Total synthesis of koninginin D, B and E

Article abstract of DOI:10.1055/s-2001-9741

Total synthesis of koninginin D, E and B was described. The structures of koninginin B and F, which were deduced as C₄ epimer of koninginin E and D, respectively, have been corrected.

Full text of DOI:10.1055/s-2001-9741

PAPER
119
Total Synthesis of Koninginin D, B and E
Gong Liu,† Zhiqin Wang*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-ling Rd, Shanghai, China 200032
Fax 86(021)64166128; E-mail: wangzq@pub.sioc.ac.cn
Received 11 July 2000; revised 4 September 2000
By comparison with the structure of (-)-exo-brevicomin
and (-)-frontalin, Mori reasoned that the absolute config-
uration of C9 and C10 of (-)-koninginin A should be 9S
and 10S, which has been proved by the total synthesis.11
Because koninginins were isolated from a culture of the
same species of microorganisms, we suggested that kon-
inginins D, F, E and B should have the same absolute con-
figuration at C9 and C10 as that of (-)-koninginin A.
Retrosynthesis of these compounds are shown in Scheme
1. Cyclohexane-1,3-dione (8) was used in the synthesis to
construct the cyclohexenone ring of the molecule.
(+)-Tartaric acid (1) was used to create chiral centers C9
and C10 as it was used by Xu in the total synthesis of kon-
inginin A.12
Abstracts: Total synthesis of koninginin D, E and B was described.
The structures of koninginin B and F, which were deduced as C4
epimer of koninginin E and D, respectively, have been corrected.
Key words: total synthesis, antibiotics, koninginins, (+)-tartaric
acid, heterocycles
Koninginins were isolated from the metabolite produced
in the cultures of Trichorderma species, like T. koningii
and T. hazianum, etc. It has long been known that some of
the Trichoderma species produce volatile and non-vola-
tile antibiotics in vitro and received considerable attention
as biocontrol agents of soil-borne plant pathogens invol-
ved in the "damping-off" disease of young seedlings.1-9
The first structure and relative stereochemistry of the non-
volatile component, koninginin D, was established by
spectroscopic methods by Ghisallberti et al. in 1989 as a
derivative of benzopyran.2 Since then koninginins A, B,
C, E, F and G have been isolated successively and their
structures and relative stereochemistries were reported.
The potential bioactivity of these compounds encouraged
us to study the total synthesis of koninginin D, F, B and E,
which were reported as two pairs of epimers10 (Figure 1).
The synthesis of the side chain 7 is shown in Scheme 2.
According to the known procedure, (+)-tartaric acid was
transformed to diol 2,13 which was treated with tosyl chlo-
ride and C5H11MgBr successively to afford monoalkylat-
ed acetonide 4 in 51% yield. Compound 4 was
transformed to the iodo compound 5 with NaI, which re-
acted with CH2=CHMgBr in the presence of CuI to give
6. Ozonolysis of 6 afforded 7. The overall yield of 7 from
2 was 31.5% (5 steps).
The condensation of 7 and 8 was performed by the method
described by Paquette et al.,14 giving 9 and a small amount
of the Michael addition product 10 (Scheme 3). The H
OH
R
O
O
1
H
NMR spectrum shows that 9 was a 1.6:1 mixture of two
epimers. Treatment of 9 with dilute HCl in acetone result-
ed in deprotection and cyclization furnishing 11, which
upon reaction with Hg(OAc)2 in acetic acid afforded 12
and 13. X-ray diffraction analysis revealed that the C7 ac-
etoxy group of 12 was trans to C9 alkyl group.15 It meant
that the substitution was through a SN1 mechanism and the
stereochemistry was controlled by the 9a-alkyl group.
Since the chiral centers C9 and C10 of 12 were from
(+)-tartaric acid, the absolute configuration of 12 should
be 7R, 9S, 10S. No single crystal of koninginins has been
obtained yet, this was the first direct evidence of the abso-
lute configuration of the skeleton of koninginins.
H
n-Hex
O
n-Hex
H
O
OH
OH
OH
H
koninginin D 4b, R = OH
koninginin F
(proposed) 4a, R = OH
koninginin E 4b, R = H
koninginin B
koninginin A
(proposed) 4a, R = H
Figure 1
R
7
O
1
R
O
O
O
SPh
O
O
HO
HO
CO2H
CO2H
O
O
n-Hex
9
O
10
n-Hex
n-Hex
OH
5
O
H
n-Hex
4
OH
H
OH
OH
R= H or OH
Scheme 1
Synthesis 2001, No. 1, 119–127 ISSN 0039-7881 © Thieme Stuttgart · New York

120
G. Liu, Z. Wang
PAPER
O
O
O
O
O
O
O
HO
HO
CO2H
CO2H
O
O
e
d
b
R
OR
OR
n-Hex
n-Hex
n-Hex
7
6
4 R=OTs
5 R=I
2 R=H
3 R=Ts
c
1
a
Reagents and conditions: a) TsCl, CH2Cl2, Et3N, r.t., 4 h, 85%; b) C5H11MgBr, THF, Li2CuCI4, -78 °C to r.t., 10 h, 51%; c) NaI, DMF, 80 °C,
2 h, 95%; d) CH2 =CHMgBr, CuI, HMPA, THF, -30 to r.t., 5 h, 85%; e) O3, CH2Cl2, MeOH, -78 °C, 90%
Scheme 2
Both 12 and 13 when treated with acetic anhydride gave If the bromo compound 15 is first transformed to iodo
diacetate 14. Attempts to introduce a hydroxyl group to C4 compound and then treated with mercuric acetate, com-
via allylic oxidation of 14 with reagents like SeO2, pounds 19 and 20 are obtained, which upon hydrolysis
SeO2∑SiO2 and Pb(OAc)4 were unsuccessful. Allylic bro- gave 18 and 21, respectively. The spectral data (IR, MS,
1
mination of 14 with NBS via the method described by HRMS, H and 13C NMR) show that 18 and 21 are C4
Wu16 gave 15 in fairly good yield. Nucleophilic substitu- epimers. However, there were apparent differences in the
tion of 15 produced a mixture of 16 and 17, both of which 13C NMR spectra of 21 and natural koninginin F (C2 and
upon hydrolysis gave 18 as a white powder. Acetylation C4), which indicated that the structure of koninginin F
of 18 gave triacetate 19. The spectral data of 18 were iden- needed reappraisal (Table 1). Since the differences are
tical to those of natural (+)-koninginin D except for small limited to C2 and C4, it was suggested that koninginin F
deviations in the 13C NMR (C2, C4, C6 and C9). These might have a C2 instead of the C4 hydroxyl group. This
small deviations disappeared in 13C NMR spectra of kon- assumption has been confirmed by introducing a C2 hy-
inginin D triacetate and 19, since the steric hindrance of droxyl group to 14 with lead tetraacetate. A chloroben-
7b- and 4b-acetoxy group made one conformation of cy- zene solution of 14 and lead tetraacetate was heated at
clohexenone ring preferable to the other one. The overall 100-110 °C for 6 hours giving a mixture of 22 and 23,
yield of 18 from 2 was 4.2% (17 steps).
which upon hydrolysis afforded a mixture of 24 and 25.
