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. 2015 Nov 1;6(11):6407-6412.
doi: 10.1039/c5sc00814j. Epub 2015 Aug 6.

A highly convergent synthesis of the C1-C31 polyol domain of amphidinol 3 featuring a TST-RCM reaction: confirmation of the revised relative stereochemistry

Aleksandr Grisin  1 , P Andrew Evans  1
Affiliations

A highly convergent synthesis of the C1-C31 polyol domain of amphidinol 3 featuring a TST-RCM reaction: confirmation of the revised relative stereochemistry

Aleksandr Grisin et al. Chem Sci. .

Abstract

The concise enantioselective synthesis of the revised C1-C31 fragment of the polyketide amphidinol 3 was accomplished in 16 steps and 12.8% overall yield. Salient features of the strategy include chemoselective Weinreb amide coupling and concomitant CBS reduction for the preparation of the C1-C15 tris-syn-1,5-diol motif and a temporary silicon-tethered ring-closing metathesis (TST-RCM) reaction in combination with a diastereoselective hydroboration for the construction of the C16-C31 polypropionate fragment. The union of the fragments was accomplished by a regioselective ring-opening of the terminal epoxide with a phenyl sulfone stabilized carbanion, which upon reduction and deprotection permits a comparison of the relative configuration with the natural product.

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Figures

Fig. 1
Fig. 1. Structure of the polyene–polyhydroxy secondary metabolite, amphidinol 3 (1).
Scheme 1
Scheme 1. Retrosynthetic analysis of the C1–C31 polyol fragment of amphidinol 3. TIPS = triisopropylsilyl, TBS = tert-butyldimethylsilyl, TES = triethylsilyl, Bn = benzyl, PMB = p-methoxybenzyl.
Scheme 2
Scheme 2. Preparation of the C1–C9 iodide 5 and the C10–C15 epoxide 6. Conditions: (a) Acrolein, HG-II, CH2Cl2, 40 °C, then TESOTf, Et3N, CH2Cl2, –78 °C, 93%, E/Z ≥ 19 : 1; (b) AllenylSnBu3, (lIpc)2BH, Et2O, –40 °C to –20 °C, then 10, Et2O, –78 °C, 89%, ds ≥ 19 : 1; (c) TBSOTf, Et3N, CH2Cl2, 0 °C, 95%; (d) I2, Et2O, 0 °C, 99%; (e) CDI, then BnNH(OMe), CH2Cl2, 0 °C to RT, 92%; (f) Acetone, Oxone®, NaHCO3, EtOAc/H2O (1 : 1), RT, 98%; (g) (S,S)-Co-OAc, H2O, THF, RT, 60% (based on 50% conv.), ≥99% ee; HG-II = Hoveyda–Grubbs’ second-generation catalyst, Tf = trifluoromethanesulfonyl, Ipc = isopinocampheyl, CDI = 1,1′-carbonyldiimidazole, Oxone® = potassium peroxymonosulfate, THF = tetrahydrofuran.
Scheme 3
Scheme 3. Preparation of the C1–C15 fragment 3. Conditions: (a) iPrMgCl·LiCl, 15-crown-5, THF, –10 °C, 64%; (b) (S)-Me-CBS, BH3·DMS, THF, –40 °C, 99%, ds ≥ 19 : 1; (c) MTBSTFA, DMAP, MeCN, RT, 99%; (R)-Me-CBS = (R)-methyl oxazaborolidine, DMS = dimethyl sulfide, MTBSTFA = N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide, DMAP = 4-(dimethylamino)pyridine.
Scheme 4
Scheme 4. Preparation of the C16–C23 fragment 7 and the C24–C30 fragment 8. Conditions: (a) Br2, PPh3, imid, 2-methyl-2-butene, CH2Cl2, 0 °C; (b) AD-mix-α, tBuOH/H2O (1 : 1), 0 °C, 75% (over 2 steps), 92% ee; (c) TBSCl, imid, CH2Cl2, 0 °C to RT, 80%; (d) Isopropenylmagnesium bromide, Li2[CuCl4], Et2O, –78 °C to RT, 99%; (e) Boc-ON, LiHMDS, THF, 0 °C, 95%; (f) IBr, PhMe, –85 °C, ds = 15 : 1; (g) K2CO3, MeOH, RT, 81% (over 2 steps); (h) TBSCl, TMEDA, DMF, 0 °C to RT, 97%; (i) Me3SOTf, nBuLi, THF, –10 °C to 0 °C, 92%; imid = imidazole, AD = asymmetric dihydroxylation, Boc-ON = 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile, HMDS = hexamethyldisilazane, PhMe = toluene, TMEDA = tetramethylethylenediamine, DMF = dimethylformamide.
Scheme 5
Scheme 5. Construction of the C16–C30 fragment 4 using the TST-RCM/hydroboration reaction. Conditions: (a) 7, iPr2SiCl2, imid, CH2Cl2, 0 °C to RT, then 8, imid, CH2Cl2, 0 °C to RT, 84%; (b) 2 × 15 mol% G-II, CH2Cl2, 40 °C, 97%, Z/E ≥ 19 : 1; (c) BH3·THF, THF, RT, then H2O2, NaOH, 0 °C to RT; (d) TBSOTf, Et3N, CH2Cl2, –40 °C, 72% (over 2 steps), ds ≥ 19 : 1; (e) DDQ, CH2Cl2/pH 7 buffer (20 : 1), 0 °C, 87%; (f) PhSSPh, PBu3, MeCN, RT, then TPAP, NMO, 40 °C, CH2Cl2, 76%; DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, imid = imidazole, TPAP = tetra-n-propylammonium perruthenate, NMO = 4-methylmorpholine N-oxide.
Fig. 2
Fig. 2. Model for the stereocontrol in the hydroboration and the NMR analysis of the stereochemical outcome.
Scheme 6
Scheme 6. Completion of the C1–C31 fragment of amphidinol 3. Conditions: (a) 4, nBuLi, THF, –78 °C, then 3, BF3·Et2O; (b) TBSOTf, Et3N, CH2Cl2, 0 °C, 90% (over 2 steps); (c) LiDBB, THF, –78 °C, 64%; (d) TPAP, NMO, molecular sieves (4 Å), CH2Cl2, 0 °C; (e) Me(CO)C(N2)P(O) (OMe)2, K2CO3, THF/MeOH (1 : 1), 0 °C to RT, 89% (over 2 steps); LiDBB = lithium di-tert-butylbiphenylide.
Fig. 3
Fig. 3. Comparison of 1H and 13C NMR data of synthetic and natural polyol fragment of AM3.
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