1726
A. W. Baltrusch, F. Bracher
LETTER
Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min, K.-H.;
Koo, B.-A.; Kim, H.-S. Angew. Chem. Int. Ed. 1999, 38,
3545.
secondary alcohol, the PMP protective group was selec-
tively removed by oxidation with CAN in 75% yield.
Transformation of the resulting primary alcohol 15 to the
primary amine 17 (building block A) was performed by
coupling with 4,5,6,7-tetrachlorophthalimide under Mit-
sunobu conditions, followed by deprotection with ethyl-
enediamine.15 The analogous phthalimide derivative was
readily obtained from 15 under identical conditions, but
could not be hydrolyzed to the primary amine 17 in ac-
ceptable yield under various conditions.
(5) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(6) Evans, D. A.; Rieger, D. L.; Jones, T. K.; Kaldor, S. W. J.
Org. Chem. 1990, 55, 6260.
(7) (a) Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.;
Vullioud, C. Tetrahedron 1986, 42, 4035. (b) Thom, C.;
Kocienski, P. Synthesis 1992, 582.
(8) (a) Oppolzer, W.; Poli, G. Tetrahedron Lett. 1986, 27, 4717.
(b) Review articles about Oppolzer’s chiral auxiliaries:
Oppolzer, W. Tetrahedron 1987, 43, 1969. (c) Also see:
Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241.
(9) Hasegawa, T.; Yamamoto, H. Synlett 1998, 882.
(10) (a) Honda, M.; Katsuki, T.; Yamaguchi, M. Tetrahedron
Lett. 1984, 25, 3857. (b) Claßen, A.; Wershofen, S.;
Yusufoglu, A.; Scharf, H.-D. Liebigs Ann. Chem. 1987, 629.
(11) The corresponding trityl ether was also examined, but gave
ring opening products only in yields <10%. Similar
observations with bulky protective groups have already been
described.13
(12) Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetrahedron
Lett. 1985, 26, 6291.
(13) (a) Skrydstrup, T.; Bénéchie, M.; Khuong-Huu, F.
Tetrahedron Lett. 1990, 31, 7145. (b) See also: Alexakis,
A.; Jachiet, D. Tetrahedron 1989, 45, 6197.
(14) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122.
(15) (a) Debenham, J. S.; Debenham, S. D.; Fraser-Reid, B.
Bioorg. Med. Chem. 1996, 4, 1909. (b) Jia, Z. J.; Kelberlau,
S.; Olsson, L.; Anilkumar, G.; Fraser-Reid, B. Synlett 1999,
565.
Finally, amine 17 was converted to the amide 18 with car-
boxylic acid 4 and DCC/HOBT16 in 63% yield. First at-
tempts to perform a RCM of diene 18 with Grubbs’
catalyst gave absolutely no conversion. A literature search
revealed, that the , -unsaturated amide might form an
unproductive Ru-chelate with the catalyst. In accordance
with Fürstner’s observations,17 addition of 30 mol%
Ti(i-PrO)4 to the reaction mixture resulted in a clean con-
version of the diene to the unsaturated 14-membered lac-
tam 19.18 RCM reactions leading to macrocyclic
compounds give mixtures of E- and Z-olefins in most cas-
es. We did not have to care about the stereochemistry
around the double bond, since in the final step of the syn-
thesis 19 was subjected to catalytic hydrogenation with a
Pd-catalyst resulting in reduction of the double bond and
concomitant removal of the O-benzyl group to give the
target compound 6-nor-fluvirucinin B1 (3) in 83% yield
(Scheme 4).19
(16) Davies, J. S.; Mohammed, A. K. J. Chem. Soc., Perkin
Trans. 1 1981, 2982.
In conclusion, we have worked out a new approach to the
fluvirucinin ring system. Use of chiral 2-substituted
Grignard reagents derived from1-bromo-3-butenes
should also open the possibility to introduce alkyl groups
at C-6. Since our synthesis starts from readily available
chiral precursors, it should allow the free variation of ste-
reochemistry at each chiral center and the modification of
substituents on the ring to prepare further analogs of flu-
virucinin B1 for detailed investigation of structure-activity
relationships.
(17) Fürstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
9130.
