Total Syntheses of Amphidinolide T1, T3, T4, and T5

Article abstract of DOI:10.1021/ja038216z

A concise, flexible, and high yielding entry into the family of amphidinolide T macrolides, a series of cytotoxic natural products of marine origin, has been developed. All individual members, except amphidinolide T3 (3), derive from compound 39 as a comm

Full text of DOI:10.1021/ja038216z

Published on Web 11/20/2003
Total Syntheses of Amphidinolide T1, T3, T4, and T5
Christophe A¨ıssa, Ricardo Riveiros, Jacques Ragot, and Alois Fu¨rstner*
Contribution from the Max-Planck-Institut fu¨r Kohlenforschung,
D-45470 Mu¨lheim/Ruhr, Germany
Received August 29, 2003; E-mail: fuerstner@mpi-muelheim.mpg.de
Abstract: A concise, flexible, and high yielding entry into the family of amphidinolide T macrolides, a series
of cytotoxic natural products of marine origin, has been developed. All individual members, except
amphidinolide T3 (3), derive from compound 39 as a common synthetic intermediate which is formed from
three building blocks of similar size and complexity. The fragment coupling steps involve a highly
diastereoselective SnCl4 mediated reaction of the furanosyl sulfone derivative 11 with the silyl enol ether
18 and a palladium-catalyzed Negishi type coupling reaction between the polyfunctional organozinc reagent
derived from iodide 32a and the enantiopure acid chloride 24b. The 19-membered macrocyclic ring is then
formed by a high yielding ring closing metathesis (RCM) reaction of diene 33 catalyzed by the “second
generation” ruthenium carbene complex 34. The efficiency of the RCM transformation stems, to a large
extent, from the conformational bias introduced by the syn-syn-configured stereotriad at C12-C14 of the
substrate which constitutes a key design element of the synthesis plan. The use of Nysted’s reagent 38 in
combination with TiCl4 was required for the olefination of the sterically hindered ketone group in 36, whereas
more conventional alkene formations were unsuccessful for this elaboration. Finally, it is shown that the
inversion of a single and seemingly remote stereocenter (C12) in one of the building blocks not only affects
the efficiency and stereochemical outcome of the RCM step but also exerts a significant influence on the
course of the acyl-Negishi reaction, allowing a radical manifold to compete with productive cross coupling.
Introduction
chemistry of the C12-C14 region displayed on a uniform 19-
membered macrolide core. Amphidinolide T2 is the only
The amphidinolides are a rapidly growing family of mac-
rolides produced by marine dinoflagellates of the genus Am-
phidinium which live in symbiosis with the Okinawan acoel
flatworm Amphiscolops sp.1 Though structurally quite diverse,
all members are distinguished by a pronounced cytotoxicity
against various cancer cell lines, with some of them reaching
potencies comparable to those of the most cytotoxic compounds
known to date.2 In contrast to macrolide antibiotics derived from
terrestrial microorganisms, however, the majority of amphidi-
nolides features an odd-numbered macrolactone ring which is
biosynthesized by a complex, nonsuccessive mixed polyketide
pathway.3
exception as it incorporates an additional CH2-OH group in
the alkyl side chain. Structures were elucidated by careful NMR
investigations and chemical degradation studies and subse-
quently confirmed by the X-ray analysis of compound 1 as a
prototype member of this series. Because of the significant
cytotoxicity against human epidermoid carcinoma KB and
murine lymphoma L1210 cell lines4 and unusual structural
characteristics, these marine natural products constitute highly
relevant target structures for total synthesis. Outlined below is
a full account of our work which led to amphidinolide T1, T3,
T4, and T5 by a highly convergent and flexible approach.6-8
Results and Discussion
The five members belonging to the amphidinolide T subgroup
feature these characteristics.4 These extremely scarce secondary
metabolites5 differ only in the oxygenation pattern and stereo-
Strategic Considerations and Retrosynthetic Analysis. Our
retrosynthetic analysis was guided by the perception that all
(1) Reviews: (a) Ishibashi, M.; Kobayashi, J. Heterocycles 1997, 44, 543-
575. (b) Chakraborty, T. K.; Das, S. Curr. Med. Chem.: Anti-Cancer Agents
2001, 1, 131-149. (c) Kobayashi, J.; Ishibashi, M. In ComprehensiVe
Natural Products Chemistry; Mori, K., Ed.; Elsevier: New York, 1999;
Vol. 8, pp 415-649.