OAc
O
OR
n-Hex
O
O
H
O
OAc
mixture of 2α & 2β
n-Hex
22,23 R=Ac
24,25 R=H
g
2
O
OH
O
10
i
a
+
SPh
O
O
OR
O
O
OAc
O
7
+
O
SPh
O
O
c
d
b
n-Hex
8
n-Hex
n-Hex
n-Hex
O
O
OH
H
OH
H
OH
H
OAc
14
11
9
12
R=Ac
13
+
R=H
e
OR
O
O
OAc O
OR
O
OR
O
O
f
g
19
+
n-Hex
n-Hex
n-Hex
n-Hex
O
O
H
H
H
OAc
H
OR
OR
OAc
Br
OH
17
OR
OR
15
18 R=H
19 R=Ac
16
20 R= Ac
21 R= H
d
g
+
R=H
R=Ac
h
Reagents and conditions: a) PhSH, SiO2, CH2Cl2, 30-35 °C, (9, 77.8%); b) 2 N HCl, THF, r.t., 20 h, 87%; c) HOAc, Hg(OAc)2, r.t., 5 h, (12,
69%; 13, 25%); d) Ac2O, Et3N, DMAP, r.t., 1.5 h, (14, 99%; 19, 90%); e) NBS, AIBN, CCl4, reflux, 2 h, (15, 69%); f) NaI, dioxane, CaCO3,
H2O, reflux, 2 h, (16, 51%; 17, 21%); g) MeOH, K2CO3, H2O, r.t., 1 h, (18, 93%; 21, 95%; 24+25, 85%); h) i. NaI, acetone, 50 °C, ii. Hg(OAc)2,
THF, r.t., (19, 38%; 20, 10.8%); i) Pb(OAc)4, PhCl, 100-110 °C, (22+23, 69%)
Scheme 3
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PAPER
Total Synthesis of Koninginin D, B and E
121
Table 1 13C NMR Data of Koninginin D, F and Synthetic Compounds
No. C
21
18
Da
Fa,b
Mixture of
19
D, triacetatea
24 & 25c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
198.1
33.9
29.2
66.6
171.2
114.7
57.7
31.7
77.7
72.9
33.2
25.4
29.1
31.0
22.6
14.1
198.3
34.0
29.2
66.7
171.4
114.6
57.7
31.8
77.0
73.0
33.2
25.4
29.3
31.8
22.7
14.1
198.5
33.3
28.8
65.7
171.5
113.9
57.1
31.7
77.7
73.2
32.4
25.1
29.2
32.2
22.6
14.0
198.3
71.0
28.6
27.1
173.5
112.6
57.2
31.7
76.8
72.8
33.1
25.4
29.2
31.1
22.6
14.1
198.4
199.2
71.3
29.3
27.5
173.6
112.2
58.0
31.3
77.3
72.9
33.3
25.5
29.7
31.0
22.7
14.1
194.8
31.7
26.5
66.6
170.5
112.2
59.7
29.1
74.3
73.0
30.0
25.2
29.3
32.9
22.6
14.1
acetoxy-C
194.8
31.6
26.4
66.5
170.4
112.1
59.6
29.1
74.2
72.9
29.9
25.1
29.2
32.8
22.5
14.0
acetoxy-C
71.1
28.7
27.2
173.5
112.7
57.3
31.8
76.9
72.9
33.2
25.5
29.3
31.7
22.7
14.1
169.8
168.5
168.5
21.2
20.9
20.8
169.8
168.4
168.4
21.2
20.9
20.8
a Ref. 6.
b Chemical shift of C2 and C4 have been exchanged.
c According to 13C NMR , 24:25 is about 3:2.
raphy, 1H NMR and 13C NMR spectra show that the pro- 11 with reagents like Zn, Pd/C, Li-liquid NH3, etc. were
portion of the mixture was about 3:2 and the chemical unsuccessful. Refluxing 11 with nickel borohydride in
shifts of the major component 24 was identical to that of ethanol gave 27 in poor yield (47%). On the other hand,
koninginin F. It was tentatively assigned that 24 has a 2a- the thiophenyl group of 9 could be easily removed by ac-
hydroxyl group, as the substitution reaction was some- tivated Zn in saturated ammonium chloride solution giv-
what hindered by the 7b-acetoxy group.
ing compound 26 in fairly good yield (87%). When
treated with hydrochloric acid 26 gave 27 in 97% yield,
which afforded 28 (89%) by reaction with acetic anhy-
dride. Allylic bromination of 28 with NBS followed by re-
action with sodium iodide and mercuric acetate gave a
mixture of 29 and 30. Hydrolysis of the mixture gave 31
Koninginin B and E were reported to be C4 epimers. The
strategy used in the synthesis of koninginin D was adopt-
ed in the synthesis of koninginin B and E. When treated
with dilute hydrochloric acid, compound 9 gave 11
(Scheme 4). Attempts to remove the thiophenyl group of
O
SPh
O
O
O
f
n-Hex
n-Hex
n-Hex
n-Hex
+
O
O
O
O
H
H
H
H
OAc
OAc
OH
OH
OH
OH
OH
Mixture
29 4α
30 4β
11
31
32
e
a
O
O
SPh
O
n-Hex
n-Hex
O
O
H
OH
OR
27 R=H
28 R=Ac
b
d
9
c
g
O
O
O
OAc
f
O
OH
OH
O
n-Hex
n-Hex
n-Hex
n-Hex
+
O
O
O
O
H
H
H
OAc
OH
OH
33 2α
34 2β
OH
35 or 36
36 or 35
26
Reagents and conditions: a) Ni(BH4)2, EtOH, reflux, (27, 47%); b) activated Zn, sat. NH4Cl, r.t., (26, 87%); c) 2 N HCl, THF, r.t., (27, 97%);
d) Ac2O, Et3N, DMAP, r.t., (28, 89%); e) i. NBS, AIBN, CCl4, reflux, ii. NaI, acetone, iii. Hg(OAc)2, H2O, dioxane, r.t., (29+30, 35%); f)
K2CO3, MeOH/H2O, r.t.; g) Pb(OAc)4, PhCl, 100-110 °C, 70%
Scheme 4
Synthesis 2001, No. 1, 119–127 ISSN 0039-7881 © Thieme Stuttgart · New York

122
G. Liu, Z. Wang
PAPER
Table 2 13C NMR Data of Koninginins B, E and Synthetic Com-
pounds
ed on XL-300 (300 MHz for 1H and 75 MHz for 13C) in CDCl3 so-
lutions using TMS as internal reference, unless otherwise indicated.
MS were performed on Finigan-4921 and HP-5989. X-ray diffrac-
tion analysis was performed on Rigaku AFCTR. Refractive indices
were obtained on Perkin-Elmer 241C. Column chromatography
was performed on silica gel eluted with a mixture of petroleum ether
(PE)/EtOAc.
No. C 31
32
E8
B5,c
35
36
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
197.3
197.5
33.2
29.0
66.1
169.0
111.7
17.6
22.9
81.1
73.4
32.9
25.3
29.3
31.8
22.7
14.1
197.6
33.3
29.0
65.9
169.3
111.4
17.6
22.8
81.3
73.4
32.7
25.1
29.3
31.8
22.6
14.1
198.1
71.0
29.0
27.1
171.3
109.1
17.6
22.7
80.8
73.2
32.8
25.4
29.2
31.7
22.6
14.1
198.1
71.0
29.0
27.1
171.3
109.1
17.6
22.7
80.8
73.2
32.8
25.4
29.2
31.7
22.7
14.1
198.2
71.7
29.1
27.5
171.4
108.9
17.5
22.8
80.9
72.9
32.9
25.4
29.6
31.8
22.7
14.1
33.8
29.3
66.6
169.3
111.9
17.3
22.9
80.6
72.9
32.8
25.3
29.3
31.8
22.6
14.1
Compound 3
To a stirred mixture of diol 2 (1.62 g, 10 mmol), CH2Cl2 (20 mL)
and Et3N (5 mL) was added slowly p-toluene sulfonyl chloride
(4.5 g). The reaction mixture was stirred at r.t. for 4 h and then evap-
orated under reduced pressure. The residue was poured into ice wa-
ter. The solid was collected and crystallized from EtOH giving 3 (4
g, 85%) as colorless crystals.
