Synthesis of Branched Heptaglycerol Bearing Eight Hydroxyl Groups with Four Cyclic Protecting Groups

Abstract

A large series of branched oligoglycerols, BGL07 ­(heptamer) with cyclic protecting groups, was synthesized.

Key words

glycerol - water solubility - branched-type - cyclic protecting groups - oligomer - hydroxyl group

References and Notes

• 1a Serebryakov EP. Abylgaziev RI. Bull. Acad. Sci. USSR Div. Chem. Sci. (Engl. Transl.)  1985,  34:  1916 
• 1b Fröling A. Chem. Phys. Lipids  1990,  53:  289 
• 1c Urata K. Takaishi N. J. Am. Oil Chem. Soc.  1994,  71:  1027 
• 1d Engler G. Ulsperger EJ. J. Prakt. Chem.  1974,  316:  325 
• 2a Jayaraman M. Frêcher MJ. J. Am. Chem. Soc.  1998,  120:  12996 
• 2b Carnahan MA. Grinstaff MW. J. Am. Chem. Soc.  2001,  123:  2905 
• 2c Wang YA. Li JJ. Chen H. Peng X. J. Am. Chem. Soc.  2002,  124:  2293 
• Our previous papers on BGL:
• 3a Nemoto H. Wilson JG. Nakamura H. Yamamoto Y. J. Org. Chem.  1992,  57:  435 
• 3b Nemoto H. Wilson JG. Nakamura H. Yamamoto Y. J. Org. Chem.  1995,  60:  1478 
• 3c Nemoto H. Iwamoto S. Nakamura H. Yamamoto Y. Chem. Lett.  1993,  465 
• 3d Yamamoto Y. Asao N. Meguro M. Tsukada N. Nemoto H. Sadayori N. Wilson JG. J. Chem. Soc., Chem. Commun.  1993,  1201 
• 3e Nemoto H. Cai J. Yamamoto Y. J. Chem. Soc., Chem. Commun.  1994,  577 
• 3f Nemoto H. Cai J. Iwamoto S. Yamamoto Y. J. Med. Chem.  1995,  38:  1673 
• 3g Yamamoto Y. Cai J. Nakamura H. Sadayori N. Asao N. Nemoto H. J. Org. Chem.  1995,  60:  3352 
• 3h Takagaki M. Ono K. Oda Y. Kikuchi H. Nemoto H. Iwamoto S. Cai J. Yamamoto Y. Cancer Res.  1996,  56:  2017 
• 3i Nemoto H. Kikuishi J. Yanagida S. Kawano T. Yamada M. Harashima H. Kiwada H. Shibuya M. Bioorg. Med. Chem. Lett.  1999,  9:  205 
• 3j Nemoto H. Araki T. Kamiya M. Kawamura T. Hino T. Eur. J. Org. Chem.  2007,  3003 
• 4a

  In Scheme 15 of ref. 4b, the reaction of 4 and 3 with ECH to afford a mixture of 5 (4 + 4 + ECH) and asymmetrical pentaglycerol (4 + 3 + ECH), is drawn with a plain arrow but not with a dotted arrow. However, the authors mention in the main text that ‘One can imagine repeating this step to give higher degree oligomers (pentamer, heptamer,…) with dendrimer-like structures’ (around Scheme 15, our paper [3a] [b] was the only one referenced). Furthermore, no experimental details are provided for Scheme 15. It is possible that they misread our paper, [3a] [b] or mistakenly used a plain arrow rather than a dotted one. Accordingly, the preparation (either isolation or identification) of octabenzyl ether 5 has not been demonstrated.

• 4b Cassel S. Debaig C. Benvegnu T. Chaimbault P. Lafosse M. Plusquellec D. Rollin P. Eur. J. Org. Chem.  2001,  875 
• 6 Preparation of 10a. See: Forbes DC. Ene DG. Doyle MP. Synthesis  1998,  879 
• Preparation of 10b. See:
• 7a Crich D. Beckwith ALJ. Chen C. Yao Q. Davison IGE. Longmore RW. Anaya dePC. Quintero-Cortes L. Sandoval-Ramirez J. J. Am. Chem. Soc.  1995,  117:  8757 
• 7b Carlsen Per HJ. Soerbye K. Ulven T. Aasboe K. Acta Chem. Scand.  1996,  50:  185 
• 7c

  Based on ¹H NMR analysis, it is considered that 10b has a chair form bearing phenyl group at equatorial position, and hydroxyl group at axial position. The hydroxyl group may have electronic affinity among oxygen atoms of the 1,3-dioxirane ring as shown in the following Figure [3] .

• 17 Nemoto H, Yamasaki M, Suzawa T, and Yamaguchi H. inventors; WO  2004029018. BGL modification of a protein:
• 18 Nemoto H, Yamauchi M, Kusano H, Kato Y, Yamasaki M, and Suzawa T. inventors; WO  2005023844. BGL modification of a liposome:
• 19 Abrams MJ, Bridger GJ, Schwartz DA, Padmanabhan S, and Ultee ME. inventors; WO  9410149. 

