, 1475, 1356, 1266, 1097, 832, 776 cm−1. MS (ESI) m/z: 545 (M + H)+. HRMS: calculated for C30H49O5N2Si [M + H]+, 545.3405, found 545.3391. (3R,6R,7R,8S,11S,16aS)-11-Benzyl-7-hydroxy-3,6,8-trimethyldodecahydro-1H-pyrrolo[2,1-c][1,4,7]oxadiazacyclotetradecine1,9,12-trione (17a). To a THF (2.0 mL) solution of 17 (20 mg, 0.04 mmol) was added 0.06 mL of TBAF (1 M in THF) at 0 °C. After addition, the reaction mixture was warmed to room temperature and stirred for 3 h. Then, the reaction mixture was quenched with saturated NaHCO3 (2 mL) solution, extracted with EtOAc (2 × 5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane/ethyl acetate as the eluent to give compound 17a, as colourless oil. Yield: 94% (15 mg). [α]34 D = −56.2 (c = 1.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.29–7.30 (m, 5H), 6.65 (d, J = 7.2 Hz, 1H), 5.23–5.17 (m, 1H), 4.78–4.70 (m, 1H), 3.73 (dd, J = 1.4, 6.3, 1H), 3.65 (d, J = 7.5 Hz, 1H), 3.50–3.43 (m, 1H), 3.41–3.34 (m, 1H), 3.19 (dd, J = 12.5, 4.6 Hz, 1H), 2.88 (dd, J = 12.4, 11.0 Hz, 1H), 2.49–2.42 (m, 1H), 2.01–1.92 (m, 1H), 1.85–1.79 (m, 1H), 1.78–1.66 (m, 4H, merged with water peak), 1.52–1.43 (m, 1H), 1.35–1.26 (m, 1H), 1.22 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H), 0.93–0.84 (m, 1H). 13C NMR (75 MHz): 173.2, 170.8, 170.2, 136.7, 129.4, 128.6, 127.0, 74.2, 58.9, 53.0, 45.5, 43.9, 40.9, 35.4, 34.9, 28.6, 28.5, 21.9, 20.8, 18.3, 15.0. IR (KBr): 3429, 3230, 2945, 1732, 1632, 1469, 1249, 1099, 836, 773 cm−1. MS (ESI) m/z: 453 (M + Na)+. HRMS: calculated for C24H34O5N2Na [M + Na]+, 453.2349, found 453.2360. Calcaripeptide C (3) A dry DCM (2 mL) solution of 17a (10 mg, 0.02 mmol) was treated with NaHCO3 (5.9 mg, 0.07 mmol) and Dess–Martin periodinane (17.0 mg, 0.04 mmol) at 0 °C, and the resulting reaction mixture was allowed to stir for 2 h at the same temperature. The reaction mixture was quenched by the sequential addition of satd. aqueous Na2S2O3 (1 mL) and satd. aqueous NaHCO3 (1 mL) and extracted with DCM (2 × 3 mL). The combined organic phases were washed with brine (2.0 mL), dried over anhydrous Na2SO4, filtered and evaporated resulting in a residue which was purified by silica gel column chromatography using hexane/ethyl acetate as the eluent to give calcaripeptide C, 3 (7.5 mg, 88% yield). [α]34 D = −75.8 (c 0.2, MeOH). 1 H NMR (acetone-d6, 500 MHz) δ 7.65–7.57 (m, 1H), 7.32–7.28
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(m, 2H), 7.26–7.20 (m, 3H), 5.00–4.94 (m, 1H), 4.87–4.89 (m, 1H), 3.90 (d, J = 8.1 Hz, 1H), 3.65 (q, J = 6.9 Hz, 1H), 3.39–3.34 (m, 2H), 3.06 (dd, J = 12.4, 4.6 Hz, 1H), 2.92 (dd, J = 12.4, 10.0 Hz, 1H), 2.85 (m, 1H, merged with moisture peak), 1.89–1.83 (m, 2H), 1.75–1.62 (m, 2H), 1.56–1.40 (m, 3H), 1.21 (d, J = 7.0 Hz, 3H), 1.19 (d, J = 6.3 Hz, 3H), 1.12–1.04 (m, 1H), 1.01 (d, J = 6.7 Hz, 3H). 13C NMR (acetone-d6, 75 MHz) δ 209.3, 172.2, 170.9, 169.5, 138.2, 130.2, 129.2, 127.5, 74.0, 59.8, 54.3, 52.3, 46.3, 44.1, 40.6, 35.3, 31.8, 30.3, 22.4, 21.0, 15.6, 14.5 ppm. IR (KBr): ν 3295, 2938, 2851, 1735, 1640, 1626, 1472, 1259, 1094, 776 cm−1. MS (ESI) m/z: 451 (M + Na)+. HRMS (ESI) m/z calculated for C24H32N2O5Na [M + Na]+, 451.2203, found 451.2203.
Acknowledgements We are grateful to Director, IICT, for constant encouragement. Financial support was provided by the DST, New Delhi, India (Grant No. SR/S1/OC-08/2011), and ORGIN (CSC-0108) programme (CSIR) of XII Five year plan. UGC & CSIR (New Delhi) are gratefully acknowledged for awarding the fellowship to V. N. R. and R. R.
