Job/Unit: O20207
/KAP1
Date: 11-06-12 16:34:38
Pages: 41
Total Syntheses of the Gregatins A–D and Aspertetronin A
tr (E,E)-(S)-2c = 17.49 min, tr (1ЈE,3ЈZ)-(S)-2c = 15.34 min [(E,E)-(S)-2c/ stereogenic C=C bonds, both according to analytical HPLC: Chi-
ralpak AD-H column; n-heptane/iPrOH 9:1, 1.0 mLmin–1; λdetector 1296
230 nm. tr (E,E)-(5R,2ЈЈR)-4c 11.60 min, tr (E,E)-(5S,2ЈЈR)-4c
14.43 min, tr (1ЈE,3ЈZ)-(5R,2ЈЈR)-4c 9.84 min [(E,E)-(5R,2ЈЈR)-4c/
(E,E)-(5S,2ЈЈR)-4c 95:5 (Ǟ 90% de); (E,E)-(5R,2ЈЈR)-4c/
(1ЈE,3ЈZ)-(5R,2ЈЈR)-4c = 94:6]. This mixture of (E,E)-(5R,2ЈЈR)-4c,
(1ЈE,3ЈZ)-(5R,2ЈЈR)-4c, and (E,E)-(5S,2ЈЈR)-4c was separated into 1301
its constituents by preparative HPLC: Chiralpak AD-H column; n-
heptane/iPrOH 92:8, 16 mLmin–1, λdetector = 230 nm. Room temp.;
(E,E)-(R)-2c = 96.5:3.5 (Ǟ 93% ee); (E,E)-(S)-2c/(1ЈE,3ЈZ)-(S)-2c
= 93:7]. This mixture of (E,E)-(S)-2c, (1ЈE,3ЈZ)-(S)-2c, and (E,E)-
(R)-2c was separated into its constituents by preparative HPLC:
1241 Chiralpak AD-H column; n-heptane/MeOH 100:1, 16 mLmin–1;
λdetector = 230 nm. tr (E,E)-(S)-2c = 23.0 min, tr (E,E)-(R)-2c = 31.5 min,
tr (1ЈE,3ЈZ)-(S)-2c = 21.0 min. Isomer-free (E,E)-(S)-2c (obtained by
preparative HPLC) gave the following data: M.p. 69 °C (ref.[4]
72 °C). [α]2D0 = +163.8 (= first measurement; c = 0.45 in CHCl3).
1246 [α]2D0 = +166.1 (= independent second measurement; c = 0.55 in
CHCl3) {ref.[4] [α]nDo temp. = +133 (c = 0.30 in CHCl3)}. 1H NMR
(400.1 MHz, CDCl3): δ = 0.99 (t, J6Ј,5Ј = 7.5 Hz, 3 H, 6Ј-H3), 1.54
=
=
=
=
=
tr (E,E)-(5R,2ЈЈR)-4c
r (1ЈE,3ЈZ)-(5R,2ЈЈR)-4c = 15.5 min. Isomer-free (E,E)-(5R,2ЈЈR)-4c (ob-
tained by preparative HPLC) gave the following data: [α]2D0
+105.8 (= first measurement; c = 0.95 in CHCl3). [α]2D0 = +105.6
(= independent second measurement; c = 0.83 in CHCl3). [α]2D0
