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Total Synthesis of Thiostrepton, Part 2: Construction of the Quinaldic Acid Macrocycle and Final Stages of the Synthesis

2004; Wiley; Volume: 43; Issue: 38 Linguagem: Inglês

10.1002/anie.200461341

ISSN

1521-3773

Autores

K. C. Nicolaou, Mark Zak, Brian S. Safina, Sang Hyub Lee, Anthony A. Estrada,

Tópico(s)

Synthetic Organic Chemistry Methods

Resumo

The flagship of the thiopeptide class of antibiotics, thiostrepton (see formula), was synthesized by fusion of the quinaldic acid moiety onto the dehydropiperidine–thiazoline macrocycle (see above) followed by demasking of its sensitive functionalities. In the preceding Communication in this issue1 we described the construction of the thiazoline-containing macrocycle 21 as an advanced intermediate toward the total synthesis of thiostrepton (1). Herein we report the construction of suitable dipeptide (8, Scheme 1) and quinaldic acid (22, Scheme 2) fragments, their union with 2, and the final stages of the total synthesis of 1. Scheme 1 outlines the synthesis of the required dipeptide derivative 8 from 3, a known phenylseleno-substituted derivative of alanine.2 Thus, 3 was converted into allyl ester 4, which was treated with TFA to effect its conversion into the amino derivative 5. Coupling of amine 5 with Boc-L-alanine (6) proceeded under the influence of EDC–HOAt to afford dipeptide 7 (60 % overall yield from 4), whose TFA-mediated deprotection liberated primary amine 8, ready for coupling with the appropriate quinaldic acid moiety. Construction of dipeptide 8. Reagents and conditions: a) AllylOH (2.0 equiv), EDC (1.1 equiv), 4-DMAP (0.1 equiv), CH2Cl2, 25 °C, 3 h, 70 %; b) TFA/CH2Cl2 (1:1), 0 °C, 1 h; c) Boc-L-Ala-OH (1.1 equiv), HOAt (1.1 equiv), EDC (1.1 equiv), DMF, 25 °C, 2 h, 60 % (two steps); d) TFA/CH2Cl2 (1:1), 0 °C, 30 min, 99 %. EDC=1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-DMAP=4-dimethylamino pyridine; TFA=trifluoroacetic acid; Boc=tert-butoxycarbonyl; HOAt=1-hydroxy-7-azabenzotriazole; DMF=N,N-dimethylformamide. Scheme 2 delineates the synthesis of the entire quinaldic acid chain 22 which commenced from 2-quinoline carboxylic acid (9) and proceeded through asymmetric epoxidation of olefin 12 and sequential attachment to the resulting epoxide of an isoleucine residue and of dipeptide 8. Thus, 9 was converted in five steps and good overall yield as previously described3 into functionalized methyl ester 10. The latter compound was then oxygenated to afford 11 in 65 % overall yield through a Boekelheide-type sequence4 involving a) MCPBA-mediated N-oxide formation; b) TFAA-induced acylation of the generated N-oxide; and c) NaHCO3-facilitated rearrangement–hydrolysis of the resulting trifluoroacetate. Alcohol 11 was then dehydrated by treatment with Burgess reagent to afford olefin 12 in 68 % yield. The product 12 served well as the precursor to the desired compound 13 in a diastereoselective epoxidation reaction brought about by NaOCl in the presence of the Katsuki manganese–salen