First total synthesis of (+)-koninginin D

Article abstract of DOI:10.1039/a901320b

A total synthesis of (+)-koninginin D (1) is described; the absolute configuration of the immediate antecedent of 1 is shown to have the configuration 7R,9S,10S by X-ray diffraction analysis.

Full text of DOI:10.1039/a901320b

First total synthesis of (+)-koninginin D
Gang Liu and Zhiqin Wang*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Feng Lin Lu, Shanghai 200032, China.
E-mail: wangzq@pub.sioc.ac.cn
Received (in Cambridge, UK) 17th February 1999, Accepted 29th April 1999
A total synthesis of (+)-koninginin D (1) is described; the
absolute configuration of the immediate antecedent of 1 is
shown to have the configuration 7R,9S,10S by X-ray
diffraction analysis.
monoalkylated acetonide 8 in 48.5% yield. Compound 8 was
transformed to the iodo compound with NaI, which when
reacted with CH2NCHMgBr in the presence of CuI gave 9.6
Ozonolysis of 9 afforded 4. The overall yield of 4 from 7 is 30%
(5 steps).
(+)-Koninginin D, a biologically active natural product, was
isolated from the culture of Trichoderma koningii Oudem by
Ghisalberti et al. in 1989.1 The structure and relative ster-
eochemistry were determined as shown in structure 1. Since
The condensation of 4 and cyclohexane-1,3-dione 5 was
performed by the method described by Paquette et al.,7 giving
10 and a small amount of the Michael addition product 11
(Scheme 3)
Treatment of 10 with dilute HCl in acetone resulted in
deprotection and cyclization furnishing 12. Under the reaction
of Hg(OAc)2 in AcOH the PhS group of 12 was replaced by an
AcO group, affording 13 and a small amount of 14. X-Ray
diffraction analysis revealed that the C7 acetoxy group of 13 is
trans to the b-alkyl group.† Since the chiral centers C9 and C10
OH
O
O
H
H
O
O
n-Hex
H
O
H
OH
n-Hex
OH
OH
O
(–)-koninginin A
O
(+)-koninginin D 1
i,ii
OTs
n-Hex
OH
OH
6
then four congeners of koninginin D have been isolated
(koninginin A, B, C and E).2 In 1995 Mori and Abe3 and Xu and
Zhu4 published the total synthesis and absolute configuration of
(2)-koninginin A independently. Here we report the total
synthesis of (+)-koninginin D.
Mori constructed chiral centers C9 and C10 of (2)-koninginin
A via the Sharpless asymmetric dihydroxylation, while Xu used
tartaric acid as the starting material to establish the two chiral
vicinal hydroxy groups. Because koninginins A–E were
isolated from a culture of the same species of microorganism,
we suggested that (+)-koninginin D has the same absolute
configuration at C9 and C10 as that of (2)-koninginin A. Our
retrosynthetic analysis of (+)-koninginin D is shown in Scheme
1.
O
O
8
7
O
O
O
O
O
iii,iv
v
n-Hex
n-Hex
4
9
Scheme 2 Reagents and conditions: i, TsCl, CH2Cl2, Et3N, rt, 6 h, 95%; ii,
C5H11MgBr, THF, Li2CuCl4, 278 °C to rt, 5 h, 51%; iii, NaI, DMF, 80 °C,
2 h, 91%; iv, CHNCHMgBr, CuI, HMPA, THF, 230 to 10 °C, 20 h, 75%;
v, O3, CH2Cl2, MeOH, 278 °C, 91%.
The synthesis of 4 is shown in Scheme 2. According to the
known procedure5 (+)-tartaric acid was transformed to diol 7,
which when treated with TsCl and C5H11MgBr afforded
O
O
O
n-Hex
4
+
2
OH
O
OH
O
O
O
O
OH
5
i
11 (14%)
n-Hex
n-Hex
+
O
O
2
SPh
O
SPh
OH
OH
OH
O
1
ii
n-Hex
n-Hex
O
O
OH
O
O
X
O
H
OH
10 (77.8%)
12
n-Hex
iii
HO
O
OH
O
OAc
3
n-Hex
n-Hex
+
O
O
O
H
O
CO2H
CO2H
H
O
O
HO
HO
OH
OH
+
14
13
O
5
4
6
Scheme 3 Reagents and conditions: i, PhSH, SiO2, CH2Cl2, 30–35 °C; ii, 2
Scheme 1
M HCl, acetone, rt, 24 h, 87%; iii, AcOH, Hg(OAc)2, rt, 5 h, 84%.
Chem. Commun., 1999, 1129–1130
1129