Notes and references 1 (a) G. S. B. Andavan and R. Lemmens-Gruber, Mar. Drugs, 2010, 8, 810; (b) G.-M. Suarez-Jimenez, A. Burgos-Hernandez and J.-M. Ezquerra-Brauer, Mar. Drugs, 2012, 10, 963; (c) R. Lemmens-Gruber, M. R. Kamyar and R. Dornetshuber, Curr. Med. Chem., 2009, 16, 1122; (d) Y. Yamano, M. Arai and M. Kobayashi, Bioorg. Med. Chem. Lett., 2012, 22, 4877. 2 J. Silber, B. Ohlendorf, A. Labes, C. Näther and J. F. Imhoff, J. Nat. Prod., 2013, 76, 1461. 3 R. Ratnayake, L. J. Fremlin, E. Lacey, J. H. Gill and R. Capon, J. Nat. Prod., 2008, 71, 403. 4 (a) G. Kumaraswamy, R. Satish Kumar, B. Sampath, Y. Poornachandra, C. Ganesh Kumar, V. Sahithya Phani Babu and B. Jagadeesh, Bioorg. Med. Chem. Lett., 2014, 24, 4439. 5 S. Das and R. K. Goswami, J. Org. Chem., 2014, 79, 9778. 6 (a) G. Kumaraswamy, N. Jayaprakash, D. Rambabu, A. Ganguly and R. Banerjeeb, Org. Biomol. Chem., 2014, 12, 1793; (b) G. Kumaraswamy and M. Padmaja, J. Org. Chem., 2008, 73, 5198; (c) G. Kumaraswamy, G. Ramakrishna, P. Naresh, B. Jagadeesh and B. Sridhar, J. Org. Chem., 2009, 74, 8468; (d) G. Kumaraswamy, G. Ramakrishna and B. Sridhar, Tetrahedron Lett., 2011, 52, 1778; (e) G. Kumaraswamy, G. Ramakrishna, R. Raju and M. Padmaja, Tetrahedron, 2010, 66, 9814; (f ) G. Kumaraswamy, D. S. Ramakrishna and K. Santhakumar, Tetrahedron: Asymmetry, 2010, 21, 544; (g) G. Kumaraswamy and N. Jayaprakash, Tetrahedron Lett., 2010, 51, 6500; (h) G. Kumaraswamy, A. N. Murthy,
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Concise diastereoselective synthesis of calcaripeptide C via asymmetric transfer hydrogenation/Pd-induced chiral allenylzinc as a key reaction† Gullapalli Kumaraswamy,* Vykunthapu Narayanarao and Ragam Raju Synthesis of the natural product calcaripeptide C derived from the fungal metabolite mycelium KF525 of Calcarisporium sp. has been achieved. This complementary approach avoids the use of a stoichiometric
Received 9th June 2015, Accepted 30th June 2015
amount of chiral auxiliary reagents as commonly used to generate enantioenriched advanced precursors.
DOI: 10.1039/c5ob01164g
The enantioselective synthesis of calcaripeptide C is remarkable in that using catalytic reactions sets the two stereogenic centers efficiently with good levels of enantioselectivity. Further diversification of the cal-
www.rsc.org/obc
caripeptide C structures is possible by employing a complementary catalytic enantioenriched Ru-catalyst.
Introduction Macrocyclic structures composed of a polypeptide and a polyketide motif, such as cyclodepsipeptide, have attracted attention owing to their broad range of bioactivity that offers possible leads for natural product-derived drugs.1 A recent addition to this class include novel, macrocyclic structurally related calcaripeptides A (1), B (2) and C (3)2 as derived from the marine fungal metabolite mycelium KF525 of Calcarisporium sp. (Fig. 1). NMR spectroscopic data and chemical derivatization coupled with X-ray crystallography structural elucidation confirm that the calcaripeptides A–C possess a structurally varied poly ketide carbon-chain which includes methyl stereogenic centers connected to a cyclic (L-proline), acyclic amino acid (L-phenylalanine) dipeptide residue with the cis-orientation of the amide bonds. Interestingly, the calcaripeptides A–C were tested for broad panel of 43 assays; however, antibacterial, antifungal, and cytotoxic properties were not detected nor was there an inhibition of the enzyme targets. This biological observation is contrary to observations of cyclic depsipeptides and their derivatives, which exhibit a diverse spectrum of biological activities, including insecticidal, antiviral, antimicrobial, antitumor, tumor-promotive, antiinflammatory and immunosuppressive actions.3 This provides an opportunity to undertake systematic SAR monitoring of the macrocyclic structures of calcaripeptides A–C and their relative
Fig. 1
Marine cyclodepsipeptide of calcaripeptides A–C.
stereogenic centers, which influence the biological and pharmaceutical activity levels. Furthermore, variations in the configuration of the stereogenic centers are expected to lead to good activity. Thus, they show noteworthy differences in their biological profiles.4
Results and discussion Organic & Biomolecular Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 607, India. E-mail: [email protected]; Fax: +91-40-27193275; Tel: +91-40-27193154 † Electronic supplementary information (ESI) available: Copies of 1H and NMR spectra. See DOI: 10.1039/c5ob01164g
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C
Recently, a flexible total synthesis of calcaripeptides A–C was pioneered based on a set of aldol reactions, in this case Evans alkylation, Crimmins syn-aldol and Crimmins acetate aldol to install the 2S, 4R, and 7R methyl stereogenic centers that are
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embedded in sub-structures.5 We previously demonstrated that the catalytic asymmetric transfer hydrogenation is the genesis of chirality, thus accessing functionalized chiral building blocks which have the option of potential stereogenic variation by switching a complementary ligand with a low level of loading.6 In relation to this, we envisioned utilizing catalytic asymmetric transfer hydrogenation to install stereogenic centers with the highest degree of diastereo- and enantioselectivity required for calcaripeptide C, 3. From a structural viewpoint, calcaripeptide C is highlighted by the presence of 14-membered macrocyclic structures with L-proline-L-phenylalanine dipeptide residue connected to a sub-structure possessing 2S, 4R and 7R methyl stereogenic centers. At the outset, we planned to execute a synthetic strategy for the non-peptidic part 5 of calcaripeptide C, which is a smaller cyclic member of the family. The stereogenic center 7R in the critical synthons 5 is established by the catalytic asymmetric transfer hydrogenation of a prochiral keto of 6, which in turn would be accessed by Marshall’s allenylation protocol7 using a (S)-propargyl mesylate 8 and an aldehyde which would be expected to arise from 7. The commercially available Roche ester envisions providing a lone 2S stereogenic center. Preceding studies5 suggested that the L-proline-L-phenylalanine dipeptide can be connected via a macrolactamization and macrolactonization strategy. Also, 8 could be readily prepared from enantioenriched propargyl alcohol7d which in turn necessitates the employment of an ATH procedure. The probable retrosynthetic plan of calcaripeptide C is shown in Scheme 1. Accordingly, the synthesis of 5 began with PMB protection of the primary alcohol of commercially available (R)-Roche ester 9 and the subsequent reduction of the ester to provide alcohol8 7 at a yield of 87% (over two steps). The Dess–Martin periodinane9 oxidation of 7 furnished the crude aldehyde, which was then directly subjected to a Pd-catalyzed-Znmediated addition of a (S)-propargyl mesylate 8. The expected syn–anti stereotriad 10 was isolated at a yield of 84% with an excellent diastereomeric ratio (96 : 4) as an inseparable mixture
Scheme 1
(Scheme 2). The diastereomeric ratio was determined by 1H NMR. The selectivity of this addition is considerably higher than that in the previously examined7b PMB-protected (R)-aldehyde and (R)-propargyl mesylate under similar reaction conditions.10 The secondary alcohol of 10 gave TBS-ether at a yield of 91% by means of TBSOTf in DCM. The prochiral keto was then introduced by a reaction of Weinreb–Nahm ketone synthesis11 employing the Weinreb
Scheme 2
Synthesis of prochiral keto compound 6.