catalyst (R,R)-MnSal and 4-phenyl-pyridine N-oxide.5 Under these conditions, epoxide 13 was obtained as a mixture of diastereomers with the desired one predominating in ≈87:13 ratio and 82 % combined yield. Chromatographic separation of 13 followed by radical bromination led to a mixture of diastereomeric bromides 14 (40 % yield plus 26 % recovered starting material) which were eliminated by exposure to DBU to afford epoxyolefin 15 in 96 % yield. The epoxide moiety within 15 was then regio- and stereoselectively opened by the free amine of L-isoleucine allyl ester in the presence of lithium perchlorate to afford aminoalcohol 16 in 69 % yield. Presumably, the observed regioselectivity in this reaction is due to coordination of the lithium ion with the quinaldic acid nitrogen atom which simultaneously activates the epoxide moiety and deactivates the benzylic site through destabilization of the incipient carbocation at that position.6 The hydroxy group of 16 was then protected as a TBS ether by treatment with TBSOTf in the presence of iPr2NEt to furnish bis(silyl ether) 17 (96 % yield), whose methyl ester was selectively hydrolyzed by exposure to NaOH to afford carboxylic acid 18 (89 % yield). This maneuver was necessary to install a protecting group on the pyridine-bound carboxy group suitable for the subsequent and rather delicate elaboration of the growing chain of the molecule. As such a moiety, the fluorenylmethyl (Fm) group was then introduced at this position by esterification with FmOH and through the Yamaguchi7 protocol, leading to ester 19 in 64 % yield. The allyl ester group was then removed from the isoleucine residue by palladium-catalyzed reductive cleavage,8 which gave rise to the corresponding carboxylic acid 20 in good yield. Coupling of 20 with dipeptide 8 (Scheme 1) under established conditions generated quinaldic acid derivative 21 (Table 1) in 66 % yield from 19. Finally, treatment of 21 with [PdCl2(PPh3)2]–nBu3SnH liberated the targeted carboxylic acid 22 in 87 % yield, ready for incorporation into the growing frame of 1. Synthesis of quinaldic acid subunit 22. Reagents and conditions: a) MCPBA (1.0 equiv), CH2Cl2, 25 °C, 12 h; b) TFAA (3.0 equiv), CH2Cl2, 25 °C, 12 h; c) NaHCO3 (2 M), CH2Cl2, 8 h, 65 % (three steps); d) Burgess reagent (1.2 equiv), THF/benzene (1:1), reflux, 3.5 h, 68 %; e) (R,R)-MnSal (0.01 equiv), 4-Ph-py-N-oxide (0.1 equiv), NaOCl (0.79 M), phosphate buffer adjusted to pH 11.5 with NaOH (2.0 M), CH2Cl2, 25 °C, 1 h, 82 %, ≈87:13 ratio of products; f) NBS (1.1 equiv), AIBN (0.1 equiv), CCl4, 80 °C, 40 min, 40 % (and 26 % recovered starting material); g) DBU (1.1 equiv), THF, 25 °C, 2 h, 96 %; h) H-L-Ile-OAllyl (3.0 equiv), LiClO4 (5.0 equiv), MeCN, 60 °C, 22 h, 69 %; i) TBSOTf (3.0 equiv), iPr2NEt (5.0 equiv), THF, 25 °C, 3 h, 96 %; j) NaOH, MeOH, THF, 25 °C, 6 h, 89 %; k) 2,4,6-trichlorobenzoyl chloride (2.0 equiv), Et3N (6.0 equiv), toluene, 25 °C, 12 h; then FmOH (3.0 equiv), 4-DMAP (0.1 equiv), 25 °C, 12 h, 64 %; l) [PdCl2(PPh3)2] (0.1 equiv), nBu3SnH (1.1 