R. Schobert and S. Loscher
Table 2. Optical rotations[a] and 13C NMR spectroscopic chemical shifts
(d, ppm)[b] of indicative carbon atoms of natural epicoccamide D (1d)
and synthetic diastereomers (5S,7S)-1d and (5S,7R)-1d.
NaHCO3. The aqueous layer was re-extracted with CH2Cl2, the organic
phases were dried over Na2SO4 and the solvent was removed under re-
duced pressure. The crude product thus obtained was purified by flash
chromatography (flash silica gel; 5% EtOAc in cyclohexane) to yield
2.45 g of 10 (84%) as a clear oil; Rf =0.85 (EtOAc/cyclohexane 1:3).
[a]2D5 =ꢀ1.1 (c=1.0 gcmꢀ3 in chloroform); 1H NMR (300 MHz, CDCl3):
Natural 1d[2]
N
ACHTUNGTRENNUNG
[a]2D5
ꢀ40
14.8
17.0
13C NMR: 5-CH3
13C NMR: 7-CH3
d=7.39–7.19 (m, 15H; Har), 5.05–4.96 (m, 1H; 2’-H), 4.80 (d, 2J
ACHTUNGTRENNUNG
10.9 Hz, 2H; 6’OCH2), 4.68 (d, 2J
2J
4’OCHb), 4.56 (d, J
1H; 1’-H), 3.89 (dt, 2J
(dd, 2J(H,H)=10.9, 3J(H,H)=2.3 Hz, 1H; 6’-Ha), 3.75 (dd, 3J
1.4 Hz, 1H; 4’-H), 3.70 (dd, 3J
(H,H)=10.9, 1.4 Hz, 1H; 5’-H), 3.70 (dd,
3J(H,H)=4.6, 1.3 Hz, 1H; 3’-H), 3.63 (t, 3J
(H,H)=6.6 Hz, 2H; CH2OSi),
3.51 (dd, J
9.6, 3J(H,H)=6.6 Hz, 1H; 1’OCHb), 1.99 (s, 3H; CH3CO), 1.60–1.49 (m,
4H; 2ꢃCH2), 1.35–1.26 (m, 24H; 12ꢃCH2), 0.93 (s, 9H; C(CH3)3),
0.08 ppm (s, 6H; Si
(CH3)2); 13C NMR (75 MHz, CDCl3): d=169.6
ACHTUNGTRENNUNG
[a] c=0.2 gcmꢀ3 in methanol. [b] Recorded at 75 MHz in CDCl3.
A
ACHTUNGTRENNUNG
2
3
A
ACHTUNGTREN(NUNG H,H)=8.0 Hz,
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
of its NMR spectra, HPLC, and optical rotation data with
those of two synthetic diastereoisomers. The synthesis pre-
sented here is of a modular character and should thus be ap-
plicable to other natural glycotetramates and structural var-
iants. The problematic tetramic acid moiety was introduced
only at a late stage and the stereogenic centre at C-7 was es-
tablished by an asymmetric Rh-catalysed olefin hydrogena-
tion of a fully fitted 3-[w-(b-d-mannosyl)octadec-2-enoyl]-
tetramic acid with its metal chelation propensity ꢁdefusedꢂ
by formation of a BF2-chelate. This hydrogenation protocol
nicely complements our own method for the 3-enoylation of
tetramic acids by first 3-acylating them with ylide Ph3PCCO
and then Wittig-olefinating the resulting acyl ylides with car-
bonyl compounds.[17] This opens up a new route to b-
branched 3-acyltetramic acids, such as the penicillenols,[18] as
an alternative to the Yoda acylation procedure.