Retro-synthetic analysis of calcaripeptides C.
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amide and pre-performed Li-acetylide generated from n-BuLi and 11 (Scheme 2). With the prochiral keto 6 in hand, we sought to realize ATH reduction conditions in order to generate enantioenriched advanced intermediate 12. An array of chiral-reducing agents was screened for this transformation. These results are shown in Table 1. The reaction of 6 with 1 mol% of the 18-electron precursor RuCl[(1R,2R)N-p-toluenesulfonyl-1,2-diphenylethanediamine](η6-pcymene), Cat. A and a formic acid/triethylamine azeotropic mixture as a hydrogen source, while stirring at an ambient temperature, resulted in the desired alcohol 12 at a yield of 40% (Table 1, entry 1). The same reaction in DCM with Cat. B
Table 1 Catalytic asymmetric transfer hydrogenation of prochiral ketone 6a
Entry
Conditions
Yieldb (%)
drc
1
1 mol% Cat. A HCO2H : Et3N (5 : 2) DCM, rt, 24 h 1 mol% Cat. B HCO2H : Et3N (5 : 2) DCM, rt, 24 h 1 mol% Cat. B 10 mol% K2CO3 2-Propanol, rt, 24 h 0.5 mol% Cat. B 10 mol% K2CO3 2-Propanol, rt, 24 h
40
—
81
—
96
96 : 4
75
96 : 4
2 3 4
a
All reactions were carried out on a scale of 1.0 mmol. b Isolated yields but not optimized. c The dr ratio was determined by 1H NMR.
Scheme 3
led to 12 at a yield of 81% (Table 1, entry 2). On the other hand, employing 1 mol% of the chiral 16-electron Ru complexes, Cat. B with 2-propanol as a hydrogen source, the prochiral ketone 6 was reduced to enantiomerically enriched alcohol 12 at a yield of 96% by 96 : 4 dr with a substrate-to-catalyst (S/C) ratio of 100 (Table 1, entry 3). The diastereomeric ratio was determined by 1H NMR and the stereochemistry of the newly formed hydroxyl group was assigned based on Noyori’s protocol.12 The optimum catalyst loading was found to be 1 mol%, while reducing it to 0.5 mol% led to a significant drop in the yield of product 12 (Table 1, entry 4). At this stage, we propose to protect the secondary alcohol as acetate for prospective synthetic convenience. Consequently, saponification would provide carboxylic acid derived from the corresponding proline ester and alcohol eventually intended for macrolactonization. Thus, the secondary alcohol in 12 was converted to acetate (Ac2O/Et3N/DMAP) and oxidative cleavage (DDQ, DCM : H2O) of the PMB group was undertaken, led by 13 at a yield of 85% (over two steps). Then, hydrogenation under a balloon pressure over 10% Pd/C on activated charcoal failed to reduce the triple bond, with a recovery of only the starting material. Also, replacing 10% Pd/C with 10% palladium dihydroxide on activated charcoal did not cause the reaction; however, employing 10 mol% of 20 wt% of palladium dihydroxide on carbon under otherwise identical conditions successfully reduced the internal acetylene to afford 14 at a 90% isolated yield. The primary alcohol of 14 was oxidized by Dess–Martin periodinane9 and the resulting aldehyde was exposed to Pinnick oxidation13 to obtain carboxylic acid 15 at a yield of 86% (over two steps), which is set for macrolactamiza-
Synthesis of calcaripeptides C (3).
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tion. Following a similar protocol, the coupling of 414 with 15 in DMF and EDCI, HOBt, DIPEA under stirring for 13 h at an ambient temperature gave 16 at a yield of 87% (Scheme 3). As anticipated, saponification15 under basic conditions liberated peptide-carboxylic acid and C7-alcohol successfully and the crude residue was subjected to MNBA-mediated macrolactonization16 conditions. The protected cyclodepsipeptide 17 was isolated at a yield of 50% over two steps. In the end, the fluoride-induced deprotection of the TBS group delivered the expected secondary chiral alcohol, which upon oxidation with Dess–Martin periodinane led to the anticipated target compound calcaripeptide C (3) at a yield of 88% (over two steps) (Scheme 3). The physical data for the synthesized compound were in full agreement with those reported for natural calcaripeptide C (3) and a comparison of the sign of 2 23 rotation ([α]23 D = −75.8 (c 0.2, MeOH) {lit. [α]D = −79.0 (c 0.2, MeOH)}) helped to assign the relative configuration of the new and existing stereogenic centers as 2S, 4R and 7R.