(5) They only make up for 0.0001-0.005% of the algae’s wet weight.
(6) For a preliminary communication on the synthesis of amphidinolide T4,
see: Fu¨rstner, A.; A¨ıssa, C.; Riveiros, R.; Ragot, J. Angew. Chem. 2002,
114, 4958-4960; Angew. Chem., Int. Ed. 2002, 41, 4763-4766.
(7) Shortly after our preliminary communication (ref 6) had been published, a
total synthesis of amphidinolide T1 was communicated following a similar
retrosynthetic logic; cf. Ghosh, A. K.; Liu, C. J. Am. Chem. Soc. 2003,
125, 2374-2375.
(8) For total syntheses of other amphidinolides, see: (a) Williams, D. R.; Kissel,
W. S. J. Am. Chem. Soc. 1998, 120, 11198-11199. (b) Williams, D. R.;
Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945-948. (c) Williams, D. R.;
Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765-766. (d) Lam, H. W.;
Pattenden, G. Angew. Chem. 2002, 114, 526-529; Angew. Chem., Int. Ed.
2002, 41, 508-511. (e) Chakraborty, T. K.; Das, S. Tetrahedron Lett. 2001,
42, 3387-3390. (f) Maleczka, R. E.; Terrell, L. R.; Geng, F.; Ward, J. S.
Org. Lett. 2002, 4, 2841-2844. (g) Trost, B. M.; Chisholm, J. D.;
Wrobleski, S. T.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420-12421.
(2) Notably, amphidinolides H and N exhibit potencies similar to that of the
spongistatins; cf. ref 1.
(3) (a) Review: Rein, K. S.; Borrone, J. Comp. Biochem. Physiol., B 1999,
124, 117-131. (b) For representative studies, see: Kobayashi, J.; Takahashi,
M.; Ishibashi, M. J. Chem. Soc., Chem. Commun. 1995, 1639-1640. (c)
Ishibashi, M.; Takahashi, M.; Kobayashi, J. Tetrahedron 1997, 53, 7827-
7832. (d) Sato, M.; Shimbo, K.; Tsuda, M.; Kobayashi, J. Tetrahedron
Lett. 2000, 41, 503-506.
(4) (a) Kobayashi, J.; Kubota, T.; Endo, T.; Tsuda, M. J. Org. Chem. 2001,
66, 134-142. See also: (b) Tsuda, M.; Endo, T.; Kobayashi, J. J. Org.
Chem. 2000, 65, 1349-1352. (c) Kubota, T.; Endo, T.; Tsuda, M.; Shiro,
M.; Kobayashi, J. Tetrahedron 2001, 57, 6175-6179.
9
15512
J. AM. CHEM. SOC. 2003, 125, 15512-15520
10.1021/ja038216z CCC: $25.00 © 2003 American Chemical Society

Total Syntheses of Amphidinolide T1, T3, T4, and T5
A R T I C L E S
Scheme 1
species by formation of chelate complexes.12,13 From that per-
spective, the C4-C5 bond appeared to be the best compromise
as the site for the retrosynthetic disconnection, leading back to
the precursor B which we sought to assemble by a diastereo-
selective Lewis acid mediated alkylation of a silyl enol ether D
with an oxocarbenium cation derived from lactol C, and a
palladium catalyzed acylation of an organometallic reagent with
an enantiomerically pure acid chloride E.
