Communications
chromatographic separation from the epimeric product
(13%).Lactone nitrile 25 was converted into the correspond-
ing hydroxy tert-butyl thioester in the presence of trimethyl-
aluminum,[11] which in turn was transformed into ketone 26 in
high yield.The carboxylic acid prepared from 26 was used for
the enantioselective synthesis of diazoketone 13, which was
further converted into ketone 20.
Reduction of 20 with hypophosphite[12] afforded tricycle 7
in high yield.The subsequent conversion of 7 into tetracycle 2
was not trivial.The eventual successful sequence began with
an efficient Horner–Emmons reaction[13] to afford enone 27.
Rhodium(I)-catalyzed hydrosilylation[14] of 27, DIBAL reduc-
tion, and careful imine hydrolysis were carried out in one pot,
and it was possible to obtain keto aldehyde 28 (59%) and the
epimer (23%) separately after hydrolysis of the silyl enol
ether.Further transformation of 28 into the key tetracyclic
intermediate 2[15] was effected under acidic conditions, which
constituted a formal synthesis of platensimycin (1).
The approach outlined herein represents a short and facile
route to platensimycin (1); the enantioselective synthesis of
tetracycle 2 required 11 steps (20% overall yield) from
isopropyl cyanoacetate (23).More importantly, this approach
may be easily adapted for the synthesis of platensimycin
analogues, which will be the focus of our future studies.
Scheme 3. Carbonyl ylide [3+2] cycloaddition of the halogenated ole-
fins. a) 5 mol% [Rh2(OAc)4], CH2Cl2; b) 3 mol% [Rh2(OAc)4], CH2Cl2.
the desired ketone 17, with only trace amounts of the
alternative ketone 18 and a mixture of cyclopropanes 19.
Likewise, the (E)-iodide 13 gave 20 in high yield.These
results affirmed the favorable reversal of the dipolarophile
HOMO coefficient in the type III cycloaddition step.Steric
effects may also favor the formation of 17 and 20.
For completion of the asymmetric synthesis of platensi-
mycin (1), diazoketones 12 or 13 needed to be prepared in
high enantiomeric excess.An ideal choice would be the use of
chiral phase-transfer catalysts[8] in the cyanocarboxylate
allylation step (provided efficient reaction conditions were
found).[9] However, an alternative and practical approach
started with treatment of isopropyl cyanoacetate (23) with
(S)-propylene oxide (24, 99% ee; Scheme 4).The resulting
lactone[10] was allowed to react with (E)-iodoallyl iodide to
give the desired lactone nitrile 25 in 63% yield, after
Experimental Section
General procedure for the rhodium(II)-catalyzed cycloaddition:R-
hodium acetate was added to a solution of a diazoketone in CH2Cl2.
After stirring the mixture for 10 h, it was filtered through a pad of
silica gel (hexanes/EtOAc, 1:1) to remove the catalyst, and the filtrate
was then concentrated in vacuo.The products were separated by flash
column chromatography.
Synthesis of iodoketonitrile 20: In the presence of 3 mol%
[Rh2(OAc)4], 13 (300 mg) was converted into 20 (228 mg, 83%) as a
mixture of the keto and hydrate forms after chromatographic
separation; Rf = 0.20 (hexanes/acetone/CH2Cl2, 4:1:1); 1H NMR
(500 MHz, CDCl3): d = 4.43 (s, 1H), 4.22 (s, 1H), 3.05 (d, J =
7.1 Hz, 1H), 2.75 (dd, J = 11.9, 3.1 Hz, 1H), 2.47 (dd, J = 13.0,
7.1 Hz, 1H), 2.32 (d, J = 12.0 Hz, 1H), 2.22 (dd, J = 13.0, 3.2 Hz, 1H),
1.77 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d = 193.6, 115.9, 89.5,
87.5, 53.7, 53.5, 51.5, 46.8, 27.5, 23.1 ppm; IR (neat): n˜max = 3390, 2978,
2874, 2247, 1740, 1632, 1444, 1383, 1243, 1113, 1026, 825, 612 cmꢀ1
;
FABMS (relative intensity): m/z 304 ([M++1]; 6), 289 (7), 273 (4), 219
(18), 194 (13), 176 (15), 154 (95), 136 (100), 107 (32), 90 (30), 77 (37);
HRMS (FAB) calcd for C10H11O2NI [M++1]: 303.9834; found:
303.9824.
Received: February 4, 2008
Published online: April 15, 2008
Keywords: antibiotics · carbonyl ylides · natural products ·
.
total synthesis
Scheme 4. Asymmetric synthesis of tetracycle 2. a) 24, NaH, THF,
reflux; then (E)-CHICHCH2I; b) tBuSH, Me3Al, CH2Cl2, 08C; c) DMP,
CH2Cl2, 08C; d) 1n KOH, MeOH; e) ClCO2iBu, TEA, diethyl ether,
08C; then CH2N2, diethyl ether, 08C!RT; f) 3 mol% [Rh2(OAc)4],
CH2Cl2; g) H3PO2, 1-ethylpiperidine, Et3B, MeOH, 08C;
h) MeCOCH2PO(OMe)2, DIPEA, LiCl, MeCN; i) Me2PhSiH, 2 mol%
[RhCl(Ph3P)3], toluene, 608C; then DIBAL, toluene, ꢀ408C; AcOH/
H2O (1:1), 08C; j) 2n HCl, THF, 08C; k) TsOH, toluene, reflux.
DIBAL=diisobutylaluminum hydride, DIPEA=diisopropylethylamine,
DMP=Dess–Martin periodinane, Ts=para-toluenesulfonyl.
Jayasuriya, J.G.Ondeyka, K.B.Herath, C.Zhang, D.L.Zink,
N.N.Tsou, R.G.Ball, A.Basilio, O.Genilloud, M.T.Diez, F.
K.B.Herath, C.Zhang, D.L.Zink, N.N.Tsou, R.G.Ball, A.
Basilio, O.Genilloud, MT. .Diez, F.Vicente, F.Pelaez, K.
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 4009 –4011