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Carbene Complexes with Quinone Bisketal Functions.

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Since the reagent 2 is practically inactive towards monoketones (Table 1, Entries 10 and ll), we attribute the surprisingly good olefination of dicarbonyl compounds according to Scheme 4 to the effectiveness of the second carbony1 group as activating base.
6
large depletion of Al compared to 1) suggests that the
chain terminals are formed by AlC12 units, as tentatively
formulated in 7.-The moderate yield of olefin upon reaction of the yellow solid with benzaldehyde (31% per Mo
atom of 7 ) is understandable in view of the sparing solubility of this decomposition product.
Received: June 12, 1986;
revised: July 16, 1986 [Z 1813 IE]
German version: Angew. Chem. 98 (1986) 928
52YO
Scheme4. Solvent:THF. Molarratios: 5 . 2 = 1 : 1 ; 6 : 2 = 1 : 1 .
-
[I] T. Kauffmann, R. Abeln, S. Welke, D. Wingbermuhle, Angew. Chem. 98
(1986) 927; Angew. Chem. Int. Ed. Engl. 25 (1986) No. 10.
121 See [I]. and references cited therein [2].
131 a) F. N. Tebbe, G. W. Parshall, G. S. Reddy, J. Am. Chem. SOC.100 (1978)
3611; b) F. W. Hartner, Jr., J. Schwartz, S. M. Clift, ibid. 105 (1983)
3270.
[4] Cf. K. A. Brown-Wensley, S . L. Buchwald, L. Cannizzo, L. Clawson, S.
Ho, D. Meinhardt, J. R. Stille, D. Straus, R. H. Grubbs, Pure Appl. Chem.
55 (1983) 1733.
(51 Similar studies with 3 have yet to be carried out.
[6] The values determined by atomic absorption spectrometry (Mo, Al) and
combustion analysis (mean values of several measurements; oxygen
value by difference) fit very well with the empirical formula
(C~~H~4A1~CISMoS0,~).(1353.6)n
for 7 : calc. C 22.18, H 4.02, AI 3.99,
CI13.10, Mo35.44, 021.27; found C22.18, H4.19, A13.97, CI13.15,
Mo 35.84, 0 21.57.
22
70
47
79
IS
15
Carbene Complexes with
Quinone Bisketal Functions**
Table I . Examples of carbonyl olefinations [al.
No.
Reagent
1
1
2
3
4
1
1
1
Substrate
5
1
6
7
8
9
2
2
2
2
2
2
3
3 + H M P A ( I : 1)
3 + H M P A ( 1 : 2)
10
I1
12
13
14
Ph-CHO
Ph-CHO
n-C6H ,3-CH0
Ph-CO-Me
nBu-CO-Me
Ph-CHO
Ph-CHO
[cl
[cl
Ph-CO-Me
nBu-CO-Me
Ph-CO-Me
Ph-CO-Me
Ph-CO-Me
Reagent :
Substrate
1 : l
1 :2
1
1
1
1
1
1
: l
:1
:1
:l
:2
:1
I :2
1:I
Olefin
yield
[%I
98
75[b]
67
22
14
62
76 [b]
60
50
I :I
<5
<5
11
45
1 :1
59
I : I
1 :1
Substrate
recovered
[Yo]
3
6
62
46
-
3
[a] In the experiments carried out in T H F (Entries I- II), the transition metal
halide was allowed t o react with 2 molar equivalents of AIMe, at -70°C.
After 2 h, the substrate was added and the solution heated t o 20°C within
14 h. In the case of the experiments carried out in n-hexane (Entries 12-14),
WOC13(THF)2was allowed to react with 2 molar equivalents of AIMe,. 1.4
molar equivalents of CH, were evolved. After 1 h, the substrate was added
and the solution heated to 66°C within 1 h. The addition of hexamethylphosphoric triamide (HMPA) immediately followed addition of the substrate. [b]
1.5 C H 2 groups were thus transferred per Mo-atom. [c] 2-Thiophenecarbaldehyde.
The hypothetical complexes 1 and 2 are thermolabile.
Consequently, the products of carbonyl olefination are
isolable in good yields only when the molybdenum halide
is first allowed to react with trimethylaluminum at - 70°C
before addition of the substrate at the same temperature,
and the reaction mixture is then heated to 20°C until
evolution of CH, ceases. If the carbonyl compound is first
added after evolution of gas ceases, then the yield of olefin
is low. Apparently, the active carbonyl olefinating reagent
initially formed undergoes decomposition when no carbonyl groups are available.is1The decomposition has hitherto
prevented the isolation of 1 and 2, but enabled isolation
of a primary product of the decomposition of 1. This sparingly soluble, amorphous, air- and water-sensitive solid
precipitates from the T H F solution at 0°C (stable only for
a short time at this temperature) and can effect carbonyl
olefination of benzaldehyde. According to elemental analysis, it would appear that one T H F ligand is present per
M o atom, thus indicating a chain-like structure containing
five Mo(THF)02CH2 units. The Mo/AI ratio of 5 : 2 (i.e.
