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An Expeditious and Efficient Entry into the Aphidicolin and Related Natural Products Ring Skeleton.

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An Expeditious and Efficient Entry into the
Aphidicolin and Related Natural Products Ring
By K . C. Nicolaou and Robert E. Zipkid"
The potent antiviral and antimitotic properties of aphidicolin ( 1 ) [ l J ,coupled with its novel and highly unusual molecular framework present a formidable and important
challenge. Of particular interest to the synthetic chemist is
the arrangement of the rings B, C, and D. The diterpenes
stemodinone (2)[21and stemodin (3)[" are structurally related to aphidicolin ( I ) but differ from it in the stereochemistry of rings C and D. After considerable effort, total
syntheses of all three natural products have recently been
reported[31.Although elegant, these syntheses suffer from
poor yields and/or because they are multi-step routes,
whereby the construction of the C / D ring system was especially problematical.
ter (S), (60-70%, mixture of
and (2)-a$- and p,y-unsaturated isomers; in the formula scheme only the latter is
shown!) which was subjected to catalytic hydrogenation
25°C) to afford the methyl ester (6) in
quantitative yield. Base hydrolysis (LiOH, H20, CH,OH,
25°C) of (6) led to the acid (7) (loo%), which was converted to the acid chloride (8) (oxalyl chloride-pyridine,
CH2C12,O"C, 1000/0), which reacted further (CH2N2,ether,
-20°C) to give (9) (90%). (9) reacted with CF3COOH to
in 80% yield; this species
give the crystalline dienone
not only contains the correct BCD ring system of (I), (2).
and (3). but also carries appropriate functionality for
building on the A ring, via a Diels-Alder reaction. Dreiding molecular models clearly suggested a regio- and stereocontrolled approach of a diene component from the "leftside" and from the "top" (arrow). Indeed, it was found
that brief exposure of (10) to butadiene in CH2C12at 0 ° C
in the presence at SnCl, resulted in a single crystalline
product the tetracycle (11) (97%). The selectivity of this
Diels-Alder reaction was demonstrated by reacting the dienone(l0) with I-acetoxybutadiene under whereby the crystalline adduct (12) was formed in 90% yield (accompanied
by a small amount of an as yet unknown stereoisomer). ( I 1)
and (12) were characterized by spectroscopic and X-ray
crystal log rap hi^['^ measurements (Table 1 and Fig. 1).
Table 1. Selected physical properties of compounds (10)-(12).
We report here an expeditious, stereocontrolled and
highly efficient construction of the ring structures of compounds (1)-(3) which is, furthermore, conceptually different from previous methods. The strategy for this new entry
into the aphidicolin (1) and related structures depends on
two key operations; firstly a diazoketone acid-induced cycli~ation[~]
and secondly a regio- and stereocontrolled Lewis acid-catalyzed Diels-Alder reaction.
(10): m.p. 97.5-98°C;
'H-NMR (CDCI,, 250 MHz): 6=1.90-2.20 (m,
3 H ) , 2 . 4 5 - 2 . 9 5 ( m , 6 H ) , 6 . 1 5 ( d , J = l Hz,lH),6,27(dd,J=lO, 1 Hz,IH),
7.06 (d, J = 10 Hz, 1 H); IR (CCL): v= 1725, 1670, 1645 cm-'.
(11): m.p. 172-172.5"C; 'H-NMR (CDCI,, 250 MHz): 6=1.70--3.10 (m,
15H), 5.58 (m, 1 H), 5.70 (m,1 H), 5.87 (s, 1 H); 1R (CCI,): v = 1725, 1678
(12): m.p. 183-184°C; 'H-NMR (CDC13, 250 MHz): 6=1.78-2.80 (m,
1 H), 5.65 (m, I H), 5.77 (s, 1H), 5.78 (m,1 H); IR (CCI,): v= 1740, 1725, 1670
C H30
Fig. 1. X-ray crystallographic structure of (12).
These observations clearly qualify this pathway as a
rapid and highly efficient entry into the polycyclic ring
framework of the natural products (1)-(3).
