Enantioselective total synthesis of the phytotoxic lactone herbarumin I

Article abstract of DOI:10.1039/b101148k

A concise total synthesis of the potent herbicide herbarumin I (1) is presented based on an (E)-selective RCM reaction forging the 10-membered ring of this macrolide.

Full text of DOI:10.1039/b101148k

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Enantioselective total synthesis of the phytotoxic lactone herbarumin I
Alois Fürstner* and Karin Radkowski
Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany.
E-mail: fuerstner@mpi-muelheim.mpg.de; Fax: +49 208 306 2994; Tel: +49 208 306 2342
Received (in Cambridge, UK) 5th February 2001, Accepted 5th March 2001
First published as an Advance Article on the web 21st March 2001
A concise total synthesis of the potent herbicide herbarumin
I (1) is presented based on an (E)-selective RCM reaction
forging the 10-membered ring of this macrolide.
by this method still poses considerable challenges.9,10 Because
of the inherent ring strain, eight- to eleven-membered cycloalk-
enes are particularly prone to the reverse process, i.e. to ring
opening metathesis (ROM) or ring opening metathesis polymer-
ization (ROMP).
It has been shown, however, that this problem can be
circumvented in many cases by incorporating suitable con-
formational control elements forcing the substrate to adopt a
suitable conformation for ring closure. This facilitates RCM and
stabilizes the product formed against the competing ROMP
Bioassay guided fractionation of a culture broth of the fungus
Phoma herbarum recently led to the discovery of two novel
nonenolides. Named herbarumin I (1) and herbarumin II (2),
these lactones were found to exhibit significant phytotoxic
effects in an assay monitoring the radicle elongation of
Amaranthus hypochondriacus seedlings, with IC50 values being
2
5
1
as low as 5.43 3 10 for compound 1. This level of activity
together with the fact that closely related compounds such as
pinolidoxin (3)2 and lethaloxin (4)3 also exert significant
phytotoxicity renders this class of compounds promising new
lead structures in the search for novel herbicidal agents.
Described below is the first total synthesis of a member of this
family of natural products.
Our approach to herbarumin I (1) as the most active
compound of this series is guided by the perception that the
stereochemistry of its three contiguous chiral centers is matched
by the pattern displayed by
D-ribose. Therefore, the
D-
ribonolactone acetonide derivative 5 was chosen as a well
accessible starting material which is converted on a multigram
4
scale into tosylate 6 (Scheme 1). Subsequent treatment with
NaOMe in THF leads to product 7 via transesterification
followed by spontaneous closure of the epoxide ring once the
5
alkoxide at O-4 is liberated. This compound is then exposed to
.
the cuprate reagent formed from EtMgBr and CuBr Me
2
S in
THF,6 thus providing lactone 8 in 60% yield.† DIBAL-H
reduction followed by reaction of the resulting lactol 9 with
methylenetriphenylphosphorane in the presence of catalytic
7
amounts of quinuclidine delivers alcohol 10 in good yield,
which is esterified with hex-5-enoic acid in the presence of
DCC and DMAP to afford diene 11. This sets the stage for the
crucial macrocyclization reaction via ring closing olefin
metathesis (RCM).
During the last decade, olefin metathesis has evolved into a
versatile and practical tool for advanced organic chemistry.8
Despite the impressive number of applications of this reaction
to the synthesis of structurally diverse carbo- and heterocycles,
it must be kept in mind that the formation of medium sized rings
Scheme 1 Reagents and conditions: i, tosyl chloride, pyridine, 220 °C,
1
6 h, 77%; ii, NaOMe, THF, 0 °C ? rt, 16 h, 62%; iii, EtMgBr (3 eq.),
CuBr·Me
78 °C, 2 h, 97%; v, Ph
0 min, 77%; vi, hex-5-enoic acid, DCC, DMAP, CH
catalyst 12 (10 mol%), CH Cl , reflux, 7 h, 69%; viii, aq. HCl (1 M), THF,
2
S (3 eq.), THF, 278 °C ? rt, 16 h, 60%; iv, DIBAL-H, CH
PNCH (2 eq.), quinuclidine (0.2 eq.), THF, reflux,
Cl , rt, 4 d, 84%; vii,
2 2
Cl ,
2
3
3
2
2
2
2
2
50 °C, 16 h, 90%.
DOI: 10.1039/b101148k
Chem. Commun., 2001, 671–672
This journal is © The Royal Society of Chemistry 2001
671