=
17.5 min, tr (E,E)-(5S,2ЈЈR)-4c
=
22.5 min,
t
=
1306
4
(s, 3 H, 5-CH3), 2.06 (dd, J3ЈЈ,2ЈЈ = 6.8, J3ЈЈ,1ЈЈ = 1.5 Hz, 3 H, 3ЈЈ-
H3), superimposed by 2.08 (mc, possibly interpretable as br. qd,
1251 J5Ј,6Ј ≈ J5Ј,4Ј ≈ 7.6 Hz, 2 H, 5Ј-H2), 3.83 (s, 3 H, OCH3), 5.56 (d,
J1Ј,2Ј = 15.4 Hz, 1 H, 1Ј-H), 5.80 (dt, J4Ј,3Ј = 15.1, J4Ј,5Ј = 6.5 Hz,
1 H, 4Ј-H), 5.97 (br. dd, J3Ј,4Ј = 15.0, J3Ј,2Ј = 10.5 Hz, 1 H, 3Ј-H),
6.26 (dd, J2Ј,1Ј = 15.4, J2Ј,3Ј = 10.4 Hz, 1 H, 2Ј-H), 7.19 (dq, J2ЈЈ,1ЈЈ
= 15.8, J2ЈЈ,3ЈЈ = 6.8 Hz, 1 H, 2ЈЈ-H), 7.33 (dq, J1ЈЈ,2ЈЈ = 15.7, 4J1ЈЈ,3ЈЈ
=
+101.5 (= independent third measurement; c = 0.68 in CHCl3)
{ref.:[1a] [α]nDo temp. = +76.9 (c = 1.14 in CHCl3); ref.[2] [α]2D0 = +72.0
1
(c = 0.10 in CHCl3)}. H NMR (250.1 MHz, CDCl3): δ = 0.99 (t, 1311
J6Ј,5Ј = 7.5 Hz, 3 H, 6Ј-H3), 1.36 (d, J3ЈЈ,2ЈЈ = 6.2 Hz, 3 H, 3ЈЈ-H3),
1.55 (s, 3 H, 5-CH3), 2.08 (mc, possibly interpretable as br. qd, J5Ј,6Ј
≈ J5Ј,4Ј ≈ 7.2 Hz, 2 H, 5Ј-H2), 2.38 (br. d, J2ЈЈ-OH,2ЈЈ = 5.6 Hz, 1 H,
2ЈЈ-OH), AB signal (δA = 3.17, δB = 3.20, JAB = 13.6 Hz, A part
additionally split by JA,2ЈЈ = 5.1 Hz, B part additionally split by 1316
JB,2ЈЈ = 7.0 Hz, 2 H, 1ЈЈ-H2), 3.84 (s, 3 H, OCH3), 4.31 (mc, possibly
interpretable as br. ddq, J2ЈЈ,1ЈЈ-H(A) ≈ J2ЈЈ,1ЈЈ-H(B) ≈ J2ЈЈ,3ЈЈ ≈ 6.0 Hz,
1256 = 1.4 Hz, 1 H, 1ЈЈ-H) ppm. (500 MHz, C6D6): δ = 0.81 (t, J6Ј,5Ј
=
4
7.4 Hz, 3 H, 6Ј-H3), 1.37 (dd, J3ЈЈ,2ЈЈ = 7.1, J3ЈЈ,1ЈЈ = 1.7 Hz, 3 H,
3ЈЈ-H3), 1.38 (s, 3 H, 5-CH3), 1.84 (mc, possibly interpretable as br.
qd, J5Ј,6Ј ≈ J5Ј,4Ј ≈ 7.3 Hz, 2 H, 5Ј-H2), 3.53 (s, 3 H, OCH3), 5.49
(dt, J4Ј,3Ј = 15.0, J4Ј,5Ј = 6.8 Hz, 1 H, 4Ј-H), 5.56 (d, J1Ј,2Ј = 15.4 Hz,
1261 1 H, 1Ј-H), 5.82 (br. dd, J3Ј,4Ј = 15.1, J3Ј,2Ј = 10.4 Hz, 1 H, 3Ј-H),
6.39 (dd, J2Ј,1Ј = 15.4, J2Ј,3Ј = 10.4 Hz, 1 H, 2Ј-H), 6.79 (dq, J2ЈЈ,1ЈЈ