(MeO)2P(0)CH2C02Me/NaH in tetrahydrofuran (THF)
(- 50°C-25 "C) to afford a mixture of the unsaturated es-
Prof. Dr. K. C. Nicolaou, R. E. Zipkin
Department of Chemistry, University of Pennsylvania
Philadelphia, PA 19 104 (USA)
This work was supported by Griinenthal Chemie (Germany) and ICI
Americas (USA). K. C. Nicolaou is a Fellow of the A. P. Sloan Foundation (1979- 1983) and a Camille and Henry Dreyfus Teacher-Scholar
(1980- 1985).
Angew. Chem. Inr. Ed. Engi. 20 (1981) No. 9
(10): A solution of (9) (230 mg, 1.0 mmol) in anhydrous
CH2C12(12.5 mL) was added dropwise to a stirred solution
of CF3COOH (25 mL) in dry CH2CIz(12.5 mL) at -20°C
under an argon atmosphere. After 5 min the reaction mixture was diluted with CH2C12(200 ml) and washed successively with H,O ( 3 x 50 mL), saturated NaHCO, solution
(2 x 50 ml) and dried over MgS04. After evaporation of the
solvent and preparative thin layer chromatography (silica
gel, 2.5% CH,OH in ether) (10) was obtained as colorless
crystals (150 mg, 80%) and was recrystallized from ether/
(11): (10) (188 mg, 1.0 mmol) was dissolved in anhydrous
CH2C12(2 mL), cooled to 0 ° C and the solution saturated
0 Veriag Chemie GmbH. 6940 Weinheim, 1981
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with butadiene SnCl, (390 mg, 1.5 mmol) in dry CH2C12(6
mL) was added dropwise and the reaction mixture was
stirred for 2 h while being allowed to warm up to room
temperature. Ice (10 g) and ether (200 mL) were added and
the organic phase was separated and washed with H 2 0 (20
mL), saturated NaHC03 solution (20 mL), and saturated
sodium chloride solution (20 mL). Drying over MgSO,,
followed by evaporation afforded (11) which was recrystallized from chloroform/ether furnishing colorless crystals
(235 mg, 97%).
(12): A stirred solution of (10) (188 mg, 1.0 mmol) and 1acetoxylbutadiene (224 mg, 2.0 mmol) in anhydrous
CH2Clz (6 mL) were cooled to 0 ° C and treated under an
argon atmosphere with a solution of SnCI, (260 mg, 1.0
mmol) in anhydrous CH2C12(4 mL). After 30 min at 0 ° C
the reaction was quenched with ice (10 g) and ether (200
mL) and the organic phase separated and washed with
H,O (20 mL), saturated NaHCO, solution (20 mL), and saturated sodium chloride solution (20 ml). Followed by
evaporation, preparative thin-layer chromatography (silica
gel, 10% acetone in CH2C12,and recrystallization from ether/petroleum ether afforded (12) as colorless crystals (269
mg, 90%).
Received: March 5, 1981 [Z 844 IE]
German version: Angew. Chem. 93, 811 (1981)
[I] W. Dalziel. B. Hesp. K . M.Steuenson. J. A. J. Jamis, J. Chem. SOC.Perkin
Trans. 11973, 2841.
[2] P. S. Manchand. J . D. White. H . Wright, J . Clardy, J. Am. Chem. SOC.95.
2705 (1973).
[3] Aphidicolin: (a) E. J . Corey, M.A . Tius, J. Das. J. Am. Chem. SOC.102.
1744 (1980); J. E. McMurry, A . Andrus. G. M. Visander, J. H . Musser, M.
A . Johnson, ibid. 101, 1331 (1979); B. M . Trosr, Y . Nishimura. K . Yamamoto. ibid. 101. 1328 (1979): b) Stemodinone and Stemodin: E. J. Corey.
M. A . Tius, J. Das, ibid. 102, 7612 (1980).
[4] An elegant application of this type of reaction in the total synthesis of
gibberellins has recently been reported: L. Lombardo, L. N. Mander, J . V.
Turner, J. Am. Chem. SOC.102, 6626 (1980).
