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Chemo- and Stereoselective Cobalt-Mediated [2 + 2 + 2]Cycloaddition of Alkynes with Uracil Derivatives. A Novel Synthetic Entry to Modified Nucleosides

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[12] S. K. Loh, E. R. Fisher, L. Lian, R. H. Schultz, P. B. Armentrout, .
I
Phys.
Chem. 93 (1989) 3159.
[13] For the characterization of [M-HIe (M = transition metal) and [M-OH]'
ions see also a) T. J. Carlin, L. Sallans, C : J. Cassady, D. B. Jacobson, B. S.
Freiser. J. Am. Chem. SOC.105 (1983) 6320; b) L. F, Halle, F, S. Klein, J. L.
Beauchamp. h i d . 106 (1984) 2543; c) C. I. Cassady, B. S. Freiser, ibid. 106
(1984) 61 76; d) D. B. Jacobson, B. S. Freiser, ibid. 107 (1985) 72; e) C. J.
Cassady. B. S. Freiser, ibid. f08 (1986) 5690.
[14] Other processes, such as charge transfer ([Fe(O)OH]@+ CH, +
CHF + [Fe(O)OH]) or hydride abstraction ((Fe(OH),Ie + CH, +
CHY + [Fe(OH),] do not take place.
[15] The loss of formaldehyde in the system [Fe(O)OHIe/CD, is slowed down
by a considerable isotope effect. The product [DFe(OHD)Ie formed by
loss of formaldehyde exchanges its deuterium atoms rapidly with the "residual water" present in the ICR cell; a quantitative description of this
process is not possible.
[16] The signal corresponding to the elimination of C,H,D is too weak for
quantitative evaluation. This holds true also for the cleavage of D,O from
the complex [Fe(O)OHIe/CH,CD,. H,O and HDO are formed in the
ratio 1 : 1 .
1171 This value is based on the assumption that the pathway @ for the activation of methane (Scheme 1) does not occur.
Chemo- and Stereoselective Cobalt-Mediated
12 + 2 + 21Cycloaddition of Alkynes with Uracil
Derivatives. A Novel Synthetic Entry to Modified
Nucleosides""
By Roland Boese,* Jean Rodriguez,
and K . Peter C. Voilhardt*
The uracil nucleus is present in a multitude of biologically
important molecules, including the nucleic acids, and its selective modification has been a challenge in the quest for the
development of new medicinal agents, particularly those effective for the treatment of cancer and viral infections, such
as herpes and AIDS.['' In this effort, the 5,6-double bond has
played a limited role as a target for synthetic elaboration.[']
We report that [CpCoL,](L=CO, C2H4)I3]activates this unit
to undergo [2+2 21 cycloadditions to alkynes, generating
novel fused 5,6-dihydropyrimidine-2,4-dionecomplexes, in
most cases with remarkable chemo- and stereoselectivity
(Scheme 1. Table l).14]
The starting materials 1 and 4 were prepared in high yields
by adaptation or application of standard literature proced u r e ~ .The
[ ~ ~results summarized in Table 1 deserve several
comments :
1) While systematic optimization has not been carried out,
the eficiency of the cyclization is strongly affected by
changes in the reaction conditions, as noted earlier in
analogous cases.16] Thus, the yields for 6a-c are deceptively
low, because of incomplete conversions of starting materials
(the yields based on recovered 4a are 96, 89, and 94%, respectively). Indeed, simply changing the solvent to boiling
xylene increases the yield of isolated 6 b to 76 YO.
+
[*I Prof. Dr. K. P. C. Vollhardt, Dr. J. Rodriguez
Department of Chemistry
University of California at Berkeley
and
The Chemical Sciences Division,
Lawrence Berkeley Laboratory, Berkeley, CA 94720 (USA)
Dr. R. Boese
Institut fur Anorganische Chemie der Universitat-Gesamthochschule
Universitatstr. 5-7, Postfach 10 37 64, W-4300 Essen 1 (FRG)
[**I This work was supported by the National Institutes of Health (GM
22479). J. R. acknowledges the award of a postdoctoral fellowship by the
Fonds de Bourse de Recherche Scientifique et Technique de I'OTAN
(1987/1988).
Angew. Chem. Inr. Ed. Engl. 30 (1991) No. 8
0 VCH
3 syn I anti
2
1
4
6 syn I anti
5
Scheme 1. The designation syn and anfi indicates the position of the Co atom
relative to the tertiary hydrogen atoms of the cyclohexadiene ring.