Mp: 91-93 °C (Lit.17 mp: 90.5-92 °C).
[a]D20 -12.5° (c 8, CHCl3) [Lit.17 [a]D22 -12.4° (c 8.8, CHCl3)].
Compound 4
To a cold (-78 °C) stirred solution of 3 (4.7 g, 10 mmol) in THF
(10 mL) was added Li2Cu2CI4 solution (0.1 mol, 2 mL) and
n-C5H11MgBr/THF solution (2 mol, 7 mL) successively. The reac-
tion mixture was stirred for 10 h at r.t. and then H2O (1 mL) was
added under vigorous stirring with external cooling. The mixture
was poured into Et2O (50 mL), the organic phase was washed with
H2O, brine, dried (Na2SO4), and evaporated. The residue was puri-
fied by column chromatography (PE/EtOAc, 20:1) giving 4 (1.9 g,
51%).
a Ref. 8.
b Ref. 5.
c Chemical shifts of C2 and C4 have been exchanged.
and 32. Spectroscopic data revealed that 31 and 32 were
1
13
epimers. The H NMR and C NMR spectra of 31 were
identical with those of natural koninginin E. However, the
13C NMR spectrum of 32 was somewhat different from
that of koninginin B as happened in 21 and koninginin F,
which meant that koninginin B might also have a C2-hy-
droxyl group (Table 2).
[a]D20 -16.2° (c 1.17, CHCl3) [Lit.18 [a]D15 -18.9°(c 4.1, CHCl3)].
IR: n = 2987 (s), 2933 (s), 2860 (s), 1599 (m), 1458 (m), 1369 (s),
1249 (m), 1216 (m), 1190 (s), 1179 (s), 1098 (s), 984 (s), 815 (m)
cm-1.
1H NMR: d = 7.81 (d, 2H, J = 8.29 Hz), 7.36 (d, 2H, J = 8.17 Hz),
4.09 (m, 2H), 3.78 (m, 2H), 2.46 (s, 3H), 1.52 (m, 2H), 1.31(s, 3H),
1.37 (s, 3H), 1.28 (m, 8H), 0.89 (t, 3H, J = 7.30 Hz).
MS: m/z (%) = 370 (M+, 10.2), 355 (13), 354 (55.2), 313 (31.2), 141
(44.9), 123 (100), 91 (15.2).
HRMS: m/z calcd for C18H27SO5 (M+-Me): 355.1580. Found:
355.1563.
In order to prove this, 28 was treated with lead tetraacetate
to give a mixture of diacetates 33 and 34 (70%) in almost
equal amounts, which upon hydrolysis and separation by
chromatography afforded 35 and 36. The spectroscopic
data showed that they were epimers. The melting point,
1H and 13C NMR of 35 were identical to those of koningi-
nin B (Table 2). Because two half-boat conformations of
the cyclohexenone ring are possible, it was impossible to
deduce the configuration of the 2-hydroxyl group by the
coupling constants J3a,2 and J3b,2. Attempts to grow single
crystal of it were unsuccessful. Thus the configuration of
the C2-hydroxyl group of 35 is still ambiguous and the
structures of koninginin B and F are corrected as follows
(Figure 2).
Compound 5
Compound 4 (2.7 g, 7.3 mmol) was added slowly to a hot (80-
90 °C) vigorously stirred solution of NaI (3 g) in DMF (10 mL). The
mixture was stirred further at this temperature for 2 h and then
poured into Et2O (100 mL), after cooling. The Et2O solution was
washed with H2O, brine, dried (Na2SO4), and concentrated in vac-
uo. The residue was purified by chromatography (PE/EtOAc, 50:1)
giving a colorless liquid 5 (2.25 g, 95%).
[a]D20 -20.4° (c 1.125, CHCl3) [Lit.18 [a]D15 -19.8° (c 3.6, CHCl3)].
IR: n = 2987 (m), 2952 (s), 2932 (s), 2859 (m), 1458 (m), 1379 (s),
1374 (s), 1239 (s), 1168 (m), 1111 (m), 1045 (s), 890 (m) cm-1.
OH
O
O
O
OH
1H NMR: d = 3.76 (m, 1H), 3.61 (dd, 1H, J = 1.8, 7.14 Hz), 3.28
(dd, 2H, J = 5.4, 9.14 Hz), 1.63 (m, 2H), 1.43 (s, 3H), 1.39 (s, 3H),
1.32 (m, 8H), 0.87 (t, 3H, J = 6.5 Hz).
HRMS: m/z calcd for C11H20IO2 (M+-Me): 311.0507. Found:
311.0503.
OH
n-Hex
n-Hex
O
H
H
OH
OH
Koninginin F
Koninginin B
Figure 2
Compound 6
A cold mixture (-30 °C) of 5 (1.7 g, 5.2 mmol), HMPA (3.7 mL),
CuI (50 mg) and THF (5 mL) was added to a vigorously stirred so-
lution of CH2 =CHMgBr (15 mmol) in THF (10 mL). The mixture
was stirred at r.t. for 5 h (monitored by TLC), H2O (2 mL) was add-
Mps were determined on a X4 micro-melting point meter and are
uncorrected. IR spectra were obtained on Shimadzu IR-440 and
Perkin-Elmer 983 spectrometer in film. NMR spectra were record-
Synthesis 2001, No. 1, 119–127 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Koninginin D, B and E
123
ed with external cooling, and the mixture was filtered. The solid
phase was washed with Et2O (5 ¥ 15 mL). The combined organic
phase was washed with H2O, brine, dried (Na2SO4), and concentrat-
ed in vacuo. The residue was purified by chromatography (PE/
EtOAc, 50:1) giving a colorless oil 6 (1 g, 85%).
MS: m/z (%) = 434 (M+, 5.7), 419 (5.8), 358 (14.3), 321 (13.9), 249
(55.7), 247 (100), 235 (56), 217 (71.4), 113 (30.3).
Anal. calcd for C25H38O6: C, 69.09; H, 8.81. Found: C, 69.10; H,
8.94.
[a]D20 -30.4° (c 0.78, CHCl3) [Lit.18 [a]D15 -31.0° (c 2.9, CHCl3)].
Compound 11
A mixture of 9 (20 mg, 0.0463 mmol), THF (2 mL) and 2 N HCl
(1 mL) was stirred at r.t. for 20 h. The solution was neutralized with
solid NaHCO3 and concentrated in vacuo. The residue was extract-
ed with Et2O (10 mL). The Et2O solution was washed with H2O,
brine, dried (Na2SO4), and concentrated in vacuo. The residue was
purified by chromatography (PE/EtOAc, 3:1) giving a colorless oil
11 (15 mg, 87%).
IR: n = 2958 (m), 2933 (s), 2861 (s), 1644 (m), 1378 (m), 1241 (s),
1101 (m), 1058 (m), 915 (m) cm-1.
1H NMR: d = 5.84 (m, 1H, = CH), 5.10 (m, 2H, = CH2), 3.64 (m,
2H, CH), 2.31 (m, 2H, CH2), 1.52 (m, 2H, CH2), 1.37 (s, 6H, 2Me),
1.28 (m, 8H, 4CH2), 0.88 (t, 3H, J = 6.2 Hz, Me).
MS: m/z (%) = 211 (M+-Me, 74.0), 185 (28.1), 170 (34.0), 169
(15.8), 155 (10.2), 142 (30.7), 141 (41.3), 128 (23.0), 114 (46.2), 95
(26.2), 59 (100).
[a]D20 +15° (c 1.0, CH2Cl2).