equiv), CH2Cl2, 0 °C, 1 h; m) 8 (1.1 equiv), HATU (1.1 equiv), HOAt (1.1 equiv), DMF, 25 °C, 3 h, 66 % (two steps); n) [PdCl2(PPh3)2], (0.1 equiv), nBu3SnH (1.1 equiv), CH2Cl2, 0 °C, 30 min, 87 %. MCPBA=m-chloroperoxybenzoic acid; TFAA=trifluoroacetic anhydride; NBS=N-bromosuccinimide; AIBN=2,2′-azabisisobutyronitrile; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; TBS=tert-butyldimethylsilyl; OTf=trifluoromethanesulfonate; Fm=9-fluorenylmethyl; HATU=O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate. The completion of the total synthesis of thiostrepton (1) is depicted in Scheme 3. Advanced thiazoline macrocycle 21 was treated with Me3SnOH9 in 1,2-dichloroethane at 65 °C to liberate carboxylic acid 23, which was coupled with the bisphenylselenium tail derivative 24 (prepared as previously described)10 under the influence of HATU–HOAt to afford intermediate 25 (Table 1) in 83 % overall yield from 2. Exposure of 25 to [PdCl2(PPh3)2]–nBu3SnH8 cleaved its Alloc group and furnished primary amine 26 in 86 % yield in preparation for the incorporation of 22. Indeed, coupling of amino compound 26 with carboxylic acid 22 was effected once again with HATU–HOAt, leading to polypeptide 27 (Table 1) in 64 % yield. It was now time to consider the final macrocyclization to the thiostrepton skeleton from this long-sought precursor. To this end, the Fm group was ejected from 27 by exposure to Et2NH, and the resulting hydroxy acid 28 (87 % yield) was subjected to macrolactonization under the Yamaguchi7 conditions to afford polycycle 29 (42 % yield). All that now remained before reaching the coveted target, thiostrepton (1), was the unmasking of all its functionalities. First, all three phenylseleno groups within 29 were expelled by tBuOOH-mediated oxidation, followed by spontaneous syn elimination of the resulting selenoxides, to furnish 30 (68 % yield) with all three dehydroalanine subunits in place. Finally, the TES and four TBS groups were removed by exposure to excess HF⋅py in THF at ambient temperature, conditions which also caused the desired elimination of the oxygen marked with the TES group to form the required thiazoline-conjugated double bond in its proper Z geometry, leading directly to thiostrepton (1). Synthetic 1 exhibited identical physical properties (Rf, HPLC, optical rotation, 1H NMR, mixed 1H NMR, 13C NMR, and MS) to an authentic sample of 1 (Table 1).11 Completion of the total synthesis of thiostrepton (1). Reagents and conditions: a) Me3SnOH (10.0 equiv), 1,2-dichloroethane, 65 °C, 2.5 h; b) 24 (2.0 equiv), HATU (1.2 equiv), HOAt (1.2 equiv), iPr2NEt (3.0 equiv), DMF, 0 °C, 2 h, 83 % (two steps); c) [PdCl2(PPh3)2] (0.1 equiv), nBu3SnH (50.0 equiv), 0 °C, 1 h, 86 %; d) 22 (1.1 equiv), HATU (1.1 equiv), HOAt (1.1 equiv), iPr2NEt (3.0 equiv), DMF, 0 °C, 1.5 h, 64 %; e) Et2NH/CH2Cl2 (1:6.5), 25 °C, 2.5 h, 87 %; f) 1. 2,4,6-trichlorobenzoyl chloride (30 equiv), Et3N (40 equiv), concentrated in toluene, 25 °C, 24 h; 2. 