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Enantioselective Synthesis of the Antidepressant Rolipram by Michael Addition to a Nitroolefin.

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Recrystallized material, on the other hand, contains oxygen in another binding state initially and provides a spectrum (Fig. 3d) similar to that in Figure 2. After desorption
of the solvent, at least from the regions close to the surface,
the sample can be loaded like the sublimed material (Fig. 3 e)
and is then sensitive to oxidation. Spectrum 3 f was obtained
from a sample that was treated analogously to the sample
that provided spectrum 3 b and shows that brief treatment
with 0, does not cause oxidation; however, heating the
sample under a low partial pressure of CO, leads to dissolution in the bulk (decrease in the baseline to 650 K).
In summary, these experiments show that solid C,, is not
an inert van der Waals crystal, but a solid with complex
reaction behavior. The internal surface of the crystal is either
saturated with solvent molecules or contains chemisorbed
atoms of oxygen. This matches the sorption properties of
active charcoal, the surface of which takes up organic substances and/or oxygen in chemisorbed or covalently bound
forms.[s1The characteristics of solid C,, also correspond to
those of a single fullerene molecule, which is capable of binding a large variety of functional groups on its
The interaction of oxygen atoms with C,, can be of various strengths. We identified an epoxide-like binding as the
weakest; it can be converted by tempering (sublimation) into
a stronger binding mode (dry1 ether). These two types of
binding differ in their IR data and in their behavior in thermal desorption; their existence is suggested by the data from
mass spectrometry, the ESR signals, and the results of singlecrystal X-ray diffraction experiments. These oxygen adducts
differ markedly from those that produce CO, upon thermal
decomposition; this latter type forms only slowly on the
crystal surface with exclusion of light and moisture and apparently gives rise to the precursor for the total oxidationrl7, of C60.The existence of chemically activated oxygen should be taken into account in considering the behavior
of C,, under catalytically oxidizing conditions.
The differing desorption behavior of the solvents ether
and toluene suggests that an intrinsic characteristic of C,, is
its ability to enter into specific electronic interactions; however, only experiments with thin films can eliminate possible
topochemical effects superimposed on this intrinsic property. Until now we have consciously conducted our investigations to avoid a photochemically assisted adsorption+ven
in the dark the effects of small amounts of foreign atoms are
complex enough.
Received: March 31, 1992 [Z5271lE]
German version: Angen,. Chem. 1992. 104.909
CAS Registry numbers:
C60,99685-96-8; C,,.XO,.
141849-16-3; Et,O, 60-29-7; toluene, 108-88-3
[l] W. Kriltschmer, L. D. Lamb, K. Fostiropoulos, D. R. Huffman, Nulure
1990, 347, 354; R. Ettl, 1. Chao, F. Diederich, R. L. Whetten, ibid. 1991,
353, 149. We used a direct current arc with approximately 1.5 kW power
and cooled the entire apparatus with a water-jacket. A continuous flow of
helium at a total pressure of 140 mbar proved to be advantageous. An
air-tight apparatus (leakproof under static high vacuum) and pure helium
are extremely important for respectable yields. The crude extract, obtained
in a maximum of 1 5 % yield, was separated by chromatography (in the
dark, eluting with toluene) into C,,, C,,, and higher fullerenes. The purity
of the fractions was determined by UVjVIS spectroscopy. This highly
sensitive method showed that at this point there is only an insignificant
amount of fullerene oxide.[l5,16] Conventional elemental analysis showed
about 99% C and less than 1 % H.
[2] H. W Kroto, J. R. Heath, S. C. O'Brien, R. F. Curl. R. E. Smalley, Nature
1985, 318, 162; H. Kroto. Science 1988, 242, 1139.
[3] a) H. W Kroto, Angnc. Chem. 1992, f04,113; Angen,. Chem. Int. Ed. Engl.
1992, 31, 111 ; b) H. Schwarz, ibid. 1992, 104, 301 and 1992, 31, 293.
[4] D. R. Huffman, Phys. Toduy 1991, 44 ( I l l 22.
