Total syntheses of the phytotoxic lactones herbarumin I and II and a synthesis-based solution of the pinolidoxin puzzle

Article abstract of DOI:10.1021/ja020238i

A concise approach to a family of potent herbicidal 10-membered lactones is described on the basis of ring-closing metathesis (RCM) as the key step for the formation of the medium-sized ring. This includes the first total syntheses of herbarumin I (1) and

Full text of DOI:10.1021/ja020238i

Published on Web 05/22/2002
Total Syntheses of the Phytotoxic Lactones Herbarumin I and
II and a Synthesis-Based Solution of the Pinolidoxin Puzzle
Alois Fu¨rstner,* Karin Radkowski, Conny Wirtz, Richard Goddard,
Christian W. Lehmann, and Richard Mynott
Contribution from the Max-Planck-Institut fu¨r Kohlenforschung,
D-45470 Mu¨lheim/Ruhr, Germany
Received February 15, 2002
Abstract: A concise approach to a family of potent herbicidal 10-membered lactones is described on the
basis of ring-closing metathesis (RCM) as the key step for the formation of the medium-sized ring. This
includes the first total syntheses of herbarumin I (1) and II (2) as well as the synthesis of several possible
macrolides of the pinolidoxin series. A comparison of their spectral and analytical data with those of the
natural product allowed us to establish the stereostructure of pinolidoxin, a potent inhibitor of induced
phenylalanine ammonia lyase (PAL) activity, as shown in 46. This finding, however, makes clear that a
previous study dealing with the relative and absolute stereochemistry of this phytotoxic agent cannot be
correct. An important aspect from the preparative point of view is the fact that the stereochemical outcome
of the RCM reaction can be controlled by the choice of the catalyst. Thus, use of the ruthenium indenylidene
complex 16 always leads to the corresponding (E)-alkenes, whereas the second generation catalyst 17
bearing an N-heterocyclic carbene ligand affords the isomeric (Z)-olefin with good selectivity. This course
is deemed to reflect kinetic versus thermodynamic control of the cyclization reaction and therefore has
potentially broader ramifications for the synthesis of medium-sized rings in general. A further noteworthy
design feature is the fact that D-ribose is used as a convenient starting material for the preparation of both
enantiomers of the key building block 14 by means of a “head-to-tail” interconversion strategy.
Introduction
compounds that interfere with plant self-defense renders this
class of compounds highly promising lead structures in the
Bioassay guided fractionation of a culture broth of the fungus
Phoma herbarum recently led to the discovery of the two novel
nonenolides herbarumin I (1) and II (2). These lactones exhibit
significant phytotoxic effects in an assay monitoring germination
and growth of Amaranthus hypochondriacus seedlings, with IC50
values as low as 5.43 × 10-5 for compound 1.1 Not only is this
level of activity interesting per se, but recent biochemical
investigations hold even greater promise. Specifically, it has
been found that pinolidoxin, a close relative of the herbarumins
isolated from the phytopathogenic fungus Ascochyta pinoides
Jones,2 constitutes a potent inhibitor of induced phenylalanine
ammonia lyase (PAL) activity. This enzyme plays a key role
in the phenylpropanoid defense metabolism of higher plants.3
While the constitution of pinolidoxin as shown in 3 is un-
disputed, studies concerning its relative and absolute stereo-
chemistry remained inconclusive (see below). The published
biological data, however, indicate that pinolidoxin is a potent
inhibitor of induced PAL activity without any effect on the
growth and viability of the cells.3,4 The prospect of developing
search for novel herbicidal agents. This notion is further
corroborated by the significant phytotoxic activity reported for
lethaloxin 4, yet another member of this family of macrolides
isolated from Mycosphaerella lethalis.5,6
The paucity of material available from the natural sources
together with the lack of reliable information concerning the
* To whom correspondence should be addressed. E-mail: fuerstner@
mpi-muelheim.mpg.de.
(1) Rivero-Cruz, J. F.; Garc´ıa-Aguirre, G.; Cerda-Garc´ıa-Rojas, C. M.; Mata,
R. Tetrahedron 2000, 56, 5337.
(2) (a) Evidente, A.; Lanzetta, R.; Capasso, R.; Vurro, M.; Bottalico, A.
Phytochemistry 1993, 34, 999. (b) Evidente, A.; Capasso, R.; Abouzeid,
M. A.; Lanzetta, R.; Vurro, M.; Bottalico, A. J. Nat. Prod. 1993, 54, 1937.
(3) Vurro, M.; Ellis, B. E. Plant Sci. 1997, 126, 29.
(4) For a preliminary SAR study, see: Evidente, A.; Capasso, R.; Andolfi,
A.; Vurro, M.; Zonno, M. C. Nat. Toxins 1998, 6, 183.
(5) Arnone, A.; Assante, G.; Montorsi, M.; Nasini, G.; Ragg, E. Gazz. Chim.
Ital. 1993, 123, 71. Note that only the relatiVe stereochemistry of compound
4 has been established so far.
(6) (a) For a review on 10-membered lactones, see: Dra¨ger, G.; Kirschning,
A.; Thiericke, R.; Zerlin, M. Nat. Prod. Rep. 1996, 13, 365. (b) For a general
review on medium-sized rings, see: Yet, L. Chem. ReV. 2000, 100, 2963.
9
10.1021/ja020238i CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. 2002, 124, 7061-7069
7061

A R T I C L E S
Fu¨rstner et al.
Scheme 1
Scheme 2
in herbarumin.9 The fact, however, that pinolidoxin as well as
the herbarumins all show positive [R]D values together with the
rather poor resolution of the relevant NMR spectra of the Mosher
esters derivatives of 3 raises doubts as to the reliability of this
conclusion. To complicate matters even further, no information
concerning the stereochemistry at C-2 of pinolidoxin is presently
available. Therefore, we reinvestigated this problem by syn-
thesizing several possible candidates and comparing their
analytical and spectroscopic data with those of the natural
product.
For this purpose, it was essential to develop a flexible yet
stereochemically unambiguous approach (Scheme 2). Because
all targets contain a double bond, ring-closing metathesis (RCM)
seemed to be the method of choice for its inherently convergent
character.12,13 RCM allows the nonenolides to be deconvoluted
into two rather simple fragments A and B. Importantly, as shown
in Scheme 3, all possible cyclization precursors can be traced
back to D-ribose as the ultimate source of chirality if required
for structure elucidation purposes.