OAc
O
OAc
O
Notes and references
i
ii
iii
† Crystal data for 13: C18H28O5, M = 324.42, orthorhombic, a =
13 or 14
13.690(4), b = 25.900(3), c = 5.179(3) Å, V = 1836(1) Å3, T = 293 °C,
P2,2,2 (#19), Z = 4, m(Mo-Ka) = 0.84 cm21, 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. See http://www.rsc.org/suppdata/cc/1999/1129/ for crystallo-
graphic files in .cif format.
n-Hex
n-Hex
O
O
H
H
OAc
OAc
Br
15
16
OR
O
O
OH
O
‡ Selected data for 1: dH(300 MHz, CDCl3) 4.68 (dd, J 1, 2, 1H), 4.49 (q-
like, J 4.8, 1H), 4.11 (ddd, J 2.2, 4.6, 12.1, 1H), 3.72 (q, J 6.4, 1H), 2.60
(ddd, J 4.74, 5.58, 17.00, 1H), 2.30 (m, 1H), 2.20 (m, 1H), 2.00 (m, 2H),
1.60 (m, 3H), 1.40–1.25 (m, 8H), 0.88 (t, J 6.80, 3H); dC(75 MHz, CDCl3)
198.3, 171.4, 114.6, 77.0, 73.0, 66.7, 57.7, 34.0, 33.2, 31.8, 31.1, 29.3, 29.2,
25.4, 22.7, 14.1; 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)
[C16H24O4 (M 2 H2O) requires 280.1675 found 280.1683]. For 19 [a]D20
+127.4 (c 0.58, CHCl3); dH(300 MHz, CDCI3) 5.80 (m, 1H), 5.64 (t, J 4.90,
1H), 5.06 (td, J 3.82, 6.60, 1H), 4.14 (ddd, J 2.2, 3.7, 12.8, 1H), 2.63 (m,
1H), 2.39 (m, 1H), 2.20 (m, 1H), 2.13 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H), 1.99
(m, 1H), 1.75 (m, 1H), 1.65 (m, 2H), 1.25–1.30 (m, 9H), 0.87 (t, J 6.9, 3H);
dC(75 MHz, CDCl3) 194.8, 170.5, 169.8, 168.5(2), 112.2, 74.3, 73.0, 66.6,
59.7, 32.9, 31.7, 30.0, 29.3, 29.1, 26.5, 25.2, 22.6, 21.2, 20.9, 20.8, 14.1; m/z
380 (M+ 244, 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), 43
(100) (C22H32O8: calc. C, 62.24; H, 7.60. Found: C, 61.93; H, 7.74%).
iv
i
triacetate
n-Hex
n-Hex
19 (90%)
O
H
H
OAc
OH
OH
OH
17 R = H (51%)
18 R = Ac (21%)
1
Scheme 4 Reagents and conditions: i, Ac2O, Et3N, DMAP, rt, 2 h, 95%; ii,
NBS, AlBN, CCl4, reflux, 2 h, 69%; iii, NaI, dioxane, CaCO3, H2O, reflux,
48 h, 72%; iv, MeOH, Na2CO3, H2O, rt, 1 h, 91%.
of 13 came from (+)-tartaric acid the absolute configuration of
13 can be assigned as 7R,9S,10S. Both of 13 and 14 treated with
Ac2O gave 15. Attempts to introduce a hydroxy group at C4 via
allylic oxidation of 15 with reagents like SeO2, SeO2·SiO2,
Hg(OAc)2, Pb(OAc)4 and AcOBut failed.
Allylic bromination of 15 with NBS gave 16 in fairly good
yield. Nucleophilic substitution of 16 via the method described
by Wu 8 produced a mixture of 4b-hydroxy compounds 17 and
18, both of which upon hydrolysis gave (+)-koninginin D 1 as
a white powder, mp 140–142 °C (hot plate); [a]2D0 171 (c 0.125,
CHCl3) [ref. mp 122–123 °C, [a]D +166.9 (c 0.3, CHCl3)]
(Scheme 4). The H1 NMR, C13 NMR and mass spectra of 1 and
its triacetate 19 were identical with those of natural (+)-koningi-
nin D and its triacetate, respectively.‡ The overall yield of
(+)-koninginin D from tartaric acid was 4.1% (15 steps).
1 R. W. Dunlop, A. Simon, K. Sivasihamparam and E. L. Ghisalberti,
J. Nat. Prod., 1989, 52, 67.
2 E. L. Ghisalberti, C. Y. Rowland, J. Nat. Prod., 1993, 56, 1799; S. R.
Parker, H. G. Cutler and P. R. Schreiner, Biosci. Biotechnol. Biochem.,
1995, 59, 1747.
3 K, Mori and K. Abe, Polish J. Chem., 1994, 68, 2255 ; K, Mori and K,
Abe, Liebigs Ann., 1995, 943.
4 X. X. Xu and Y. H. Zhu, Tetahedron Lett., 1995, 36, 9173.
5 E. Hungerbuhler and D. Seebuch Helv. Chim. Acta, 1981, 64, 687.
6 S. H. Kang and S. B.Lee Chem. Commu., 1998, 761.
7 K. Fuchs and L. A.Paquette, J. Org. Chem., 1994, 59, 528.
8 R. B. Zhao and Y. L. Wu, Acta Chim. Sinica, 1989, 87.
Communication 9/01320B
1130
Chem. Commun., 1999, 1129–1130