Angew Chem l n t .
Ed. Engl. 25 (1986) No. I0
By Karl Heinz Dotz,* Michael Popall, Gerhard MiiIler.
and Klaus Ackermann
Carbene(carbony1) transition-metal complexes are useful as synthetic building blocks for anthracyclin~nes."-~l
For example, the rings B and C of the daunomycinone
skeleton can be constructed by regiospecific annelation of
arylcarbene complexes. In order to avoid the necessity of
subsequent selective oxidation,[51it would be useful to introduce the quinone ring C directly via the carbene complex. For this reason, we have investigated the synthesis
and reactivity of carbene complexes having quinone bisketal functions.
n
OMe 0
nH
o
OH bH
The lithiated quinone bisketals that are obtained from 1
and 8 by halogen-metal exchange undergo addition to
hexacarbonylchromium and -tungsten at low temperatures
with formation of the ocher-colored acylmetalates 2 and
I*]
[**I
Priv.-Doz. Dr. K. H. Dotz, M. Popall, Dr. G. Miiller,
Dr. K. Ackermann
Anorganisch-chemisches Institut der Technischen Universitat Munchen
Lichtenbergstrasse 4, D-8046 Carching (FRG)
Carbene Ligands as Anthracyclinone Synthons, Part 4. This work was
supported by the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie. Part 3 - 131.
0 V C H Verlagsgesellschaji mbH. 0-6940 Wemherm. 1986
0570-0833/86/1010-0911 $ 02.50/0
91 1
9a, b. Their conversion into the neutral carbene complexes
is strongly dependent on the transition metal, the alkylating agent, and the reaction medium. Whereas 2 undergoes
methylation with Me,OBF, in pentane/water to give 3, it
reacts with Et,OBF, in dichloromethane to give 6 (aromatization), which partially undergoes immediate decarbony-
9
C62
I,ition to r i \ e 7.""
Me0
OMe
X
1ltBuLi
OMe
1
OMe
Me0
OMe
6
I
Me
Me0
4
Me
7
Me0
OMe
b
OH
0 OMe
tie
The bisketal compound 3 also undergoes facile elimination of a CO ligand in the cis position. The chelate carbene
complex thereby formed, 4, was shown by X-ray structure
analysis[71to have a five-membered metallacycle with short
Cr-C(carbene) and long C r - 0 bonds (2.226(2)
(Fig. 1,
above). The five-membered ring has an approximate envelope conformation, while the quinone bisketal six-membered ring, owing to the coordination of 0 3 1 to the Cr
atom, is not exactly planar. The molecular geometry provides an explanation for the rapid exchange of the Crcoordinated methoxy group with the geminal, free methoxy group in acetone solution at room temperature. An
activation enthalpy of 9 kcal/mol can be estimated for this
process from the coalescence temperature of - 73 oC.L81
The facile opening of the chelate ring under mild conditions allows the coordination of an alkyne, which-as exemplified by I-pentyne-is incorporated into the hydroquinone skeleton, the annelation of the carbene ligand occurring regiospecifically.
The alkylation of the 1,Cnaphthoquinone bisketal derivatives 9a, b with oxonium salts in dichloromethane leads
ultimately to aromatic products.[91In the case of tungsten,
the bisketal carbene intermediate 10b"O1may be detected,
although it undergoes slow aromatization in solution to
form l l b . In contrast to the cyclohexadienyl system 2 , the
acylmetalate 9a is transformed by even traces of He into
the golden dihydronaphthylidene complex 12a. This unexpected fragmentation is presumed to occur via an initially
formed hydroxycarbene complex.
