A formal total synthesis of roseophilin: cyclopentannelation approach to the macrocyclic core.

Article abstract of DOI:10.1021/ol990124k

[formula: see text] The formal total synthesis of the macrocyclic core of roseophilin 4 has been accomplished in 12 steps from 5-hexenal 8. The cyclopentannelation reaction was used to form the aliphatic five-membered ring of 3. Diene 2 was assembled by m

Full text of DOI:10.1021/ol990124k

ORGANIC
LETTERS
1999
Vol. 1, No. 4
649-651
A Formal Total Synthesis of
Roseophilin: Cyclopentannelation
Approach to the Macrocyclic Core
Paul E. Harrington and Marcus A. Tius*
Department of Chemistry, UniVersity of Hawaii at Manoa, 2545 The Mall,
Honolulu, Hawaii 96822
tius@gold.chem.hawaii.edu
Received June 10, 1999
ABSTRACT
The formal total synthesis of the macrocyclic core of roseophilin 4 has been accomplished in 12 steps from 5-hexenal 8. The cyclopentannelation
reaction was used to form the aliphatic five-membered ring of 3. Diene 2 was assembled by means of a Stetter reaction. Ring-closing metathesis
of 2, reduction, and Knorr reaction of the 1,4-diketone 5 gave the ketopyrrole 3.
Roseophilin 4, a structurally unique metabolite, was recently
isolated from the culture broth of Streptomyces griseoViridis
by Seto et al.1 It shows high activity against K562 and KB
cell lines in the sub-micromolar range. The high activity
coupled with the unique structure has made roseophilin 4 a
popular target for synthesis.2 The first total synthesis was
accomplished by Fu¨rstner et al.2f Their concise synthesis
utilized 3 as an advanced intermediate that, after protection
of the pyrrole nitrogen atom with a SEM group, was coupled
with the pyrrolylfuran side chain. Deprotection followed by
loss of water gave racemic roseophilin 4. During the same
period, Fuchs reported a synthesis of the macrocyclic core
via a difficult ring-closing metathesis reaction of a confor-
mationally biased diene.2c
Scheme 1
Our retrosynthetic approach to the roseophilin core 3 is
shown in Scheme 1. A potentially challenging step in the
(1) Hayakawa, Y.; Kawakami, K.; Seto, H.; Furihata, K. Tetrahedron
Lett. 1992, 33, 2701-2704.
(2) (a) Nakatani, S.; Kirihara, M.; Yamada, K.; Terashima, S. Tetrahedron
Lett. 1995, 36, 8461-8464. (b) Kim, S. H.; Fuchs, P. L. Tetrahedron Lett.
1996, 37, 2545-2548. (c) Kim, S. H.; Figueroa, I.; Fuchs, P. L. Tetrahedron
Lett. 1997, 38, 2601-2604. (d) Fu¨rstner, A.; Weintritt, H. J. Am. Chem.
Soc. 1997, 119, 2944-2945. (e) Luker, T.; Koot, W.-J.; Hiemstra, H.;
Speckamp, W. N. J. Org. Chem. 1998, 63, 220-221. (f) Fu¨rstner, A.;
Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817-2825. (g) Mochizuki,
T.; Itoh, E.; Shibata, N.; Nakatani, S.; Katoh, T.; Terashima, S. Tetrahedron
Lett. 1998, 39, 6911-6914. (h) Fu¨rstner, A.; Gastner, T.; Weintritt, H. J.
Org. Chem. 1999, 64, 2361-2366.
synthesis, the macrocyclization via a ring-closing metathesis
reaction,3 was not envisioned to be problematic for the
10.1021/ol990124k CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/15/1999

relatively unstrained, conformationally flexible diene 2. Two
key steps in the synthesis, the cyclopentannelation reaction
and the attachment of the 7-carbon alkene fragment, provide
diene 2. The five-membered ring formation by the cyclo-
pentannelation reaction,4 a variant of the Nazarov cyclization,
allows for the rapid assembly of the substituted R-methyl-
enecyclopentenone. Peterson olefination provides the R,â-
unsaturated aldehyde 6 with the desired E stereochemistry.