IR: n = 3429 (br), 2930 (m), 1640 (m), 1609 (s), 1456 (m), 1439
Anal. Calcd for C14H26O2: C, 74.28; H, 11.58. Found: C, 74.60; H,
11.80.
(m), 1399 (s), 1079 (s) cm-1.
1H NMR: d = 7.54 (m, 2H, Ph-H), 7.28 (m, 3H, Ph-H), 4.45 (m, 1H,
C7-H), 4.38 (m, 1H, C9-H), 3.63 (m, 1H, C10-H), 2.42 (m, 3H,
C2,4-H), 1.93 (m, 5H, C3,4,8-H), 1.57 (m, 2H, C11-H), 1.21 (m,
8H, C12-15-H), 0.87 (t, 3H, J = 3.90, C16-H).
MS: m/z (%) = 375 (M++1, 2.7), 265 (100), 247 (22.5), 217 (5.46),
153 (45.1), 149 (17.2), 113 (7.4).
Compound 7
A cold solution (-78 °C) of 6 (5 g) in CH2Cl2 (40 mL) and MeOH
(5 mL)was ozonized until a pale blue color of the solution persisted.
After being swept with N2 and addition of methyl sulfide, the solu-
tion was stirred overnight at r.t., washed with 5% NaHCO3, brine,
and concentrated in vacuo giving a pale yellow liquid 7 (4.5 g,
90%).
1H NMR (60 MHz, CDCl3): d = 9.70 (1H), 3.80 (2H), 2.65 (2H),
1.90 (2H), 1.50-1.20 (14H), 0.90 (3H).
Anal. calcd for C22H30SO3: C, 70.55; H, 8.08. Found: C, 70.54; H,
8.40.
Compounds 12 and 13
A mixture of 11 (50 mg, 0.134 mmol), HOAc (2 mL) and Hg(OAc)2
(100 mg) was stirred at r.t. for 5 h (monitored by TLC). Et2O
(15 mL) was added. The Et2O solution was washed with H2O, 5%
NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by chromatography (PE/EtOAc, 3:1) giving 12
(30 mg, 69%) and 13 (10 mg, 25%).
Compounds 9 and 10
To a mixture of 7 (4.0 g. 17.5 mmol), CH2Cl2 (50 mL), silica gel
(6.0 g, 100-200 mesh) and thiophenol (12 mL) was added 8 (1.0 g,
9.3 mmol) under vigorous stirring. The stirred mixture was heated
at 30-35∞C for 48 h and concentrated in vacuo. The residue was pu-
rified by chromatography (PE/EtOAc, 6:1) giving a colorless solid
mixture of 9 (3 g, 40%) and 10 (280 mg).
12:
Mp: 124-126 ∞C.
[a]D20 +131° (c 0.7, CH2Cl2).
9:
Mp: 84-92 ∞C.
[a]D20 -26.7° (c 0.4, CH2Cl2).
IR: n = 3418 (br),, 2938 (m), 1728 (s), 1642 (s), 1598 (s), 1251 (s),
1189 (s) cm-1.
IR: n = 3059 (br), 2932 (m), 1733 (m), 1585 (s), 1378 (s), 1275 (s),
1H NMR: d = 5.81 (t, 1H, J = 1.11 Hz, C7-H), 4.01 (ddd, 1H, J-
2.35, 4.65, 12.65 Hz, C9-H), 3.64 (dd, 1H, J = 5.01, 11.6 Hz, C10-
H), 2.48 (m, 2H, C2-H), 2.39 (m, 2H, C4-H), 2.03 (s, 3H, OAc),
2.01 (m, 2H, C3-H), 1.57 (m, 5H, C8,11,12-H), 1.31 (m, 7H, C12-
15-H), 0.89 (t, 3H, J = 6.90 Hz, C16-H).
13C NMR: d = 196.1, 174.0, 170.1, 110.7, 76.4, 72.8, 60.1, 36.7,
33.0, 31.7, 29.6, 29.2, 28.7, 25.4, 22.6, 21.3, 20.5, 14.1.
1246 (s), 1193 (m), 1088 (s), 740 (m), 692 (m) cm-1.
1H NMR: d = 9.11, 8.80 (br, 1:0.6, 1H, OH), 7.26 (m, 5H, Ph-H),
5.09 (t, 0.63H, J = 6.70 Hz, C1¢-H), 4.77 (q, 0.37H, J = 5.90 Hz,
C1¢-H), 3.61 (m, 2H, C3¢,4¢-H), 2.35 (m, 3H, C2,4-H), 2.02 (m, 2H,
C3,4-H), 1.81 (m, 1H, C3-H), 1.65 (m, 2H, C2¢-H), 1.49 (m, 2H,
C5¢-H), 1.38 (s, 3H, Me), 1.35 (s, 3H, Me), 1.27 (m, 8H, C6¢-9¢-H),
0.88 (t, 3H, J = 4.60 Hz, C10¢-H).
MS: m/z (%) = 281(M+-43, 100), 265 (48.6), 247 (10.8), 179 (9.9),
165 (12.0), 149 (52.7), 150 (50.1), 113 (26.4).
MS: m/z (%) = 321 (M+-111, 10.2), 277 (48.6), 265 (15.66), 250
(8.8). 217 (58.3), 185 (48.5), 165 (48.1), 149 (100), 109 (56.3).
Anal. calcd for C18H28O5: C, 66.64; H, 8.70. Found: C, 66.31; H,
8.73.
Anal. calcd for C25H36SO4: C, 69.41; H, 8.39. Found: C, 69.00; H,
8.55.
13:
10:
[a]D20 +156.8° (c 0.4, CH2Cl2).
Mp: 90-92 ∞C.
[a]D20 -39° (c 0.8, CH2Cl2).
IR: n = 3369 (br), 2926 (m), 1639 (s), 1606 (s), 1252 (s), 1188 (s),
1008 (s) cm-1.
IR: n = 3448 (br), 2932 (m), 1721 (m), 1668 (s), 1625 (s), 1381 (s),
1H NMR: d = 4.68 (d, 1H, J = 2.20 Hz, C7-H), 4.06 (ddd, 1H,
J = 2.2, 4.5. 12.3 Hz, C9-H), 3.66 (m, 1H, C10-H), 2.46-2.35 (m,
4H, C2,4-H), 1.93 (m, 2H, C3-H), 1.62 (m, 4H, C8,11-H), 1.30 (m,
8H, C12-15-H), 0.89 (t, 3H, J = 7.0 Hz, C16-H).
13C NMR: d = 199.2, 173.1, 115.3, 76.5, 73.0, 57.9, 36.5, 33.2, 31.8,
31.2, 29.3, 28.4, 25.5, 22.7, 20.6, 14.1.
1176 (m) cm-1.
1H NMR: d = 12.96 (br, OH), 4.17 (dd, 1H, J = 6.5, 8.5 Hz, C1¢-H),
3.55 (m, 1H, C3¢-H), 3.42 (m, 1H, C4¢-H), 2.52 (m, 4H, C2-H), 2.35
(m, 4H, C4-H), 1.95 (m, 4H, C3-H), 1.45-1.31 (m, 12H, C2¢,5¢-9¢-
H), 1.34 (s, 3H, Me), 1.31 (s, 3H, Me), 0.88 (t, 3H, J = 6.9 Hz, C10¢-
H).
MS: m/z (%) = 282 (M+, 2.12), 266 (17.0), 265 (100), 247 (10.6),
165 (16.4), 139 (42.0), 111 (13.9).
Synthesis 2001, No. 1, 119–127 ISSN 0039-7881 © Thieme Stuttgart · New York

124
G. Liu, Z. Wang
PAPER
Anal. calcd for C16H26O4: C, 68.04; H, 9.29. Found: C, 67.75; H,
9.45.
