Chemoenzymatic Synthesis of the C3–C11-Fragment of Borrelidin
(m, 1 H, 6-H), 3.17 (dd, J = 9.0, 7.0 Hz, 1 H, 7-Ha), 3.31 (dd, J = as described elsewhere.[34] Hydroxylation of 8 (500 mg, 1.3 mmol)
9.0, 5.2 Hz, 1 H, 7-Hb), 3.39 (dd, J = 10.4, 6.6 Hz, 1 H, β-Ha), 3.45 was conducted in potassium phosphate buffer (100 mL, 50 mm,
(dd, J = 10.4, 5.9 Hz, 1 H, β-Hb), 3.80 (s, 3 H, OCH3), 4.40 (d, J
pH 7.5) containing sodium formate (300 mm), catalase
= 11.7 Hz, 1 H, OCH2 PMP), 4.44 (d, J = 11.7 Hz, 1 H, (600 U mL–1), NAD+ (0.1 mm), CAVASOL W7 M Pharma
OCH2PMP), 6.85–6.89 (m, 2 H, m-H, PMB), 7.24–7.27 (m, 2 H,
(20 mm), NAD+-dependent formate dehydrogenase from Pseudo-
o-H, PMB) ppm. 13C NMR (125 MHz, CDCl3): δ = 16.1 (α-CH3), monas sp. 101 (110 U), and CYP102A1 3mDS (1.5 μm). The reac-
18.3 (6-CH3), 20.3, 20.7 (2-CH3, 4-CH3), 27.1 (C-4), 27.4 (C-2), tion mixture was stirred at room temperature for 16 h, afterwards
30.8 (C-6), 33.2 (C-α), 40.0 (C-1), 41.9 (C-5), 45.9 (C-3), 55.3
(OCH3), 69.2 (C-β), 72.6 (CH2-PMP), 75.7 (C-7), 113.7 (C-mPMB),
acidified with HCl to pH 3, extracted twice with Et2O, and the
solvents evaporated to dryness. Purification by column chromatog-
129.1 (C-oPMB), 130.9 (C-iPMB), 159.0 (C-pPMB) ppm. FTIR (ATR): raphy on SiO2 (hexanes/EtOAc, 4:1) yielded 14 as a colorless oil
ν = 3327 (br.), 2954 (s), 2916 (s), 2870 (m), 1967 (s), 1514 (vs), 1248
(184 mg, 0.85 mmol, 34%) with 82:18dr (by GC); Rf = 0.26; [α]2D0
= –35.7 (c = 1.0, CH2Cl2). H NMR (500 MHz, CDCl3): δ = 0.85
˜
1
(vs) cm–1. MS (EI): m/z (%) = 336 (20) [M]+, 137 (40), 121 (100).
HRMS (EI): calcd. for C21H36O3 336.2664; found 336.2662.
(d, J = 6.8 Hz, 3 H, 6-CH3), 0.91 (d, J = 6.5 Hz, 3 H, 4-CH3), 0.96
(ddd, J = 13.5, 9.2, 5.4 Hz, 1 H, 5-Ha), 1.00 (ddd, J = 13.9, 9.7,
4.6 Hz, 1 H, 3-Ha), 1.12 (d, J = 6.3 Hz, 3 H, 8-H), 1.15 (d, J =
6.9 Hz, 3 H, 2-CH3), 1.31 (ddd, J = 13.5, 8.6, 4.7 Hz, 1 H, 5-Hb),
1.40–1.50 (m, 1 H, 4-H), 1.58–1.69 (m, 2 H, 6-H, OH), 1.77 (ddd,
J = 13.9, 10.4, 3.9 Hz, 1 H, 3-Hb), 2.58 (dqd, J = 10.4, 6.9, 4.6 Hz,
1 H, 2-H), 3.65 (qd, J = 6.3, 5.1 Hz, 1 H, 7-H), 3.67 (s, 3 H, OCH3)
ppm. 13C NMR (125 MHz, CDCl3): δ = 14.7 (6-CH3), 18.5 (2-
CH3), 19.1 (C-8), 20.7 (4-CH3), 28.5 (C-4), 37.1 (C-6), 37.5 (C-2),
40.7 (C-5), 40.8 (C-3), 51.5 (OCH3), 71.8 (C-7), 177.4 (C-1) ppm.
General Procedure for the Dess–Martin Periodinane (DMP) Oxi-
dation: A solution of the respective alcohol (1.0 equiv.) in CH2Cl2
(2 mL) and DMP (2.25 equiv.) was stirred at room temperature for
3 h. The solvent was removed under vacuum, and the residue was
purified by chromatography on SiO2 [hexanes/EtOAc, 20:1 (for 13);
or hexanes/EtOAc, 8:1 (for 2)].