A)
Fig. 1. Crystal structures of 4 (above) and 12a (belou) (OKTEP, thermal ellipsoids at the 50% probability level, H atoms with arbitrary radii, without
and bond angles ["I: 4 : Cr-CI
methyl H atoms) 171. Selected bond lengths
1.978(3), Cr-C8 1.895(3), Cr-031 2.226(2), C r . . , 0 3 2 3.332(2), C I - 0 0 1
1.321(3), Cl-C2 1.497(4), C2-C3 1.505(4), C3-C4 1.505(4), C4-C5 1.323(4),
C5-C6 1.501(4), C6-C7 1.499(4), C2-C7 1.328(4), C3-031 1.441(3), C3-032
1.431(3); Cr-CI-C2 l16.0(2), Cr-C1-001 136.1(2), OOl-Ci-C2 108.0(2), C I C2-C3 I14.7(2), C2-C3-03 I 103.6(2), C3-031-Cr 109.6( I); torsion angle CrCI-C2-C3 -9.2, dihedral angle Cr, C I , C2, C3/Cr, 031, C3 44.3.- 12a: CrC12 2.045(3), Cr-CI 1.897(4), C12-CI3 1.410(4), C13-CI4 1.376(4), C14-06
1.333(4), C14-CI5 1.460(4), C15-C20 1.403(4), C20-CI 1 1.532(4), C I l - C l 2
1.541(4); Cr-CI2-Cl3 121.4(2), Cr-Cl2-CII 122.8(2), Cll-CI2-Cl3 115.8(3).
[A]
I n view of the absence of heteroatom substituents in a
position at the carbene carbon atom, the thermal stability
of 12a is remarkable. It is due to conjugation of the carbene-metal and enol ether functions (vinylogous stabilization) as well as to the incorporation of the carbene carbon
atom into a relatively rigid six-membered ring, as revealed
by the molecular structure"' (Fig. 1, below). The dihydronaphthylidene skeleton is nearly planar.
Experimental Procedure
Me0
OMe
Me0
Me0
OMe
OMe
OMe
OMe
3 : 2 ( 5 mmol) was dissolved in 50 mL of ice water and a layer of 100 mL of
pentane was added. After addition of Me,OBF, (7.5 mmol), the mixture was
extracted repeatedly with pentane and the extracts were dried over Na2S0,
and chromatographed on silica gel (Merck, type 60). Elution of the red,
main zone with CH2Cl2and recrystallization from etherlpentane afforded 3
in the form of light red needles (m.p.=47"C). Yield 58%. IR (pentane):
a,M=Cr
b, M= W
9 12
OMe
2/9a, b: A solution of tert-butyllithium (30 mmol) in hexane was slowly added t o a stirred solution of 1 or 8 (15 mmol) [ I I ] in 60 mL of ether at -75°C.
The resulting orange suspension was stirred at this temperature for ca. 15 h
and then added to a solution of Cr(CO)6 or W(CO), (15 mmol) in 150 rnL of
ether at -60°C. The mixture was allowed to warm to room temperature over
4 h and the solvent then removed. After washing with pentane, the acylmetalate 2 or 9a, 9b was obtained.
0 VC'H Verlagsyesellschafr mhH. D-6940 Weinheim. 1986
0570-0833/86/1010-09/2 $ OZ.S0/0
Angew. Chem. Int. Ed. Engl. 25 (1986) No. 10
C(C=0)=2064 ( s ) , 1994 (s), 1985 (vs), 1942 c m - ' (vs). ' H - N M R
(CD,COCD,): 6=6.07 (m, 3 H; 3, 8, 6-H), 4.73 (5, 3 H: carbene O C H A 3.33
(s, 6 H : 1.1-OCH,), 3.27 (s, 6 H ; 4,4-OCHi). "C-NMR (CDICOCDI):
6=355.5 (c<,$,,,<,,*),
228.4 (trQnS-CO), 216.1 (cis-co),123.8 (c-2), 130.7 (c-3),
126.1 (C-5.6). 96.4, 92.4 (C-l,4), 67.7 (carbene OCH,): 48.8, 48.6 (l,I,4,4OCH2). MS: m/z 434 (Me).
4 : 3 (5 mmol) was heated in 10 mL of fert-butyl methyl ether at reflux for
4 h. After recrystallization, 4 was obtained in the form of dark brown crystals
(m.p.= 100°C). Nearly quantitative yield. 1R (pentane): J(C=O)=2019 ( s ) ,
1952 (s), 1938 (vs), 1868 c m - ' (vs). 'H-NMR (CD3COCD3):6=6.34 (m,3 H.
3,8,6-H), 4.80 ( s , 3 H ; carbene OCHI), 3.36 (s, 6 H ; 1,1-OCH3), 3.30 ( s , 6 H ;
4,4-OCH,). "C-NMR (CD,COCD,): 6 ~ 3 4 1 . 8(C,,,,,,.,),
233.1, 232.3 (tronsCO), 217.6, 216.9 (cis-CO), 148.1 (C-2); 133.8, 125.4, 119.6 (C-3,5,6), 100.0,
94.4 (C-l,4), 68.8 (carbene OCH,), 56.8 (I,I-OCH3), 50.3 (4,4-OCH,). MS:
m/z 408 (M").