Conclusion In conclusion, we have developed a concise synthesis for cyclodepsipeptide calcaripeptide C in which two stereogenic centers were installed by efficient catalytic asymmetric transfer hydrogenation (ATH) together with Marshall’s allenylation. This process is significant in how it demonstrated that a single Ru-asymmetric catalyst is the basis for the synthesis of two variant intermediates with high diastereo- and enantioselectivity. Further, a set of diastereo-divergent congeners of this family can be realized by employing a complementary catalyst. In general, its high catalytic competence, enantioselectivity and operational expediency can make this process adoptable for analogous biologically active natural molecules. Further optimization and application of this strategy for the diastereo-divergent congeners of calcaripeptide C in particular and in general cyclodepsipeptide family members are at present under investigation in our lab.
Experimental General information All reactions were conducted under an inert atmosphere. The apparatus used for reactions were oven dried. THF was distilled over sodium benzophenone ketyl before use and DCM was distilled over calcium hydride. (S)-But-3-yn-2-yl methanesulfonate was prepared according to the reported procedure.7d All other chemicals used were commercially available. Progress of the reactions was monitored by TLC on pre-coated silica gel 60 F-254. Evaporation of solvents was performed at reduced pressure on a rotary evaporator. Column chromatography was carried out with silica gel grade 60–120 and 100–200 mesh. 1H NMR spectra were recorded at 300 & 500 MHz and 13C NMR at 75 MHz in CDCl3. Chemical shifts (δ) are reported in ppm. Tetramethylsilane (δ = 0.00 ppm for 1H) and CDCl3 (δ =
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77.00 ppm for 13C) were used as the internal standards. Scalar coupling constants ( J) are reported in hertz (Hz). The following abbreviations are used to designate the multiplicities: s = singlet, d = doublet, t = triplet, dd = doublet of doublets, ddd = doublet of doublet of doublets, m = multiplet, br.s = broad singlet. Mass spectral data were compiled using MS (ESI), and high resolution mass spectra (HRMS) were recorded by using the ESI probe in positive mode using an ORBITRAP analyzer. Optical rotations were recorded on a high sensitive polarimeter with a 1 mL cell. (2R,3R,4R)-1-((4-Methoxybenzyl)oxy)-2,4-dimethylhex-5-yn3-ol (10). A DCM (30 mL) solution of 7 (1.5 g, 7.14 mmol) was treated with NaHCO3 (1.8 g, 21.42 mmol) and Dess–Martin periodinane (6.05 g, 14.29 mmol) at 0 °C, and the resulting reaction mixture was allowed to stir for 1 h at the same temperature. Then, the reaction mixture was quenched by the sequential addition of satd. aqueous Na2S2O3 (15 mL) and satd. aqueous NaHCO3 (15 mL) and extracted with DCM (2 × 30 ml). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford an aldehyde as a pale yellow oil, which was taken onto the next step without purification. To a stirring solution of Pd(OAc)2 (75.38 mg, 0.34 mmol) in THF (20 mL) at −78 °C was added PPh3 (88.10 mg, 0.34 mmol), aldehyde (1.40 g, 6.73 mmol), and mesylate (S)-8 (1.49 g, 10.10 mmol) in the same order. To this reaction mixture, diethylzinc (20.2 mL, 1 M in hexane) was added over a period of 10 min, and stirring was maintained for 15 min. Then, the mixture was warmed to −20 °C and stirred overnight at the same temperature. The reaction mixture was quenched with NH4Cl : Et2O (1 : 1), and the layers were separated. The aqueous layer was extracted with Et2O (2 × 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the residue which was purified by silica gel column chromatography using hexane/ethyl acetate as the eluent to give 10 (1.48 g, 84%) as an inseparable mixture of isomers 1 (dr = 96 : 4, based on nmr). [α]35 D = −7.12 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ 7.25 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.44 (s, 2H), 3.81 (s, 3H), 3.60–3.41 (m, 3H), 2.73–2.60 (m, 1H), 2.13 (d, J = 2.5 Hz, 1H), 2.10–1.87 (m, 2H), 1.20 (d, J = 7.0 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H). 13C NMR (75 MHz): 159.1, 130.2, 129.1, 113.7, 86.2, 75.6, 73.5, 72.8, 70.4, 55.2, 36.1, 30.4, 17.7, 10.9. IR (KBr): 3424, 2935, 2865, 1639, 1378, 1095, 982, 916, 742 cm−1. MS (ESI) m/z: 285 (M + Na)+. tert-Butyl(((2R,3R,4R)-1-((4-methoxybenzyl)oxy)-2,4-dimethylhex-5-yn-3-yl)oxy)dimethylsilane (11). To a solution of 10 (1.2 g, 4.58 mmol) in CH2Cl2 (15 mL) were added 2,6-lutidine (0.64 mL, 5.50 mmol) and TBSOTf (1.2 mL, 5.04 mmol) at 0 °C. After being stirred at 0 °C for 30 min, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with DCM (2 × 30 mL). The organic layer was washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic contents were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure, followed by