At the same time, however, one has to keep in mind that the
formation of medium-sized rings by RCM still poses consider-
able challenges. Ring strain predisposes cycloalkenes of 8-11
ring atoms for the reverse process, that is, for ring-opening
metathesis (ROM) or ring-opening metathesis polymerization
(ROMP). Therefore, the number of successful applications of
RCM to this series is still rather limited.14-17
actual structures of 3 and 4,5 however, constitute major
handicaps to a systematic evaluation of the structure/activity
profile of these important leads.4 A full account of our work in
this area comprising the first total syntheses of herbarumin I7
and II as well as a synthesis-driven solution of the puzzle
concerning the stereostructure of pinolidoxin which ensued from
the contradictory evidence in the literature is described below.
Results and Discussion
Structural Considerations and Strategy. A well-docu-
mented study of the herbarumins 1 and 2 leaves no doubt about
the constitution, configuration, and conformation of these
compounds.1 Unfortunately, however, for pinolidoxin the situ-
ation is far from clear. Two preliminary reports suggested a
7/8-anti, 8/9-anti arrangement of the oxygen substituents at these
three contiguous stereocenters as shown in 3a.8 However, one
group later revised its conclusions and suggested a 7,8-anti but
8/9-syn relationship for this domain (3b).9 This analysis was
largely based on degradations of the natural product and
comparison of the samples thus obtained with synthetic material
prepared from either rac-tartaric acid or 2,3-O-isopropylidene-
D-erythrose 5 (Scheme 1). Thereby, the addition of n-propyl-
magnesium chloride to 5 played a key role, which was assumed
to provide alcohol 6 with a syn arrangement between C-8 and
C-9 (pinolidoxin numbering).9 This assignment, however, has
not been rigorously proven and is inconsistent with previous
reports demonstrating that Grignard additions to 5 (and related
hemiacetals) follow the Felkin-Ahn model and uniformly
deliver 8,9-anti configured products 7 with high selectivity.10,11
The same authors also assigned the absolute stereochemistry at
C-7 and C-8 of pinolidoxin as being opposite to the one found
One approach to circumvent this problem is to incorporate
control elements that force the cyclization precursors to adopt
conformations suitable for ring closure.13 An isopropylidene
protecting group spanning O-7 and O-8 should exert this
function by aligning the olefinic side chains in a cyclization-
(11) For examples showing that Grignard additions to isopropylidene protected
lactols of sugars other than erythrose also give anti-relationships, see: (a)
Kinoshita, M.; Arai, M.; Tomooka, K.; Nakata, M. Tetrahedron Lett. 1986,
27, 1811. (b) Buchanan, J. G.; MacLean, K. A.; Wightman, R. H.; Paulsen,
H. J. Chem. Soc., Perkin Trans. 1 1985, 1463. (c) Buchanan, J. G.; Dunn,
A. D.; Edgar, A. R. J. Chem. Soc., Perkin Trans. 1 1975, 1191.
(12) For a discussion of strategic advantages related to RCM, see: Fu¨rstner, A.
Synlett 1999, 1523.
(13) Reviews: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(b) Fu¨rstner, A. Angew. Chem. 2000, 112, 3140; Angew. Chem., Int. Ed.
2000, 39, 3012. (c) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(d) Fu¨rstner, A. Top. Catal. 1997, 4, 285. (e) Schuster, M.; Blechert, S.
Angew. Chem. 1997, 109, 2124; Angew. Chem., Int. Ed. Engl. 1997, 36,
2037. (f) Schrock, R. R. Top. Organomet. Chem. 1998, 1, 1. (g) Maier, M.
E. Angew. Chem. 2000, 112, 2153; Angew. Chem., Int. Ed. 2000, 39, 2073.
(14) For syntheses of 10-membered rings by RCM, see: (a) Fu¨rstner, A.; Mu¨ller,
T. Synlett 1997, 1010. (b) Chang, S.; Grubbs, R. H. Tetrahedron Lett. 1997,
38, 4757. (c) Gerlach, K.; Quitschalle, M.; Kalesse, M. Synlett 1998, 1108.
(d) Fink, B. E.; Kym, P. R.; Katzenellenbogen, J. A. J. Am. Chem. Soc.
1998, 120, 4334. (e) Oishi, T.; Nagumo, Y.; Hirama, M. Chem. Commun.
1998, 1041. (f) Quitschalle, M.; Kalesse, M. Tetrahedron Lett. 1999, 40,
7765. (g) Delgado, M.; Martin, J. D. J. Org. Chem. 1999, 64, 4798. (h)
Bamford, S. J.; Goubitz, K.; van Lingen, H. L.; Luker, T.; Schenk, H.;
Hiemstra, H. J. Chem. Soc., Perkin Trans. 1 2000, 345. (i) Nakashima, K.;
Ito, R.; Sono, M.; Tori, M. Heterocycles 2000, 53, 301. (j) Cho, S. C.;
Dussault, P. H.; Lisec, A. D.; Jensen, E. C.; Nickerson, K. W. J. Chem.
Soc., Perkin Trans. 1 1999, 193. (k) Nevalainen, M.; Koskinen, A. M. P.
Angew. Chem. 2001, 113, 4184; Angew. Chem., Int. Ed. 2001, 40, 4060.
(l) Heinrich, M. R.; Steglich, W. Tetrahedron Lett. 2001, 42, 3287. (m)
Banwell, M. G.; Bray, A. M.; Edwards, A. J.; Wong, D. J. New J. Chem.
2001, 25, 1347. (n) Telser, J.; Beumer, R.; Bell, A. A.; Ceccarelli, S. M.;
Montio, D.; Gennari, C. Tetrahedron Lett. 2001, 42, 9187. (o) For an
indirect approach, see: Me´ndez-Andino, J.; Paquette, L. A. Org. Lett. 2000,
2, 1263.
(7) For a preliminary communication on the total synthesis of herbarumin I,
see: Fu¨rstner, A.; Radkowski, K. Chem. Commun. 2001, 671.
(8) (a) De Napoli, L.; Evidente, A.; Lasalvia, M.; Piccialli, G.; Piccialli, V.
Abstract of the 9th Int. Congress of Pesticide Chemistry; London, United
Kingdom, 1998 (http://www.chemsoc.org/chempest/html/3C-0007.html). (b)
Pilli, R. A.; Sabino, A. A. Abstract of the 22nd IUPAC Int. Symp. Chem.
Nat. Prod.; Sa˜o Carlos, SP, Brazil, 2000.
(9) de Napoli, L.; Messere, A.; Palomba, D.; Piccialli, V.; Evidente, A.; Piccialli,
G. J. Org. Chem. 2000, 65, 3432.
(10) (a) Mekki, B.; Singh, G.; Wightman, R. H. Tetrahedron Lett. 1991, 32,
5143. (b) Jiang, S.; Singh, G.; Wightman, R. H. Chem. Lett. 1996, 67.