The synthesis starts with the formation of the tert-
butylimine of 5-hexenal5 7 in 94% yield (Scheme 2).6
The hydrolytically labile R-TMS imine of 7 was carried on
without purification after aqueous workup. Deprotonation
with LDA followed by addition of isobutyraldehyde gave
the R,â-unsaturated imine after aqueous workup. Imine
hydrolysis with oxalic acid in THF/H2O (1:1) and column
chromatography gave the aldehyde 6 in 71% yield as a single
isomer following column chromatography. Oxidation of 6
under standard conditions8 with NaClO2 and 2-methyl-2-
butene with a KH2PO4 buffer gave the R,â-unsaturated acid,
which was used crude in the next step. Amide formation
with CBr4, PPh3, and morpholine9 gave 1 in 88% yield over
two steps from aldehyde 6. Formation of the protected
R-methylenecyclopentenone 9 was accomplished via addition
of R-(methoxy)methoxy-R-lithioallene at -78 °C to the
morpholine amide10 1 followed by quenching with a solution
of acetic acid in THF at -78 °C. Cyclization to the
R-methylenecyclopentenone occurs spontaneously during
workup without addition of strong acid.11 Protection of the
hydroxy group as the benzoate ester gave the R-methyl-
enecyclopentenone 9 in 49% yield from morpholine amide
1. Addition of the acyl carbanion equivalent of 6-heptenal
to cyclopentenone 9 could have been accomplished in a
number of different ways.12 The addition was accomplished
in a single step by means of the underutilized Stetter
reaction.13 Heating a mixture of 9 and 2 equiv of 6-heptenal14
in the presence of catalytic Et3N and 3-benzyl-5-(hydroxy-
ethyl)-4-methylthiazolium chloride in 1,4-dioxane gave trans-
diene 215 in 60% yield.16 It should be noted that loss of the
benzoate under these conditions, which was envisioned to
be a potential problem, did not occur to any appreciable
extent. Diene 2 was accompanied by 9% of the cis isomer,
which was easily separated by column chromatography.
Additionally, no products arising from addition of 6-heptenal
to the less reactive endocyclic â-carbon were isolated.
Scheme 2
(a) t-BuNH2, rt, 94%; (b) LDA, TMSCl, THF, -78 to +10 °C;
(c) LDA, i-PrCHO, -78 to +10 °C; (d) (COOH)2, THF, H2O, 71%
(three steps); (e) NaClO2, KH2PO4, 2-methyl-2-butene; (f) CBr4,
PPh3, morpholine, 88% (two steps); (g) (i) R-(methoxy)methoxy-
R-lithioallene, THF, -78 °C; (ii) AcOH; (h) BzCl, Et3N, 49% (two
steps); (i) 6-heptenal, Et3N, 3-benzyl-5-(hydroxyethyl)-4-methylthi-
azolium chloride, 1,4-dioxane, 60%; (j) Grubbs’ catalyst, 0.0005
M, 40 °C, 90%; (k) H2, Pd/C, THF, 92%; (l) (NH4)2CO3, propionic
acid, 140 °C, 10 h, 52%.
Two complementary strategies suggest themselves for the
conversion of 2 to 3: ring-closing metathesis, reduction,
(7) (a) Kang, S. H.; Jun, H.-S.; Youn, J.-H. Synlett 1998, 1045-1046.
(b) Schlessinger, R. H.; Poss, M. A.; Richardson, S.; Lin, P. Tetrahedron
Lett. 1985, 26, 2391-2394. (c) Corey, E. J.; Enders, D.; Bock, M. G.
Tetrahedron Lett. 1976, 27, 7-10.