= 15.8, J2ЈЈ,3ЈЈ = 7.0 Hz, 1 H, 2ЈЈ-H), 7.52 (dq, J1ЈЈ,2ЈЈ = 15.8, 4J1ЈЈ,3ЈЈ
= 1.5 Hz, 1 H, 1ЈЈ-H) ppm. 13C NMR (125.6 MHz, CDCl3): δ =
13.37 (C-6Ј), 19.40 (C-3ЈЈ), 22.57 (5-CH3), 25.74 (C-5Ј), 51.67
1266 (OCH3), 90.49 (C-5), 103.78 (C-3), 120.86 (C-1ЈЈ), 126.23 (C-1Ј),
127.85 (C-3Ј), 131.56 (C-2Ј), 139.35 (C-4Ј), 144.79 (C-2ЈЈ), 163.54
(C-1ЈЈЈ), 185.28 (C-2), 198.39 (C-4) ppm. 13C NMR (125.6 MHz,
C6D6): δ = 13.42 (C-6Ј), 18.66 (C-3ЈЈ), 22.50 (5-CH3), 25.88 (C-5Ј),
50.99 (OCH3), 90.15 (C-5), 104.61 (C-3), 121.23 (C-1ЈЈ), 127.38 (C-
1271 1Ј), 128.47 (C-3Ј), 131.46 (C-2Ј), 138.67 (C-4Ј), 143.23 (C-2ЈЈ),
1 H, 2ЈЈ-H), 5.54 (d, J1Ј,2Ј = 15.5 Hz, 1 H, 1Ј-H), 5.81 (dt, J4Ј,3Ј
15.2 Hz, J4Ј,5Ј = 6.3 Hz, 1 H, 4Ј-H), 5.98 (br. dd, J3Ј,4Ј = 15.2 Hz,
J3Ј,2Ј = 10.2 Hz, 1 H, 3Ј-H), 6.31 (dd, J2Ј,1Ј = 15.4 Hz, J2Ј,3Ј
10.0 Hz, 1 H, 2Ј-H) ppm. H NMR (499.6 MHz, C6D6): δ = 0.82
(t, J6Ј,5Ј = 7.4 Hz, 3 H, 6Ј-H3), 1.03 (d, J3ЈЈ,2ЈЈ = 6.0 Hz, 3 H, 3ЈЈ-
H3), 1.33 (s, 3 H, 5-CH3), 1.85 (mc, possibly interpretable as br. qd,
J5Ј,6Ј ≈ J5Ј,4Ј ≈ 7.4 Hz, 2 H, 5Ј-H2), 2.07 (br. d, J2ЈЈ-OH,2ЈЈ = 6.0 Hz,
=
=
1321
1
1 H, 2ЈЈ-OH), AB signal (δA = 2.85, δB = 2.91, JAB = 13.2 Hz, A 1326
part additionally split by JA,2ЈЈ = 4.7 Hz, B part additionally split
by JB,2ЈЈ = 7.7 Hz, 2 H, 1ЈЈ-H2), 3.47 (s, 3 H, OCH3), 4.05 (mc, 1
H, 2ЈЈ-H), 5.52 (d, J1Ј,2Ј = 15.8 Hz, 1 H, 1Ј-H), superimposed by
5.56 (dt, J4Ј,3Ј = 14.9 Hz, J4Ј,5Ј = 6.9 Hz, 1 H, 4Ј-H), 5.82 (br. dd,
163.74 (C-1ЈЈЈ), 184.70 (C-2), 196.67 (C-4) ppm. IR [CH(!)Cl ]: ν
˜
3
= 3025, 2960, 2930, 2870, 2840, 1745 (shoulder), 1705, 1645, 1555,
1435, 1395, 1305, 1255, 1200, 1165, 1130, 1050, 990, 975, 920 830,
775, 670 cm–1. HRMS (EI, 70 eV): calcd. for C16H20O4 [M]+
1276 276.13616; found 276.13590 (Δ = –0.9 ppm). C16H20O4 (276.3):
calcd. C 69.55, H 7.30; found C 69.56, H 7.41.