9
7062 J. AM. CHEM. SOC. VOL. 124, NO. 24, 2002

Syntheses of the Lactones Herbarumin I and II
A R T I C L E S
Scheme 3
friendly conformation. The extent of bias, if any, conferred by
such a group on the stereochemistry of the newly formed double
bond is much less obvious and cannot be predicted with
certainty. In general, RCM reactions in the macrocyclic series
tend to give mixtures of the (E)- and (Z)-configured cyclic
olefins, and a reliable and general method of controlling the
geometry of the newly formed double bond has yet to be
found.18,19 Therefore, semiempirical calculations have been
carried out for the acetal-protected herbarumin I which indicate
(15) See ref 29 and the following for leading references on the RCM-based
synthesis of natural products incorporating an eight-membered ring: (a)
Martin, S. F.; Wagman, A. S. Tetrahedron Lett. 1995, 36, 1169. (b) Martin,
S. F.; Liao, Y.; Wong, Y.; Rein, T. Tetrahedron Lett. 1994, 35, 691. (c)
Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am. Chem. Soc.
1995, 117, 2108. (d) Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61,
8746. (e) White, J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am. Chem. Soc.
1998, 120, 7359. (f) Stefinovic, M.; Snieckus, V. J. Org. Chem. 1998, 63,
2808. (g) Joe, D.; Overman, L. E. Tetrahedron Lett. 1997, 38, 8635. (h)
Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 127. (i) Paquette, L. A.;
Efremov, I. J. Am. Chem. Soc. 2001, 123, 4492. (j) Paquette, L. A.; Tae,
J.; Arrington, M. P.; Sadoun, A. H. J. Am. Chem. Soc. 2000, 122, 2742.
(k) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653. (l)
Martin, S. F.; Humphrey, J. M.; Ali, A.; Hillier, M. C. J. Am. Chem. Soc.
1999, 121, 866. (m) Krafft, M. E.; Cheung, Y. Y.; Abboud, K. A. J. Org.
Chem. 2001, 66, 7443. (n) Boyer, F.-D.; Hanna, I.; Ricard, L. Org. Lett.
2001, 3, 3095. (o) Papaioannou, N.; Evans, C. A.; Blank, J. T.; Miller, S.
J. Org. Lett. 2001, 3, 2879. (p) Harrison, B. A.; Verdine, G. L. Org. Lett.
2001, 3, 2157. (q) Codesido, E. M.; Castedo, L.; Granja, J. R. Org. Lett.
2001, 3, 1483. (r) Vo-Thanh, G.; Boucard, V.; Sauriat-Dorizon, H.; Guibe´,
F. Synlett 2001, 37. (s) Creighton, C. J.; Reitz, A. B. Org. Lett. 2001, 3,
893. (t) Boiteau, J.-G.; van de Weghe, P.; Eustache, J. Tetrahedron Lett.
2001, 42, 239. (u) Fellows, I. M.; Kaelin, D. E.; Martin, S. F. J. Am. Chem.
Soc. 2000, 122, 10781. (v) Hanna, I.; Ricard, L. Org. Lett. 2000, 2, 2651.
(w) Krafft, M. E.; Cheung, Y. Y.; Juliano-Capucao, C. A. Synthesis 2000,
1020. (x) Reichwein, J. F.; Liskamp, R. M. J. Eur. J. Org. Chem. 2000,
2335. (y) Agami, C.; Couty, F.; Rabasso, N. Tetrahedron Lett. 2000, 41,
4113. (z) Buszek, K. R.; Sato, N.; Jeong, Y. Tetrahedron Lett. 2002, 43,
181.
(16) For the synthesis of nine-membered rings by RCM see ref 29 and the
following for leading references: (a) Baba, Y.; Saha, G.; Nakao, S.; Iwata,
C.; Tanaka, T.; Ibuka, T.; Ohishi, H.; Takemoto, Y. J. Org. Chem. 2001,
66, 81. (b) Crimmins, M. T.; Emmitte, K. A. J. Am. Chem. Soc. 2001,
123, 1533. (c) Crimmins, M. T.; Emmitte, K. A. Synthesis 2000, 899. (d)
Clark, J. S.; Hamelin, O. Angew. Chem. 2000, 112, 380; Angew. Chem.,
Int. Ed. 2000, 39, 372. (e) Sasaki, M.; Noguchi, T.; Tachibana, K.
Tetrahedron Lett. 1999, 40, 1337. (f) Crimmins, M. T.; Choy, A. L. J.
Org. Chem. 1997, 62, 7548. (g) Barrett, A. G. M.; Baugh, S. P. D.; Gibson,
V. C.; Giles, M. R.; Marshall, E. L.; Procopiou, P. A. Chem. Commun.
1996, 2231. (h) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama,
M.; Oguri, H.; Satake, M. Science 2001, 294, 1904.
Figure 1. Calculated minimum energy conformation of compound (E)-8.
that lactone (Z)-8 is ca. 3.5 kcal mol-1 more stable than the
isomeric (E)-8.20 This comparison of the minimum energy
conformations21 (Figures 1 and 2) suggests that thermodynamic
control during RCM will likely be counterproductiVe en route
to the targeted (E)-alkenes 1-3; only under kinetic control might
it be possible to obtain the desired products with reasonable
selectivity. This, in turn, determines the choice of the metathesis
catalyst because one should avoid those complexes that are
known to favor the retro-reaction and hence lead to an
equilibration of the products initially formed.22-24
(18) The problem starts with eight-membered rings. For a pertinent example
showing that RCM can lead to an (E)-configured cyclooctene, see: (a)
Bourgeois, D.; Pancrazi, A.; Ricard, L.; Prunet, J. Angew. Chem. 2000,
112, 741; Angew. Chem., Int. Ed. 2000, 39, 725. (b) Bourgeois, D.;
Mahuteau, J.; Pancrazi, A.; Nolan, S. P.; Prunet, J. Synthesis 2000, 869.
(19) Note that cycloalkenes of g12 ring atoms can be selectively formed by
ring-closing alkyne metathesis followed by semi-reduction. Rings with
8-11 ring atoms, however, are hardly accessible by this method due to
ring strain at the cycloalkyne stage, cf. the following references and literature
cited therein: (a) Fu¨rstner, A.; Seidel, G. Angew. Chem. 1998, 110, 1758;
Angew. Chem., Int. Ed. 1998, 37, 1734. (b) Fu¨rstner, A.; Guth, O.; Rumbo,
A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108. (c) Fu¨rstner, A.; Mathes,
C.; Lehmann, C. W. Chem.-Eur. J. 2001, 7, 5299.
(20) PC Spartan Pro 1.0.7, Wave function Inc.