Preparation of the Building Blocks. The tetrahydrofuran
derivative 11 as a synthetic equivalent of synthon C was derived
from commercial hydroxyester 6 which was tosylated prior to
reduction with Dibal-H. Reaction of the resulting aldehyde with
(-)-Ipc2B-allyl14 at low temperature afforded alcohol 8 in
diastereomerically pure form on a multigram scale. While the
tosylate is sufficiently stable and serves as a protecting group
for the primary alcohol during the hydride reduction and the
allylation steps, it can be directly used as an appropriate leaving
group in the subsequent reaction with KCN. The resulting nitrile
9 was reduced with Dibal-H to afford hemiacetal 10 after acidic
workup, which was converted into sulfone 11 upon treatment
with an excess of PhSO2H in the presence of CaCl2 as the dehy-
drating agent (Scheme 2).15 The 2,5-trans orientation of the allyl
and the PhSO2 group on the tetrahydrofuran ring were confirmed
by the X-ray structure analysis of this compound (Figure 1).
The required coupling partner (synthon D) was obtained from
N-propionyl oxazolidinone 1217 by a sequence of high yielding
members of this family (except T2) are accessible from a
common advanced intermediate A by simple permutations of
the final deprotection/oxidation steps, followed by stereochem-
ical adjustments where necessary (Scheme 1). This strategy
relies on a judicious choice of orthogonal protecting groups R1
and R2 for the vicinal hydroxyl groups of the key intermediate.
For the sake of convergency, compound A itself should be
assembled from the building blocks C-E of similar size and
complexity, using a ring closing metathesis (RCM) reaction for
the formation of the macrocyclic scaffold.9 The 19-membered
lactone ring of amphidinolide T1 (1) is known to be very
compact (as evident from transannular interactions between the
C3-C5 and the C14-C25 domains observed from NOESY
spectra in solution as well as from X-ray diffraction studies)
and features a methyl branch (C24) that is oriented in toward
the macrocycle.4c Thus, it seems advisable to preorganize the
substrate B in a cyclization friendly conformation to ensure
high efficiency in this maneuver. A syn-syn stereotriad at
C12-C14 should be able to shape B in a proper way and might
therefore be preferred over other possible stereochemical
alignments in this part of the molecule.10,11 Under this premise,
we envisaged that amphidinolide T3 (3) might be more
accessible by inversion of the hydroxy group at C12 rather than
by cyclization of a precursor with the correct configuration at
that center. Moreover, one has to take into account that the
efficiency of macrocyclizations by RCM is strongly affected
by heteroelements in proximity to the reacting alkenes which
can attenuate the reactivity of the emerging metal carbene
(10) This expectation is based on molecular modeling studies, the careful
inspection of Dreiding models, as well as on an analysis of the dihedral
angles of amphidinolide T1 in the solid state; cf. ref 4c. Although we have
not performed a full analysis of the entire conformational space of various
derivatives differing in their individual substitution pattern, the models
suggest that the conformational bias should be enhanced by increasing the
steric demand of the protecting groups R1 and R2.
(11) For reviews on the control of the conformational space populated by acyclic
compounds, see: (a) Hoffmann, R. W. Angew. Chem. 2000, 112, 2134-
2150; Angew. Chem., Int. Ed. 2000, 39, 2054-2070. (b) Go¨ttlich, R.; Kahrs,
B. C.; Kru¨ger, J.; Hoffmann, R. W. Chem. Commun. 1997, 247-252.
(12) (a) Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942-3943. (b)
Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792-803.
(13) Fu¨rstner, A.; Thiel, O. R.; Lehmann, C. W. Organometallics 2002, 21,
331-335.
(14) (a) Racherla, U. S.; Liao, Y.; Brown, H. C. J. Org. Chem. 1992, 57, 6614-
6617. (b) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092-
2093.
(15) Brown, D. S.; Bruno, M.; Davenport, R. J.; Ley, S. V. Tetrahedron 1989,
45, 4293-4308.