J3Ј,4Ј = 15.3 Hz, J3Ј,2Ј = 10.6 Hz, 1 H, 3Ј-H)A, 6.42 (dd, J2Ј,1Ј
= 1331
15.4 Hz, J2Ј,3Ј = 10.4 Hz, 1 H, 2Ј-H)A ppm; A the indicated protons
were distinguished in a DQF-COSY spectrum [“H,H-COSY spec-
trum” (499.6 MHz, C6D6)] by their crosspeaks with protons that
had previously been assigned unequivocally [δH(1H) ↔ δH(1H)]: δ
Methyl {(R)-5-[(E,E)-Hexa-1,3-dienyl]-2-[(R)-2-hydroxypropyl]-5-
methyl-4-oxo-4,5-dihydrofuran-3-yl}carboxylate [(+)-(E,E)-(5R,2ЈЈR)-
4c] = Gregatin D
= 5.82 (dd, 3Ј-H) ↔ δ = 5.56 (dt, 4Ј-H) and δ = 5.82 (dd, 3Ј-H) ↔ 1336
δ = 6.42 (dd, 2Ј-H); δ = 6.42 (dd, 2Ј-H) ↔ δ = 5.52 (d, 1Ј-H) and
δ = 6.42 (dd, 2Ј-H) ↔ δ = 5.82 (dd, 3Ј-H). 13C NMR (125.6 MHz,
C6D6): δ = 13.39 (C-6Ј)A, 22.38 (5-CH3)A, 23.91 (C-3ЈЈ)A, 25.88 (C-
5Ј)A, 40.31 (C-1ЈЈ)A, 51.13 (OCH3)A, 66.20 (C-2ЈЈ)A, 91.29 (C-5)B,
108.08 (C-3)B, 126.53 (C-1Ј)A, 128.44 (C-3Ј)A, 131.95 (C-2Ј)A, 1341
138.91 (C-4Ј)A, 164.45 (C-1ЈЈЈ)B, 195.57 (C-2)B, 196.41 (C-4)B; A the
indicated nuclei – they are non-quaternary – were identified in an
edHSQC spectrum (“short-range C,H-COSY spectrum”; 125.6/
499.6 MHz, C6D6) by their crosspeaks with directly bonded pro-
tons (these had previously been assigned unequivocally) [δH(1H) ↔ 1346
δC(13C)]: δH = 0.82 (t, 6Ј-H3) ↔ δC = 13.39 (C-6Ј), δH = 1.03 (d,
3ЈЈ-H3) ↔ δC = 23.91 (C-3ЈЈ), δH = 1.33 (s, 5-CH3) ↔ δC = 22.38
(5-CH3), δH = 1.85 (mc, 5Ј-H2) ↔ δC = 25.88 (C-5Ј), δH = 2.85 (dd,
1ЈЈ-H1) and 2.91 (dd, 1ЈЈ-H2) ↔ δC = 40.31 (C-1ЈЈ), δH = 3.47 (s,
OCH3) ↔ δC = 51.13 (OCH3), δH = 5.52 (d, 1Ј-H) ↔ δC = 126.5.3 1351
(C-1Ј), δH = 5.56 (dt, 4Ј-H) ↔ δC = 138.91 (C-4Ј), δH = 5.82 (dd,
3Ј-H) ↔ δC = 128.44 (C-3Ј), δH = 6.42 (dd, 2Ј-H) ↔ δC = 131.95
(C-2Ј); B the indicated nuclei – they are quaternary – were distin-
guished in an HMBC spectrum [“long-range C,H-COSY spec-
trum” (125.6 MHz/499.6 MHz), C6D6] by their crosspeaks due to 1356
2J and/or 3J and/or 4J couplings to “remote” protons (these had
1281 A mixture (93:7) of (E,E)-(5R,2ЈЈR)-80c and (1ЈE,3ЈZ)-(5R,2ЈЈR)-
80c (86.0 mg, 210 μmol) was dissolved in a mixture [4:1:2 (v/v/v),
7.0 mL] of THF/MeOH/HCl (10%) and stirred at room temp. for
6 h. A buffered aqueous phosphate solution (pH = 7.0, 7.0 mL)
was added, and the resulting mixture was extracted with EtOAc
1286 (4ϫ 10 mL). Drying of the combined organic phases with MgSO4,
removal of the volatiles under reduced pressure, and purification
by flash chromatography[77] (2.5 cm, 20 mL, C6H12/EtOAc 1:1, #5–
6 and #8–18) provided gregatin A [(E,E)-(R)-2c; slightly yellow so-
lid, 2.0 mg, 3.4%] in fractions 5–6 and the title compound (54.4 mg,
1291 88%) as a colorless oil in fractions 8–18. The diastereopurity of
product (E,E)-4c corresponded to 90% de with respect to the ste-
reocenter at C-5 and the diastereopurity of the major diastereomer
(5R,2ЈЈR)-4c to an (E,E)/(1ЈE,3ЈZ) ratio of 94:6 with respect to the
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