(m, 3H, C8,11,12-H), 1.30 (m, 8H, C11-15-H), 0.89 (t, 3H, J = 6.8
Hz, C16-H).
MS: m/z (%) = 341 (M++1, 2.0), 323 (38.7), 306 (10.3), 305 (50.2),
279 (6.9), 263 (65.3), 262 (34.9), 245 (39.2), 191 (26.4), 165 (80.3),
43 (100).
Compound 14
A mixture of 12 (100 mg, 0.308 mmol), Ac2O (2 mL), Et3N
(1.5 mL) and DMAP (5 mg) was stirred at r.t. for 1.5 h. and then
MeOH (2 mL) was added under cooling. The solution was stirred
for additional 0.5 h and poured into Et2O (30 mL). The Et2O solu-
tion was washed with H2O, brine, dried (Na2SO4), and concentrated
in vacuo. The residue was purified by chromatography (PE/EtOAc,
10:1) affording a colorless solid 14 (110 mg, 99%).
HRMS: m/z calcd for C18H28O6: 340.1886. Found: 340.1886.
17:
[a]D20 +86.7°(c 0.15, CHCl3).
IR: n = 3415 (br), 2930 (m), 1741 (s), 1663 (s), 1619 (s), 1236 (s),
1071 (s), 1023 (s) cm-1.
[a]D20 +84.6° (c 0.55, CH2Cl2).
1H NMR: d = 5.80 (dd, 1H, J = 2.4, 3.3 Hz, C7-H), 5.10 (m, 1H,
C10-H), 4.51 (dd, 1H, J = 4.8, 8.8 Hz, C4-H), 4.19 (ddd, 1H,
J = 2.4, 5.1, 12.8 Hz, C9-H), 2.60 (m, 1H, C2-H), 2.35 (m, 1H, C2-
H), 2.20-2.00 (m, 2H, C3,8-H), 2.10 (s, 3H, OAc), 2.03 (s, 3H,
OAc), 1.65 (m, 3H, C3,8,11-H), 1.30 (m, 9H, C11-15-H), 0.88 (t,
3H, J = 7.0 Hz, C16-H).
IR: n = 2929 (m), 1742 (s), 1733 (s), 1657 (s), 1622 (s), 1240 (s),
1028 (s) cm-1.
1H NMR: d = 5.80 (d, 1H, J = 2.1 Hz, C7-H), 5.08 (m, 1H, C10-H),
4.17 (ddd, 1H, J = 2.1, 4.0, 14.2 Hz, C9-H), 2.46 (m, 2H, C2-H),
2.37 (m, 2H, C4-H), 2.09 (s, 3H, OAc), 2.02 (s, 3H, OAc), 1.95 (m,
2H, C3-H), 1.70 (m, 3H, C8,11-H), 1.30 (m, 9H, C11-15-H), 0.89
(t, 3H, J = 7.1 Hz, C16-H).
MS: m/z (%) = 339 (M+-43, 4.3), 323 (8.9), 279 (23.2), 263 (16.1),
262 (15.0), 245 (7.4), 191 (13.2), 165 (47.4), 147 (18.9), 43 (100).
13C NMR: d = 196.2, 174.2, 170.4, 170.0, 110.6, 73.8, 73.4, 60.0,
36.7, 31.6, 30.1, 29.5, 29.0, 28.6, 25.2, 22.5, 21.2, 20.9, 20.5, 14.0.
Compound 18
A mixture of 16 (20 mg, 0.059 mmol), CH3OH (1.5 mL) and K2CO3
[30 mg in H2O (1 mL)] was stirred at r.t. for 1 h (monitored by
TLC), neutralized with 3 N HCl, evaporated, and extracted with
EtOAc (3 ¥ 5 mL). The EtOAc solution was washed with H2O,
brine, dried (Na2SO4), and concentrated in vacuo. The residue was
purified by chromatography (PE/EtOAc, 1:1) giving 18 (16.3 mg,
93%). Crystallization from CHCl3 and n-hexane afforded colorless
needles.
MS: m/z (%) = 323 (M+-43, 19.3), 264 (14.3), 263 (55.5), 247
(17.4), 218 (10.6), 165 (20.8), 149 (100), 139 (61.5), 119 (26.8).
Anal. calcd for C20H30O6: C, 65.54; H, 8.25. Found: C, 65.42; H,
8.44.
Compound 15
To a stirred solution of 14 (50 mg, 0.136 mmol) in CCl4 (2 mL) was
added NBS (40 mg 0.225 mmol) and AIBN (0.5 mg). The mixture
was refluxed for 2 h (monitored by TLC), cooled to r.t., and filtered.
The solid was washed with CCl4. The combined organic phase was
concentrated in vacuo, and the residue was purified by chromatog-
raphy (PE/EtOAc, 10:1) giving a colorless oil 15 (42 mg, 69%).
Mp: 140-142 ∞C (Lit.2 mp: 122-123 °C).
[a]D20 +171° (c 0.125, CHCl3) [Lit.2 [a]D +166.9° (c 0.3, CHCl3)].
IR: n = 3293 (br), 2926 (s), 1660 (s), 1617 (s), 1259 (s), 1091 (s)
cm-1.
1H NMR: d = 4.68 (dd, 1H, J = 1.0, 2.0 Hz, C7-H), 4.49 (q-like, 1H,
J = 4.8 Hz, C4-H), 4.11 (ddd, 1H, J = 2.2, 4.6, 12.1 Hz, C9-H), 3.72
(q, 1H, J = 6.4 Hz, C10-H), 2.60 (ddd, 1H, J = 4.7, 5.6, 17.0 Hz, C2-
H), 2.30 (m, 1H, C2-H), 2.20 (m, 1H, C3-H), 2.00 (m, 2H, C3,8-H),
1.60 (m, 3H, C8,11,12-H), 1.40-1.25 (m, 8H, C11-15-H), 0.88 (t,
3H, J = 6.8 Hz, C16-H).
IR: n = 2931 (m), 1739 (s), 1670 (s), 1625 (s), 1228 (s), 1185 (s),
1021 (s) cm-1.
1H NMR: d = 5.81 (m, 1H, C7-H), 5.08 (ddd, 1H, J = 4.4, 6.8, 6.6
Hz, C10-H), 4.76 (t, 1H, C4-H), 4.12 (ddd, 1H, J = 1.9, 3.9, 12.5
Hz, C9-H), 2.76 (m, 1H, C2-H), 2.35 (m, 2H, C2,3-H), 2.10 (s, 3H,
OAc), 2.02 (s, 3H, OAc), 2.00 (m, 1H, C3-H), 1.72 (m, 3H, C8,11-
H), 1.30 (m, 9H, C11-15-H), 0.88 (t, 3H, J = 6.7 Hz, C16-H).
13C NMR: see Table 1.
MS: m/z (%) = 402 (M+-43, 8.9), 400 (8.8), 386 (4.8), 384 (6.0),
342 (23.5), 340 (22.5), 323 (31.6), 305 (27.5), 263 (56.8), 245
(26.0), 43 (100).
MS: m/z (%) = 298 (M+, 1.3), 281 (32.9), 262 (20.1), 242 (7.1), 209
(6.6), 191 (8.3), 166 (29.0), 165 (100), 155 (26.0), 139 (25.2), 109
(14.2).
HRMS: m/z calcd for C16H24O4 (M-H2O): 280.1675. Found:
280.1683.