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pathway. The isopropylidene acetal of compound 11 may act as
such a temporary constraint which adequately shapes this
particular diene and simultaneously confers bias upon the
stereochemistry of the newly formed double bond.11
3b), 1.54 (ddt, 1H, J = 14.4, 9.7, 4.8 Hz, H-10b), 1.35 (m, 1H, H-11a), 1.27
13
(
m, 1H, H-11b), 0.89 (t, 3H, J = 7.3 Hz, 2Me); C NMR (75 MHz,
CDCl ) d 176.3, 130.7, 124.7, 73.6, 73.3, 70.1, 34.4, 33.7, 33.3, 24.6, 17.9,
1
1
3
+
3.8; MS (EI): m/z (rel. intensity): 228 (3, [M ]), 200 (5), 144 (10), 143 (40),
26 (16), 125 (100), 97 (33), 95 (12), 86 (29), 84 (11), 83 (24), 81 (12), 79
We were pleased to find that this is indeed the case.
Treatment of compound 11 with catalytic amounts of the
+
(19), 70 (19), 69 (14), 57 (52), 55 (28); MS (ESI): 251 ([M + Na] ), 479
+
([2M + Na] ).
ruthenium indenylidene complex 1212 in refluxing CH
2 2
Cl
affords the desired ten-membered lactone 13 as the only product
in 69% isolated yield. Although applications of RCM to the
synthesis of medium-sized and macrocyclic cycloalkenes are
1
J. F. Rivero-Cruz, G. Garcia-Aguirre, C. M. Cerda-Garcia-Rojas and R.
Mata, Tetrahedron, 2000, 56, 5337.
2 L. de Napoli, A. Messere, D. Palomba, V. Piccialli, A. Evidente and G.
Piccialli, J. Org. Chem., 2000, 65, 3432. Note that the stereochemistry
at C-2 of compound 3 has not yet been unequivocally determined.
According to the conclusions reached in ref. 1, however, this center is
likely (S)-configurated as shown in the inserted structure.
frequently plagued by the formation of E/Z-mixtures,8
,13
compound 13 was obtained as a single diastereoisomer which
was assigned the E-configuration based on detailed NMR
investigations.‡ This particular example also nicely features the
excellent application profile of the ruthenium complex 12 which
is equipotent or even superior to the more popular Grubbs
3
A. Arnone, G. Assante, M. Montorsi, G. Nasini and E. Ragg, Gazz.
Chim. Ital., 1993, 123, 71. Note that only the relative stereochemistry of
compound 4 has been established so far.
L. Hough, J. K. N. Jones and D. L. Mitchell, Can. J. Chem., 1958, 36,
1720.
3 2 2
P) (Cl)
RuNCHPh14 yet easier to make from stable
carbene (Cy
and commercially available precursors.
4
12
Final cleavage of the acetal group with dilute aq. HCl occurs
uneventfully and provides herbarumin I 1 in 90% yield as a low
melting solid. Although the [a] value of the synthetic sample
D
deviates from the reported one to some extent,§ there is no
doubt as to the constitution and configuration of this compound
since the high resolution NMR spectra (Bruker DMX 600) as
well as the IR and MS data are in excellent agreement with the
proposed structure and perfectly match those reported in the
literature.§
5 (a) R. W. Hoffmann and W. Ladner, Chem. Ber., 1983, 116, 1631; (b)
See also: R. M. Ortuno, R. Merce and J. Font, Tetrahedron, 1987, 43,
4
497.
H. Takahata, Y. Uchida and T. Momose, J. Org. Chem., 1995, 60,
628.
6
5
7
8
W. V. Dahlhoff, Liebigs Ann. Chem., 1992, 109.
(a) A. Fürstner, Angew. Chem., 2000, 112, 3140; Angew. Chem., Int.
Ed., 2000, 39, 3012; (b) R. H. Grubbs and S. Chang, Tetrahedron, 1998,
5
4, 4413; (c) M. Schuster and S. Blechert, Angew. Chem., 1997, 109,
2124; Angew. Chem., Int. Ed. Engl., 1997, 36, 2036; (d) R. Roy and
S. K. Das, Chem. Commun., 2000, 519; (e) A. Fürstner, Top. Catal.,
1997, 4, 285; (f) S. K. Armstrong, J. Chem. Soc., Perkin Trans. 1, 1998,
In summary, a concise total synthesis of the potent phyto-
pathogenic macrolide herbarumin I is presented. The approach
3
71.
M. E. Maier, Angew. Chem., 2000, 112, 2153; Angew. Chem., Int. Ed.,
000, 39, 2073.
using -ribonolactone as a convenient source of chirality is
D
9
based on a highly efficient and diastereoselective RCM reaction
for the formation of the ten-membered ring of the target, which
is delivered in enantiomerically pure form in only 8 steps
starting from 5 in ~ 11% overall yield. Extensions of this
methodology to other members of this series of herbicidal
agents are underway and will be disclosed in the near future.
Generous financial support by the Deutsche Forschungs-
gemeinschaft (Leibniz award) and the Fonds der Chemischen