2) The reaction is remarkably chemoselective; especially
noteworthy is the synthesis of 6, in which the heterocyclic
double bond is engaged in an entirely intermolecular fashion, a synthetic variant that has failed in the cases of the
indole, pyrrole, and imidazole nuclei.[6]
3) As expected,[61products 3 emerge mainly in the anticonfiguration. Interestingly, however, the syn-isomers of
6a-c are formed exclusively.
Table 1. Results of the respective cyclizations of I and 4 with 2 and 5 mediated
by CPCO [4l la].
Uracil derivatives
114
la
la
R'=C&CO
Ib
R'=H
4a
R]=R~=cH,
4b
R'=CH,
CH30/-\
4c
R'=CH3
Cocyclizing
alkyne
Products
(yield [%I) [b]
Sb
Q(94) [45:41:11
OCH,
I
CH30
4d
R'=H
61 (37)[1:1:1:11
[a] Conditions: 3:To 1 (1 equiv.) and 2a (co-solvent) or 2b (5 equiv.) in T H F
is added [CpCo(CO),] (1.5-1.8 equiv.) in TH F at room temperature under N,
over a period of 17-21 h (syringe pump) while irradiating the reaction mixture
with a slide projector lamp (Sylvania ELH 300 W). 6a-d: To irradiated 4a
(1 equiv.) in boiling toluene (or 4b in xylene) is added under N, a mixture of 5
(2 equiv.) and [CpCo(CO),] (2 equiv.) in toluene over a period of 18-22 h
(syringe pump). 6e,f: To irradiated 4 (1 equiv.) in boiling THF is added under
argon simultaneously via two syringes 5b (2 equiv.) and [CpCo(CH,CH,),] in
T H E [b] The diastereomeric ratios were determined 'H-NMR spectroscopically on the crude products after flash chromatography on SO, and before further
chromatographic purification.
Verlagsgesellschaft mbH, W-6940 Weinheim, 1991
0570-0833/91/0808-0993$3.50+.25/0
993
4) Most promising for future exploration are the cocyclizations of the enantiomerically pure nucleoside models
4b-d, bearing what might be considered chiral auxiliary
sugar substituents. Their potential utility is demonstrated in
the highly diastereoselective construction of 6e.
5) As discussed previously,[3,61 the position of the cobalt
atom relative to those of the adjacent cyclohexadiene tertiary
hydrogens is readily ascertained exploiting the metal's distinctive magnetic anisotropy. In this way, the major diastereomer of 6d and 6e was assigned the syn-configuration.
To corroborate these conclusions and perhaps obtain some
clues with respect to the selectivity of the addition of 4c to
5t1, an X-ray structural analysis of 6e (major isomer) was
performed (Fig. l).[']
CDCI3):6=1.83(m,4H),2.70(d,J=8Hz,1H),2.78(m,1H),2.94(d,
J = 8 Hz, 1 H), 3.74 (s, 3H), 3.81 (s, 3H),4.51 (m,1H),4.90 (s, 5H), 5.56
( s , 1H), 7.49 (s, 1 H); "CNMR (75 MHz, CD,CI,): 6 = 23.9, 34.2, 43.6,
45.9, 52.1, 52.8, 55.0, 61.2, 72.3, 78.2, 78.9, 83.5, 151.6, 168.5, 170.9, 172.2;
MS (70eV): m / z 445 ( M e , 6%), 444(28), 442(2), 383(2), 378(4), 318(42),
288(34), 287(100). 6b (free ligand): colorless crystals, m.p. 112-114 "C; IR
(C,H,)O=2940,2860, 1715,1675,1480,1415,1280, llOOcm-'; ' H N M R
(300MHz,C6D,):6= 1.16(m,2H),1.33(m,2H),1.91(m,3H),2.17(m,
1 H), 2.54 (dd, J = 7.6,6.6 Hz, 1 H), 2.69 (s, 3 H), 3.24 (s, 3 H), 3.33 (m, 1 H),
5.83 (bd, J = 1 . 7 H z 9 lH), 5.50(d, J = 6 H z , 1H); 13CNMR (75MHz,
C,D,): 6 = 24.4,27.7, 30.8, 30.9, 33.5,39.7, 52.9, 117.7, 118.4, 136.2, 138.3,