(9) Reviews: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-
29. (b) Fu¨rstner, A. Angew. Chem. 2000, 112, 3140-3172; Angew. Chem.,
Int. Ed. 2000, 39, 3012-3043. (c) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413-4450. (d) Schrock, R. R. Top. Organomet. Chem. 1998,
1, 1-36. (e) Schuster, M.; Blechert, S. Angew. Chem. 1997, 109, 2124-
2144; Angew. Chem., Int. Ed. Engl. 1997, 36, 2037-2056. (f) Fu¨rstner, A.
Top. Catal. 1997, 4, 285-299.
9
J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003 15513

A R T I C L E S
A¨ıssa et al.
Scheme 2 a
Scheme 3 a
a Synthesis of segment C: [a] TsCl, Et3N, DMAP, CH2Cl2, 94%; [b]
Dibal-H, toluene, -95 °C; [c] (-)-Ipc2B-allyl, Et2O, -100 °C, 70% (over
both steps); [d] KCN, DMSO, 99%; [e] Dibal-H, CH2Cl2, -78 °C, 91%;
[f] PhSO2H, CaCl2, CH2Cl2, 0 °C, 87%.
a Synthesis of segment D: [a] (i) Bu2BOTf, Et3N; (ii) methacrolein, 90%;
[b] MOMCl, (iPr)2NEt, CH2Cl2, 93%; [c] LiBH4, Et2O, 92%; [d] TBSCl,
imidazole, DMF, 90%; [e] O3, then PPh3, CH2Cl2, 86%; [f] TBSOTf, Et3N,
Et2O, 0 °C f rt, 91%.
Scheme 4 a
Figure 1. Molecular crystal structure of compound 11. Anisotropic
displacement parameters are drawn at the 50% probability level.16
a Synthesis of segment E: [a] NaHMDS, THF, -78 °C, then allyl
bromide, 60%; [b] LiOH, H2O2, THF/H2O, 93%; [c] [((R)-Binap)-
RuCl2]2(NEt3) catalyst, H2 (10 atm), MeOH, 95 °C, 84%; [d] EDCI, DMAP,
CH2Cl2, 93%; [e] F3CCOOH, Et3SiH, CH2Cl2, quantitative; [f] (COCl)2,
CH2Cl2/DMF catalyst, quantitative.
steps. Specifically, an aldol reaction of the (Z)-boron enolate
of 12 with methacrolein provided syn-aldol 1318 on a multi-
gram scale for subsequent O-protection by an MOM group prior
to reduction with LiBH4. Primary alcohol 15 was converted to
the TBS ether 16 which was ozonized to provide methyl ke-
tone 17 in excellent overall yield (Scheme 3).19 Treatment
with TBSOTf and Et3N delivered silyl enol ether 18 as the
nucleophilic reaction partner for the envisaged coupling reaction.
This compound can be conveniently purified by flash chroma-
tography without noticeable decomposition, whereas the cor-
responding Me3Si- and Et3Si-enol ethers were too labile for
practical use.
The last segment was accessible on a large scale by the route
shown in Scheme 4. Thus, â-keto ester 21 was hydrogenated
in the presence of [((R)-Binap)RuCl2]2(NEt3) as the catalyst to
give product 22 in excellent enantiomeric purity (98% ee).20
This alcohol was then esterified with acid 20 which in turn was
derived from the N-acyl oxazolidinone 19 by an asymmetric
allylation reaction following known procedures.21 Deprotection
of the tert-butyl ester in 23 with F3CCOOH in the presence of
Et3SiH and subsequent conversion of the resulting acid 24a into
the corresponding acid chloride 24b furnished the remaining
building block E for the planned total synthesis effort.
Assembly. With the required building blocks in hand, the
assembly of the metathesis precursor was investigated. For this
purpose, sulfone 11 was activated with a variety of Lewis acids
and the resulting oxocarbenium ion was trapped by admixed
silyl enol ether 18 (Scheme 5).15 Careful optimization of the
individual reaction parameters showed that the use of SnCl4 in
CH2Cl2 at -78 °C afforded the best results, furnishing the
desired ketone 25 in 86% yield after hydrolytic workup. Other
Lewis acids (AlCl3, BF3‚Et2O, TMSOTf, HgCl2) gave signifi-
cantly lower yields in this reaction.