Compounds 16 and 17
A mixture of 15 (100 mg, 0.225 mmol), Ca2CO3 (200 mg), NaI
(20 mg, 0.133 mmol), dioxane (5 mL) and H2O (1 mL) was refluxed
under stirring for 2 h. After cooling, the mixture was filtered and the
solid was washed with CH2Cl2 (3 ¥ 5 mL). Combined filtrate was
evaporated to dryness and extracted with Et2O (3 ¥ 10 mL). The
Et2O solution was washed with H2O, brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by chromatography
(PE/EtOAc, 4:1) giving a colorless oil 16 (39 mg, 51%) and 17
(18 mg, 21%).
Compound 19
See procedure for 14. Compound 18 (10 mg, 0.0336 mmol) gave a
colorless oil 19 (13 mg, 90%).
[a]D20 +127.4° (c 0.58, CHCl3).
IR: n = 2930 (s), 1748 (s), 1671 (s), 1639 (s), 1234 (s), 1039 (s)
cm-1.
1H NMR: d = 5.80 (dd, 1H, J = 1.49, 1.55 Hz, C7-H). 5.64 (t, 1H,
J = 4.90 Hz, C4-H), 5.06 (td, 1H, J = 3.82, 6.82 Hz, C10-H), 4.14
(ddd, 1H, J = 2.2, 3.7, 12.8 Hz, C9-H), 2.63 (m, 1H, C2-H), 2.39 (m,
1H, C2-H), 2.20 (m, 1H, C3-H), 2.13 (s, 3H, OAc), 2.07 (s, 3H,
OAc), 2.01 (s, 3H, OAc), 1.99 (m, 1H, C8-H), 1.75 (m, 1H, C8-H),
1.65 (m, 2H, C3,11-H), 1.25-1.30 (m, 9H, C11-15-H), 0.87 (t, 3H,
J = 6.9 Hz, C16-H).
16:
[a]D20 +106.4° (c 0.125, CHCl3).
IR: n = 3422 (br), 2930 (s), 1741 (s), 1647 (s), 1619 (s), 1235 (s),
1019 (s) cm-1.
1H NMR: d = 5.11 (ddd, 1H, J = 5.1, 5.3, 7.9 Hz, C10-H), 4.67 (t,
1H, J = 3.5Hz, C7-H), 4.46 (dd, 1H, J = 4.8, 8.9 Hz, C4-H), 4.27
(ddd, 1H, J = 2.4, 4.8, 11.5 Hz, C9-H), 2.60 (m, 1H, C2-H), 2.30 (m,
2H, C2,3-H), 2.11 (s, 3H, OAc), 1.95 (m, 2H, C3,8-H), 1.80-1.60
13C NMR: see Table 1.
Synthesis 2001, No. 1, 119–127 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Koninginin D, B and E
125
MS: m/z (%) = 380 (M+-44, 11.3), 365 (17.7), 322 (14.7), 321
(25.0), 305 (67.4), 279 (7.9), 262 (14.4), 245 (44.4), 233 (14.0), 191
(15.8), 165 (15.3), 149 (17.0), 43 (100).
1H NMR: d = 5.84-5.73 (m, 1H, C4-H), 5.31 (m, 1H, C2-H), 5.07
(m, 1H, C10-H), 4.15 (m, 1H, C9-H), 2.65-1.97 (m, 5H, C3, 7,
8-H), 2.16, 2.10, 2.09, 2.03, 2.00 (s, 9H, OAc), 1.70-1.64 (m, 3H,
C8,11-H), 1.30-1.25 (m, 8H, C12-15-H), 0.88 (t, 3H, J = 6.8 Hz,
C16-H).
13C NMR: d = 190.59, 190.37, 173.65, 172.83, 170.71, 170.61,
170.42, 170.27, 169.91, 169.80, 109.58, 109.22, 74.35, 74.30, 73.14
(2C), 72.05, 71.98, 59.93, 59.58, 31.58 (2C), 30.35, 30.07 (2C),
29.33, 28.98 (2C), 27.23, 27.17, 26.20, 26.06, 25.12 (2C), 22.5
(2C), 21.24, 21.14, 20.85 (4C), 14.01 (2C).
Anal. calcd for C22H32O8: C, 62.23; H, 7.60. Found: C, 61.93; H,
7.74.
Compounds 19 and 20
A mixture of 15 [prepared from 14 (50 mg)], acetone (5 mL) and
NaI (200 mg) was stirred at 50-60 ∞C for 6 h. Et2O (20 mL) was
added after cooling. The Et2O solution was filtered and concentrat-
ed in vacuo giving an iodo compound. A mixture of the iodo com-
pound, Hg(OAc)2 (150 mg) and anhyd THF (5 mL) was stirred at
r.t. for 5 h (monitored by TLC) and then poured into Et2O (20 mL).
The Et2O solution was washed with H2O, brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by chromatography
(PE/EtOAc, 4:1) giving a colorless oil 19 (22 mg, 38%) and 20
(6 mg, 10.8%).
MS: m/z (%) = 423 (M+-1, 0.9), 380 (M+-44, 3.1), 364 (10.7), 321
(20.2), 320 (13.3), 304 (6.2), 279 (7.6), 263 (15.4), 262 (34.5), 233
(6.4), 165 (9.9), 139 (11.0), 43 (100).
HRMS: m/z calcd for C22H32O8: 424.2097. Found: 424.2120.
Mixture of 24 and 25
See procedure for 18. A mixture 22 and 23 (10 mg.) gave a colorless
solid mixture of 24 and 25 (6 mg, 85%).
20:
[a]D20 +54° (c 0.3, CHCl3).
IR: n = 3406 (br), 2946 (s), 2918 (s), 1644 (s), 1604 (s), 1249 (s),
IR: n = 2927 (s), 2856 (m), 1743 (s), 1668 (s), 1625 (s), 1372 (s),
1201 (s), 1027 (s), 987 (s) cm-1.
1231 (s), 1092 (m), 1040 (s) cm-1.
1H NMR: d = [4.81 (br s), 4.63 (t, J = 1.4 Hz), 1H, C7-H], 4.08 (m,
1H, C9-H), 3.79-3.65 (m, 2H, C2,10-H), 2.70-2.25 (m, 3H, C3,4-
H), 1.90-1.75(m, 2H, C3,8-H), 1.65-1.55 (m, 3H, C8,11,12-H),
1.30 (m, 8H, C11-15-H), 0.89 (t, 3H, J = 6.9 Hz, C16-H).
1H NMR: d = 5.81 (dd, 1H, J = 2.3, 3.3 Hz, C7-H), 5.75 (dd, 1H,
J = 5.1, 9.0 Hz, C4-H), 5.10 (q-like, 1H, J = 6.5 Hz, C10-H), 4.14
(ddd, 1H, J = 2.3, 5.8, 12.7 Hz, C9-H), 2.60-2.00 (m, 4H, C2,3,8-
H), 2.14 (s, 3H, OAc), 2.09 (s, 3H, OAc), 2.02 (s, 3H, OAc), 1.70-
1.60 (m, 3H, C3,8,11-H), 1.40-1.25 (m, 9H, C11-15-H), 0.88 (t,
3H, J = 7.0 Hz, C16-H).
13C NMR: d = 194.3, 170.6, 170.2, 169.9, 169.2, 111.8, 74.8, 73.2,
66.9, 59.6, 34.2, 31.7, 30.1, 29.2, 29.0, 26.7, 24.9, 22.6, 21.2, 20.9,
20.8, 14.1.
13C NMR: see Table 1.
MS: m/z (%) = 299 (M++1, 2.3), 282 (11.1), 281 (49.9), 280 (23.1),
262 (8.6), 209 (5.4), 195 (4.1), 181 (6.0), 166 (16.5), 165 (14.6), 155
(21.7), 139 (18.5), 124 (22.9), 113 (32.2), 43 (100).
HRMS: m/z calcd for C16H26O5: 298.1780. Found: 298.1774.