153.2, 170.0; MS (70eV): m / r 247 ( M e ,18%). 246(100), 245(95), 217(40),
104(76), 91(69). 6 e (major isomer): yellow crystals, m.p. 156-158 "C; IR
(C,H,): O = 3090, 3035. 2980, 2930, 2820, 1705, 1670, 1460, 1355, 1285,
1205, 1200, 1130, 1110, 1100, 1060cm-'; 'HNMR (400 MHz, CD,CI,):
6 = 1.67 (m.lH), 1.76 (m. lH), 2.03 (m. 5H), 2.24(m, lH), 2.28(m, lH),
2.33 (m, lH), 2.69 (dd, J = 10, 5.7 Hz, lH), 2.88 (s. 3H), 3.03 (d,
J = 5.7 Hz, 1 H), 3.29 (m, 1 H), 3.33 (s, 1 H), 3.46 (s, 1 H), 3.59 (m, 2 H), 3.92
(at, J = 6 . 1 , 3.2Hz, lH), 3.98 (m,2H), 4.71 (s, 5H), 5.89 (dd, J=8.3,
6.1 Hz,1 H); "CNMR (75 MHz, C,D,): 6 = 23.5, 23.7, 27.6, 28.8, 29.2,
35.2, 39.8.44.5. 52.5, 53.5, 56.5, 58.9, 73.6,81.1, 81.7, 82.3, 87.0,92.2,95.0,
151.7, 171.8; MS (70eV): m/z 501 ( M e , 4%), 500(15), 356(15), 354(20),
256(9), 159(33), 124(25), 113(35), 87(20), 45(100).
[5] a) K. A. Cruickshank, J. Jiricny, C . B. Reese, Tetrahedron Lett. 25 (1984)
681; b) R. W. Chambers, Biochemistry 4 (1965) 219; c) R. B. Baker, G. B.
Chheda, J. Pharm. Sci. 54 (1965) 25; d) E. Wittenburg, Chem. Ber. 99 (1966)
2380; e) J. ZemliEka, J. Smrt, F. S6rm. Coil. Czech. Chem. Commun. 29
(1964) 635; f ) I. Ciucanu, F. Kerek, Carbohydr. Res. 131 (1984) 209.
[6] K. P. C. Vollhardt, Lect. Heterocycl. Chem. 9 (1987) 59.
[7] Crystal size: 0.36 x 0.26 x 0.25 mm3. orthorhombic, wace
. -arouD P2.2.2.,
.._
20,,, = 50". u = 8.913(1), b = 11.269(1), c = 23.7910) A, a = p = y = 90",
V = 2389.7(5) A3, Z = 4,
= 1.391 g ~ m - p
~=
, 0.75 mm-', NicoletR3m/V diffractometer with Mo,, radiation at 125 K; 4240 reflections collected, 3856 treated as observed [F, t 4u(F)]; structure solved by direct
methods and refinement with full matrix least squares, 324 parameters, rigid
groups for hydrogen atoms; common isotropic Uvalues for each group and
anisotropic U values for all other atoms, except 0 2 6 and 026A which are
disordered and calulated with site occupation factors of 0.5; the absolute
structure was established by refinement of q = 1.033(23) [8], R = 0.035,
R , = 0.033, w-' = [u2(F,) 1.5 x 10-4g]. Maximum residual electron
density 0.43 e k 3 . Further details of the crystal structure investigation may
be obtained from the Fachinformationszentrum Karlsruhe, Gesellschaft fur
wissenschaftlich-technische Information mbH, W-7514 Eggenstein-Leopoldshafen 2 (FRG), on quoting the depository number CSD-320197, the
names of the authors, and the journal citation.
D. Rogers, Acta Crystallogr. Sect. A37 (1981) 734.
See, for example, J. H. Prestegard, S. I. Chan, J. Am. Chem. SOC.91 (1969)
2843; M. P. Schweizer, J. T. Witkowski, R. K. Robins, ibid. 93 (1971) 277;
H . Dugas, B. J. Blackburn, R. K. Robins, R. Deslauriers, I. C. P. Smith,
ibid. 93 (1971) 3468; T. C. Thurber, L. B. Townsend, J. Heterocycl. Chem. 9
(1972) 629; M. P. Schweizer, E. B. Banta, J. T. Witkowski, R. K. Robins, J.
Am. Chem. SOC.95 (1973) 3770; G . I. Birnbaum, G. A. Gentry, ibid. 105
(1983) 5398; G. W. M. Visser, R. E. Herder, P. Noordhuis, 0. Zwaagstra,
J. D. M. Herscheid, F. J. J. de Kanter, J. Chem. Soc. Perkin Trans, 1 1988
2547; P . C. Kline, A. Serianni, J. Am. Chem. SOC.112 (1990) 7373.