5 : A solution of 4 ( 5 mmol) in 20 mL of terf-butyl methyl ether was heated to
58°C and. after addition of 5.5 mmol of I-pentyne, allowed to stir for 0.5 h. 5
was precipitated by addition of pentane. IR (KBr): G(C=O)= 1938 ( s ) , 1885
c m - ' ( s ) . MS: m/z 474 (Me).
6/7:A solution of 2 (5 mmol) in 100 mL of CHzClz was treated at 0 ° C with
7.5 mmol of Ft,ORF,. After I h, the solvent was removed under high vacuum
and the residue was dissolved in ether and quickly filtered over Alz03 (neutral) at - 20°C. Column chromatography o n silica gel afforded 6 and 7 in a
ratio of 1 0 . I .
I2a: A solution of 9a (8 mmol) in 200 mL etherlwater (1 : 1) was allowed to
stir for I h at room temperature. After removal of the solvent (high vacuum),
column chromatography on silica gel (Merck, type 60) with dichloromethanelpenlane (2 . I ) followed by recrystallization from etherlpentane afforded 12a in the form of golden crystalline platelets (m.p. = 100°C). Yield
56%. IR (pentane): C(C=0)=2047 (s), 1988 (m), 1962 (vs), 1926 e m - ' (5).
' H - N M R (CD.,COCDI): 6=8.91 (s, 1 H; 3-H), 8.05 (m, 2 H ; 5,8-H), 7.62 (m,
2 H ; 6,7-H), 4.45 ( s , 3 H ; 4-OCH3), 2.78 ( s , 6 H ; I,l-OCH,). MS: m/z 410
Regioselective and Atropoisorneric-Selective Aryl
Coupling to Give Naphthyl Isoquinoline Alkaloids:
The First Total Synthesis of ( - )-Ancistrocladine""
By Gerhard Bringmum,* Johannes R . Jansen, and
Heinz-Peter Rink
Dedicated to Professor Burchard Franck
on the occasion of his 60th birthday
(-)-Ancistrocladine 1[11is regarded as "the most unusual of all the isoquinoline alkaloids"[21on account of the
methyl group at C-3 of a tetrahydroisoquinoline, the two
oxygen functions at C-6 and C-8 in mutual meta positions,
and the peculiar naphthalene substituent at C-5. For a
thorough investigation of the biological activity of 1 , as
well as for a reexamination of the insufficiently established
structures of several related natural products,'31 the molecular skeleton of 1 -with the highly substituted biphenyl
system that is configurationally stable to above 200'Crepresents a n attractive synthetic goal.
(Ma).
Received: May 21, 1986;
supplemented: June 28, 1986 [Z 1785 IE]
German version: Anqew. Chem. 98 (1986) 909
[ I ] Review: K. H. Dotz, Anqew. Chem. 96 (1984) 873; Anqew. Chem. I n f . Ed.
Enql. 23 (1984) 887.
[2] K. H. Dotz, M. Popall, Tetrahedron 41 (1985) 5797.
[3] K. H. Dotz, M. Popall, J. Organornet. Chem. 291 (1985) CI.
141 W. D. Wulff, P. C. Tang, J . Am. Chem. SOC.106 (1984) 434.
[5] Recent reviews: a) F. Arcamone: Doxorubicin Anticancer Antibiotics. Academic Press, New York 1981; b) H. S . El Khadem (Ed.):Anthrucycline
Antrbiofics, Academic Press, New York 1982: c) K. Krohn, Anqew.
Chem. 98 (1986) 788; Anqew. Chem. I n f . Ed. Engl. 25 (1986) 790.
[6] Cf. K. H. Dotz, W. Sturm, M. Popall, J. Riede, J. Orqanomef. Chem. 277
(1984) 267.