(16) Crystal data for compound 11: C14 H18 O3 S, M ) 266.34 g mol-1, colorless,
crystal dimensions 0.31 × 0.28 × 0.08 mm3, orthorhombic P212121 (no.
19), at 100 K, a ) 8.6145(2) Å, b ) 8.85250(10) Å, c ) 18.0214(2) Å, U
) 1374.31(4) Å3, Z ) 4, F ) 1.287 mg m-3, µ ) 0.233 mm-1, λ ) 0.710 73
Å. X-ray diffraction data were collected using a Nonius Kappa CCD
diffractometer employing CCD scans to cover reciprocal space up to 27.50°
with 98.0% completeness; integration of raw data yielded a total of 5201
reflections, merged into 2996 unique reflections with Rint ) 0.0233 after
applying Lorentz, polarization, and absorption correction. The structure was
solved by direct method using SHELXS-97 (Sheldrick, 1997), and atomic
positions and displacement parameters were refined using full matrix least-
squares based on F2 using SHELXL-97 (Sheldrick, 1997). Refinement of
163 parameters using all reflections converged at R ) 0.025, wR ) 0.076,
highest residual electron density peak 0.3 Å3. Complete lists of atom
coordinates and anisotropic displacement parameters as well as tables of
bond lengths and bond angles are available as Supporting Information.
Crystallographic data have been deposited with the Cambridge Crystal-
lographic Data Centre and can be obtained free of charge by applying to
the following: The Director, CCDC, 12 Union Road, Cambridge, CB2
1EZ, United Kingdom, quoting the reference no. CCDC-213618.
(17) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83-91.
Importantly, compound 25 was obtained with excellent
diastereoselectivity in favor of the desired trans isomer (trans/
(18) For leading references on Evans-aldol reactions with methacrolein, see:
(a) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1987, 109, 7151-7157.
(b) Evans, D. A.; Fitch, D. M. J. Org. Chem. 1997, 62, 454-455. (c)
Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747-5750. (d)
Smith, A. B.; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem. Soc. 1995,
117, 10777-10778.
(20) Reviews: (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (b) Ohkuma, T.; Noyori, R. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 1, pp 199-246.
(21) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104,
1737-1739.
(19) For a similar sequence, see: Makino, K.; Kimura, K.; Nakajima, N.;
Hashimoto, S.; Yonemitsu, O. Tetrahedron Lett. 1996, 37, 9073-9076.
9
15514 J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003

Total Syntheses of Amphidinolide T1, T3, T4, and T5
A R T I C L E S
Scheme 5 a
Table 1. Diastereoselective Reduction of Ketone 25 in THF
isolated yield, %
entry
reducing agent
L-Selectride
LiHBEt3
LiAlH4 (5 equiv) + LiI (10 equiv) -100
T, °C
-78
-78 f rt
26
27
1
2
3
72
19
11
3
32
70
numbering) with the desired syn-syn stereotriad at the three
contiguous chiral centers, whereas the use of LiAlH4 in
combination with excess LiI24 inverts the stereochemical bias
and leads to the preferential formation of the corresponding
(12R)-isomer 27 (Table 1). This outcome is best explained by
invoking chelate complexes such as H or I in the Li+-rich
medium, either of which should favor the formation of alcohol
27 upon attack of an external hydride.24c This ability to control
the course of the reduction of the ketone group by the proper
choice of the reducing agent was ultimately decisive for the
success of this total synthesis project (see below).
a Coupling of compounds 11 and 18: [a] SnCl4, CH2Cl2, -78 °C, 86%;
[b] see Table 1; [c] PMBBr, KHMDS, THF, 77%; [d] TBAF, THF, 93%;
[e] I2, PPh3, imidazole, CH2Cl2, 34%.