[ 5 ] P. A. Heiney, J. E. Fischer, A. R. McGhie. W. J. Romanow, A. M. Den-
nenstein, J. P. McCauley, Jr., A. B. Smith 111, Phys. Rev. Lett. 1991, 66,
H. Werner. W. Bensch, R. Schlogl, Solid Slate Commun. 1992, in press.
K. Holczer, 0 .Klein, S. M. Huang, P. B. Kauer, K. J. Fu, R. L. Whetten,
F. Diederich, Science 1991,252. 1154.
R. C. Bansal, J. B. Donnet, F. Stoeckli, Active Carbon, Marcel Dekker,
New York, 1988, p. 335.
H. D. Beckhaus, C. Riichardt, M. Kao, F. Diederich, C. S. Foote, Angew.
Chem. 1992, 104. 69; Angen,. Chem. I n f . Ed. Engl. 1992, 31, 63.
C. S. Yannoni, R. D. Johnson, G. Meijer, D. S. Bethune, J. R. Salem, J.
Phys. Chem. 1991, 95. 9.
R. C. Haddon, L. F. Schneemeyer. J. V. Waszczak, S. H. Glarum, R. Tycko, G. Dabbagh, A. R. Kortan, A. J. Muller, A. M. Mujsce, M. J. Rosseinsky, S . M. Zahurak, A. V. Makhija, F. A. Thiel, K. Raghavachari, E.
Cockayne, V. Elser, Nature 1991, 350, 46.
P. M. Allemand, G. Srdanov, A. Koch, K. Khemani, F. Wudl, Y Rubin,
F. Diederich, M. M. Alvarez, S. J. Anz, R. L. Whetten, J Am. Chem. Soc.
1991. 113, 2780; P. N. Keizer, J. R. Morton, K. F. Preston, A. K. Sudgen,
J. Phys. Chem. 1991, 95, 7117.
D. Heymdnn, J. C . Stormer, M. L. Pierson, Carbon 1991, 29, 1053.
0. Ermer, Helv. Chim. Ada. 1991, 74,1339; S. M. Gorun, K. M. Creegan,
R. D. Sheerwood, D. M. Cox, V. W. Day, C. S. Day, R. M. Upton, C. E.
Briant, J. Chem. SOL..Chem. Commun. 1991, 1556.
K. M. Creegan. J. L. Robbms, W. K. Robbins, J. M. Millar, R. D. Sherwood, P. J. Tindall, D. M. Cox, J. P. Mc Cauley, Jr., D. R. Jones, T. T.
Gallagher. A. M. Smith III, J. Am. Chem. SOC.1992, f14, 1103.
Y. Elemes, S. K. Silverman, C. Sheu, M. Kao, C. S. Foote, M. M. Alvarez,
R. L. Whetten, Angrw. Chem. 1992,104,364; Angew. Chem. Int. Ed. Engl.
1992, 31, 351
G. H. Kroll, P. J. Benning, Y. Chen, T. R. Ohno, J. H. Weaver, L. P. F.
Chibante, R. E. Smalley, Chem. Phys. Leu. 1991, 181, 112.
J. M. Wood, B. Kahr, S. A. Hooke 11, L. Dejarme, R. G. Cooks, D. BenAmotz, J. Am. Chem. Soc. 1991, 113, 5907.
Our freshly recrystallized C,,[l] showed four IR bands at 1429,1184,577,
528cm-' andone '3CNMRsignalinsolutionat6=143[3a]withasignalto-noise ratio of 270.
The band at 1627 cm- I was assigned to a skeletal vibration of the aromatic
system that is intensified by oxygen;[l6] the band at 1537cm-' is also
described in the literature[4,21] and may be due to a C-H vibration of the
(CH,), derivatives [18] present in trace amounts. This band is found only
in dry samples. The accompanying C-H stretching vibration can be suppressed.[21]
H. Gaber, R. Hiss, H.-G. Busmann, J. V. Hertel, Verh. Dtsch. Phys. Ces.
1992, 3, 763.