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purification by silica gel column chromatography using hexane/ethyl acetate as the eluent to afford the protected alcohol 11 (1.56 g, 94%) as a colourless oil. [α]34 D = −1.6 (c = 1.2, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.25 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.3 Hz, 2H), 4.42 (s, 2H), 3.81 (s, 3H), 3.79–3.75 (m, 1H), 3.48–3.40 (m, 1H), 3.32–3.24 (m, 1H), 2.67–2.56 (m, 1H), 2.14–2.05 (m, 1H), 2.03 (d, J = 3 Hz, 1H), 1.18 (d, J = 7.5 Hz, 3H), 0.95–0.84 (m, 13H), 0.09 (s, 3H), 0.04 (s, 3H). 13C NMR (75 MHz): 159.1, 130.7, 129.2, 113.7, 87.3, 74.4, 73.1, 72.4, 70.0, 55.2, 36.9, 31.6, 26.1, 17.5, 12.1, −3.9, −4.2. IR (KBr): 2955, 2931, 2857, 2208, 1613, 1513, 1462, 1361, 1085, 835, 632 cm−1. MS (ESI) m/z: 399 (M + Na)+. HRMS: calculated for C22H36O3NaSi [M + Na]+, 399.2326, found 399.2344. (5R,6R,7R)-6-((tert-Butyldimethylsilyl)oxy)-8-((4-methoxybenzyl)oxy)-5,7-dimethyloct-3-yn-2-one (6). TBS protected alcohol 11 (1.5 g, 3.99 mmol) was dissolved in THF (15 mL) under argon and cooled to −78 °C. Then, a 2.5 M solution of n-butyllithium in hexane (1.9 mL, 4.79 mmol) was added and warmed to −30 °C, and stirred for 30 min at this temperature. Again the reaction mixture was cooled to −78 °C, then Nmethoxy-N-methylacetamide (616 mg, 5.98 mmol) in THF (2 mL) was added. The resulting reaction mixture was stirred at −30 °C (3 h), followed by quenching by addition of saturated NH4C1 solution (20 mL). The aqueous layer was extracted with EtOAc (2 × 30 mL), washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure resulting in a crude residue which was purified by silica gel column chromatography using hexane/ethyl acetate as the eluent and gave keto compound 6 (1.19 g, 71%) as a colourless oil. [α]34 D = +6.48 (c = 1.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.25 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 4.41 (s, 2H), 3.81 (s, 3H), 3.8 (t, J = 4 Hz, 1H), 3.45–3.40 (m, 1H), 3.30–3.25 (m, 1H), 2.80–2.75 (m, 1H), 2.28 (s, 3H), 2.08–1.98 (m, 1H), 1.22 (d, J = 7.17 Hz, 3H), 0.93 (d, J = 6.86 Hz, 3H), 0.91 (s, 9H), 0.1 (s, 3H), 0.05 (s, 3H). 13C NMR (75 MHz): 184.7, 159.1, 130.5, 129.2, 113.7, 96.5, 82.8, 74.5, 72.54, 72.52, 55.2, 37.8, 32.7, 32.0, 26.0, 18.3, 17.3, 12.2, −4.1. IR (KBr): 2955, 2931, 2857, 2212, 1752, 1677, 1613, 1513, 1462, 1359, 1249, 1085, 836, 775 cm−1. MS (ESI) m/z: 441 (M + Na)+. HRMS: calculated for C24H38O4NaSi [M + Na]+, 441.2432, found 441.2447. (2R,5R,6R,7R)-6-((tert-Butyldimethylsilyl)oxy)-8-((4-methoxybenzyl)oxy)-5,7-dimethyloct-3-yn-2-ol (12). To a solution of 6 (1.0 g, 2.39 mmol) in isopropanol (10.0 mL) was added pre-dissolved ruthenium catalyst B6a [14.8 mg, 0.024 mmol in DCM (2.0 mL)] and K2CO3 (33.0 mg, 0.24 mmol) successively under argon. The resulting reaction mixture was stirred for 12 h at room temperature, and then the solvent was evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography using EtOAc in hexane as the eluent resulting in alcohol 12 (965 mg, 96% yield). [α]34 D = +13.4 (c = 1.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.26 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.68 Hz, 2H), 4.42 (s, 2H), 3.81 (s, 3H), 3.77–3.72 (m, 1H), 3.47–3.38 (m, 1H), 3.32–3.23 (m, 1H), 2.68–2.55 (m, 1H), 2.14–2.02 (m, 1H), 1.69 (br.s, 1H), 1.38 (d, J = 6.42 Hz, 3H), 1.15 (d, J = 7.17 Hz, 3H), 0.94–0.86 (m, 13H), 0.08 (s, 3H), 0.03 (s, 3H). 13C NMR (75 MHz): 159.1, 130.7,