(17) For the synthesis of 11-membered rings by RCM see the following for
leading references: (a) Arisawa, M.; Kato, C.; Kaneko, H.; Nishida, A.;
Nakagawa, M. J. Chem. Soc., Perkin Trans. 1 2000, 1873. (b) Winkler, J.
D.; Holland, J. M.; Kasparec, J.; Axelsen, P. H. Tetrahedron 1999, 55,
8199. (c) Hoye, T. R.; Promo, M. A. Tetrahedron Lett. 1999, 40, 1429.
(21) Although this comparison disregards the conformational space of the
medium ring, it seems valid because in both series the next lowest
conformers are uniformly 2-3 kcal mol-1 higher in energy than the most
stable ones.
(22) Lee, C. W.; Grubbs, R. H. Org. Lett. 2000, 2, 2145.
9
J. AM. CHEM. SOC. VOL. 124, NO. 24, 2002 7063

A R T I C L E S
Fu¨rstner et al.
Scheme 4 a
Figure 2. Conformation of lowest energy of compound (Z)-8 which is ca.
3.5 kcal mol-1 more stable than the corresponding (E)-alkene shown in
Figure 1.
Total Synthesis of Herbarumin I. Our approach to her-
barumin I (1) as the biologically most active compound of this
family of phytotoxins is based on the fact that the stereochem-
istry of its three contiguous chiral centers can be matched by
the pattern displayed by D-ribose.7 Therefore, the D-ribonolac-
tone acetonide derivative 9 was chosen as a readily accessible
starting material which is converted on a multigram scale into
tosylate 10 (Scheme 4).25 Subsequent treatment with NaOMe
in THF leads to product 11 via transesterification followed by
spontaneous closure of the epoxide ring once the alkoxide at
O-4 is liberated.26 This compound is then exposed to the cuprate
reagent formed from EtMgBr and CuBr‚Me2S in THF,27
providing lactone 12 in 60% yield. Attempts to prepare
compound 12 more directly by reacting tosylate 10 with various
ethyl donors invariably turned out to be low yielding and could
not compete with the route depicted in Scheme 4.
a [a] Tosyl chloride, pyridine, -25 °C, 77%; [b] NaOMe, THF, 0 °C f
room temperature, 62%; [c] EtMgBr, CuBr‚Me2S, THF, -78 °C f room
temperature, 60%; [d] Dibal-H, CH2Cl2, -78 °C, 97%; [e] Ph3PdCH2,
quinuclidine cat., THF, reflux, 62-77%; [f] 5-hexenoic acid, DCC, DMAP,
CH2Cl2, room temperature, 84%.
Scheme 5 a
Dibal-H reduction of 12 followed by reaction of the resulting
lactol 13 with methylenetriphenylphosphorane in the presence
of catalytic amounts of quinuclidine28 delivers alcohol 14 in
good yield, which is esterified with 5-hexenoic acid in the
presence of DCC and DMAP to afford diene 15. This sets the
stage for the crucial macrocyclization reaction via RCM and
allows the hypotheses concerning thermodynamic versus kinetic
preferences of ring closure outlined above to be tested.
The preparative results obtained using two different metathesis
catalysts turned out to be most gratifying and are fully consistent
with the predictions made above (Scheme 5). Specifically,
exposure of diene 15 to a catalytic amount of the ruthenium
indenylidene complex 1629,30 in refluxing CH2Cl2 affords the
desired lactone (E)-8 as the major product, which is isolated in
a [a] Complex 16 cat., CH2Cl2, reflux, 69%; [b] complex 17 cat., CH2Cl2,
reflux, 86%; [c] aqueous HCl, THF, 47% ((Z)-1), 90% ((E)-1).
69% yield (9% of the (Z)-isomer can also be detected). This
example nicely features the excellent application profile of 16
which is equipotent with or even superior to the more popular
Grubbs carbene (Cy3P)2(Cl)2RudCHPh,31 yet easier to make
(23) Fu¨rstner, A.; Thiel, O. R.; Kindler, N.; Bartkowska, B. J. Org. Chem. 2000,
65, 7990.
(24) For further examples illustrating how the reversible nature of RCM can be
deliberately exploited in synthesis, see: (a) Smith, A. B.; Adams, C. M.;
Kozmin, S. A. J. Am. Chem. Soc. 2001, 123, 990. (b) Fu¨rstner, A.; Thiel,
O. R.; Ackermann, L. Org. Lett. 2001, 3, 449. (c) Xu, Z.; Johannes, C.
W.; Houri, A. F.; La, D. S.; Cogan, D. A.; Hofilena, G. E.; Hoyveda, A.
H. J. Am. Chem. Soc. 1997, 119, 10302.
(25) Hough, L.; Jones, J. K. N.; Mitchell, D. L. Can. J. Chem. 1958, 36, 1720.
(26) (a) Hoffmann, R. W.; Ladner, W. Chem. Ber. 1983, 116, 1631. (b) Ortun˜o,
R. M.; Merce, R.; Font, J. Tetrahedron 1987, 43, 4497.
(27) Takahata, H.; Uchida, Y.; Momose, T. J. Org. Chem. 1995, 60, 5628.
(28) Dahlhoff, W. V. Liebigs Ann. Chem. 1992, 109.
(29) Fu¨rstner, A.; Guth, O.; Du¨ffels, A.; Seidel, G.; Liebl, M.; Gabor, B.; Mynott,
R. Chem.-Eur. J. 2001, 7, 4811.
(30) (a) Fu¨rstner, A.; Hill, A. F.; Liebl, M.; Wilton-Ely, J. D. E. T. Chem.
Commun. 1999, 601. (b) Fu¨rstner, A.; Grabowski, J.; Lehmann, C. W. J.
Org. Chem. 1999, 64, 8275. (c) Fu¨rstner, A.; Thiel, O. R. J. Org. Chem.
2000, 65, 1738. (d) Fu¨rstner, A.; Grabowski, J.; Lehmann, C. W.; Kataoka,
T.; Nagai, K. ChemBioChem 2001, 2, 60. (e) Reetz, M. T.; Becker, M. H.;
Liebl, M.; Fu¨rstner, A. Angew. Chem. 2000, 112, 1294; Angew. Chem.,
Int. Ed. 2000, 39, 1236. (f) Schmidt, B.; Wildemann, H. J. Chem. Soc.,
Perkin Trans. 1 2000, 2916.
9
7064 J. AM. CHEM. SOC. VOL. 124, NO. 24, 2002

Syntheses of the Lactones Herbarumin I and II
A R T I C L E S
Scheme 6 a
Figure 3. Molecular structure of compound (E)-8 in the solid state.