~
Fig. 1. Structure of 6 e (major isomer) in the crystal (SHELXTL). Selected
distances [A] and angles ["I: Co-C6 2.014(3), CO-C7 1.960(3), Co-C12 1.991(3),
Co-Cl3 2.001(3), Co-Cp (ring centroid) 1.675, N1-C2 1.357(3), Nl-Cl4
1.47613). C2-N3 1.405(3), N3-C4 1.401(4), C4-C5 1.50614). C5-C6 1.529(4),
C5-Cl4 1.527(4),C6-C71.428(4),C7-C12 1.410(4),C12-C13 1.439(4),C13-C14
1.530(4), C6-C7-C12-C13 5.3, C6-C5-C14-C13 25.9, C4-CS-Cl4-Nl 34.5.
While it is probably premature to speculate on the origin
of the diastereoselectivity observed in the formation of 6e
(and the lack thereof on route to 6d and 6f), it is nevertheless
presumed that the conformation of the sugar substituents in
the starting materials is decisive.[y1
6) As noted previously,r3. the [CpCo(diene)] complexes
are subject to oxidative degradation, liberating hitherto unavailable heterocyclic ligands [e.g. CpCo-free 6b, CuCI,
(4 equiv.), Et,N (12 equiv.), THF/H,O O T , 2 min,
91 Yo)].[41
Extension of this methodology to other nucleic acid bases,
and to the "tagging" of the nucleic acids themselves, are
currently under investigation.
Received: March 22, 1991 [Z 4527 IE]
German version: Angew. Chem. 103 (1991) 1032
[l] a) For selected recent references, see: D. M. Coe, P. L. Myers, D. M. Parry,
S. M. Roberts, R. Storer, J. Chem. SOC.Chem. Commun. 1990, 151; b) K .
Hirota, H. Sajiki, Y. Maki, H. Inoue, T. Ueda, ibid. 1989, 1659; c) R. W.
Armstrong, S. Gupta, F. Whelihan, Tetrahedron Lett. 30(1989) 2057; d) N.
Bischofsberger, hid. 30 (1989) 1621 ;e) J. C. Martin (Ed.): Nucfeotide Anurogues as Antiviral Agents (ACS Symp. Ser. 401) Am. Chem. SOC.
Washington, DC, USA 1989.
121 a) D. J. Brown in A. R. Katritzky, C . W. Reese (Eds.): Comprehensive Heterocyclic Chemistry, Vol. 3, Pergamon, New York 1984, p. 57; b) S. T. Reid,
Adv. Heterocycl. Chem. 30 (1980) 239.
[3] K. P. C. Vollhardt, Angew. Chem. 96 (1984) 525; Angew. Chem. Int. Ed.
Engl. 23 (1984) 539.
[4] All new compounds gave satisfactory analytical and/or spectral data. For
example: 3 d : orange-red crystals, m.p. = 210 "C (decomp.); IR (CHCI,):
a = 3390, 2950, 1710, 1485, 1450, 1430, 1265cm-'; 'HNMR (300MHz,
994
0 VCH
Verlagsgesellschaft mbH, W-6940 Weinherm. 1991
+
Arsenic Compounds in Organic Synthesis:
Pentamethinium Salts from Aminoarsanes
and Pyrylium Salts
By Yves Madaule, Myriam Ramarohetra, Jean-GCrard WOE*
Jean-Paul Declercq, and Antoine Dubourg
Compared to the well known arsenic ylides, Wittig
reagents frequently used in natural products synthesis,"]
other organoarsenic compounds are seldom used as synthetic intermediates in preparative organic chemistry. Examples
[*] Dr. J. G. Wolf, Dr. Y Madaule, M. Ramarohetrd,
University Paul Sabatier, URA CNRS 471
F-31062 Toulouse Cedex (France)
Prof. Dr. J. P. Declercq
University of Louvain-la-Neuve (Belgium)
Dr. A. Dubourg
University of Montpellier (France)
0570-0833/91/0808-0994$3.50+ .25/0
Angew. Chem. Int. Ed. Engl. 30 (1991) No. 8
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stereoselective, cycloadditions, alkynes, cobalt, derivatives, mediated, synthetic, entry, uracil, chem, modified, novem, nucleoside
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