Conversion of 7 to the R-TMS derivative was accomplished
by deprotonation with LDA followed by addition of TMSCl.7
(3) For reviews of the ring-closing metathesis reaction see: (a) Grubbs,
R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (b) Nicolaou, K. C.;
King, N. P.; He, Y. In Topics in Organometallic Chemistry; Fu¨rstner, A.,
Ed.; Springer-Verlag: Berlin, Heidelberg, 1998; Vol. 1, pp 73-104.
(4) For recent examples of the use of the cyclopentannelation reaction
in synthesis, see: (a) Tius, M. A.; Hu, H.; Kawakami, J. K.; Busch-Petersen,
J. J. Org. Chem. 1998, 63, 5971-5976. (b) Tius, M. A.; Busch-Petersen,
J.; Yamashita, M. Tetrahedron Lett. 1998, 39, 4219-4222. For related work
involving Nazarov cyclizations of allenyl ketones, see: Hashmi, A. S. K.;
Bats, J. W.; Choi, J.-H.; Schwarz, L. Tetrahedron Lett. 1998, 39, 7491-
7494.
(8) (a) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175-
1176. (b) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888-
890.
(9) Einhorn, J.; Einhorn, C.; Luche, J.-L. Synth. Commun. 1990, 20,
1105-1112.
(10) Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J. Synlett 1997,
1414-1416.
(11) Tius, M. A.; Kwok, C.-K.; Gu, X.-q.; Zhao, C. Synth. Commun.
1994, 24, 871-885.
(12) For a review of acyl anion equivalents, see: Albright, J. D.
Tetrahedron 1983, 39, 3207-3233.
(5) Parry, R. J.; Ju, S.; Baker, B. J. J. Labelled Compds. Radiopharm.
1991, 29, 633-643.
(6) Campbell, K. N.; Sommers, A. H.; Campbell, B. K. J. Am. Chem.
Soc. 1944, 66, 82-84.
(13) For a review of the Stetter reaction, see: Stetter, H.; Kuhlmann, H.
In Organic Reactions; Paquette, L. A., Ed.; John Wiley & Sons: New York,
1991; Vol. 40, pp 407-496. See also: Stetter, H.; Haese, W. Chem. Ber.
1984, 117, 682-693.
650
Org. Lett., Vol. 1, No. 4, 1999

followed by Knorr reaction, or the reverse sequence. Fuchs
has observed the exclusive formation of dimeric products
from the ring-closing metathesis reaction of an intermediate
in which the bicyclic core structure is present.2c To circum-
vent the problem, Fuchs performed the ring-closing metath-
esis reaction on a conformationally biased diene. The control
was achieved by the use of a strategically placed OTIPS
group. In view of Fuchs’ result, performing the ring-closing
metathesis reaction on the more conformationally mobile 2
seemed the more attractive approach. In the event, heating
a 0.0005 M solution of 2 with 30 mol % of Grubbs’ catalyst
gave macrocycle 10 in 90% yield as a cis,trans mixture.17
Catalytic hydrogenation of the mixture gave the 1,4-diketone
5 in 92% yield. Formation of the ketopyrrole 3, the
intermediate in Fu¨rstner’s synthesis,2f was accomplished by
heating a 0.04 M solution of 5 and 35 equiv of ammonium
carbonate in propionic acid in a sealed tube.18 The keto-
pyrrole 3 was isolated in 52% yield after 10 h at 140 °C.
The first step in this process is loss of the benzoate ester
function from 5. When the reaction was sampled prior to
completion, only benzamide and ketoenol 11 were present.
That ketoenol 11 has the structure shown was proven by
isolation, followed by benzoylation, which returned 5 as the
exclusive product. It was subsequently determined that
hydrolysis of the benzoate group in 2 led to ketoenol 12. In
both cases, ketoenols 11 and 12 were strongly favored
1
(>95%) as evidenced by H NMR. The reason for the
preferential enolization of one of the two keto groups in 11
and 12 is not obvious. In the case of 11, it is likely that the
regiochemistry for the enolization is critical for the success
of the Knorr reaction.