[7] Crystal structure data: 4: orthorhombic, space group P2,2,2,,
a = ll.69l(l), b=11.970(1),c=12.760(1)A, V=1785.7 A3,~ca~c,,=1.811
g
cm for 2 = 4 at -35°C. F(O00)=840,p(MoK,)=6.7 e m - ' . 4631 measured reflections, of which 2758 were unique and 2645 "observed" with
1>2.00(1) (0 scan, Am= 1.0". + h , i k , il,(sinfl/A),,~,=0.594, MoKnr
A =0.71069 A, graphite monochromator, Synteh P2,). Lp, but no absorption correction, Patterson methods R =0.028, R,, =0.032, w = l/a2(Fo)
for 280 refined parameters (anisotropic, CH, as rigid groups, all other H
atoms constant, App,,,(max/min)=0.40/-0.37 e/A', the refinement of
the inverse set of coordinates gave R,, =0.047, SHELX76).-12a: triclinic, space group P i , o= 7.262(1), b = 11.151(2), c= 12.138(3)
a=89.78(2), p = 104.50(2), y=112.48(1)", V=874.7 A', , ~ ~ . , , ~ ~ = 1 .g8 5 8
cm-', 2 = 2 , T= -35"C, F(000)=420, p(MoKn)=6.8 cm-'. 2740 measured, unique reflections, 2386 "observed" with l L 2.00(1) ( + h, ? k,
it,(sin$/A),..,,=0.572).
Patterson methods, R=0.040, R,, =0.046 (244
refined parameters, anisotropic, H atoms constant, &,,,(max/
min)= t 0 . 4 1 e/A'). Further details of the crystal structure investigations may be obtained from the Fachinformationszentrum Energie, Physik, Mathematik GmbH, D-7514 Eggenstein-Leopoldsbafen2 (FRG), on
quoting the depository number CSD-51981, the names of the authors,
and the journal citation.
[ S ] We thank Priv.-Doz. Dr. H . G . A l f , Bayreuth, and Dr. P. Hiirter, Munich,
for recording the D N M R spectra.
[9] By the introduction of cyclic bisketal functions, the aromatization can
be suppressed.
[lo] lob: IR (pentane): V(C=0)=2070 (w), 1952 (s, sh), 1945 c m - ' (vs). 'HNMR (CD2COCD2): S=7.56 (m, 4 H ; 8,6,7,8-H), 6.46 (s, I H ; 3-H), 5.14
(q, 2 H : C H d , 3.27 ( s , 6 H ; I,I-OCHx), 3.12 ( s , 6 H ; 4,4-OCH>), 1.73 (1,
3 H; CH,).
[ I I ] I. S. Swenton, P. W. Raynolds, J . Am. Chem. Soc. 100 (1978) 6188.
-'
A,
Angen Chem. In,. Ed. Enql. 25 (1986) No. 10
1
Neither 1 nor other Ancisrrocladus alkaloids could so far
be synthesized. We recently reported the first synthesis of a
naphthyl isoquinoline alkaloid, the less sterically crowded
and fully aromatic, albeit racemic, Triphyophyllum alkaloid
0-rnethyltetradehydrotriphy~phylline.~~~
We describe here the first, and, at the same time, asymmetric, synthesis of the main alkaloid ( -)-ancistrocladine
1. The required starting material for the synthesis of. the
optically active tetrahydroisoquinoline building block 5 is
the arylpropanone 2aJ5] which may be regarded as a
simpler analogue of the a ~ s u m e d ' ~ biosynthetic
.~'
diketo
precursor 2b (Scheme 1).
Reductive amination[81 of 2a with (S)-1-phenylethylamine (de 92%) and subsequent hydrogenolysis selectively
affords the desired?' enantiomerically pure,"'] primary
amine 3 [84% yield, m.p. of the hydrochloride= 151.5"C,
[a]g= 14.8 (c= 1.0, MeOH)]. After Bischler-Napieralski
cyclization to the (3s)-configurated dihydroisoquinoline
4 [76%, m.p. of the hydrobromide=202OC, [a];'= - 141
(c= 1.0, MeOH], the heterocyclic molecular half, e.g., of
the spasmolytically active ancistr~cladidine,[~l
also the second center of chirality (C-1) can stereoselectively be built
up. Reduction of 4 with LiAIH, in the presence of AIMe3'"I
affords the (1Qconfigurated tetrahydroisoquinoline 5
[85%, m.p. of the hydrobromide = 293 "C, [a]g'= + 7.6
(c = 1.0, MeOH)] with remarkably good stereoselectivity ( d e
92%).[12]A trans arrangement of the two secondary methyl
+
[*I Priv.-Doz. Dr. G. Bringmann, DiplLChem. J. R. Jansen, H.-P. Rink
[**I
Organisch-chemisches Institut der Universitat
Orleansring 23, D-4400 Miinster (FRG)
Acetogenic Isoquinoline Alkaloids, Part I I . This work was supported by
the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen
1ndustrie.-Part 10: [6].
0 VCH Verlaqsqesellschufi mbH. 0-6940 Weinheim. 1986
OS70-0833/86/1010-0913 $ 02.50/0
9 13
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