(2S,4R,6R,8R,10R)-2,4,6,8,10-Pentamethyldodecanal (13): From 12
(20.0 mg, 78.0 μmol), chromatography gave 13 as a colorless oil;
yield: 18 mg, 72 μmol, 92%; Rf = 0.50; [α]2D0 = +2.4 (c = 1.0,
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.81–1.10 (m, 19 H, 2-
CH3, 4-CH3, 6-CH3, 8-CH3, 3-Ha, 5-Ha, 7-Ha, 9-Ha, 10-H) 1.08 (d,
J = 6.9 Hz, 3 H, α-CH3), 1.11–1.27 (m, 3 H, 3-Hb, 5-Hb, 7-Hb),
1.27–1.48 (m, 4 H, 1-Ha,b, 8-H, 9-Hb), 1.49–1.68 (m, 2-H, 4-H, 6-
H), 9.62 (d, J = 1.8 Hz, 1 H, CHO) ppm. 13C NMR (75 MHz,
CDCl3): δ = 11.2 (C-10), 13.1 (α-CH3), 20.0, 20.1, 20.8, 21.0 (2-
CH3, 4-CH3, 6-CH3, 8-CH3), 27.3, 27.39, 27.42 (C-2, C-4, C-6),
28.8 (C-9), 31.5 (C-8), 37.0 (C-1), 44.3 (C-α), 44.6, 45.5, 45.6 (C-3,
FTIR (ATR): ν = 3439 (br.), 2968 (s), 2931 (m), 2361 (w), 1737
˜
(vs), 1195 (m), 1172 (m) cm–1. HRMS (ESI): calcd. for [C12H24O3
+ Na]+ 239.1618; found 239.1617.
Methyl (2R,4R,6S)-2,4,6-Trimethyloct-7-enoate (15): To a solution
of 14 (88 mg, 0.41 mmol) in CH2Cl2 (1.5 mL) at 0 °C was added
a solution of Martin’s sulfurane (766 mg, 1.22 mmol) in CH2Cl2
(1.5 mL), and the reaction mixture was stirred at room temperature
for 5 h. After removal of the solvent under vacuum, the residue
was purified by chromatography on SiO2 (pentane/Et2O, 30:1 Ǟ
15:1) to give 15 as a colorless oil (79 mg, 0.40 mmol, 97%); Rf =
0.40 (hexanes/Et2O, 20:1); [α]2D0 = –12.0 (c = 1.0, CH2Cl2). 1H NMR
(500 MHz, CD2Cl2): δ = 0.86 (d, J = 6.5 Hz, 3 H, 4-CH3), 0.95 (d,
J = 6.7 Hz, 3 H, 6-CH3), 1.03 (ddd, J = 13.5, 8.8, 5.6 Hz, 1 H, 5-
Ha), 1.10 (d, J = 6.9 Hz, 3 H, 2-CH3), 1.11–1.15 (m, 1 H, 3-Ha),
1.23 (ddd, J = 13.5, 9.1, 5.1 Hz, 1 H, 5-Hb), 1.38–1.48 (m, 1 H, 4-
H), 1.64 (ddd, J = 13.5, 9.0, 5.6 Hz, 1 H, 3-Hb), 2.18–2.28 (m, 1
H, 6-H), 2.53 (dqd, J = 9.0, 6.9, 5.9 Hz, 1 H, 2-H), 3.62 (s, 3 H,
OCH3), 4.89 (ddd, J = 10.2, 2.0, 0.7 Hz, 1 H, 8-Ha), 4.95 (ddd, J
= 17.1, 2.0, 1.1 Hz, 1 H, 8-Hb), 5.67 (ddd, J = 17.1, 10.2, 8.0 Hz,
1 H, 7-H) ppm. 13C NMR (125 MHz, CD2Cl2): δ = 18.1 (2-CH3),
19.7 (4-CH3), 21.2 (6-CH3), 28.7 (C-4), 35.8 (C-6), 37.6 (C-2), 42.1
(C-3), 44.6 (C-5), 51.6 (OCH3), 112.7 (C-8), 145.1 (C-7), 177.6 (C-
C-5, C-7), 205.4 (CHO) ppm. FTIR (ATR): ν = 2957 (vs), 2913
˜
(vs), 2873 (m), 2843 (m), 2704 (w), 1729 (s), 1460 (s), 1378 (s) cm–1.
MS (EI): m/z (%) = 254 (4) [M]+, 196 (20), 141 (20), 123 (30), 85
(60), 71 (70), 57 (100). HRMS (EI): calcd. for C17H34O 254.2610;
found 254.2620.