(18) Ring-closing metathesis: A solution of diene 18 (30 mg,
0.075 mmol) and Ti(i-PrO)4 (6 mg, 0.02 mmol) in 50 mL
anhydrous CH2Cl2 was refluxed under N2 for 1 hour. Then 2
mg (0.002 mmol) benzylidene-bis(tricyclohexylphos-
phine)dichlororuthenium, dissolved in 0.5 mL CH2Cl2, was
added and the mixture was refluxed for 4 days. Purification
by flash column chromatography (silica, hexanes–ethyl
acetate 5:2) gave 20 mg (72%) 19 as colorless crystals, mp
176 °C. [ ]D20 = +35.4 (CHCl3); 1H NMR (400 MHz, CDCl3)
(ppm) 0.84 (t, J = 7.4 Hz, 3 H), 0.90 (t, J = 7.5 Hz, 3 H),
1.20–1.60 (m, 13 H), 2.00 (m, 2 H), 2.08 (m, 1 H), 2.39 (m,
1 H), 2.65 (m, 1 H), 3.21 (m, 1 H), 3.50 (m, 1 H), 3.75 (m, 1
H), 4.42 (d, J = 11.1 Hz, 1 H), 4.54 (d, J = 11.1 Hz,
1 H), 5.38 (m, 1 H), 5.42 (m, 2 H), 7.30 (m, 5 H). 13C NMR
(100 MHz, CDCl3) (ppm) 11.0, 12.2, 21.9, 23.4, 24.8, 25.1,
26.9, 29.7, 31.5, 35.3, 39.4, 42.5, 50.3, 72.1, 81.5, 127.4,
127.8 (2 C), 128.3 (2 C), 131.5, 131.7, 139.0, 175.0. MS (EI,
70 eV): m/z 371 (6, M+), 280 (100), 263 (12), 100 (12), 91
(91).
Acknowledgement
This work was generously supported by the Deutsche Forschungs-
gemeinschaft (DFG) and the Fonds der Chemischen Industrie.
References
(1) Hedge, V. R.; Patel, M. G.; Gullo, V. P.; Ganguly, A. K.;
Sarre, O.; Puar, M. S.; McPhail, A. T. J. Am. Chem. Soc.
1990, 112, 6403.
(2) Naruse, N.; Tsuno, T.; Sawada, Y.; Konishi, M.; Oki, T. J.
Antibiot. 1991, 44, 741.
(3) (a) Houri, A. F.; Xu, Z.; Cogan, D. A.; Hoveyda, A. H. J. Am.
Chem. Soc. 1995, 117, 2944. (b) Xu, Z.; Johannes, C. W.;
Houri, A. F.; La, D. S.; Cogan, D. A.; Hofilena, G. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 10302.
(4) (a) Trost, B. M.; Ceschi, M. A.; König, B. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1486. (b) Martin, M.; Mas, G.; Urpi,
F.; Vilarrasa, J. Angew. Chem. Int. Ed. 1999, 38, 3086. (c)
For the synthesis of the related aglycone fluvirucinin A1 see:
(19) Analytical data of 3: Mp 208 °C. [ ]D20 = +50.8 (CHCl3); 1H
NMR (400 MHz, CDCl3–CD3OD 1:1) (ppm) 0.88 (t, J =
7.5 Hz, 3 H), 0.89 (t, J = 7.1 Hz, 3 H), 1.20–1.75 (m, 22 H),
2.15 (m, 1 H), 2.71 (dt, J = 4.4 and 13.7 Hz, 1 H), 3.48 (m, 1
H), 3.65 (m, 1 H), 5.40 (s, 1 H). 13C NMR (100 MHz, CDCl3/
CD3OD 1:1) (ppm) 10.9, 12.3, 21.7, 22.1, 26.0 (2 C), 26.3,
26.4, 27.4, 27.6, 32.4, 33.5, 39.6, 44.9, 52.9, 73.7, 178.2. MS
(EI, 70 eV): m/z 283 (44, M+), 265 (51), 212 (22), 184 (30),
171 (49), 156 (26), 128 (51), 115 (43), 100 (38), 81 (29), 69
(46), 55 (100), 43 (50).
Synlett 2002, No. 10, 1724–1726 ISSN 0936-5214 © Thieme Stuttgart · New York