Enantioselective synthesis of 6-nor-fluvirucinin B1

Article abstract of DOI:10.1055/s-2002-34214

An enantioselective synthesis of the 6-nor-derivative 3 of the antiviral macrocyclic lactam fluvirucinin B₁ (2) is presented. Key steps are two regioselective ring opening reactions of chiral epoxides, and a ring-closing metathesis with Grubbs'

Full text of DOI:10.1055/s-2002-34214

1724
LETTER
Enantioselective Synthesis of 6-nor-Fluvirucinin B1
S
ynthesis of 6-Norn-Fluvirucinin B1 e W. Baltrusch,a Franz Bracher*b
a
Institut für Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstr. 55, 38106 Braunschweig, Germany
b
Department für Pharmazie–Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstr. 5–13,
81377 München, Germany
Fax +49(89)21807802; E-mail: Franz.Bracher@cup.uni-muenchen.de
Received 8 August 2002
In this letter we present a new enantioselective access to
the fluvirucinin skeleton, again utilizing RCM.5 But in our
case Grubbs’ ruthenium-catalyst [benzylidene-bis(tri-
cyclohexylphosphine)dichlororuthenium], which is easier
Abstract: An enantioselective synthesis of the 6-nor-derivative 3
of the antiviral macrocyclic lactam fluvirucinin B1 (2) is presented.
Key steps are two regioselective ring opening reactions of chiral ep-
oxides, and a ring-closing metathesis with Grubbs’ catalyst. The
choice of appropriate protective groups was essential for the success to handle than Schrock’s catalyst, can be used to connect
and efficiency of the synthesis.
C-4 and C-5 of the lactam.
Key words: asymmetric synthesis, epoxides, fluvirucin, natural
products, metathesis
In order to work out a general approach to the fluvirucinin
skeleton first, we decided to omit the methyl group at C-6
of the lactam. The target compound, 6-nor-fluvirucinin B1
(3) was disconnected into two main fragments, (R)-2-eth-
In 1990 and 1991 two independent groups at Schering–
Plough1 and Bristol–Myers–Squibb2 described the iso-
lation and structure elucidation of a novel group of 14-
membered lactams called fluvirucines from fermentation
broths of the actinomycete Actinomadura vulgaris. These
macrolactams, especially fluvirucin B1 ( = Sch 38516; 1),
exhibit potent antifungal and antiviral activities. The agly-
cones, e. g. fluvirucinin B1 (2) still retain significant activ-
ity against influenza A virus.
yl-4-pentenoic acid (4) and an amino olefin A. The 14-
membered ring should be constructed by amide synthesis
from the two building blocks, followed by RCM, and sub-
sequent reduction of the double bond (Scheme 1). The
main challenge was the enantioselective synthesis of
building block A. This should be accomplished by ring
opening of a chiral epoxide of type B with an appropriate
metalated butene.
A first total synthesis of the aglycone fluvirucinin B1 (2,
Figure 1) was reported by Hoveyda with one key step be-
ing a ring-closing metathesis (RCM) with Schrock’s mo-
lybdenum catalyst to connect C-5 and C-6 of the
macrolactam. Later this method was extended to the total
synthesis of the glycoside fluvirucin B1 (1, Scheme 1).3
Meanwhile a few other approaches to the fluvirucinines
have been published using different macrolactamization
methods to build up the macrocycles.4
Scheme 1 Retrosynthetic analysis of 3 (X = protected amino group
or a precursor of a primary amine).
Building block 46 was prepared in two steps in enan-
tiopure form from Oppolzer’s N-crotyl-(+)-camphor-
sultam 5 (Scheme 2).7 Conjugate hydride addition with
L-selectride,8 followed by trapping of the resulting enolate
with allyl bromide gave, after recrystallization, pure 6 in
71% yield. Carboxylic acid 4 was obtained from 6 in 93%
yield using Yamamoto’s optimized hydrolysis proce-
dure.9 The standard protocol (LiOH, H2O2)8 gave dramat-
ically lower yields.
Figure 1
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1724,1726,ftx,en;G22102ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Synthesis of 6-nor-Fluvirucinin B1
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the best results in the ring opening reaction. The rarely
used 4-methoxyphenyl (PMP) protective group12 was
found to be ideal for our purpose, since it is stable to orga-
nometallic reagents and to catalytic hydrogenation, as
needed for the selective removal of a O-benzyl group
later. On the other hand, PMP ethers can be removed by
Ce4+-oxidation without affecting benzyl ethers and ole-
fins.
Under carefully controlled conditions13 epoxide 8 was
opened in a regioselective manner by treatment with an
alkynyl alanate prepared from 9 and n-butyllithium–
Me3Al, in the presence of BF3, to give 10 in 49% yield.
Scheme 2 a) L-Selectride, THF, –78 °C, 30 min; then allyl bromide,
90 min (71%); b) tetrabutylammonium hydroxide, H2O2, 2-methyl-2-
butene, 1,2-dimethoxyethane, 0 °C, 2 h (93%).
For the synthesis of building block A R,R-configurated
epoxy alcohol 7, prepared by Sharpless epoxidation of
(E)-pent-2-en-1-ol,10 was first converted to the benzyl
ether 8.11 This intermediate should be subjected to a regio-
and stereoselective nucleophilic ring opening reaction
with a C3-synthon covering C-11 to C-13 of the target
compound.
In the absence of BF3 we obtained no conversion of the
epoxide at all. Catalytic hydrogenation of 10 resulted in
reduction of the alkyne group and removal of the benzyl
protective group. The diol 11 was obtained in 85% yield.
In order to allow the introduction of a C-5 C-7 fragment,
the diol was converted to the epoxide 12 under complete
retention at the stereocentres in a single operation with N-
(2,4,6-triisopropylbenzenesulfonyl)imidazole (N-TrisIm)
and NaH.14 Next, this epoxide was opened with 3-butenyl-
magnesium bromide–CuI to give the secondary alcohol
13. But it was even more efficient to perform these two
steps consecutively in one flask, and so 13 was obtained
from 11 in 58% overall yield. After benzylation of the
It appeared reasonable to use propargylamine or propynol
derivatives for this purpose, since these compounds bear
an acidic alkyne group and a terminal functional group
that should enable us to introduce the ring nitrogen. By
examining numerous C3-building blocks of these types,
we found that propargyl 4-methoxyphenylether (9) gave
Scheme 3 a) NaH, THF, 30 min; then benzyl bromide, 24 h (71%); b) 9, n-BuLi, THF, –20 °C; then Me3Al–heptane; then 8 and BF3 OEt2,
–30 °C, 2 h (49%); c) H2, Pd/C, MeOH, 2 h (85%); d) NaH, THF, 0 °C, 1 h; then N-TrisIm, 1 h; e) H2C=CH-CH2-CH2MgBr, CuI, –30 °C, 2 h
(58% from 11); f) NaH, THF, 30 min; then benzyl bromide, 48 h (79%); g) (NH4)2Ce(NO3)6, CH3CN, H2O, –20 °C, 20 min (75%); h) 4,5,6,7-
tetrachlorophthalimide, Ph3P, DEAD, THF, 12 h (60%); i) ethylenediamine, EtOH, THF, 60 °C, 4 h (79%); j) 4, CH2Cl2, DCC, HOBT, 5 min;
then 17, 12 h (63%); k) Ti(i-PrO)4, CH2Cl2, 1 h; then Grubbs’ catalyst, reflux, 4 d (72%); l) H2, Pd/C, MeOH, 2 h (83%).
Synlett 2002, No. 10, 1724–1726 ISSN 0936-5214 © Thieme Stuttgart · New York

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
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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