Several samples of nominally pure C,, were examined by EPR spectroscopy in the solid state at 200K. The intensities correspond to spin
per C atom, the linewidth B is given in Gauss.
densities of up to N x
The following values for N , g, and B were obtained: Sublimed sample
(N=25, g=2.00007, B=4.3), recrystallized sample (N=125, g=2.00211,
B=0.90), a mixture of C,, and 10% C,, (N=125, ,p2.00187, B=1.3),
sublimation residue (N=1600, g=2.00262, B=0.58).
U. Gobel, W. Bensch, R. Schlogl, J. Anal. Chem. 1992, in press. For the
measurements. 10 mg of the crystalline powder was heated on a preheated
mbar) with a linear temperature
stainless steel substrate in UHV (1 x
program. The mass spectra of the desorbed material (Bakers QMG 112
quadropoie mass spectrometer) were corrected for the background signals.
For technical reasons the background signal at m / i 2 is so intense that
hydrogen desorption cannot be observed with certainty.
H. Werner, U. Tegtmeier, J. Blocker, D. Herein, R. Schlogl, T. SchedelNiedrig, M. Keil, A. M. Bradshaw, Chem. Phys. Let!. 1992, in press.
Verlugs~esellschaftmbH, W-6940 Weinheim, 1992
Enantioselective Synthesis of the Antidepressant
Rolipram by Michael Addition to a Nitroolefin
By Johann Mulzer,* R a y Zuhse, and Ralph Schmiechen
Chirally branched pyrrolidones like Rolipram 1 a are highly active antidepressants with novel postsynaptic modes of
action."] The advantages of Rolipram over conventional antidepressants are the low required dosage (3 x 0.75 mg per
day) and the absence of uncomfortable and sometimes even
dangerous anticholinergic side effects like dryness of mouth,
[*] Prof. Dr. J. Mulzer, Dr. R. Zuhse
Institut fur Organische Chemie der Freien Universitlt
Tdkustrasse 3, D-W-1000 Berlin 33 (FRG)
Dr. R. Schmiechen
Forscbungslaboratorium der Schering AG, Berlin
$3.50+ .25jO
Angew. Chem. Int. Ed. Engl. 1992, 31, No. 7
sight problems, and cardiotoxicity. The pharmacological activity depends on the R group and the absolute configuration; for 1 a the (R)-(-) enantiomer is the more effective.
, R=cyclopentyl
, Rzbenzyl
The known synthesesl2I are limited to the preparation of
racemates, which are then separated into the enantiomers by
chromatography. We describe here the first enantioselective
synthesis of each enantiomer of 1 a-c in multigram quantities. Since by Williamson etherification (R)-1 c can be converted to a variety of ethers, this is a key compound in the
series. The main preparative problem is the introduction of
the chiral center in the aminocarboxylic acid 2. Among the
numerous possibilities (for example, alkylation of a chiral
enolate, Claisen or [2,3] sigmatropic rearrangement, opening
of an epoxide with a cuprate etc.) we considered the Michael
addition of chiral enolate 4 to o-nitrostyrene 3 to be especially convenient (Scheme
As shown in Scheme 2, aldehyde
nishing 1 a. Since the enantiomer of 8 is also available, the (S)
series is equally accessible.
The stereochemical course of the addition of 4 to 3 follows
the model proposed previously by Seebach et al. for the
addition of enamines to nitrostyrenes[*] which is based on
the following assumptions: 1. The formal double bonds are
syn oriented as in 9/10, 2. The donor (NR,) and acceptor
functions (NO,) are as close to each other as possible, leading to a preference for the reactive intermediate 10 over 9.
Our example deviates significantly from the Seebach model,
since instead of an enamine a chiral, metalated O,N-acetal'']
4 is used. As part of an imide unit the amino function of 4 is
a weaker donor than the enolate oxygen. Of the possible
reactive intermediates 11 and 12 the latter appears to be
favored, in analogy to Seebach's findings. This means, how-
Scheme 1. Retrosynthetic analysis of 1
5[41was converted into nitrostyrene 6 and allowed to react
with the enolate (R)-4 of N-acetyloxazolidone 8.['l Compound 7 and its C(3') diastereomer were produced in a ratio
of 94:6 (analysis by HPLC and 13C NMR spectroscopy).