5

BGL07 is a heptamer containing triply repetitive glyceryl units. In contrast, compound 16, recently reported by us, [3j] contains a doubly repetitive glyceryl unit attached to a disparate trifunctionalized molecule (iminodiacetic acid). This octabenzyl ether 16 should be called BGL06 (Figure [2] ).

8

Preparation of 11a
To a vigorously stirred mixture of 10a (500 mg, 3.78 mmol), TBAI (61.0 mg, 0.19 mmol), finely ground KOH in a mortar (187.3 mg, 2.84 mmol), and H₂O (0.04 mL) was added ECH (87.5 mg, 0.95 mmol) slowly and dropwise. After stirring for 40 h at 60 °C, the resulting mixture was diluted with EtOAc, and the resulting suspension was filtered. The filtrate was dried over anhyd K₂CO₃, and concentrated in vacuo. The residue was purified by silica gel column chromatography using hexane-EtOAc (1:3) as an eluent to afford 11a as a colorless oil (169.7 mg, 0.53 mmol, 56% yield) and 10a (250 mg, 1.89 mmol, 50% recovered). FT-IR (KBr): 518, 561, 731, 829, 949, 1016, 1086, 1124, 1120, 1254, 1333, 1377, 1452, 1473, 2879, 2973, 3442 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 4.04-3.89 (m, 5 H), 3.83-3.73 (m, 4 H), 3.63-3.51 (m, 4 H), 3.49-3.41 (m, 2 H), 2.81 (br s, 1 H), 1.43 (s, 6 H), 1.41 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 98.0 (2 × C), 70.8 (2 × CH), 69.6 (2 × CH₂), 69.5 (CH), 62.3 (4 × CH₂), 23.5 (2 × CH₃), 23.4 (2 × CH₃). Anal. Calcd for C₁₅H₂₈O₇: C, 56.23; H, 8.81. Found: C, 55.88; H, 8.73.

9

Preparation of 11b
To a mixture of 10b (5.613 g, 31.2 mmol), TBAB (0.518 g, 1.56 mmol), finely ground KOH in a mortar (1.543 g, 31.2 mmol), and H₂O (0.04 mL) was added Et₂O (adequate amount for stirring). To the resulting suspension was added ECH (0.61 mL, 7.79 mmol) slowly and dropwise while stirring vigorously at r.t. The mixture was then stirred for 5 h at 40 °C, for 5 h at 60 °C, and then for 17 h at 80 °C. The mixture was poured into H₂O (50 mL), and extracted with EtOAc (5 × 50 mL). The combined organic layers were washed with brine, dried over anhyd K₂CO₃, and concentrated in vacuo. The residue was purified by silica gel column chromatography using hexane-EtOAc (1:4) as an eluent to afford 11b (2.212 g, 5.32 mmol, 73% yield based on conversion of 10b) and 10b (2.955 g, 16.4 mmol, 53% recovered). FT-IR (neat): 700, 750, 800, 839, 916, 980, 1011, 1092, 1153, 1217, 1238, 1277, 1340, 1392, 1454, 2860, 2974, 3477 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.54-7.43 (m, 4 H), 7.40-7.32 (m, 6 H), 5.54 (s, 2 H), 4.41-4.31 (m, 4 H), 4.10-3.98 (m, 5 H), 3.79-3.65 (m, 4 H), 3.77-3.67 (m, 2 H), 2.85 (d, J = 5.6 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 137.9 (2 × C), 128.6 (2 × CH), 127.9 (4 × CH), 125.8 (4 × CH), 100.9 (2 × CH), 70.9 (2 × CH), 69.5 (CH), 69.1 (2 × CH₂), 68.7 (4 × CH₂). HRMS (EI): m/z calcd for C₂₃H₂₈O₇ [M⁺]: 416.1809; found: 416.1835.

10

The recovered yield of 11 was calculated using the following equation (Equation [1] ). Accordingly, 50% is the ideal value for entries 1-6, and 0% is the ideal value for entries 7-9 (Table [1] ). Equation [2] was also used to calculate the yield of 12 since 12 consists of two moieties of 11 and an excess of 11 was used.

11

Compound 12a: FT-IR (neat): 521, 733, 827, 941, 1084, 1120, 1252, 1286, 1375, 1454, 1651, 1716, 2877, 2991, 3417 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 4.00-3.86 (m, 9 H), 3.80-3.50 (m, 22 H), 3.48-3.40 (m, 4 H), 1.43 (s, 12 H), 1.40 (s, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 98.1 (4 × C), 78.7 (2 × CH), 71.9 (2 × CH₂), 70.9 (4 × CH), 69.6 (CH), 68.7, 68.6 (4 × CH₂), 62.4, 62.4, 62.3, 62.3 (8 × CH₂), 30.9, 29.6, 24.0, 24.0, 23.1, 23.0 (8 × CH₃). ESI-HRMS: m/z calcd for C₃₃H₆₀O₁₅Na [M + Na]⁺: 719.3830; found: 719.3832.