(2S,4R,6S,8S)-9-[(4-Methoxybenzyl)oxy]-2,4,6,8-tetramethyl-
nonanal (2):[16] From the alcohol (27.0 mg, 0.08 mmol), chromatog-
raphy gave 2 as a colorless oil; yield: 23 mg, 0.07 mmol, 86%; Rf =
0.75; [α]2D0 = +6.3 (c = 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3):
δ = 0.85 (d, J = 6.5 Hz, 3 H, CH3), 0.86 (d, J = 6.5 Hz, 3 H, CH3),
0.90 (ddd, J = 13.7, 7.4, 7.0 Hz, 1 H, 5-Ha), 0.92 (d, J = 6.7 Hz, 3
H, 6-CH3), 0.97 (ddd, J = 13.6, 8.0, 6.4 Hz, 1 H, 3-Ha), 1.06 (d, J
= 6.9 Hz, 3 H, α-CH3), 1.22 (ddd, J = 13.6, 7.6, 6.0 Hz, 1 H, 3-
Hb), 1.27 (ddd, J = 13.6, 9.3, 4.6 Hz, 1 H, 1-Ha), 1.31 (ddd, J =
13.7, 6.8, 6.7 Hz, 1 H, 5-Hb), 1.41 (ddd, J = 13.6, 9.5, 5.0 Hz, 1 H,
1-Hb), 1.53–1.66 (m, 2 H, 2,4-H), 1.78–1.88 (m, 1 H, 6-H), 2.37–
2.44 (m, 1 H, α-H), 3.17 (dd, J = 9.0, 6.9 Hz, 1 H, 7-Ha), 3.31 (dd,
J = 9.0, 5.2 Hz, 1 H, 7-Hb), 3.80 (s, 3 H, OCH3), 4.40 (d, J =
11.7 Hz, 1 H, OCH2PMP), 4.44 (d, J = 11.7 Hz, 1 H, OCH2PMP),
6.86–6.89 (m, 2 H, m-H, PMB), 7.24–7.27 (m, 2 H, o-H, PMB),
9.61 (d, J = 1.9 Hz, 1 H, CHO) ppm. 13C NMR (125 MHz,
CDCl3): δ = 13.1 (α-CH3), 18.3 (6-CH3), 20.0, 20.7 (2-CH3, 4-CH3),
27.1 (C-4), 27.4 (C-2), 30.8 (C-6), 37.0 (C-1), 41.7 (C-5), 44.2 (C-
α), 45.3 (C-3), 55.3 (OCH3), 72.7 (CH2-PMP), 75.6 (C-7), 113.7
(C-mPMB), 129.1 (C-oPMB), 130.9 (C-iPMB), 159.0 (C-pPMB), 205.4
1) ppm. FTIR (ATR): ν = 2956 (m), 2914 (m), 1737 (vs), 1461 (m),
˜
1265 (s), 1170 (s) cm–1. MS (ESI): m/z = 221 [M + Na]+, 199, 167,
121. HRMS (ESI): calcd. for [C12H22O2 + H]+ 199.1693; found
199.1685.
Methyl (2R,4R,6S)-7-Hydroxy-2,4,6-trimethylheptanoate: A stream
of ozone was bubbled through
a solution of 15 (246 mg,
1.24 mmol) in CH2Cl2 (15 mL) at –78 °C until quantitative conver-
sion was monitored by TLC. The excess amount of ozone was re-
moved by passing N2 through this mixture. Then a solution of
NaBH4 (703 mg, 19.0 mmol) in MeOH (13 mL) was added at
–78 °C, and the reaction mixture was heated at reflux for 4 h. After
neutralization with 1 m HCl at room temperature, the organic layer
was separated, and the aqueous layer was extracted with CH2Cl2
(3ϫ20 mL). The combined organic layers were dried (MgSO4) and
concentrated. The residue was purified by chromatography on SiO2
(hexanes/EtOAc, 5:1 Ǟ 3:1) to give the product as a colorless oil
(CHO) ppm. FTIR (ATR): ν = 2956 (s), 2918 (s), 2871 (m), 2846
˜
(m), 1726 (s), 1513 (s), 1247 (vs) cm–1. MS (EI): m/z (%) = 334 (20)
[M]+, 137 (50), 121 (100). HRMS (EI): calcd. for C21H34O3
334.2508; found 334.2507.
Methyl (2R,4R,6S)-7-Hydroxy-2,4,6-trimethyloctanoate (14): Het-
erologous expression of CYP102A1 3mDS in Escherichia coli
BL21(DE3) using the pET28a(+) expression vector was performed
(196 mg, 0.97 mmol, 78%); Rf = 0.21 (hexanes/EtOAc, 4:1); [α]2D0
=
–31.2 (c = 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 0.91 (d,
J = 6.5 Hz, 6 H, 4-CH3, 6-CH3), 0.95 (ddd, J = 13.6, 7.8, 6.6 Hz,
Eur. J. Org. Chem. 2011, 4241–4249
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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