The stereochemistry of alcohols 26 and 27 was rigorously
established during an unintended deviation from the projected
course of the synthesis. After protection of compound 26 as
the corresponding PMB ether and cleavage of the terminal silyl
group, we had planned to convert the resulting primary alcohol
28 into the corresponding iodide under standard conditions.25
However, the only product isolated from the reaction mixture
was the tetrahydrofuran 29, which was formed by an intramo-
lecular attack of the PMB ether oxygen onto the transient
iodide.26 NOE effects in combination with the pertinent coupling
constants (3JH12,H13 ) 4.5 Hz, 3JH13,H14 ) 2.0 Hz) revealed the
cis orientation of the hydrogen atoms H12 and H13 in this
compound and therefore permitted deduction of the (12S)-
configuration of alcohol 26 (Scheme 5, amphidinolide number-
ing). This assignment was ultimately corroborated by the
successful completion of the total synthesis project.
The ease of formation of tetrahydrofuran 29 makes clear that
the O12-protecting group not only must be orthogonal to the
terminal -OTBS function but also has to attenuate the nucleo-
philicity of the ether oxygen. The TBDPS group fulfills these
criteria,27 although its introduction was efficient only when
KHMDS was used as the base. Compound 30 thus obtained
can be selectively transformed into the primary alcohol 31 on
exposure to TsOH in aq MeOH, which behaved properly and
Scheme 6
cis g 26:1) as can be deduced from the strong NOE effect
indicated in Scheme 5. This stereochemical outcome is in accord
with previous observations, showing that a substituent as small
as a methyl group at C3 of a furanoid oxocarbenium cation
suffices to bias nucleophilic attack with high 1,3-anti selectiv-
ity.22,23 This pattern is explained by assuming that the carboca-
tion prefers an envelope conformation where the [CdO]+ unit
resides in the flattened portion of the ring, which is attacked
by the nucleophile from “inside” for stereoelectronic reasons.22
When applied to the present case (Scheme 6), it is rather obvious
that transition state F should be favored over G because of the
equatorial orientation of the larger substituent and the more open
“inside” trajectory for the incoming silyl enol ether.
(24) (a) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron Lett. 1988,
29, 5419-5422. (b) Nicolaou, K. C.; Piscopio, A. D.; Bertinato, P.;
Chakraborty, T. K.; Minowa, N.; Koide, K. Chem.sEur. J. 1995, 1, 318-
333. (c) For a comprehensive discussion of chelation controlled hydride
reductions of carbonyl compounds, see: Mengel, A.; Reiser, O. Chem. ReV.
1999, 99, 1191-1223.
Reduction of ketone 25 with L-Selectride affords the (12S)-
configured alcohol 26 as the major product (amphidinolide
(25) (a) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980,
2866-2869. (b) Fu¨rstner, A.; Jumbam, D.; Teslic, J.; Weidmann, H. J.
Org. Chem. 1991, 56, 2213-2217.
(22) Larsen, C. H.; Ridway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem.
Soc. 1999, 121, 12208-12209.
(23) (a) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40-42. (b) Schmitt, A.; Reissig,
H.-U. Eur. J. Org. Chem. 2001, 1169-1174.
(26) For similar cyclizations, see: (a) Martin, O. R.; Yang, F.; Xie, F.
Tetrahedron Lett. 1995, 36, 47-50. (b) De´sire´, J.; Prandi, J. Eur. J. Org.
Chem. 2000, 3075-3084.
(27) Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975-2977.
9
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A R T I C L E S
A¨ıssa et al.
Scheme 7 a
Scheme 8 a
a Assembly of the RCM precursor: [a] KHMDS, TBDPSCl, THF,
77%; [b] TsOH, aq MeOH, 75%; [c] I2, PPh3, imidazole, toluene, 80%;
[d] (i) Zn/Cu couple, TMSCl, toluene, DMA; (ii) 24b, Pd2(dba)3 catalyst,
P(2-furyl)3 catalyst, 40-50% (33) + 20-30% (32b).
converted into the required iodide 32a without interference of
a neighboring group (Scheme 7).