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129.2, 87.3, 83.9, 74.5, 73.2, 72.5, 58.5, 55.3, 37.0, 31.8, 26.0, 24.5, 18.3, 17.3, 12.3, −4.1, −4.3. IR (KBr): 3424, 2955, 2931, 2855, 2225, 1733, 1612, 1513, 1462, 1371, 1249, 1084, 836, 774 cm−1. MS (ESI) m/z: 443 (M + Na)+. HRMS: calculated for C24H40O4NaSi [M + Na]+, 443.2588, found 443.2598. (2R,5R,6R,7R)-6-((tert-Butyldimethylsilyl)oxy)-8-((4-methoxybenzyl)oxy)-5,7-dimethyloct-3-yn-2-yl acetate (12a). To a DCM (10.0 mL) solution of propargyl alcohol 12 (900 mg, 2.14 mmol) were added triethylamine (0.5 mL, 3.21 mmol), and acetic anhydride (0.3 ml, 2.79 mmol) and a catalytic amount of 4-dimethylaminopyridine (10.0 mg) was added to the mixture and the resulting contents were stirred at ambient temperature for 12 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (2 × 30 mL), washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography over silica gel using hexane/ethyl acetate as the eluent affording protected alcohol 12a (886 mg, 90%) as a colourless oil. [α]34 D = +49.7 (c = 1.2, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.26 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 5.50–5.39 (m, 1H), 4.42 (s, 2H), 3.81 (s, 3H), 3.72 (t, J = 4.5, 8.3, 1H), 3.49–3.40 (m, 1H), 3.32–3.21 (m, 1H), 2.69–2.56 (m, 1H), 2.10–1.99 (m, 4H), 1.42 (d, J = 6.8 Hz, 3H), 1.15 (d, J = 6.8 Hz, 3H), 0.96–0.86 (m, 13H), 0.08 (s, 3H), 0.04 (s, 3H). 13C NMR (75 MHz): 169.9, 159.0, 130.1, 129.1, 113.7, 88.1, 80.1, 74.6, 73.0, 72.4, 60.8, 55.3, 37.3, 31.6, 26.0, 21.7, 21.1, 18.3, 17.8, 12.2, −4.1, −4.2. IR (KBr): 2956, 2932, 2856, 2246, 1743, 1612, 1513, 1462, 1370, 1242, 1052, 836, 774 cm−1. MS (ESI) m/z: 485 (M + Na)+. HRMS: calculated for C26H42O5NaSi [M + Na]+, 485.2694, found 485.2705. (2R,5R,6R,7R)-6-((tert-Butyldimethylsilyl)oxy)-8-hydroxy5,7-dimethyloct-3-yn-2-yl acetate (13). To a stirred and cooled (0 °C) solution of 12a (800 mg, 1.73 mmol) in DCM/H2O (20 : 1, 10 mL) was added DDQ (472 mg, 2.08 mmol). The resulting reaction mixture was stirred for 45 min, and quenched with saturated aqueous NaHCO3 (10 mL), the aqueous layer was extracted with DCM (2 × 20 mL), and the combined organic layers were washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane/ ethyl acetate as the eluent to afford alcohol 13 (556 mg, 94%) 1 as a colourless oil. [α]34 D = +49.58 (c = 1.2, CHCl3). H NMR (500 MHz, CDCl3): δ 5.43–5.38 (m, 1H), 3.71–3.66 (m, 2H), 3.60–3.56 (m, 1H), 2.70–2.64 (m, 1H), 2.05 (s, 3H), 2.0–1.87 (m, 2H), 1.45 (d, J = 6.7 Hz, 3H), 1.18 (d, J = 7.0 Hz, 3H), 0.91 (s, 9H), 0.88 (d, J = 7.0 Hz, 3H), 0.08 (d, J = 3.2 Hz, 6H). 13C NMR (75 MHz): 170.2, 87.5, 80.5, 76.0, 65.5, 60.8, 39.6, 30.4, 25.9, 21.5, 21.1, 18.2, 17.7, 12.9, −4.2, −4.5. IR (KBr): 3462, 2856, 2929, 2856, 2241, 1742, 1460, 1372, 1242, 1038, 837, 774 cm−1. MS (ESI) m/z: 365 (M + Na)+. HRMS: calculated for C18H34O4NaSi [M + Na]+, 365.2119, found 365.2126. (2R,5R,6R,7R)-6-((tert-Butyldimethylsilyl)oxy)-8-hydroxy-5,7dimethyloctan-2-yl acetate (14). Compound 13 (500 mg, 1.46 mmol) was dissolved in MeOH (5.0 mL) and 20% Pd(OH)2/C (20% w/w; 50 mg) catalyst was added. The reaction
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flask was purged with H2 three times and the solution was left stirring under an atmosphere of H2 for 10 h. The solution was then filtered through a pad of celite and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane/ ethyl acetate as the eluent to afford compound 14 (457 mg, 1 90%) as a colourless oil. [α]34 D = −8.5 (c = 1.2, CHCl3). H NMR (500 MHz, CDCl3): δ 4.89–4.82 (m, 1H), 3.62–3.59 (m, 1H), 3.58–3.53 (m, 1H), 3.49–3.44 (m, 1H), 2.03 (s, 3H), 1.91–1.83 (m, 2H), 1.70 (br.s, 1H), 1.63–1.48 (m, 4H), 1.21 (d, J = 6.4 Hz, 3H), 0.92–0.88 (m, 13H), 0.86 (d, J = 6.9 Hz, 3H), 0.07 (s, 3H), 0.05 (s, 3H). 13C NMR (75 MHz): 170.8, 76.4, 71.5, 66.4, 38.6, 37.5, 34.0, 28.9, 26.0, 21.4, 19.9, 18.3, 16.5, 11.7, −3.9, −4.3. IR (KBr): 3451, 2956, 2927, 2855, 1737, 1462, 1374, 1249, 1099, 836, 773 cm−1. MS (ESI) m/z: 369 (M + Na)+. HRMS: calculated for C18H38O4NaSi [M + Na]+, 369.2432, found 369.2449. (2S,3R,4R,7R)-7-Acetoxy-3-((tert-butyldimethylsilyl)oxy)-2,4dimethyloctanoic acid (15). A solution of 14 (400 mg, 1.16 mmol) in dry DCM (10 mL) was treated with NaHCO3 (292 mg, 3.47 mmol) and Dess–Martin periodinane (980 mg, 2.31 mmol) at 0 °C, and the resulting reaction mixture was allowed to stir at the same temperature until completion as indicated by TLC analysis (∼1 h). Then, the reaction mixture was quenched by the sequential addition of satd. aqueous Na2S2O3 (8.0 mL) and satd. aqueous NaHCO3 (8.0 mL). The aqueous layer extracted with DCM (2 × 30 mL) and the combined organic contents were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford the crude aldehyde as a pale yellow oil, which was taken to the next step without purification. The above aldehyde (380 mg, 1.11 mmol), 2-methyl2-butene (0.6 mL, 5.55 mmol), and NaH2PO4 (147 mg, 1.22 mmol) were dissolved in t-BuOH/H2O (4 : 1, v/v, 6 mL) and the resulting suspension was cooled to 0 °C. Then, NaClO2 (360 mg, 3.60 mmol) was added and the resultant mixture was stirred at room temperature for 50 min. The reaction mixture was diluted with H2O, cooled to 0 °C, and acidified with 0.5 M aqueous HCl. The resultant mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane/ethyl acetate as the eluent to afford compound 15 (360 mg, 86% over two steps) as a colourless oil. [α]34 D = +5.8. 