Anisotropic displacement parameters are shown at 50% probability level;
hydrogen atoms are omitted for clarity.
from stable and commercially available precursors.29 The
(E/Z)-ratio does not evolve with time, indicating that the
selective formation of this thermodynamically less stable (E)-
isomer is likely the result of kinetic control. This is corroborated
by the finding that the use of the “second generation” metathesis
catalyst 1732 results in the selective formation of the diastereo-
meric product (Z)-8 in 86% isolated yield. Complex 17 and
congeners, due to their higher overall activity, are able to
isomerize the cycloalkenes formed during the course of the
reaction and hence enrich the mixture in the thermodynamically
favored product.22-24,33 These two particular applications may
therefore be considered the first example of a rationally designed
synthesis of either stereoisomer of a given olefinic target via
RCM by tuning the activity of the catalyst.
a [a] (i) NaN(SiMe3)2, THF, -78 °C; (ii) trans-3-phenyl-2-(phenylsul-
fonyl) oxaziridine, 89%; [b] (MeO)2CH2, P4O10, room temperature, 78%;
[c] aqueous LiOH, aqueous H2O2 (30% w/w), THF/H2O (4/1), 0 °C, 89%;
[d] alcohol 14, DCC, DMAP, CH2Cl2, room temperature, 67%; [e] complex
16 cat., CH2Cl2, reflux, 79%; [f] aqueous HCl, MeOH/H2O (2/1), 60 °C,
84%.
[R]D value of the synthetic sample 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 (cf. Supporting Informa-
tion).1,34
Total Synthesis of Herbarumin II and Its C-2 Epimer.
The ribose-derived alcohol 14 serves as a common platform,
allowing the synthesis of herbarumin II 2 as well. The required
carboxylic acid synthon 21 was prepared by exploiting the facial
guidance exerted by an Evans auxiliary during the R-hydroxy-
lation of the sodium enolate derivated from 18,35 followed by
MOM-protection36 of crude 19 and hydrolytic cleavage of the
oxazolidinone in 20 under standard conditions (Scheme 6).37
Esterification of the resulting acid 21 with alcohol 14 affords
diene 22 which readily cyclizes on exposure to catalytic amounts
of the ruthenium indenylidene complex 1629 in refluxing
CH2Cl2. The desired 10-membered lactone (E)-23 is obtained
in 79% isolated yield, and only traces of the corresponding (Z)-
isomer can be detected in the crude mixture (<5%). Treatment
of 23 with aqueous HCl leads to the concomitant cleavage of
the isopropylidene acetal and the MOM group, affording
herbarumin II 2 in 84% yield.
The stereochemical assignment of the RCM products by NMR
is hampered by the fact that compound (E)-8 populates two
slowly interconverting conformers in solution (ratio ≈ 3:1) as
evident from 2D-NOESY spectra which contain exchange cross-
peaks between the major and a minor component. Only after
an unambiguous assignment of both sets of signals was it
possible to extract from the high-resolution 2D-HSQC spectrum
3
the indicative JH-5,H-6 ) 15.6 ( 0.5 Hz for the major
3
conformer and the corresponding JH-5,H-6 ) 16.2 ( 0.5 Hz
for the minor conformer, establishing that both are (E)-alkenes.
Moreover, we were able to grow crystals of this key compound
suitable for X-ray analysis. The structure in the solid state
(Figure 3) confirms this assignment. The macrocycle adopts a
conformation bringing the propyl side chain into an equatorial
orientation, and the lactone has the expected S-cis conformation
of the C-O bond (O1-C1-O10-C9 19.96°); for details, see
the Supporting Information.
Cleavage of the acetal group in (E)-8 with dilute aqueous
HCl occurs uneventfully and provides herbarumin I (E)-1 in
90% yield as a low melting solid (Scheme 5). Although the
Crystals of 2 suitable for X-ray analysis were grown from
CH2Cl2. The molecular structure in the solid state (Figure 4)
confirms unambiguously that the synthetic material is identical
with the proposed structure for herbarumin II (for details, see
the Supporting Information). Therefore, we were quite surprised
to see that the NMR spectra recorded at 600 MHz only partly
(31) (a) Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1993,
115, 9858. (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100.
(32) (a) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem.
Soc. 1999, 121, 2674. (b) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs,
R. H. Tetrahedron Lett. 1999, 40, 2247. (c) Ackermann, L.; Fu¨rstner, A.;
Weskamp, T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron Lett. 1999, 40,
4787. (d) Weskamp, T.; Kohl, F. J.; Hieringer, W.; Gleich, D.; Herrmann,
W. A. Angew. Chem. 1999, 111, 2573; Angew. Chem., Int. Ed. 1999, 38,
2416. (e) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (f) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan,
S. P. J. Org. Chem. 2000, 65, 2204. (g) Fu¨rstner, A.; Ackermann, L.; Gabor,
B.; Goddard, R.; Lehmann, C. W.; Mynott, R.; Stelzer, F.; Thiel, O. R.
Chem.-Eur. J. 2001, 7, 3236.
(34) For an alternative approach to 1, see: Sabino, A. A.; Pilli, R. A. Tetrahedron
Lett. 2002, 43, 2819.
(35) (a) Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem. Soc. 1985,
107, 4346. (b) Davis, F. A.; Chen, B.-C. In StereoselectiVe Synthesis,
Methods of Organic Chemistry (Houben-Weyl), 4th ed.; Helmchen, G.,
Hoffmann, R. W., Schaumann, E., Eds.; Thieme: Stuttgart, 1995; Vol.
E21e, p 4497.
(33) This interpretation is also supported by a control experiment showing that
pure (E)-8 is slowly isomerized to (Z)-8 in the presence of catalyst 17 if
the reaction is performed under an atmosphere of ethylene.
(36) Xu, Z.; Byun, H.-S.; Bittman, R. J. Org. Chem. 1991, 56, 7183.
(37) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83.
9
J. AM. CHEM. SOC. VOL. 124, NO. 24, 2002 7065

A R T I C L E S
Fu¨rstner et al.
Scheme 7 a
Figure 4. Molecular structure of herbarumin II (2) in the solid state (major
component of the disordered n-propyl side chain shown). Anisotropic
displacement parameters are shown at 50% probability level; solute CDCl3
and hydrogen atoms are omitted for clarity.
a [a] (i) KN(SiMe3)2, THF, -50 °C; (ii) trans-3-phenyl-2-(phenylsulfonyl)
oxaziridine, -78 °C, 37% (+62% recovered substrate).