4-DMAP (30 equiv), toluene (0.5 mM), 24 h, 25 °C, 42 %; g) tBuOOH (6.0 M in decane)/CH2Cl2 (1:10), 25 °C, 3 h, 68 %; h) HF⋅py/THF (1:5), 25 °C, 24 h, 52 %. Alloc=allyloxycarbonyl; TBS=tert-butyldimethylsilyl; TES=triethylsilyl. 21: Rf=0.3 (silica gel, EtOAc/hexanes 1:5); [α]=+44 (CHCl3, c=0.045); IR (film): max=3302, 2954, 2857, 1739, 1647, 1517, 1458, 1249, 1211, 1124, 1090 cm−1; 1H NMR (600 MHz, CD3CN, 70 °C): δ=8.10 (s, 1 H), 7.85–7.75 (m, 4 H), 7.54–7.52 (m, 2 H), 7.44–7.41 (m, 2 H), 7.39–7.34 (m, 2 H), 7.28–7.26 (m, 4 H), 6.99 (br d, J=3.0 Hz, 1 H), 6.89 (d, J=10.0 Hz, 1 H), 6.40 (dd, J=10.1, 5.3 Hz, 1 H), 5.89–5.82 (m, 1 H), 5.29–5.18 (m, 4 H), 4.80 (d, J=3.5 Hz, 1 H), 4.75–4.63 (m, 4 H), 4.51–4.48 (m, 1 H), 4.46–4.40 (m, 2 H), 4.35–4.32 (quint, J=7.3, 7.0 Hz, 1 H), 3.49–3.46 (m, 1 H), 3.35–3.23 (m, 4 H), 3.07 (d, J=5.3 Hz, 1 H), 1.70–1.60 (br s, 1 H), 1.38 (d, J=6.6 Hz, 3 H),1.30 (d, J=7.0 Hz, 3 H), 0.94 (t, J=5.1 Hz, 3 H), 0.90 (s, 9 H), 0.86 (d, J=7.1 Hz, 1 H), 0.14 (s, 3 H), 0.10 (s, 3 H), −0.015 (s, 3 H), −0.098 ppm (s, 3 H); 13C NMR (150 MHz, CD3CN, 70 °C): δ=174.8, 173.5, 171.3, 166.5, 157.5, 152.6, 147.3, 145.5, 145.5, 144.4, 143.7, 142.7, 134.6, 134.5, 134.5, 133.8, 133.5, 130.8, 130.6, 129.2, 128.8, 128.6, 128.3, 126.8, 126.6, 123.3, 123.1, 121.4, 119.0, 76.1, 68.2, 68.1, 67.0, 65.7, 65.6, 58.8, 54.2, 50.0, 48.5, 39.9, 30.3, 29.1, 27.8, 26.7, 26.6, 26.5, 19.5, 19.3, 19.2, 19.2, 19.1, 18.9, 16.7, 14.2, 12.2, −3.5, −3.8, −4.0, −4.2 ppm; HRMS (ESI-TOF): calcd for C59H80N4O8SeSi2 [M+Na+]: 1131.4572; found: 1131.4598. 25: Rf=0.40 (silica gel, 7 % MeOH/CH2Cl2); 1H NMR (600 MHz, CD3CN, 70 °C): δ=8.16 (s, 1 H), 8.03 (d, J=7.0 Hz, 1 H), 7.90 (d, J=9.2 Hz, 1 H), 7.80–7.57 (m, 2 H), 7.56–7.52 (m, 1 H), 7.50–7.49 (m, 2 H), 7.39 (s, 1 H), 7.28–7.27 (m, 4 H), 7.24–7.23 (m, 3 H), 5.93 (br s, 1 H), 5.79–5.75 (m, 1 H), 5.58 (d, J=9.2 Hz, 1 H), 5.39–5.38 (m, 1 H), 5.24 (br s, 1 H), 5.20 (dd, J=17.1, 1.3 Hz, 1 H), 5.09 (dd, J=10.6, 1.1 Hz, 1 H), 5.00 (dt, J=9.2, 1.4 Hz, 1 H), 4.86–4.84 (m, 1 H), 4.72–4.65 (m, 2 H), 4.6 (br s, 1 H), 4.52–4.48 (m, 2 H), 4.32–4.25 (m, 4 H), 4.12 (q, J=6.1, 2.4 Hz, 1 H), 4.00 (quint, J=6.6, 2.5 Hz, 1 H), 3.69–3.64 (m, 1 H), 3.58 (d, J=9.2 Hz, 2 H), 3.44–3.19 (m, 6 H), 2.89 (br s, 1 H), 2.46 (br s, 1 H), 1.33 (d, J=6.1 Hz, 3 H), 1.25 (d, J=4.0 Hz, 3 H), 1.24 (d, J=3.0 Hz, 3 H), 1.22 (d, J=6.6 Hz, 3 H), 1.10 (d, J=6.1 Hz, 3 H), 0.98 (s, 9 H), 0.97–0.94 (m, 9 H), 0.95 (s, 9 H), 0.66 (q, J=7.9 Hz, 6 H), 0.20 (s, 3 H), 0.19 (s, 3 H), 0.12 (s, 3 H), 0.09 ppm (s, 3 H); HRMS (ESI-TOF): calcd for C82H117N15O15S5Se2Si3 [M+Na+]: 1978.4987; found: 1978.4973. 27: Rf=0.55 (silica gel, 7 % MeOH/CH2Cl2); 1H NMR (600 MHz, CD3CN, 70 °C): δ=8.15 (s, 1 H), 8.09 (s, 1 H), 8.02 (d, J=7.9 Hz, 1 H), 7.87 (d, J=8.3 Hz, 1 H), 7.84–7.82 (m, 2 H), 7.76 (d, J=7.9 Hz, 1 H), 7.73 (d, J=7.0 Hz, 1 H), 7.57–7.56 (m, 2 H), 7.50–7.48 (m, 2 H), 7.46 (br s, 1 H), 7.41–7.38 (m, 2 H), 7.32 (t, J=7.4 Hz, 2 H), 7.26–7.15 (m, 9 H), 7.14 (d, J=4.0 Hz, 1 H), 6.87 (s, 1 H), 6.86 (d, J=10.1 Hz, 1 H), 6.36 (dd, J=10.1 Hz, 1 H), 5.56 (d, J=9.7 Hz, 1 H), 5.37 (s, 1 H), 5.25–5.23 (m, 2 H), 4.97 (m, 1 H), 4.84–4.82 (m, 1 H), 4.77 (d, J=3.5 Hz, 1 H), 4.72–4.60 (m, 5 H), 4.52–4.49 (m, 2 H), 4.41 (t, J=6.0 Hz, 1 H), 4.38–4.31 (m, 2 H), 4.28–4.24 (m, 2 H), 4.19 (t, J=8.2 Hz, 1 H), 4.10–4.05 (m, 2 H), 3.63–3.55 (m, 4 H), 3.48–3.45 (m, 1 H), 3.44–3.32 (m, 4 H), 3.30–3.10 (m, 2 H), 2.96–2.86 (m, 1 H), 2.45 (br s, 1 H), 1.35 (d, J=7.0 Hz, 3 H), 1.32 (d, J=6.1 Hz, 3 H), 1.24–1.21 (m, 9 H), 1.16–1.15 (d, J=6.1 Hz, 3 H), 1.09 (d, J=6.1 Hz, 3 H), 1.03 (s, 3 H), 0.97–0.90 (m, 27 H), 0.88 (s, 9 H), 0.82 (d, J=6.6 Hz, 3 H), 0.75 (s, 9 H), 0.66 (q, J=8.3 Hz, 6 H), 0.17 (s, 3 H), 0.16 (s, 3 H), 0.11 (s, 3 H), 0.10 (s, 3 H), 0.09 (s, 3 H), 0.08 (s, 3 H), −0.03 (s, 3 H), −0.11 ppm (s, 3 H); HRMS (ESI-TOF): calcd for C134H187N19O20S5Se3Si5 [M+H+]: 2922.9217; found: 2922.9215. 1 (thiostrepton, synthetic and natural): 1H NMR (600 MHz, [D8]THF, thiostrepton is more soluble and stable in this solvent than in CDCl3; for proton numbering and abbreviations, see: ref. 11): δ=10.03 (s, 1 H; CONH), 9.69 (s, 1 H; CONH), 9.30 (s, 1 H; CONH), 8.65 (s, 1 H; CONH), 8.39 (s, 1 H; Ar-H), 8.31 (br s, 1 H; OH or NH), 8.29 (s, 1 H; Ar-H), 8.20 (s, 1 H; Ar-H), 8.03 (br s, 1 H; CONH), 7.62 (d, J=5.6 Hz, 1 H; CONH), 7.58 (d, J=10.3 Hz, 1 H; CONH), 7.54 (br s, 1 H; Thstn 3-OH), 7.53 (s, 1 H; Ar-H), 7.48 (br s, 1 H; OH or NH), 7.42 (d, J=7.7 Hz, 1 H; CONH), 7.32 (s, 1 H; Ar-H), 7.07 (d, J=7.7 Hz, 1 H; Q 8-OH), 6.99 (br s, 1 H; OH or NH), 6.92 (d, J=9.7 Hz; Q 5-H), 6.75 (d, J=2.0 Hz, 1 H; Deala-H), 6.58 (d, J=7.5 Hz, 1 H; CONH), 6.56 (s, 1 H; Deala-H), 6.45 (q, J=6.1 Hz, 1 H; Thr(2) 3-H), 6.32 (dd, J=9.7, 5.6 Hz; Q 6-H), 6.13 (q, J=7.1 Hz, 1 H; But 3-H), 5.89 (d, J=9.8 Hz, 1 H; Thr(2) 2-H), 5.84 (d, J=9.2 Hz, 1 H; Thstn 2-H), 5.77 (s, 1 H; Deala-H), 5.55 (s, 1 H; Deala-H), 5.49 (s, 1 H; OH or NH), 5.47–5.46 (m, 1 H, Pip 6-Hβ), 5.30 (q, J=6.1 Hz, 1 H; Q 11-H), 5.20 (s, 1 H; Deala-H), 5.04 (dd, J=8.7, 4.1 Hz, 1 H; Cys 4-Hβ), 4.84 (t, J=7.7 Hz, 1 H; Ala(2) 2-H), 4.73 (d, J=7.1 Hz, 1 H; Q 8-H), 4.35 (dd, J=7.9, 3.5 Hz, 1 H; Thr(1) 2-H), 4.29 (d, J=4.6 Hz, 1 H; Q 7-Hβ), 4.20–4.15 (m, 2 H; Pip 4-Hα, Thstn 4-OH), 3.90 (quint, J=6.5 Hz, 1 H; Ala(1) 2-H), 3.85 (quint, J=5.7 Hz, 1 H; Thstn 4-H), 3.24 (t, J=12.3 Hz, 1 H; Cys 5-Hα), 3.00–2.93 (m, 2 H; Ile 2-H, Pip 3-Hα), 2.39–2.35 (m, 1 H; Pip 4-Hβ), 1.60 (d, J=7.2 Hz, 3 H; CH3), 1.33 (d, J=3.5 Hz, 3 H; CH3), 1.32 (d, J=3.1 Hz, 3 H; CH3), 1.27 (d, J=6.6 Hz, 3 H; CH3), 1.16 (s, 3 H; CH3), 1.14 (s, 3 H; CH3), 1.06 (d, J=6.1 Hz, 3 H; CH3), 0.96 (t, J=7.0 Hz, 3 H; CH3), 0.88 ppm (d, J=6.6 Hz, 3 H; CH3). The chemistry described herein and in the preceding Communication in this issue1 constitutes a highly convergent and stereoselective synthesis of the most complex member of the thiopeptide class of antibiotics, thiostrepton (1). With the impressive range of biological effects exhibited by members of this proliferating family of natural products, these studies may facilitate chemical biology and drug-discovery efforts in diverse areas of current interest.

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