12

Compound 12b: FT-IR (neat): 699, 749, 799, 841, 916, 982, 1011, 1092, 1216, 1238, 1278, 1278, 1344, 1392, 1454, 1496, 1604, 2864, 3034, 3477 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.60-7.44 (m, 8 H), 7.43-7.29 (m, 12 H), 5.60-5.41 (s, 4 H), 4.43-4.22 (m, 8 H), 4.02-3.87 (m, 9 H), 3.85-3.56 (m, 14 H), 3.40-3.25 (s, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 137.7 (4 × C), 128.0 (4 × CH), 127.3 (8 × CH), 125.4 (8 × CH), 100.2 (4 × CH), 78.1 (2 × CH), 71.0 (2 × CH₂), 70.4 (4 × CH), 69.1 (CH), 68.2, 67.9 (8 × CH₂), 67.7, 67.5 (4 × CH₂). HRMS-FAB: m/z calcd for C₄₉H₆₁O₁₅ [M + H]⁺: 889.4018; found: 889.4010.

13

Structure of the glycidyl ether (Figure [4] ):

14

A molar ratio 11a/ECH = 4:1 was finally applied, otherwise nucleophilic attack by 11a to the glycidyl ether (11a + ECH) slowed down, affording an unidentified mixture and some identified oligomers such as an asymmetrical tetramer (11a + ECH + H₂O) and an asymmetrical undecamer (12a + ECH + 11a = three of 11a + two of ECH).

15

In contrast to the reaction with 11a, [14] compounds with high molecular weight such as undecamers, were not detected when 11b was used. Therefore, a molar ration of 11b/ECH = 2:1 was applied.

16

Compound 14a: pale yellow oil. FT-IR (neat): 520, 665, 754, 827, 941, 995, 1087, 1373, 1454, 1553, 1666, 1739, 1783, 1815, 2875, 2941, 2993, 3334, 3508 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 6.63 (d, J = 8.8 Hz, 1 H), 4.18-4.08 (m, 1 H), 3.98-3.87 (m, 8 H), 3.77-3.64 (m, 10 H), 3.61-3.44 (m, 12 H), 3.42-3.33 (m, 4 H), 2.80 (s, 4 H), 2.65 (t, J = 7.2 Hz, 2 H), 2.30 (t, J = 7.2 Hz, 2 H), 2.03 (quin, J = 7.2 Hz, 2 H), 1.42-1.34 (m, 24 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.3 (C), 168.9 (2 × C), 168.1 (C), 98.1 (2 × C), 98.0 (2 × C), 78.7 (2 × CH), 71.0 (2 × CH), 70.9 (2 × CH), 68.8 (2 × CH₂), 68.7 (2 × CH₂), 68.6 (2 × CH₂), 62.5 (4 × CH₂), 62.3 (2 × CH₂), 62.2 (2 × CH₂), 49.3 (CH), 34.3 (CH₂), 30.0 (CH₂), 25.5 (2 × CH₂), 23.9 (2 × CH₃), 23.6 (2 × CH₃), 23.6 (2 × CH₃), 23.3 (2 × CH₃), 20.5 (CH₂). ESI-HRMS: m/z calcd for C₄₂H₇₀N₂O₁₉Na [M + Na]⁺: 929.4470; found: 929.4470.
Compound 14b: pale yellow oil. FT-IR (neat): 699, 749, 799, 1012, 1092, 1208, 1389, 1454, 1495, 1529, 1667, 1739, 1783, 1813, 2862, 3346 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.51-7.42 (m, 8 H), 7.41-7.29 (m, 12 H), 6.83-6.73 (m, 1 H), 5.48 (s, 4 H), 4.40-4.22 (m, 8 H), 4.19-4.08 (m, 1 H), 4.04-3.85 (m, 8 H), 3.82-3.46 (m, 14 H), 3.35-3.21 (m, 4 H), 2.71 (s, 4 H), 2.45 (t, 2 H, J = 8.0 Hz), 2.06 (t, 2 H, J = 8 Hz), 1.83 (quin, 2 H, J = 8.0 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 171.4 (C), 169.5 (C), 168.1 (C), 138.1 (4 × C), 128.6 (4 × CH), 127.9 (8 × CH), 125.9 (8 × CH), 100.9, 100.8 (4 × CH), 78.6 (2 × CH), 71.1, 71.0 (4 × CH), 69.0, 68.9, 68.6, 68.5 (8 × CH₂), 67.9 (2 × CH₂), 49.4 (CH), 34.1 (CH₂), 29.8 (CH₂), 25.4 (2 × CH₂), 20.3 (CH₂). HRMS-FAB: m/z calcd for C₅₈H₇₁N₂O₁₉ [M + H]⁺: 1099.4633; found: 199.4651.