Table 1. Correct Set of NMR Data of Herbarumin II (2) Recorded
with a Bruker DMX-600 Spectrometer in Methanol-d4 (Arbitrary
Numbering as Shown)a
enolate from the R-face away from the dipoles and the sterically
encumbering pseudoaxially oriented isopropylidene acetal.
Deprotection of crude 24 with HCl provided the herbarumin II
analogue 25. An analysis of the NMR data shows that this
compound - in contrast to 2 - exists as a single conformer in
CDCl3 solution in which the macrocycle adopts a chair-chair-
chair conformation bringing the propyl side chain into a
pseudoequatorial position, whereas all other substituents are
pseudoaxially oriented. As it turned out later, this product
represents the pinolidoxin core structure.
Pinolidoxin. As outlined above, the absolute and relative
stereochemistry of pinolidoxin, a highly promising lead structure
for the development of novel herbicidal agents, has not been
rigorously assigned.8,9 The available data suggest an absolute
stereochemistry as depicted in 3a or 3b,9 opposite to that found
in the herbarumins. Hence, L-ribose would be required as the
starting material if a route analogous to the one described above
were pursued. The prohibitively high price of this substrate,
however, forced us to devise an alternative entry. It is based on
simple symmetry considerations which indicate that D-ribose
can be used as substrate to enter into both enantiomeric series
(cf. Scheme 3). While elaboration of the C-5 position into a
propyl chain followed by olefination of the anomeric center are
the key steps en route to synthon A, a “head-to-tail inter-
change”38 should result in the formation of the enantiomeric
product ent-A.
position
δ 1H (ppm)
multiplicity
JH,H (Hz)
δ
13C (ppm)
1
2
176.90 (s)
73.56 (d)
34.99 (t)
3.84
1.89
1.79
2.29
2.09
5.49
dd
m
m
dm
m
J ) 10.6, 3.0 Hz
3a
3b
4a
4b
5
J ) 13.1 Hz
29.71 (t)
123.47 (d)
134.06 (d)
dddd
J ) 15.6, 10.3,
4.3, 2.2 Hz
J ) 15.6, 2.1,
0.8 Hz
J ) 2.1 Hz
J ) 9.7, 2.5 Hz
J ) 9.3, 2.8 Hz
6
5.55
ddd
7
8
9
10a
10b
11a
11b
12
4.34
3.51
5.15
1.82
1.52
1.41
1.32
0.92
quint
dd
td
m
m
m
m
t
73.93 (d)
74.11 (d)
71.90 (d)
35.17 (t)
18.66 (t)
14.41 (q)
J ) 7.4 Hz
a All assignments are unambiguous and have been made using COSY,
NOESY, and 13C,1H-chemical shift correlated spectra; for further informa-
tion and the compilation of data in CDCl3, see the Supporting Information.
matched the reported ones.1 While some signals were in
excellent agreement with the literature data, the resonances of
H(C)-7, 8, and 9 clearly deviated from the reported values.
Because our assignment of all signals is unambiguous (cf. the
Supporting Information) and in view of the X-ray analysis
described above, this partial mismatch could not be explained.
Gratifyingly, however, copies of the original spectra of her-
barumin II have been made available to us for comparison. These
original spectra and the spectra of our sample are superim-
posable. The apparent discrepancies are due to some typo-
graphical errors in the original publication.1 The correct set of
spectral data of herbarumin II is now compiled in Table 1.
An even shorter entry into herbarumin II 2 might consist in
the diastereoselective hydroxylation of herbarumin I 1 (Scheme
7). Not unexpectedly, however, this reaction affords the C-2
epimer 24 as the only product. This stereochemical course
ensues from a trajectory in which the oxygen donor attacks the
This plan was reduced to practice as depicted in Scheme 8.
Protection of D-ribose as the isopropylidene acetal 2639 followed
by acetylation under standard conditions afford compound 27
which is converted into C-glycoside 28 on treatment with
allyltrimethylsilane and TMSOTf in acetonitrile as the solvent.40
This reaction affords the desired product in respectable yield
together with a trace amount of the corresponding R-anomer
(R:â ≈ 1:10). The isopropylidene group in 27 which shields
the R-side of the intermediate oxocarbenium cation at C-1
explains the observed stereochemical course which becomes
apparent from an analysis of the pertinent coupling constants.
(38) (a) Fu¨rstner, A.; Weidmann, H. J. Org. Chem. 1990, 55, 1363. (b) Fu¨rstner,
A. Tetrahedron Lett. 1990, 31, 3735. (c) Fu¨rstner, A.; Baumgartner, J.
Tetrahedron 1993, 49, 8541.
(39) Kaskar, B.; Heise, G. L.; Michalak, R. S.; Vishnuvajjala, B. R. Synthesis
1990, 1031.
(40) (a) Takahashi, S.; Hirota, S.; Nakata, T. Heterocycles 2000, 52, 1079. (b)
McDevitt, J. P.; Lansbury, P. T. J. Am. Chem. Soc. 1996, 118, 3818.
9
7066 J. AM. CHEM. SOC. VOL. 124, NO. 24, 2002

Syntheses of the Lactones Herbarumin I and II
A R T I C L E S
Scheme 8 a
Scheme 9 a
a [a] (i) NaN(SiMe3)2, THF, -78 °C; (ii) trans-3-phenyl-2-(phenylsul-
fonyl) oxaziridine, 83%; [b] p-methoxybenzyl trichloroacetimidate, CF3SO2OH
cat., Et2O, room temperature, 48%; [c] aqueous LiOH, aqueous H2O2 (30%
w/w), THF/H2O (4/1), 0 °C, 94%.
a [a] Ac2O, pyridine, room temperature, 97%; [b] allyltrimethylsilane,
TMSOTf (0.3 equiv), 0 °C, 58% (â-anomer) + 5% (R-anomer); [c] H2,
Pd/C (5%), CH2Cl2, quant.; [d] NaOMe cat., MeOH, room temperature,
85%; [e] I2, PPh3, imidazole, CH2Cl2, room temperature, 89%; [f] Zn(Ag)-
graphite, room temperature, 86%; [g] acid 41, DCC, DMAP, CH2Cl2, room
temperature, 87%; [h] complex 16 cat., CH2Cl2, reflux, 82%; [i] DDQ,
CH2Cl2/H2O (18/1), room temperature, 84%; [j] sorbic acid chloride,
pyridine, CH2Cl2, 0 °C f room temperature, 84%; [k] aqueous HCl, MeOH/
H2O (2/1), 60 °C, 56%.
Figure 5. Molecular structure of compound 37 in the solid state.
Anisotropic displacement parameters are shown at 50% probability level;
solute water and hydrogen atoms are omitted for clarity.