With this compound in hand, the remaining coupling was
achieved by a palladium catalyzed acyl-Negishi reaction.28,29
Thus, exposure of 32a to a Zn/Cu couple, which was activated
in situ with TMSCl immediately prior to use, gave the
corresponding organozinc reagent. This intermediate reacted
with the enantiomerically pure acid chloride 24b in the presence
of Pd2(dba)3 catalyst and tris(2-furyl)phosphine as the ligand
to give the desired ketone 33, together with the reduced product
32b. The reaction must be carried out in toluene in the presence
of DMA as a cosolvent, since THF is cleaved under these
conditions. Attempts to perform this coupling with nucleophiles
other than the organozinc reagent and/or different catalysts and
ligand sets were unrewarding.30 Notably, this reaction constitutes
one of the most advanced examples of an acyl-Negishi coupling
reported to date31 and sets the stage for the envisaged macro-
cyclization via RCM.
Completion of the Total Synthesis of Amphidinolides T1,
T4, and T5. In line with our expectations,32 the formation of
the macrocyclic ring by RCM of diene 33 worked exquisitely
well when carried out under standard conditions in the presence
of the “second generation” ruthenium carbene complex 34 as
the precatalyst bearing an imidazol-2-ylidene ligand (Scheme
8).33 Hydrogenation of the resulting cycloalkene 35 (E:Z ) 6:1)
delivers compound 36 in high yield ready for the introduction
of the exo-methylene group of the final target.
a Macrocyclization and olefination: [a] catalyst 34, CH2Cl2, reflux, 86%;
[b] H2 (1 atm), Pd/C, EtOAc, 86%; [c] PH3PdCH2, THF, quantitative; [d]
Nysted’s reagent 38 (excess), TiCl4, THF, reflux, 64%.
proved to be too basic and led only to a â-elimination of the
aldol with concomitant opening of the macrocycle to give acid
37. The use of a modified Peterson reagent for this olefination
met with complete failure.34 Semiempirical calculations35
showed that the difficulties encountered in the attempted
olefinations are likely steric in origin. In line with the results
reported by Kobayashi et al. concerning the conformational
compression of the macrocycle in amphidinolide T1,4c the
(32) These expectations derive from our experiences gained in the following
total syntheses: (a) Fu¨rstner, A.; Kindler, N. Tetrahedron Lett. 1996, 37,
7005-7008. (b) Fu¨rstner, A.; Langemann, K. J. Am. Chem. Soc. 1997,
119, 9130-9136. (c) Fu¨rstner, A.; Mu¨ller, T. J. Org. Chem. 1998, 63, 424-
425. (d) Fu¨rstner, A.; Gastner, T.; Weintritt, H. J. Org. Chem. 1999, 64,
2361-2366. (e) Fu¨rstner, A.; Seidel, G.; Kindler, N. Tetrahedron 1999,
55, 8215-8230. (f) Fu¨rstner, A.; Mu¨ller, T. J. Am. Chem. Soc. 1999, 121,
7814-7821. (g) Fu¨rstner, A.; Grabowski, J.; Lehmann, C. W. J. Org. Chem.
1999, 64, 8275-8280. (h) Fu¨rstner, A.; Thiel, O. R.; Kindler, N.;
Bartkowska, B. J. Org. Chem. 2000, 65, 7990-7995. (i) Fu¨rstner, A.;
Radkowski, K. Chem. Commun. 2001, 671-672. (j) Fu¨rstner, A.; Stelzer,
F.; Rumbo, A.; Krause, H. Chem.sEur. J. 2002, 8, 1856-1871. (k)
Fu¨rstner, A.; Jeanjean, F.; Razon, P. Angew. Chem. 2002, 114, 2203-
2206; Angew. Chem., Int. Ed. 2002, 41, 2097-2101. (l) Fu¨rstner, A.;
Jeanjean, F.; Razon, P.; Wirtz, C.; Mynott, R. Chem.sEur. J. 2003, 9,
320-326. (m) Fu¨rstner, A.; Leitner, A. Angew. Chem. 2003, 115, 320-
323; Angew. Chem., Int. Ed. 2003, 42, 308-311.