After a single recrystallization from methanol, 7 was 99 %
diastereomerically pure.[61The conversion of 7 into (R)-1 c
was achieved in one step by catalytic hydrogenation,['] via
the intermediates 2 b and (R)-1 b, which were not isolated.
Compound 1c was alkylated with cyclopentylbromide fur-
< 6
ever, that it is not so much the donor effect of the enamine
nitrogen that matters for the diastereoselectivity of the addition, but rather its syn orientation to the nitroolefin unit. A
pericyclic shift of the metal cation to the nitro group as
required in the Zimmerman-Traxler mechanism of the aldol
addition"'] does not appear to play a role because of the
unfavorable ring size (eight-membered ring). The high
stereoselectivity in the formation of 7 is also noteworthy,
since enolates of type 4 which have no substituents on the C
atom, do not react stereoselectively in, for example, aldol
additions." '1
Received: February 1, 1992 [Z5165IE]
German version: Angew. Chem. 1992, 104, 914
7 (94 : 6 )
Scheme 2. Synthesis of (R)-la (Rolipram). a: CH,NO,, NH,OAc, HOAc, reflux, 73%; b: 1) NaN(SiMe,),, THF, 2) 6,65% after recrystallization; c: H,,
Raney nickel, EtOAc/EtOH (l:l), 3 bar, 22°C. 20h, 72%; d: C,H1,Br, NaH,
THF, reflux, 60%.
Angew. Chem. Int. Ed. Engl. 1992, 31, N o . 7
[l] H. H. Schneider, R. Schmiechen, M. Brenzinski, J. Seidler, Eur. Phurmacol. 1986, 127, 105-115.
[2] J. Crossland, Drugs ofthefuture 1988, 13, 38-41.
[31 After the completion of our work Evans' oxazolidinones were used in
Michael additions, however, with completely different substitution patterns: D. A. Evans, M. T. Bilodeau, T. C. Somers, J. Clardy, D. Cherry, Y.
Kato, 1 Org. Chem. 1991,56, 5750-5752.
[4]C. Schopf, L. Winterhalder, Liebigs. Ann. Chem. 1940, 544, 62-71.
[5] Compound 8 was prepared according to the literature procedure for Nacyloxazolidinones: D. A. Evans, A. E. Weber, J Am. Chem. Snc. 1986,
108, 6757-6761.
[6] Analytical data for (4S, 3'R)-3-[3-(3-benzyloxy-4-methoxyphenyl)-4nitrpbutyryl]-4-beqzyl-2-oxazolidinone
7: M.p. 153 "C; [a]:' = - 28.05
(c = 2.3 in chloroform); 'H NMR (250 MHz, CDCI,, 25 "C, TMS):
S = 2.72 (dd, Jv,c = 9 Hz,.IEcrn
= 13.5 Hz,1H;-CHHPh), 3.22 (dd. Jvi,=
3.8 Hz, Jgem= 13.5Hz, 1 H ; -CHHPh), 3.27 (dd, A,, = 6.3 Hz,
Verlugsgesellschufi mbH. W-6940 Weinheim, 1992
0570-0833/92j0707-0871 $3.50+ .2Sj0
Js.,=17.5Hz, 1 H ; H2'),3.47 (dd, JV,,=7.5Hz. Jg,,=l7.5Hz, 1 H ;
H2'),3.82(s,3H;-OCH3),3.95-4.10(m, lH;H3'),4.06-4.14(m,2H;
= 13 Hz, 1 H ;
H 5). 4.45-4.59 (m, 1 H ; H4), 4.53 (dd, J,,, =7.9Hz, Jscm
H 4 ) , 4.65 (dd, JY,,=7.5Hz, JEI,,,=I3Hz, 1 H ; H 4 ) . 5.16 (s, 2H; OCH,Ph), 6.80-6.88 (m, 3 H ; arene-H), 7.14-7.50 (m, 10H; arene-H);
I3C NMR (63 MHz, CDC13,25 "C): 6 = 37.70,38.64,39.13(-CH,Ph. C2'
and C3'), 55.00, 55.94, (C4 and - O m , ) , 66.31 (C-5), 71.23 (-OCH,Ph),
79.60(C4'), 112.20, 113.90, 120.40, 127.35, 127.50, 127.84, 128.47, 128.90,
129.28, 130.80, 134.96, 136.83, 148.31, 149.46 (arene-C), 153.30 (Cl'),
170.04(C2). IR(KBr):t[cm-'] = 1785vs, 1700%1550s;MS(SOeV):m/z
504 (2%, M ' ) , 457 (3), 281 (3). 238 (4), 91 (100, C,H:). 65 (5).