Exposure of 5 to benzylamine in propionic acid at 200
°C for 10 d produced N-benzylpyrrole 13, an intermediate
in the Fu¨rstner synthesis of roseophilin, in 34% yield. At
the end of the reaction, only a small amount (<5%) of 11
remained in the mixture. Lower temperatures and longer
reaction times did not improve the yield of 13. Additionally,
the use of Lewis acids or high pressure (13 kbar) did not
result in an improvement in the yield. The stark difference
between the two reactions leading to 3 and 13, respectively,
will be discussed in a future publication.
In conclusion, we have completed a convergent 12 step
synthesis of the macrocyclic core of roseophilin. The
ketopyrrole 3 junctions with Fu¨rstner’s synthesis; therefore,
this work represents a formal total synthesis of racemic
roseophilin 4. The overall yield of 3, 7.4%, is comparable
to Fu¨rstner’s overall yield of 6.6%.2h Work in progress is
directed toward the development of an enantioselective
synthesis of 3.
(14) 6-Heptenal was prepared in 65% yield by reduction of commercially
available 6-cyano-1-hexene with DIBAL.
(15) Stereochemistry was determined by NOE.
(16) Diene 2. To a mixture of cyclopentenone 9 (150 mg, 0.483 mmol)
and 6-heptenal (120 mg, 1.07 mmol) was added 1.0 mL of a solution of
3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride (42 mg, 0.16 mmol)
and triethylamine (100 µL, 72.6 mg, 0.717 mmol) in 1,4-dioxane (2.9 mL).
The reaction mixture was heated to 70 °C in a sealed tube. After 18 h, the
reaction mixture was diluted with Et2O and water. The aqueous phase was
extracted with ether (3×), and the combined organic extracts were washed
with brine (1×) and dried over MgSO4. Purification by flash column
chromatography on silica (EtOAc gradient in hexanes) gave the trans-diene
2 (123 mg, 60% yield) as a colorless oil: Rf ) 0.16 (10% EtOAc in
hexanes); IR (neat) 2975, 2945, 1750, 1725, 1665, 1265, 1100, 1070, 715
cm-1; 1H NMR (300 MHz, CDCl3) δ 8.14 (dm, J ) 7.1 Hz, 2H), 7.62 (tt,
J ) 7.4, 1.2 Hz, 1H), 7.48 (t, J ) 7.6 Hz, 2H), 5.87-5.72 (m, 2H), 5.09-
4.92 (m, 4H), 2.80-2.73 (m, 2H), 2.69-2.57 (m, 3H), 2.43 (t, J ) 7.3 Hz,
2H), 2.38-2.18 (m, 4H), 2.05 (q br, J ) 7.2 Hz, 2H), 1.59 (quint br, J )
7.6 Hz, 2H), 1.43-1.33 (m, 2H), 1.06 (d, J ) 6.8 Hz, 3H), 0.85 (d, J ) 6.8
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 208.0, 200.8, 164.2, 163.3, 145.6,
138.4, 136.8, 133.6, 130.3, 128.6, 128.5, 115.8, 114.6, 49.7, 44.3, 43.0,
40.7, 33.5, 30.6, 28.44, 28.41, 26.7, 23.2, 21.1, 16.3; mass spectrum m/z
190 (20), 106 (15), 105 (100), 77 (45); exact mass calcd for C27H34O4
422.2457, found 422.2467.
Acknowledgment. We thank the National Institutes of
Health (GM57873) for generous support. M.A.T. thanks the
Japan Society for the Promotion of Science for a fellowship
in 1998. We thank Professor Phil Fuchs for kindly providing
spectra of compound 3.
Supporting Information Available: Experimental pro-
1
cedures for compounds 1-3, 5-7, 9, 10, and 13. IR, H
NMR, 13C NMR, and mass spectra and full characterization
for compounds 1-3, 5-7, 9, and 13. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) Ring-closing metathesis of the cis isomer of 2 proceeded in much
lower yield (ca. 10%) under the same conditions.
(18) Wasserman, H. H.; Bailey, D. T. J. Chem. Soc., Chem. Commun.
1970, 107-108.
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