MS: m/z (%) = 424 (M+, 0.2), 380 (M+-44, 9.1), 364 (17.5), 321
(31.6), 320 (36.4), 305 (41.9), 279 (12.9), 262 (27.3), 245 (32.8),
233 (20.9), 207 (10.0), 191 (14.3), 165 (34.9), 149 (31.5), 43 (100).
Compound 26
A mixture of 9 (800 mg, 1.85 mmol), THF (20 mL), activated Zn (4
g) and sat. NH4Cl (12 mL) was stirred at r.t. for 24 h. After remov-
ing the solvent, the residue was extracted with Et2O (3 ¥ 30 mL).
The organic layer was washed with H2O, brine, dried (Na2SO4), and
concentrated in vacuo. The residue was purified by chromatography
(PE/EtOAc, 6:1) giving a colorless oil 26 (520 mg, 87%).
Anal. calcd for C22H32O8: C, 62.24; H, 7.60. Found: C, 61.93; H,
7.74.
Compound 21
See procedure for 18. Compound 20 (6 mg, 0.014 mmol) gave a col-
orless solid 21 (4 mg, 95%), recrystallized from CHCl3/n-hexane.
[a]D20 +16.8° (c 2.05, CHCl3).
IR: n = 3433 (br), 2932 (s), 1714 (s), 1670 (s), 1593 (s), 1380 (s),
Mp: 135-137 ∞C.
1176 (s), 1131 (m), 959 (m) cm-1.
IR: n = 3289 (br), 2964 (s), 1660 (s), 1617 (s), 1262 (s), 1093 (s),
1H NMR: d = 3.56 (t, 2H, J = 3.1 Hz, C3¢,4¢-H), 2.34 (m, 5H,
C1¢,2,4-H), 2.27 (m, 1H, C1¢-H), 1.90 (m, 2H, C3-H), 1.30-1.50
(m, 12H, C2¢,5¢-9¢-H), 1.29 (s, 3H, Me), 1.27 (s, 3H, Me), 0.86 (t,
3H, J = 4.7 Hz, C10¢-H).
MS: m/z (%) = 324 (M+, 0.57), 308 (4.85), 267 (6.9), 249 (6.7), 229
(6.9), 217 (4.5), 170 (22.4), 146 (45.3), 128 (26.6), 114 (67.6), 70
(100).
1019 (s), 800 (s) cm-1.
1H NMR: d = 4.71 (m, 1H, C7-H), 4.53 (dd, 1H, J = 4.8, 9.1 Hz, C4-
H), 4.14 (ddd, 1H, J = 2.1, 4.9, 13.1 Hz, C9-H), 3.74 (q, 1H, J = 5.4
Hz, C10-H), 2.62 (td, 1H, J = 5.5, 17.5 Hz, C2-H), 2.35-2.25 (m,
2H, C2,3-H), 2.00 (m, 2H, C3,8-H), 1.70-1.60 (m, 3H, C8,11,12-
H), 1.40-1.25 (m, 8H, C11-15-H), 0.91 (t, 3H, J = 6.6 Hz, C16-H).
13C NMR: see Table 1.
HRMS: m/z calcd for C19H32O4: 324.2300. Found: 324.2289.
MS: m/z (%) = 281 (M+-OH, 11.8), 280 (M+-H2O, 8.8), 262 (4.5),
221 (6.2), 195 (6.7), 177 (13.5), 166 (58.4), 149 (37.0), 148 (42.3),
137 (35.8), 120 (41.6), 109 (41.6), 43 (100).
Compound 27
See procedure for 11. Compound 26 (450 mg, 1.39 mmol) gave 27
(360 mg, 97%).
Mp: 59-61 ∞C (Lit.11 mp: 60-61 °C).
[a]D20 +163° (c 1.25, CHCl3) [Lit.11 [a]D25 +180° (c 1.00, CHCl3)].
Mixture of 22 and 23
A mixture of 14 (20 mg, 0.054 mmol), chlorobenzene (2 mL) and
Pb(OAc)4 (200 mg) was heated at 100-110 °C under stirring for 8
h, cooled, and filtered. The solid was washed with CH2Cl2. The
combined organic phase was washed with H2O, brine, dried
(Na2SO4), and evaporated to dryness. Chromatographic separation
(PE/EtOAc, 8:1) of the residue gave a colorless liquid mixture of 22
and 23 (16 mg, 69%).
IR: n = 3419 (br), 2929 (s), 2856 (s), 1640 (m), 1612 (s), 1399 (s),
1251 (m), 1185 (m), 1080 (s) cm-1.
1H NMR: d = 3.78 (ddd, 1H, J = 2.3, 5.6, 10.8 Hz, C9-H), 3.62 (m,
1H, C10-H), 2.30-2.52 (m, 5H, C2, 6, 8-H), 1.88-2.18 (m, 4H, C3,
8-H), 1.66 (m, 1H, C8-H), 1.25-1.60 (m, 10H, C11-15-H), 0.89 (t,
3H, J = 6.6 Hz, C16-H).
IR: n = 2932 (s), 2860 (m), 1743 (s), 1680 (s), 1623 (s), 1372 (s),
1235 (s), 1023 (s) cm-1.
Synthesis 2001, No. 1, 119–127 ISSN 0039-7881 © Thieme Stuttgart · New York

126
G. Liu, Z. Wang
PAPER
MS: m/z (%) = 267 (M++1, 100), 265 (M+-1, 35.8), 249 (2.5), 151
(3.9), 139 (13.2), 126 (10.0), 113 (5.0).
MS: m/z (%) = 283 (M++1, 5.0), 264 (6.1), 246 (3.3), 168 (6.7), 150
(100), 149 (60.3), 135 (8.8), 122 (17.8), 107 (12.2), 83 (24.7).
HRMS: m/z calcd for C16H26O4: 282.1831. Found: 282.1826.
Compound 27 from 11
To a clear solution of 11 (40 mg, 0.107 mmol) and NiCl2∑6H2O
(240 mg, 1.01 mmol) in EtOH (8 mL) was added slowly NaBH4
(37 mg, 1 mmol). The mixture was stirred at r.t. for 1 h, refluxed for
3 h, and filtered. The solid was washed with EtOAc. The combined
organic phase was concentrated in vacuo, and the residue was puri-
fied by chromatography (PE/EtOAc, 6:1) giving a colorless solid 27
(13.5 mg, 47%).
Mixture of 33 and 34
See procedure for mixture of 22 and 23. Compound 28 (30 mg) gave
a mixture of 33 and 34 (25 mg, 70%).
Mixture of 35 and 36
See procedure for 18. A mixture of 33 and 34 (30 mg, 0.08 mmol)
gave equal amounts of 35 and 36 (total 21 mg, 91%).
35:
Compound 28
Mp: 74-76 ∞C (Lit.4 mp: 72-74 °C).
[a]D20 +194.6° (c 0.45, CHCl3) [Lit.8 [a]D +162.9°, acetone].
See procedure for 14. Compound 27 (300 mg) gave a colorless liq-
uid 28 (310 mg, 89.3%).
[a]D20 +124° (c 1.05, CHCl3), [Lit.11 [a]D25 +120° (c 1.05, CHCl3)].
IR: n = 3439 (br), 2932 (s), 2856 (m), 1651 (s), 1614 (s), 1244 (m),
1193 (m), 1080 (s), 1029 (m) cm-1.
IR: n = 2955 (s), 2931 (s), 2859 (s), 1741 (s), 1685 (s), 1625 (s),
1398 (s), 1237 (s), 1184 (s), 1079 (s), 1025 (s) cm-1.