Industrie is gratefully acknowledged. We thank Dr R. Mynott
and C. Wirtz for their help with the interpretation of the NMR
spectra of compound 13.
2
1
0 Syntheses of ten-membered rings by RCM are still scarce; for leading
references see: (a) A. Fürstner and T. Müller, Synlett., 1997, 1010; (b)
S. Chang and R. H. Grubbs, Tetrahedron Lett., 1997, 38, 4757; (c) K.
Gerlach, M. Quitschalle and M. Kalesse, Synlett, 1998, 1108; (d) B. E.
Fink, P. R. Kym and J. A. Katzenellenbogen, J. Am. Chem. Soc., 1998,
120, 4334; (e) T. Oishi, Y. Nagumo and M. Hirama, Chem. Commun.,
1998, 1041; (f) M. Quitschalle and M. Kalesse, Tetrahedron Lett., 1999,
4
4
0, 7765; (g) M. Delgado and J. D. Martin, J. Org. Chem., 1999, 64,
798; (h) S. J. Bamford, K. Goubitz, H. L. van Lingen, T. Luker, H.
Schenk and H. Hiemstra, Perkin Transactions 1, 2000, 345; (i) K.
Nakashima, R. Ito, M. Sono and M. Tori, Heterocycles, 2000, 53,
3
01.
1
1 For a recent example showing the dramatic influence of protecting
groups on the stereochemical course of RCM see: A. Fürstner, O. R.
Thiel and G. Blanda, Org. Lett., 2000, 2, 3731.
Notes and references
†
Competitive attack of bromide ions on epoxide 7 could not be fully
supressed; small amounts of 5-bromo-2,3-isopropylidene- -ribono-1,4-lac-
tone thus formed are separated by flash chromatography. In this context it
should also be noted that all attempts to prepare compound 8 more directly
D
12 (a) The preparation is described by Hill, although the structure was
erroneously assigned as an allenylidene complex, cf.: K. J. Harlow, A. F.
Hill and J. D. E. T. Wilton-Ely, J. Chem. Soc., Dalton Trans., 1999, 285;
(b) The correct phenylindenyl structure has been revealed in: L.
Jafarpour, H.-J. Schanz, E. D. Stevens and S. P. Nolan, Organome-
tallics, 1999, 18, 5416; (c) The catalytic activity has been demonstrated
by: A. Fürstner, A. F. Hill, M. Liebl and J. D. E. T. Wilton-Ely, Chem.
Commun., 1999, 601; (d) For applications in total synthesis see: A.
Fürstner and O. R. Thiel, J. Org. Chem., 2000, 65, 1738; (e) A. Fürstner,
J. Grabowski, C. W. Lehmann, T. Kataoka and K. Nagai, Chem-
BioChem, 2001, 2, 60.
by reaction of tosylate 6 with various ethyl donors (Et
CuBr·Me S) turned out to be low yielding and could not compete with the
route depicted in Scheme 1.
2
CuLi or EtMgBr +
2
‡
NMR investigations at this stage are hampered by the fact that compound
13 exists in two slowly interconverting conformers in solution. The
assignment of the stereochemistry of the double bond, however, is
unambiguous and is ultimately corroborated by the successful completion of
3
the synthesis, providing synthetic 1 which exhibits a coupling constant of J
=
15.8 Hz for the vicinal olefinic protons. Details on the structural
13 For a complementary approach delivering (Z)-cycloalkenes stereo-
selectively see: (a) A. Fürstner and G. Seidel, Angew. Chem., 1998, 110,
1758; Angew. Chem., Int. Ed., 1998, 37, 1734; (b) A. Fürstner, C.
Mathes and C. W. Lehmann, J. Am. Chem. Soc., 1999, 121, 9453; (c) A.
Fürstner, O. Guth, A. Rumbo and G. Seidel, J. Am. Chem. Soc., 1999,
121, 11108; (d) A. Fürstner, K. Grela, C. Mathes and C. W. Lehmann,
J. Am. Chem. Soc., 2000, 122, 11 799; (e) A. Fürstner, K. Radkowski, J.
Grabowski, C. Wirtz and R. Mynott, J. Org. Chem., 2000, 65, 8758; (f)
A. Fürstner and A. Rumbo, J. Org. Chem., 2000, 65, 2608.
14 P. Schwab, R. H. Grubbs and J. W. Ziller, J. Am. Chem. Soc., 1996, 118,
100.
assignment of 13 will be reported in a forthcoming full paper.
20
§
Synthetic 1: [a]
EtOH). Spectroscopic data of synthetic 1: IR: 3450, 3033, 2960, 2929, 2872,
716, 1631, 1203, 1058, 982 cm21; 1H NMR (600 MHz, CDCl
) d 5.58
ddd, 1H, J = 15.8, 1.7, 1.0 Hz, H-6), 5.49 (dddd, 1H, J = 15.8, 10.3, 4.0,
.3 Hz, H-5), 4.92 (td, 1H, J = 9.6, 2.6 Hz, H-9), 4.40 (quint., 1H, J = 2.3
Hz, H-7), 3.48 (dd, 1H, J = 9.8, 2.3 Hz, H-8), 2.39 (br s, 1H, 2OH), 2.38
br d, 1H, J = 12.3 Hz, H-4a), 2.30 (ddd, 1H, J = 14.0, 5.8, 2.4 Hz, H-2a),
.14 (br s, 1H, 2OH), 1.98 (ddd, 1H, J = 14.0, 12.9, 2.0 Hz, H-2b), 1.92
m, 1H, H-4b), 1.87 (m, 1H, H-3a), 1.86 (m, 1H, H-10a), 1.71 (m, 1H, H-
D
D
+10.8° (c 0.51, EtOH); ref. 1: [a] +28.0° (c 0.1,
1
(
2
3
(
2
(
672
Chem. Commun., 2001, 671–672