[SJ D. J. Beames, L. N. Mander. Aust. J. Chem. 27, 1257 (1974).
161 Structure (10) represents the isomer corresponding to the aphidicolin ( I )
skeleton. The other enantiomer which was also obtained in this reaction
corresponds to the skeleton of stemodinone (2) and stemodin (3).
[7] We are indebted to Dr. Patrick Carroll (Department of Chemistry, University of Pennsylvania) for his assistance in solving the X-ray crystallographic structure of (12).
the acids, which act as bidentate Iigands. The sector rule
could also be derived non-empirically for the Cotton effect
at about 420 nm using qualitative MO theory“].
(2b). R = E t
(2e) , R = t B u
(3b), R = R’ = Et
(3c), R = M e ,
R’= i-C3H,
Of the alkyl(pheny1)thiophosphinic 0-acids (21, only (24
gave C D bands in DMSO in the presence of ( I ) ; surprisingly, however, we were able to observe two or three
strong Cotton effects for (2a-c) in trifluoroacetic acid.
Thus, despite the enormous excess of achiral, potential
F,CCO; ligands, the thiophosphinic acids complex suffciently enough to yield easily measurable C D curves which
retain their shape and magnitude over sufficiently long periods. (2) possibly does not occur as bidentate ligand, but
as an additional axial substituent at one or both ends of
the Mo2 dumbbell. In crystals of [Mo2(02CR),]-complexes,
this position is usually occupied by an oxygen atom[’’ of a
neighboring molecule. This is also evidenced by the fact
that practically no C D could be measured with acids such
as phenylalanine in CF3CO2H.
All (+)-@)-acids give a negative Cotton effect at about
490 nm, a further one about two to three times more positive at about 400 nm, and, at higher concentration, an additional slightly positive Cotton effect can be observed at
about 540 nm (Fig. 1). The seleno-analogue behaves in exactly the same way. In the case of the (-)-(S)-enantiomers
the C D curves are enantiomorphic. Similar Cotton effects
are obtained in acetic acid, but they are not so intense.
Determination of the Absolute Configuration of
Alkyl(pheny1)thiophosphinic 0-Acids and of 0-Alkyl
Alkylthiophosphonates from the Circular Dichroism
of Their Complexes with [Mo2(0,CCH3)41r*’’
By Jan Omelanczuk and Giinther Snatzke‘’]
In situ complexes of optically active carboxylic acids
with the readily accessible and stable “parent complex”
[Mo2(O2CCH3),]( I ) exhibit several Cotton effects between
800 and 300 nm in dimethyl sulfoxide (DMSO); the signs
of the two C D bands between 450 and 300 mn could be
empirically correlated with the absolute configurations of
[*I Prof. Dr. G. Snatzke, Dr. J. Omelanczuk [‘I
Lehrstuhl fiir Strukturchemie der Universitat
Postfach 102148, D-4630 Bochum 1 (Germany)
[‘I Alexander-von-Humboldt fellow, present address:
Institute for Molecular and Macromolecular Research
of the Polish Academy of Sciences
Boczna 5, PL 90-362 t o d i (Poland)
This work was supported by the Deutsche Forschungsgemeinschaft, the
Fonds der Chemischen Industrie, and an Alexander-von-Humboldt fellowship grant.
7 86
0 Verlag Chemie GmbH, 6940 Weinheim, 1981
Fig. 1. CD spectra of alkyl(pheny1)thiophosphinic acids [(R)-and (S)-forml
of (R)-tert-butyl(pheny1)selenophosphinic acid and of methyl a-naphthyl
thiophosphate in CF3CO2H.
In pyridine the Cotton effects were recognizable, but
much smaller; they rapidly changed their shape and became weaker. Nevertheless, these CD curves are also characteristic and can be used for the determination of the absolute configuration of (2): the (+)-(R)-forms give three
broad positive Cotton effects at about 590 nm (weak), 450
nm (strong) and 360 nm (medium). It is well-known that
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Angew. Chem. In[. Ed. Engl. 20 (1981) No. 9
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expeditions, entry, efficiency, natural, skeleton, ring, aphidicolin, product, related
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