A
ACHTUNGTRENNUNG
2
3
2
AHCTUNGTREG(NUNN H,H)=10.9, JACHNUTRTGENNUNG ACHTUNGTRENNUNG(H,H)=
(H,H)=2.3 Hz, 1H; 6’-Hb), 3.46 (dt, J
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(CH3CO), 138.4 (4’OCCipso), 138.3 (3’OCCipso), 138.1 (6’OCCipso), 128.6,
128.5, 128.2, 128.0, 127.9, 127.8, 127.7 (15ꢃCar), 101.2 (C-1’), 83.2 (C-3’),
78.2 (C-4’), 75.4 (C-5’), 75.2 (3’OCH2), 75.1 (4’OCH2), 73.7 (6’OCH2),
73.4 (C-2’), 69.8 (1’OCH2), 69.0 (C-6’), 63.5 (CH2OSi), 33.0 (2ꢃCH2), 29.8
(6ꢃCH2), 29.7 (CH2), 29.6 (CH2), 29.5 (CH2), 27.1 (CH2), 26.15 (CH2),
26.1 (C
G
AHCTUNGTRENNG(NU CH3)2); IR (thin film): n˜ =2925, 2853, 1751, 1497, 1461, 1454, 1361, 1229,
1147, 1090, 1058, 1028, 1005, 938, 906, 834, 814, 774, 733, 696, 602 cmꢀ1
HRMS (ESI): m/z: calcd for C51H78O8SiK [M+K]+: 885.5103; found:
885.5081.
Thioester glycoside 2 from HWE-olefination of 4: A solution of phos-
phonate 3 (76 mg, 0.234 mmol, 1.4 equiv) in dry THF (3 mL) at ꢀ788C
was treated dropwise with a 1.6m solution of nBuLi in hexanes (290 mL,
0.47 mmol, 2.8 equiv) and stirred at ꢀ788C for 15 min. Aldehyde 4
(115 mg, 0.167 mmol) dissolved in THF (3 mL) was added dropwise, and
the resulting mixture was stirred for 30 min and then warmed up to RT
and stirring was continued for a further 3 h. The reaction was quenched
with sat. aqueous NH4Cl, extracted three times with diethyl ether and
the combined organic layers were dried over Na2SO4 and concentrated.
The crude product was purified by column chromatography (silica gel;
10% EtOAc in cyclohexane) affording 2 (114 mg, 80%) as a transparent
oil; a 3:1:1 mixture of a major keto-E-isomer, a minor enol-E-isomer A
and a minor keto-Z-isomer B. Rf =0.72 (diketo form), 0.65 (enol form)
(EtOAc/cyclohexane 1:2). Only the major isomer is described under-
neath, for data of the other isomers see the Supporting Information.
[a]2D5 =ꢀ14.5 (c=1.0 gcmꢀ3 in chloroform); 1H NMR (300 MHz, CDCl3):
Experimental Section
General remarks: Melting points (uncorrected): Electrothermal 9100 ap-
paratus. IR spectra: Perkin–Elmer Spectrum One FTIR spectrophotome-
ter with ATR sampling unit. Optical rotations: Perkin–Elmer Polarimeter
343 (l=589 nm). NMR spectra: recorded under conditions as indicated
on Bruker Avance 300 and Bruker Avance DRX-500 spectrometers.
Chemical shifts are given in parts per million (d) downfield from Me4Si
as internal standard for 1H and 13C NMR spectra. HRMS were obtained
with a Bruker UPLC/Q-TOF MS system in ESI+ mode. Analytical
HPLC was performed on a Beckman system with solvent module 126
and a diode array detector 168 equipped with a Phenomenex Geminix
NX 5 mm C-18 reversed-phase column sized 250ꢃ4.6 mm. Starting
eluent: MeOH/H2O 1:1. After 5 min, the methanol level was raised to
95% over a period of 15 min. For chiral HPLC analysis, the same system
was used with a Macherey–Nagel Nucleodex CD-b-OH column 150ꢃ
4.0 mm and an isocratic eluent (15% H2O, 0.1% HCOOH, 85% acetoni-
trile). For flash chromatography Merck silica gel 60 (230–400 mesh) and
for column chromatography Merck silica gel 60 (70–230 mesh) was em-
ployed. Prontosil Solvents (HPLC grade) were purchased from Merck.
THF and toluene were dried over Na, methanol, and CH2Cl2 over P2O5.