1H NMR (500 MHz, CDCl3): δ 4.89–4.81 (m, 1H), 3.88 (t, J = 5.1, 10.1, 1H), 2.66–2.60 (m, 1H), 2.02 (s, 3H), 1.61–1.45 (m, 4H), 1.20 (d, J = 6.3 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H), 0.92–0.85 (m, 13H), 0.06 (s, 3H), 0.02 (s, 3H). 13C NMR (75 MHz): 180.9, 170.9, 76.9, 71.3, 42.6, 38.1, 33.9, 29.8, 27.9, 25.9, 21.4, 19.9, 18.3, 16.0, 11.7, −4.2, −4.3. IR (KBr): 2938, 2855, 1718, 1462, 1374, 1249, 1099, 836, 773 cm−1. MS (ESI) m/z: 383 (M + Na)+. HRMS: calculated for C18H36O5SiNa [M + Na]+, 383.2224, found 383.2238. (S)-Methyl 1-((S)-2-((2S,3R,4R,7R)-7-acetoxy-3-((tert-butyldimethylsilyl)oxy)-2,4-dimethyloctanamido)-3-phenylpropanoyl)pyrrolidine-2-carboxylate (16). A solution of dipeptide 4 (251 mg, 0.67 mmol) in DCM (4.0 mL) was treated with TFA
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(1.0 mL) and stirred at rt. Then, the solvent was evaporated under reduced pressure to get the corresponding Boc deprotected compound. The crude Boc deprotected residue was dissolved in anhydrous DMF (3.0 mL) under argon and cooled to 0 °C. DIPEA (0.20 mL, 1.11 mmol) was added, and the mixture was stirred for 15 min at 0 °C. Acid 15 (200 mg, 0.56 mmol) dissolved in anhydrous DMF (2 mL) and HOBt (91 mg, 0.67 mmol) was then added, successively. Stirring was continued further at the same temperature for 15 min before addition of EDCI (104 mg, 0.67 mmol). The combined reaction contents were warmed slowly to room temperature and stirred further overnight. DMF was removed under reduced pressure, and the resultant residue was extracted with EtOAc. The organic layers were washed with saturated NH4Cl solution, water, and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane/ethyl acetate as the eluent to afford compound 16 (303 mg, 87%) as a colourless liquid (mixture of rotamers). 1 [α]34 H NMR D = −21.5 (c = 1.2, CHCl3). Major rotamer: (500 MHz, CDCl3): δ 7.31–7.20 (m, 5H), 6.44 (d, J = 7.9 Hz, 1H), 4.97–4.91 (m, 1H), 4.78–4.73 (m, 1H), 4.50–4.45 (m, 1H), 3.80–3.73 (m, 4H), 3.70–3.64 (m, 1H), 3.20–3.09 (m, 2H), 2.95 (dd, J = 13.7, 6.3 Hz, 1H), 2.38–2.31 (m, 1H), 2.22–2.14 (m, 1H), 2.0 (s, 3H), 1.97–1.88 (m, 3H), 1.55–1.39 (m, 5H), 1.15 (d, J = 6.3 Hz, 3H), 1.05 (d, J = 7.0 Hz, 3H), 0.91–0.82 (m, 12H); 0.03 (s, 3H), −0.01 (s, 3H). 13C NMR (75 MHz): 174.6, 172.2, 170.7, 170.4, 136.1, 129.7, 128.3, 126.8, 77.1, 71.3, 59.0, 52.2, 51.6, 46.9, 44.2, 38.5, 38.2, 33.9, 29.0, 27.5, 26.0, 24.9, 22.7, 21.4, 19.7, 18.3, 16.0, 14.6, −4.1, −4.2. IR (KBr): ν = 2948, 2793, 1749, 1642, 1443, 1327, 1097, 852, 779 cm−1. MS (ESI) m/z: 641 (M + Na)+. HRMS: calculated for C33H54O7N2NaSi [M + Na]+, 641.3593, found 641.3610. (3R,6R,7R,8S,11S,16aS)-11-Benzyl-7-((tert-butyldimethylsilyl)oxy)-3,6,8-trimethyldodecahydro-1H-pyrrolo[2,1-c][1,4,7]oxadiazacyclotetradecine-1,9,12-trione (17). To a solution of compound 16 (100 mg, 0.16 mmol) in THF : H2O (3 : 1, 4 mL) was added LiOH·H2O (40.3 mg, 0.96 mmol) and the resulting contents were stirred for 5 h at room temperature. The solvent was removed under reduced pressure, and the resultant residue was extracted with EtOAc. The organic layers were dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude residue of the corresponding hydroxy acid (85 mg) which was then subjected to the next reaction without purification. To a stirred solution of 2-methyl-6-nitrobenzoic anhydride (83 mg, 0.24 mmol) and DMAP (45.7 mg, 0.38 mmol) in anhydrous DCM (80 mL) under argon was added dropwise a solution of the above crude residue of hydroxy acid (85 mg, 0.15 mmol) dissolved in anhydrous DCM (45 mL). The resulting reaction mixture was stirred for 16 h at ambient temperature and quenched with saturated NaHCO3 (10 ml) solution. The organic layer was separated and washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the residue which was purified by silica gel column chromatography using hexane/ethyl acetate