[7] Analytical data for (4S)-4-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidone
I c : M.p. = 126°C; [a];' = - 36.7 ( c = 1.8 in chloroform); 'H NMR
(250 MHz, CDCI,, 2 5 ° C TMS): 6 = 2.47 (dd, J,,, = 9.4 Hz, Jse,=
- 2
a: R =
D. d:
in the degenerate rearrangement 1 a $ 3 a, which can be observed only in the substituted compounds lc, d.
A high-yielding synthesis for the already known hydrocarwas developed, which also gave access to targeted
16.5H~,lH;-CHHCO),2.70(dd,J,,,=8.4Hz,J,.,=16.5Hz,lH;-bon 1
CHHCO), 3.39 (dd, Julc
=7.5 Hz, JBEm
= 8.5 Hz, I H ; -CHHNH), 3.61
substituted derivatives (Scheme 1). Under irradiation buta-
(quint, J = 8 . 5 H z , 1 H ; H4), 3.72 (dd, JVi,=Jg,,=8.5Hz, 1 H ;
-CHHNH), 3.89 (s, 3 H;-OCH,), 5.94(s, lH;-NH),6.38 (s, 1 H;-PhOH),
6.69-6.86 (m. 3 H ; arene-H); "CNMR (63 MHz, DMSO, 25°C):
S = 37.93 (C5), 40.49 (C4), 48.80 (C3), 55.71 (-OCH,), 112.39, 114.12,
117.27, 135.60, 146.34, 146.54 (arene-C), 176.02 (-CO); IR (KBr):
3 [cm-'] = 3260br m, 1685vs, 1520% 1445111, 1295m, 1280m, 12401%
1055m, 1030m. MS (80eV); m/i 207 ( 5 5 % , M + ) , 150 (100). 135 (40).
[Sl D. Seebach, J. Golinski, Helv. Chirn. Acta 1981,65,1413- 1423; S. J. Blarer, W. B. Schweizer. D. Seehach, ibid. 1982, 65, 1637-1654.
[9] D. A. Evans in Asymmefric Synthesis Vul. 3 (Ed.: J. Morrison), Academic Press, New York. 1984, p. 1
[lo] H. E. Zimmerman, M. D. Traxler,J.Am. Chem. Soc. 1956,79,1920-1923.
[ l l ] D. A. Evans, J. Bartoli, T. L. Shih, J. A m . Chem. SOC.1981, 103, 21272129; D. A. Evans, E. B. Sjogren, J. Bartoli, R. L. Dow, Tetrahedron Leu.
1986,27,4957-4960; D. A. Evans, J. S. Clark, R. Metternich.V. J. Novak,
G. S. Sheppard, J. A m . Chem. Sor. 1990, 112, 866-868.
a: R = H. b
R = Br.
1 4
c: R = D, d:
Scheme 1. a) Benzene, hv (lamp Q 1200 Hanau), 140 h, 12%. b) CCI,, 1,3-di-
bromo-5,5-dimethylhydantoin,1.6 equiv, 80 "C, 2 h, 72%. c) Dimethylformamide, Zn, IOequiv, sonation, 7 h, 81 %. d) 1) THF, n-butyllithium,
The Benzene Ring as Dienophile in an
Intramolecular [4+ 21 Cycloaddition:
Degenerate Rearrangement of
1.1 equiv, -78"C, 10min;2)DZO,30equiv, -78"Cto2OUC,70%.e) 1 ) T H E
n-hutyllithium, 1.I equiv, - 78 "C, 10 min; 2) methyl iodide, 4 equiv, - 78 "C to
20"C, 20%.