Replacement of TMSOTf by BF3‚Et2O as the promotor and/or
the use of CH2Cl2 instead of MeCN led to inferior results in
terms of yield and selectivity. Hydrogenation of the double bond
of 28 followed by deprotection of the acetyl group in 29 proceed
without incident. At this stage, the minor R-anomer produced
in the C-glycosylation reaction can be conveniently separated
on a preparative scale by routine flash chromatography. The
hydroxyl group of 30 is then converted into the corresponding
iodide 3141 which, on treatment with highly activated Zn(Ag)-
graphite42 according to a protocol previously described by our
laboratory,43 undergoes a smooth reductive elimination reaction
delivering the desired product 32 ()ent-14) in 86% yield.
With this alcohol in hand, the completion of the synthesis of
the proposed structure of pinolidoxin was straightforward.
Esterification of 32 with acid 41 (prepared via the Evans
R-hydroxylation protocol and PMB-protection as shown in
Scheme 9)35 affords the cyclization precursor 33 in excellent
yield. In line with the results described above, treatment of the
latter with catalytic amounts of the ruthenium indenylidene
complex 1629 in refluxing CH2Cl2 effects a clean RCM reaction
with formation of (E)-34 in 82% yield together with small
amounts of the (Z)-isomer (10%). Oxidative cleavage of the
PMB group44 liberates alcohol 35 which gives access to both
possible C-2 epimers of pinolidoxin.
Specifically, esterification of 35 with sorbic acid chloride45
under retention of configuration affords product 36 which is
then deprotected to give compound 37 in good overall yield.
Its structure in the solid state is depicted in Figure 5 (for details,
see the Supporting Information). This analysis not only rigor-
ously confirms the structural assigment but also reveals the
highly conserved conformational preference of the nonenolide
ring in all compounds of this series. This aspect is nicely
featured by the overlap of the shapes of compounds 2, (E)-8,
and 37 displayed in Figure 6. The NMR data of 37, however,
clearly deviate from those published for pinolidoxin2 and hence
exclude that this compound represents the natural product (cf.
Table 2 and the Supporting Information).
Therefore, we prepared the C-2 epimeric ester by converting
the hydroxyl group of 35 into the corresponding triflate 42 which
reacts with the potassium salt of sorbic acid to produce the
targeted ester 43 (Scheme 10).46 Deprotection with aqueous HCl
then affords product 44. As can be judged from Table 2, its
(41) (a) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980,
2866. (b) Bennett, S. M.; Biboutou, R. K.; Zhihong, Z.; Pion, R.
Tetrahedron 1998, 54, 4761.
(42) (a) Fu¨rstner, A. Angew. Chem. 1993, 105, 171; Angew. Chem., Int. Ed.
Engl. 1993, 32, 164. (b) Fu¨rstner, A.; Weidmann, H.; Hofer, F. J. Chem.
Soc., Dalton Trans. 1988, 2023.
(43) (a) Fu¨rstner, A.; Weidmann, H. J. Org. Chem. 1989, 54, 2307. (b) Fu¨rstner,
A.; Jumbam, D.; Teslic, J.; Weidmann, H. J. Org. Chem. 1991, 56, 2213.
(44) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23,
885. (b) Fu¨rstner, A.; Radkowski, K.; Grabowski, J.; Wirtz, C.; Mynott,
R. J. Org. Chem. 2000, 65, 8758.
(45) Prepared as described in: Oppolzer, W.; Poli, G.; Kingma, A. J.;
Starkemann, C.; Bernardinelli, G. HelV. Chim. Acta 1987, 70, 2201.
(46) For a related example of the preparation and nucleophilic substitution of
an R-triflyloxyester, see: Fu¨rstner, A.; Konetzki, I. J. Org. Chem. 1998,
63, 3072.
9
J. AM. CHEM. SOC. VOL. 124, NO. 24, 2002 7067

A R T I C L E S
Fu¨rstner et al.
Scheme 11 a
Figure 6. Overlap of the structures of 2 (red), (E)-8 (blue), and 37 (green)
revealing the highly conserved conformation of their 10-membered lactone
core structures.
Table 2. Comparison of the 13C NMR Data (CDCl3) Reported for
Pinolidoxin2 with Those of Compounds 37, 44, and 46 Recorded
with an Accuracy of (0.1 ppma
a [a] Sorbic acid chloride, pyridine, CH2Cl2, 0 °C f room temperature,
76%; [b] aqueous HCl, MeOH/H2O (2/1), 60 °C, 80%.
Table 3. Comparison of the 1H NMR Data (CDCl3) Reported for
Pinolidoxin 3 (400 MHz)2 with Those of Compound 46 Recorded
on a Bruker AV 400 Spectrometer (400 MHz), Showing the
Excellent Agreement of These Sets of Dataa
pinolidoxin (3)2
compound 46
multiplicity, J
position
δ
multiplicity, J
δ
position
pinolidoxin2
37
44
46 ()ent-44)
15
7.32
dd, J ) 9.8, 15.4 Hz
7.32
6.23
dd, J ) 9.8, 15.5 Hz
1
13
15
17
6
16
5
14
8
7
9
2
10
3
171.9
166.1
145.9
140.3
132.6
129.7
122.8
118.1
73.0
72.9
71.3
69.8
33.6
172.1
166.0
146.3
140.2
132.0
129.7
122.6
117.8
73.2
73.0
71.5
73.1
33.9
171.9
166.1
145.9
140.3
132.4
129.7
123.0
118.2
73.2
73.1
71.3
69.8
33.6
171.9
166.1
145.9
140.2
132.4
129.7
123.0
118.2
73.2
73.1
71.3
69.8
33.7
16
17
14
6
6.30
6.20
5.87
5.66
5.53
m
m
m
d, J ) 15.4 Hz
5.87
5.67
5.54
d, J ) 15.5 Hz
dd, J ) 1.4, 15.8 Hz
dd, J ) 1.2, 15.8 Hz
5
m, J ) 1.4, 15.8,
dddd, J ) 2.3, 4.0,
15.8 Hz
10.6, 15.5 Hz
dd, J ) 1.9, 5.5 Hz
td, J ) 2.7, 9.4 Hz
br s
br s
m
m
2
9
7
8
5.25
5.05
4.44
3.52
2.41
2.20
2.00
1.89
1.78
1.50
1.33
1.22
0.87
dd, J ) 1.7, 5.6 Hz
5.27
5.04
4.44
3.52
2.44
2.23
2.03
1.89
1.77
1.51
1.31
1.22
0.87
td, J ) 2.6, 9.4 Hz
br s, J ) 1.4, 2.5 Hz
dd, J ) 2.5, 9.4 Hz
4a
m
m
m
3a/4b
3b
18
10a
10b
11a
11b
12
m
29.8
27.4
18.7
17.4
31.0
27.8
18.7
17.7
29.9
27.4
18.7
17.5
29.9
27.4
18.7
17.4
d, J ) 5 Hz
m
m
m
d, J ) 5.3 Hz
m
m
m
4
18
11
12
13.9
13.9
13.9
13.9
m
m
t, J ) 7.3 Hz
t, J ) 7.3 Hz
a These data exclude that pinolidoxin corresponds to compound 37.