Starting compounds were prepared according to literature procedures or
purchased from the usual suppliers.
d=7.41–7.19 (m, 15H; Har), 6.66 (td, 3J
1H; 16-H), 4.90 (d, 2J(H,H)=10.9 Hz, 1H; 4’OCHa), 4.78 (d, 2J
11.9 Hz, 1H; 3’OCHa), 4.67 (d, 2J(H,H)=11.9 Hz, 1H; 3’OCHb), 4.63 (d,
2J(H,H)=12.2 Hz, 1H; 6’OCHa), 4.56 (d, 2J
(H,H)=12.2 Hz, 1H;
6’OCHb), 4.54 (d, 2J(H,H)=10.9 Hz, 1H; 4’OCHb), 4.41 (d, 3J
(H,H)=
0.9 Hz, 1H; 1’-H), 4.11 (dd, J
(H,H)=9.8, 3J(H,H)=6.9 Hz, 1H; 1’OCHa), 3.85 (t, 3J
1H; 4’-H), 3.84 (s, 2H; OCCH2CO), 3.79 (dd, 2J(H,H)=10.8, 3J
(H,H)=5.3 Hz, 1H; 6’-Hb),
(H,H)=9.4, 3.1 Hz, 1H; 3’-H), 3.50 (dt, 2J(H,H)=9.6, 3J-
(H,H)=6.9 Hz, 1H; 1’OCHb), 3.43 (ddd, 3J
(H,H)=9.4, 5.3, 2.1 Hz, 1H;
5’-H), 2.27 (qui, 3J(H,H)=6.8 Hz, 2H; 15-H), 1.79 (d, 4J
(H,H)=1.3 Hz,
3H; CH3C=C), 1.63 (q, 3J
(H,H)=6.9 Hz, 2H; OCH2CH2), 1.47 (s, 9H;
(H,H)=7.3, 4J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
3
2
AHCTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
2
3
2.1 Hz, 1H; 6’-Ha), 3.71 (dd, J
ACHUTGTNREN(NUG H,H)=10.8, JACHTNUGTRENNUNG
3.57 (dd, 3J
G
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
tBu), 1.37–1.24 ppm (m, 24H; 12ꢃCH2); 13C NMR (75 MHz, CDCl3):
d=193.8 (C2C=O), 193.4 (COS), 146.3, (H3CC=C), 138.4 (4’OCCipso),
138.3 (3’OCCipso), 137.9 (6’OCCipso), 137.1 (H3CC=C), 128.6, 128.5, 128.4,
128.2, 128.0, 127.95, 127.9, 127.8, 127.6, (15ꢃCar), 99.8 (C-1’), 81.7 (C-4’),
75.4 (C-5’), 75.3 (4’OCH2), 74.4 (C-3’), 73.6 (6’OCH2), 71.4 (3’OCH2),
69.9 (1’OCH2), 69.4 (C-6’), 68.5 (C-2’), 54.0 (OCCH2CO), 48.9 (CMe3),
In the following, experimental details are provided for selected key com-
pounds and procedures. All other data are listed in the Supporting Infor-
mation file including NMR spectra of all new compounds.
Sugar 10 from glycosylation of donor 6 with acceptor 5: A mixture of 2 g
powdered 4 ꢄ molecular sieve, dried under vacuum at 6008C for 20 min,
alcohol 5 (2.19 g, 5.86 mmol, 1.7 equiv), and CH2Cl2 (70 mL) was treated
at RT with imidate 6 (2.2 g, 3.45 mmol), then cooled to ꢀ788C and treat-
ed with BF3·OEt2 (64 mL, 0.52 mmol, 0.15 equiv). Stirring was continued
at ꢀ788C until completion (TLC control; ca. 2 h). The reaction mixture
was filtered over Celite and the Celite pad was rinsed several times with
CH2Cl2 and the combined organic phases were washed with sat.
29.8 (CACTHNUGRTNE(UNG CH3)3), 29.8 (CH2), 29.7 (CH2CH2C=C), 29.7, 29.6, 29.55 (8ꢃ
CH2), 29.5 (CH2), 29.4 (CH2), 29.0 (CH2C=CCH3), 28.6 (CH2), 26.1
(CH2CH2C=C), 11.4 ppm (CH3C=C); IR (thin film): n˜ =3482, 2923, 2853,
1688, 1660, 1641, 1584, 1497, 1454, 1364, 1301, 1208, 1159, 1100, 1064,
1027, 992, 907, 875, 788, 735, 697 cmꢀ1; HRMS (ESI): m/z: calcd for
C52H74O8SNa: 881.4997 [M+Na]+; found: 881.5006.
10622
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 10619 – 10624