Convergent Synthesis of Antiparallel Cyclobolaphiles Having Two Diacetyl-enes: Mimetics of Membrane Components That are Found in Archaea

Abstract

Chiral 48-membered antiparallel cyclobolaphiles and their diastereomer having two diacetylenes were convergently synthesized utilizing both cross-coupling method (CuI, pyrrolidine) and Glaser intramolecular cyclization, starting from commercially available d- and l-1,2-O-isopropylidene-sn-glycerol as chiral sources.

Key words

caldarchaeol - diacetylene - antiparallel cyclobolaphile - convergent synthesis - mimetics

References

• 1a

  We term caldarchaeol with a parallel arrangement of glycerol units ‘parallel caldarchaeol’, and that with an antiparallel arrangement ‘antiparallel caldarchaeol’.

• 1b Nishihara M. Morii H. Koga Y. J. Biochem.  1987,  101:  1007 
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• 16 Hansen WJ. Murari R. Wedmid Y. Baumann WJ. Lipids  1982,  17:  453 
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• 21 Menger FM. Chen XF. Brocchini S. Hopkins HP. Hamilton D. J. Am. Chem. Soc.  1993,  115:  6600 . The ‘untethered’ lipids are also archaeal membrane lipid analogues, and include linear saturated long alkyl chains that are connected to the glycerol backbone by means of ether linkage. If one may take into account the ”dimer-like structure" of the cyclobolaphiles, it seems reasonable to assume that (2S,27S)-1 is comparable to the ”untethered" lipid with chains of 10 carbons. Menger et al. have reported the Tm values for the ‘untethered’ lipids with chains of only 14-20 carbons, ranging from 26.9 to 66.5 °C in this report. Thus, we currently consider that the introduction of cyclic structure and diacetylene units leads to higher thermostability, although exact comparison between the cyclobolaphile and 10-carbon ”untethered" lipid remains to be made

6

Our working hypothesis has been that each stereochemical combination of parallel-antiparallel caldarchaeol analogues provides a nanostructure with various degrees of thermo-stability, and that some optimal combinations give a considerably thermostable nanostructure that is robuster than the natural one. Our ultimate goal is to find such optimal combinations. Note that the applicability of Kakinuma’s strategy to the construction of all stereoisomers and diacetylene-containing derivatives (see in text) remains unclear, although they did not refer to such possibility (see ref. 4a and 5a). As a first step toward this goal, therefore, alternative strategy that is applicable to the synthesis of all stereoisomers is required.

7

Amphiphilic molecules that contain a polar head group at the end of a hydrophobic segment have been termed; ‘bolaamphiphiles’ (Fuhrhop, J.-H.; Mathiewu, J. Angew. Chem., Int. Ed. Engl. 1984, 23, 100) or ‘bolaphile’ (Jayasuriya, N.; Bosak, S.; Regen, S. L. J. Am. Chem. Soc. 1990, 112, 5844). While amphiphiles having a macrocyclic ring as a hydrophobic segment have been termed ‘macro-cyclic bolaamphiphiles’ (see Ref. 5b), we prefer to adopt the abbreviated and more readily pronounceable term, ‘cyclobolaphile’.

9

Intense examination of macrocyclic synthetic methods that have been previously reported indicate that only our strategy has the potential to provide antiparallel cyclobolaphiles that contain diacetylene units (see ref. 5).

14

A solution of the precursor of 13 (0.10 g, 0.10 mmol) in acetone (5 mL) was added to a stirred solution of CuCl (0.20 g, 2.1 mmol) and TMEDA (310 µL, 2.1 mmol) in p-xylene (36 mL) under oxygen over 7 h at 130 °C.

17

(2R, 27R)-1, (2S, 27S)-1, and (2R, 27S)-1 were successfully purified by flash chromatography (SiO₂, CHCl₃/MeOH/H₂O, 65:25:4, v/v/v).

18

All new compounds gave satisfactory analytical and spectral data. Selected physical data are as follows: 14: Stage pale yellow oil, R_f = 0.13 [hexane/ethyl acetate (2:1, v/v)], [α]_D ²⁵ -9.0 (c 0.61, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 3.70-3.38 (m, 18 H), 2.23 (t, J = 6.9 Hz, 8 H), 2.17 (brs, 2 H), 1.60-1.43 (m, 16 H), 1.36-1.23 (m, 32 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 78.42, 72.40, 71.65, 71.11, 70.33, 65.32, 63.00, 29.97, 29.50, 29.30, 29.15, 28.98, 28.63, 28.22, 25.97, 19.16 ppm. LRMS (FAB): m/z = 725 [(M + H)⁺]. Anal. Calcd for C₄₆H₇₆O₆: C, 76.20; H, 10.56%. Found: C, 75.91; H, 10.41%. 17: [α]_D ²⁵ +7.8 (c 0.85, CHCl₃). 20: [α]_D ²⁸ 0.0 (c 0.50, CHCl₃). The spectral data of 17 and 20 were identical with those of 14 except the optical rotations. (2R, 27R)-1: Stage pale yellow solid, R_f = 0.10 [CHCl₃/MeOH/H₂O (65:25:4, v/v/v)], [α]_D ²⁵ +4.2 (c 0.70, MeOH). ¹H NMR [500 MHz, CDCl₃/CD₃OD (97:3, v/v)]: δ = 4.21 (brs, 4 H), 3.83 (brs, 4 H), 3.60 (brs, 4 H), 3.56-3.51 (m, 8 H), 3.43-3.33 (m, 6 H), 3.19 (s, 18 H), 2.19 (t, J = 6.7 Hz, 8 H), 1.47-1.42 (m, 16 H), 1.33-1.15 (m, 32 H) ppm. ¹³C NMR (125 MHz, CD₃OD): δ = 79.50, 77.98, 72.50, 72.03, 71.43, 67.47, 66.60, 66.23, 60.38, 54.71, 31.13, 30.79, 30.62, 30.41, 30.26, 29.96, 29.86, 29.59, 29.52, 27.29, 19.82 ppm. ³¹P NMR [200 MHz, CDCl₃/CD₃OD (99:1, v/v)]:
δ = -0.69 (s)ppm. LRMS (FAB): m/z = 1054 [M⁺], 995
[(M - (Me)₃N)⁺]. Anal. Calcd for C₅₆H₁₀₀N₂O₁₂P₂·2 H₂O: C, 61.63; H, 9.60; N, 2.57%. Found: C, 61.62; H, 9.50; N, 2.42%. (2S,27S)-1: [α]_D ²⁷ -4.9 (c 0.49, MeOH). (2R,27S)-1: [α]_D ²⁸ 0.0 (c 0.70, MeOH). The spectral data of (2R,27S)-1 and (2S,27S)-1 were identical with those of (2R,27R)-1 except the optical rotations.

19

Multilamellar suspension for hs-DSC measurement was prepared as follows. First, 1 mL of methanol solution of (2S, 27S)-1 (4.7 mM) was transferred to a test tube. The methanol was then evaporated under a stream of nitrogen, thereby leaving the lipid as a thin film on the walls of the test tube. The remaining solvent was removed by subjecting the lipid film to high vacuum for at least 2 h. 3 mL of milli-Q water was added and the mixture was sonicated for 1 h at 972 °C. Calorimetric measurement was performed with a MC-2 differential scanning calorimeter purchased from Microcal, Inc.