Arbitrary numbering of the skeleton as shown in the insert. All assign-
ments are unambiguous and have been made using COSY, NOESY, and
13C,1H-chemical shift correlated spectra as described in the Supporting
Information.
a Arbitrary numbering of the skeleton as shown in the insert in Table 2.
All assignments are unambiguous and have been made using COSY,
NOESY, and 13C,1H-chemical shift correlated spectra as described in the
Supporting Information.
Scheme 10 a
(i) the absolute stereochemistry of pinolidoxin as it appears in
3a,b has previously been misassigned,9 and (ii) the stereo-
triade from C-7 through C-9 is identical to that found in the
herbarumins 1 and 2.1
As a result, esterification of alcohol 24 prepared en route to
2 with sorbic acid must produce pinolidoxin (Scheme 11). The
NMR data of 46 compiled in Tables 2 and 3 show that this is
indeed the case. They are not only superimposable with those
of the enantiomer 44 described above, but also match the spectra
of the natural product in all regards.2 An analysis of the coupling
constants indicates that 46 exists as a single conformer in
CH2Cl2 solution at ambient temperature, with the 10-membered
ring adopting a chair-chair-chair conformation which must be
similar to the one found in the solid state for its analogues 2,
(E)-8, and 37 (cf. Figure 6). The specific optical rotations of
a [a] Triflic anhydride, pyridine, CH2Cl2, 0 °C, 80%; [b] potassium
sorbinate, DMF, room temperature, 63%; [c] aqueous HCl, MeOH/H2O
(2/1), 65 °C, 95%.
NMR spectra are not only fully consistent with the proposed
structure but are also in excellent agreement with those of the
natural product.2 Importantly, however, the [R]D values of our
sample and of the natural product have opposite signs! Thus,
25
the synthetic sample 46 ([R]D ) +143.2, c ) 0.25, CHCl3)
and of the natural product ([R]D25 ) +142.9, c ) 0.31, CHCl3)
are also in excellent agreement. Taken together, this highly
9
7068 J. AM. CHEM. SOC. VOL. 124, NO. 24, 2002

Syntheses of the Lactones Herbarumin I and II
A R T I C L E S
Scheme 12 a
hemiacetal 5 opposite to the isopropylidene group, and disproves
the syn relationship previously advocated in the literature.9
Taken together, this information and the synthetic work
described above result in a fully consistent and complete picture.
Conclusions
The first total syntheses of the potent phytotoxic lactones
herbarumin I (1), herbarumin II (2), and pinolidoxin (46) are
described. The latter rigorously establishes the previously elusive
stereostructure of this promising herbicidal agent and corrects
an earlier analysis published in the literature.9 Thereby, a sound
basis is set out for further studies on the structure/activity profile
of this promising family of lead compounds. The flexibility of
our synthesis route should be of great advantage in this respect.
Potentially broader ramifications for synthesis has the finding
that the choice of the metathesis catalyst allows for the control
of the stereochemistry of the resulting cycloalkene. This is
illustrated by the RCM reaction of diene 15 which delivers the
(E)-configured olefin (E)-8 on exposure to the ruthenium
indenylidene complex 16, but the (Z)-configured product (Z)-8
with the ruthenium-NHC catalyst 17. The selectivity in either
case is excellent, and the stereochemical course likely reflects
kinetic versus thermodynamic control. Although the generality
of this finding has yet to be shown by a larger set of substrates,
this notion provides a first reasonable guideline on how to
address the as yet unresolved problem of stereocontrol in RCM
reactions furnishing medium-sized rings.18,19 Studies along these
lines and further applications of metathesis to the synthesis of
bioactive target molecules are being actively pursued in this
laboratory and will be reported soon.
a [a] n-Propylmagnesium chloride, THF, 0 °C f room temperature, 82%;
[b] p-bromobenzoyl chloride, pyridine, CH2Cl2, 76%.
Figure 7. Molecular structure of the bis(p-bromobenzoyl) derivative 48
in the solid state. Anisotropic displacement parameters are shown at 50%
probability level; hydrogen atoms are omitted for clarity.
consistent set of data obtained for the whole series of products
described above leaves no doubt whatsoever as to the structure
of pinolidoxin which is as it appears in 46 rather than in 3a,b,
although we were unable to examine a sample of the natural
product ourselves. Hence, the assignments of the relative and
absolute stereochemistry of this molecule previously made are
incorrect.9
Identification of the Misleading Signpost. As outlined in
the Introduction, the stereostructure of pinolidoxin had not been
established at the outset of this investigation; in retrospect,
however, it is clear that the aVailable pieces of information in
ref 9 were misleading in terms of both relatiVe and absolute
stereochemistry. Because we had speculated that the assumed
stereochemical course of the addition of n-propylmagnesium
chloride to the erythrose derivative 5 might have led to the
erroneous assignments (vide supra), a rigorous proof of this
aspect was called for. Therefore, this key experiment was
repeated, and the resulting product 47 was converted into the
crystalline bis(p-bromobenzoyl) derivative 48 (Scheme 12).
The structure of this compound in the solid state (Figure 7)
unequivocally confirms the anti-orientation of the oxygen
substituents at C-8/C-9 (pinolidoxin numbering) resulting from
the attack of the nucleophile from the less hindered face of
Acknowledgment. Generous financial support by the Deut-
sche Forschungsgemeinschaft (Leibniz award to A. F.) and the
Fonds der Chemischen Industrie is gratefully acknowledged.
We thank Mr. A. Deege and his team for their help with several
analytical and preparative HPLC separations, Dipl.-Chem. D.
Song for assistance in the semiempirical calculations, as well
as Dr. C. M. Cerda-Garcia-Rojas and Dr. R. Mata, Universidad
Nacional Autonoma de Mexico, for kindly providing copies of
the original spectra of herbarumin II for comparison. We are
also indebted to Prof. R. A. Pilli, University of Campinas, Brazil,
for sharing his insights into the stereochemistry of pinolidoxin
with us.
Supporting Information Available: Complete experimental
section and information concerning the X-ray structures of
compounds (E)-8, 2, 37, and 48 (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA020238I
9
J. AM. CHEM. SOC. VOL. 124, NO. 24, 2002 7069