1H NMR: (600 MHz, CDCl3): d = 4.05 (dd, 1H, J = 5.4, 12.6 Hz,
C2-H), 3.79 (ddd, 1H, J = 2.1, 5.1, 10.8 Hz, C9-H), 3.64 (dd, 1H,
J = 5.4, 11.0 Hz, C10-H), 2.60 (ddd, 1H, J = 2.0, 4.4, 17.0 Hz, C4-
H), 2.47 (m, 1H, C4-H), 2.36 (m, 1H, C3-H), 2.10-1.98 (m, 3H,
C7,8-H), 1.80 (m, 1H, C3-H), 1.70-1.55 (m, 3H, C8,11-H), 1.30
(m, 8H, C12-15-H), 0.89 (t, 3H, J = 6.9 Hz, C16-H).
1H NMR: d = 5.06 (td, 1H, J = 5.0, 6.5 Hz, C10-H), 3.94 (ddd, 1H,
J = 2.4, 5.0, 10.0 Hz, C9-H), 2.25-2.47 (m, 5H, C2, 4, 7-H), 2.08
(s, 3H, OAc), 2.04-2.19 (m, 1H, C4-H), 1.80-2.00 (m, 3H, C3,
8-H), 1.55-1.72 (m, 3H, C8, 11-H), 1.20-1.40 (m, 8H, C12-15-H),
0.87 (t, 3H, J = 5.6 Hz, C16-H).
MS: m/z (%) = 309 (M++1, 21.5), 308 (M+, 100), 306 (20.0), 264
(4.8), 248 (15.1), 247 (10.8), 246 (16.7), 177 (6.0), 149 (12.8), 43
(46.2).
13C NMR: see Table 2.
MS: m/z (%) = 282 (M+, 7.2), 264 (8.6), 209 (5.0), 196 (5.3), 168
(17), 155 (19.8), 153 (16.3), 149 (22.0), 142 (15.5), 139 (18.6), 129
(13.6), 126 (100), 113 (17.2).
Mixture of 29 and 30
See procedure for 15, 19 and 20. Compound 28 (50 mg) gave a col-
orless liquid mixture of 29 and 30 (21 mg, 35%).
HRMS: m/z calcd for C16H26O4: 282.1831. Found: 282.1821.
36:
Mp: 95-97 ∞C.
[a]D20 +68.8° (c 0.6, CHCl3).
Mixture of 31 and 32
See procedure for 18. A mixture of 29 and 30 (20 mg) gave a mix-
ture of 31 and 32 (14.3 mg, 93%), which can be separated by chro-
matography (PE/EtOAc, 4:1).
IR: n = 3428 (br), 2933 (m), 2851 (m), 1647 (m), 1614 (s), 1410
(m), 1258 (m), 1197 (m), 1081 (m) cm-1.
1H NMR (600 MHz, CDCl3): d = 4.04 (dd, 1H, J = 4.8, 12.6 Hz,
C2-H), 3.90 (ddd, 1H, J = 2.4, 5.1, 12.9 Hz,C9-H), 3.63 (dd, 1H,
J = 5.4, 11.4 Hz, C10-H), 2.61 (ddd, 1H, J = 2.4, 5.4, 15.6 Hz, C4-
H), 2.45 (m, 1H, C2-H), 2.38 (m, 1H, C3-H), 2.15-1.95 (m, 3H,
C7,8-H), 1.70 (m, 2H, C3,8-H), 1.55-1.65 (m, 2H, C11-H), 1.30
(m, 8H, C12-15-H), 0.89 (t, 3H, J = 6.9 Hz, C16-H).
31:
Mp: 103-105 °C (Lit.6 mp: 94-96 °C).
[a]D20 +74° (c 1.70, CHCl3) [Lit.6 [a]D25 +107°, CHCl3; Lit.8 [a]D
+0.6°, acetone].
IR: n = 3387 (br), 927 (s), 2856 (s), 1731 (m), 1616 (s), 1398 (m),
1253 (s), 1194 (m), 1089 (s) cm-1.
13C NMR: see Table 2.
1H NMR: d = 4.40 (t, 1H, J = 5.3 Hz, 1H, C4-H), 3.81 (ddd, 1H,
J = 1.9, 6.0, 10.6 Hz, C9-H), 3.65 (dd, 1H, J = 2.9, 7.2 Hz, C10-H),
2.61 (m, 1H, C2-H), 2.45 (m, 1H, C3-H), 2.35 (m, 1H, C2-H), 2.20-
1.95 (m, 3H, C3,7-H), 1.75-1.60 (m, 4H, C8,11-H), 1.30 (m, 8H,
C12-15-H), 0.89 (t, 3H, J = 6.8 Hz, C16-H).
MS: m/z (%) = 283 (M++1, 15.2), 282 (8.1), 264 (8.8), 238 (2.2),
209 (3.8), 168 (15.3), 149 (61.7), 139 (16.6), 126 (100), 125 (47.4),
113 (19.7).
HRMS: m/z calcd for C16H26O4: 282.1831. Found: 282.1826.
13C NMR: see Table 2.
References and Notes
MS: m/z (%) = 283 (M++1, 58.2), 281 (4.4), 264 (11.4), 247
(5.5),179 (6.5), 168 (12.2), 151 (18.8), 150 (100), 123 (16.4),111
(11.1), 43 (53.2).
† Current address: Department of Chemistry, Texas Christian
University, Fort Worth, Texas 76129 USA.
(1) Papavizas, G. C. Annu. Rev. Phytopathol. 1985, 23, 23.
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E. L. J. Nat. Prod. 1989, 52, 67.
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1991, 39, 977.
HRMS: m/z calcd for C16H26O4: 282.1831. Found: 282.1845.
32:
[a]D20 +94° (c 0.185, CHCl3).
IR: n = 3436 (br), 2927 (s), 1732 (m), 1595 (s), 1407 (m), 1249 (s),
1218 (s), 1029 (s), 1075 (s) cm-1.
1H NMR: d = 4.45 (dd, 1H, J = 3.0, 5.2 Hz, C4-H), 3.86 (ddd, 1H,
J = 2.6, 5.6, 10.1 Hz, C9-H), 3.69 (dd, 1H, J = 5.5, 11.3 Hz, C10-
H), 2.59 (m, 1H, C2-H), 2.44 (m, 1H, C3-H), 2.35-1.92 (m, 5H,
C2,3,7,8-H), 1.75-1.55 (m, 3H, C8,11-H), 1.30 (m, 8H, C12-15-
H), 0.89 (t, 3H, J = 6.8 Hz, C16-H).
(5) Almassi, F.; Ghisalberti, E. L.; Narbey, M. J. J. Nat. Prod.
1991, 54, 396.
(6) Ghisalberti, E. L.; Rowland, C. Y. J. Nat. Prod. 1993, 56,
1799.
13C NMR: see Table 2.
Synthesis 2001, No. 1, 119–127 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Koninginin D, B and E
127
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(8) Parker, D. S. P; Cutler, H. G.; Schreiner, P. R. Biosci.
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(9) Parker, S. T.; Cutler, H. G.; Schreiner, P. R. Biosci.
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(10) Liu, G.; Wang, Z. Q. Chem. Commun. 1999, 1129.
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T = 293 °C, P2,2,2(#19), Z = 4, m(Mo-Ka) = 0.84 cm-1, 2487
reflections measured, 2487 unique (Rint = 0.000) which were
used in all calculations. The final wR(F2) was 0.057 [for 1140
observed reflections with I > 2.00s(I)]. CCDC 182/1244.
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a = 13.690(4), b = 25.900(3), c = 5.179(3) A, V = 1836(1) A3,
Article Identifier:
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Synthesis 2001, No. 1, 119–127 ISSN 0039-7881 © Thieme Stuttgart · New York