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as the eluent to afford the desired compound 17 (43 mg, 50% over two steps) as a colourless liquid. [α]34 D = −56.2 (c = 1.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.31–7.20 (m, 5H), 6.52 (d, J = 7.2 Hz, 1H), 5.20–5.11 (m, 1H), 4.76–4.68 (m, 1H), 3.71 (d, J = 5.2, 1H), 3.53 (d, J = 7.3 Hz, 1H), 3.44–3.32 (m, 2H), 3.23 (dd, J = 12.4, 4.4 Hz, 1H), 2.87–2.81 (m, 1H), 2.38–2.32 (m, 1H), 2.07–1.96 (m, 1H), 1.85–1.56 (m, 5H), 1.44–1.36 (m, 1H), 1.27–1.34 (m, 1H), 1.22 (d, J = 6.1 Hz, 3H), 1.11 (d, J = 7.0 Hz, 3H), 0.93–0.79 (m, 13H); 0.14 (s, 3H), 0.06 (s, 3H). 13C NMR (75 MHz): 173.3, 170.7, 170.1, 136.8, 129.4, 128.6, 126.9, 74.0, 58.7, 53.2, 45.4, 44.5, 41.1, 35.0, 32.0, 29.4, 29.3, 28.5, 25.9, 22.0, 20.9, 18.1, 15.3, 14.1, −4.2, −4.8. IR (KBr): 2938, 2853, 1735, 1642, 1475, 1356, 1266, 1097, 832, 776 cm−1. MS (ESI) m/z: 545 (M + H)+. HRMS: calculated for C30H49O5N2Si [M + H]+, 545.3405, found 545.3391. (3R,6R,7R,8S,11S,16aS)-11-Benzyl-7-hydroxy-3,6,8-trimethyldodecahydro-1H-pyrrolo[2,1-c][1,4,7]oxadiazacyclotetradecine1,9,12-trione (17a). To a THF (2.0 mL) solution of 17 (20 mg, 0.04 mmol) was added 0.06 mL of TBAF (1 M in THF) at 0 °C. After addition, the reaction mixture was warmed to room temperature and stirred for 3 h. Then, the reaction mixture was quenched with saturated NaHCO3 (2 mL) solution, extracted with EtOAc (2 × 5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane/ethyl acetate as the eluent to give compound 17a, as colourless oil. Yield: 94% (15 mg). [α]34 D = −56.2 (c = 1.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.29–7.30 (m, 5H), 6.65 (d, J = 7.2 Hz, 1H), 5.23–5.17 (m, 1H), 4.78–4.70 (m, 1H), 3.73 (dd, J = 1.4, 6.3, 1H), 3.65 (d, J = 7.5 Hz, 1H), 3.50–3.43 (m, 1H), 3.41–3.34 (m, 1H), 3.19 (dd, J = 12.5, 4.6 Hz, 1H), 2.88 (dd, J = 12.4, 11.0 Hz, 1H), 2.49–2.42 (m, 1H), 2.01–1.92 (m, 1H), 1.85–1.79 (m, 1H), 1.78–1.66 (m, 4H, merged with water peak), 1.52–1.43 (m, 1H), 1.35–1.26 (m, 1H), 1.22 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H), 0.93–0.84 (m, 1H). 13C NMR (75 MHz): 173.2, 170.8, 170.2, 136.7, 129.4, 128.6, 127.0, 74.2, 58.9, 53.0, 45.5, 43.9, 40.9, 35.4, 34.9, 28.6, 28.5, 21.9, 20.8, 18.3, 15.0. IR (KBr): 3429, 3230, 2945, 1732, 1632, 1469, 1249, 1099, 836, 773 cm−1. MS (ESI) m/z: 453 (M + Na)+. HRMS: calculated for C24H34O5N2Na [M + Na]+, 453.2349, found 453.2360. Calcaripeptide C (3) A dry DCM (2 mL) solution of 17a (10 mg, 0.02 mmol) was treated with NaHCO3 (5.9 mg, 0.07 mmol) and Dess–Martin periodinane (17.0 mg, 0.04 mmol) at 0 °C, and the resulting reaction mixture was allowed to stir for 2 h at the same temperature. The reaction mixture was quenched by the sequential addition of satd. aqueous Na2S2O3 (1 mL) and satd. aqueous NaHCO3 (1 mL) and extracted with DCM (2 × 3 mL). The combined organic phases were washed with brine (2.0 mL), dried over anhydrous Na2SO4, filtered and evaporated resulting in a residue which was purified by silica gel column chromatography using hexane/ethyl acetate as the eluent to give calcaripeptide C, 3 (7.5 mg, 88% yield). [α]34 D = −75.8 (c 0.2, MeOH). 1 H NMR (acetone-d6, 500 MHz) δ 7.65–7.57 (m, 1H), 7.32–7.28
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(m, 2H), 7.26–7.20 (m, 3H), 5.00–4.94 (m, 1H), 4.87–4.89 (m, 1H), 3.90 (d, J = 8.1 Hz, 1H), 3.65 (q, J = 6.9 Hz, 1H), 3.39–3.34 (m, 2H), 3.06 (dd, J = 12.4, 4.6 Hz, 1H), 2.92 (dd, J = 12.4, 10.0 Hz, 1H), 2.85 (m, 1H, merged with moisture peak), 1.89–1.83 (m, 2H), 1.75–1.62 (m, 2H), 1.56–1.40 (m, 3H), 1.21 (d, J = 7.0 Hz, 3H), 1.19 (d, J = 6.3 Hz, 3H), 1.12–1.04 (m, 1H), 1.01 (d, J = 6.7 Hz, 3H). 13C NMR (acetone-d6, 75 MHz) δ 209.3, 172.2, 170.9, 169.5, 138.2, 130.2, 129.2, 127.5, 74.0, 59.8, 54.3, 52.3, 46.3, 44.1, 40.6, 35.3, 31.8, 30.3, 22.4, 21.0, 15.6, 14.5 ppm. IR (KBr): ν 3295, 2938, 2851, 1735, 1640, 1626, 1472, 1259, 1094, 776 cm−1. MS (ESI) m/z: 451 (M + Na)+. HRMS (ESI) m/z calculated for C24H32N2O5Na [M + Na]+, 451.2203, found 451.2203.
Acknowledgements We are grateful to Director, IICT, for constant encouragement. Financial support was provided by the DST, New Delhi, India (Grant No. SR/S1/OC-08/2011), and ORGIN (CSC-0108) programme (CSIR) of XII Five year plan. UGC & CSIR (New Delhi) are gratefully acknowledged for awarding the fellowship to V. N. R. and R. R.
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