By Wolfram Grimme,* Thomas Grommes,
Wolfgang R. Roth,* and Rolf Breuckmann
The R bonds of benzene rings can-at higher temperatures-participate in pericyclic reactions. Besides the wellknown Claisen rearrangement,"] a sigmatropic hydrogen
shift and several electrocyclic ring openings131involving
benzene x bonds have been described. Benzene also funcHere we retions as diene in some [4 + 21 cycl~additions.[~~
port the first case of a [4+2] cycloaddition in which one of
the R bonds of a benzene ring reacts as dien0phi1e.I~'
We chose an intramolecular cycloaddition for the investigation of the role of benzene as dienophile, because this
reaction proceeds even with weakly reactive dienophiles for
entropy reasons. Moreover, because the cycloaddition at the
benzene ring is endothermic and easily reversible, its detection requires a molecule which yields a Diels-Alder intermediate that can return to two different products.
The 7,8-benzobicyclo[4.2.2]deca-2,4,7,9-tetraene
1 a fulfills these prerequisites : The diene bridge is spatially close to
the benzene R bond of the bicycle, and the symmetrical
cycloadduct 2a can return to the aromatic state along two
paths (formation of l a or 3a). The intramolecular [4+2]
cycloaddition with participation of the benzene ring results
[*] Prof. Dr. W. Grimme, Dr. T. Grommes
Institut fur Organische Chemie der Universitat
Greinstrasse 4, D-W-5000 Koln 41 (FRG)
Prof. Dr. W. R. Roth, R. Breuckmann
Fakultat fur Chemie der Universitat
Postfach 102148, D-W-4630 Bochum 1 (FRG)
This work was supported by the Fonds der Chemischen Industrie.
VCH Verlagsgesellschu/t mhH, W-6940 Wrinheim, 1992
diene added to navhthalene o affa d the [4+ 41 cycloadduct
4,['1 which was doubly or triply brominated with 1,3-dibromo-5,5-dimethylhydantoinin the planarizable allylic positions. The 1:1 mixture of 5 a and 5b obtained was debrominated with zinc, and the products separated by flash
chromatography (silica gel, cyclohexane). After halogenmetal exchange with n-butyllithium, the bromide 1 b yielded
the bicycle l c , d deuterated or methylated in position 2 on
treatment with D,O or methyl iodide.
A prior investigation had shown that the thermolysis of 1 a
leads to cis-4 b,8 a-dihydrophenanthrene; 1' therefore the
attempt to detect the rearrangement 1 c e 3c had to be performed close to the activation threshold for this thermolysis.
Bicycle 1 c (97% D1) in the gas phase was heated to 235 "C
for 93 h, and the crude product was then dehyrogenated with
(DDQ) in CCl,.
The excess DDQ was reduced with cyclohexa-1,4-diene, and
the product filtered through silica gel. Separation by gas
chromatography furnished the benzobicyclic isomers and
phenanthrene in the ratio 3: 1. The 'H NMR spectrum of the
benzobicyclic isomers revealed a 1: 1 mixture of 1 c and 3c
with 81 % D, deuteration. The [4+2]cycloaddition with the
benzene ring as dienophile therefore takes place under the
chosen conditions, and leads to the equilibrium distribution
of the marked isomers.
The phenanthrene obtained is 64 YOmonodeuterated according to the mass spectrometric analysis, and its 'H NMR
spectrum shows that 60 YOof the deuterium atoms are situated in positions 9 and 10. When the preequilibrium 1 c e 3c
is considered, these values are in accord with the previously
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synthesis, michael, nitroolefins, additional, enantioselectivity, rolipram, antidepressants
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