(33) (a) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am. Chem.
Soc. 1999, 121, 2674-2678. (b) Scholl, M.; Trnka, T. M.; Morgan, J. P.;
Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247-2250. (c) Ackermann,
L.; Fu¨rstner, A.; Weskamp, T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron
Lett. 1999, 40, 4787-4790. (d) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.;
Schanz, H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204-2207.
(34) Johnson, C. R.; Tait, B. D. J. Org. Chem. 1987, 52, 281-283.
(35) Using Spartan 02, 2001, software at the PM3 level.
However, the seemingly routine transformation of 36 into
39 turned out to be quite problematic. Specifically, Ph3PdCH2
(28) (a) Negishi, E.; Liu, F. In Metal-catalyzed Cross-coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; pp 1-47.
(b) Sugihara, T. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley: New York, 2002; Vol. 1, pp 635-647.
(29) (a) Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F.-T.; Miller, J. A.; Stoll,
A. T. Tetrahedron Lett. 1983, 24, 5181-5184. (b) Tamaru, Y.; Ochiai,
H.; Sanda, F.; Yoshida, Z. Tetrahedron Lett. 1985, 26, 5529-5532.
(30) This includes (i) the use of Pd(0) in combination with tri-o-tolylphosphine,
dppf, or tri-(p-methoxyphenyl)phosphine as the ligands; (ii) the use of CoBr2
or (PPh3)2Rh(CO)Cl as catalysts instead of Pd(0); and (iii) attempts to
transmetalate the organozinc species with CuCN‚2LiCl, CuBr‚Me2S,
PhSCuLi, MnI2, or MnCl2‚2LiCl prior to cross coupling.
(31) For another advanced example, see: (a) Fu¨rstner, A.; Weintritt, H. J. Am.
Chem. Soc. 1998, 120, 2817-2825. (b) Fu¨rstner, A. Angew. Chem., Int.
Ed. 2003, 42, 3582-3603.
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Total Syntheses of Amphidinolide T1, T3, T4, and T5
A R T I C L E S
Scheme 9 a
Figure 2. Lowest energy conformation of compound 36, illustrating the
steric shielding of the carbonyl group at C16.
overall structure of ketone 36 was found to be very compact.
As can be seen from the representation depicted in Figure 2,
one side of the ketone group is strongly shielded by the
macrocycle which is locked in an unfavorable conformation by
the large sOTBDPS group, while the trajectory to the other
π-face is severely hindered by the propyl side chain.
a Completion of the total synthesis of compounds 1 and 4: [a]
[(Me2N)3S][Me3SiF2], MeCN, 84%; [b] Dess-Martin periodinane, CH2Cl2,
93%; [c] Dowex AG 50W-X4, MeOH, 52%; [d] TMSCl, nBu4NBr, CH2Cl2,
0 °C, 85%; [e] Dess-Martin periodinane, CH2Cl2, 83%; [f] HF‚pyridine,
MeCN, 87%.
It should be possible to improve the access to this hidden
carbonyl group by increasing the conformational flexibility of
the macrocycle. This can be done either by cleavage of the bulky
TBDPS ether or by increasing the reaction temperature. Since
we were unable to find conditions allowing to remove the
TBDPS group without concomitant opening of the macrocyclic
ring to give acid,37 we searched for a reagent with strictly
nonbasic characteristics to avoid the destructive retro-Michael
pathway; ideally, this reagent should operate at higher temper-
atures. The Takai olefination using CH2Br2 in the presence of
TiX4 (X ) Cl, OiPr)/Zn fulfilled these stringent criteria and
gave the desired olefin, but the yields were rather variable.36
Consistent results, however, were obtained by applying Nysted’s
reagent 38 (cyclo-dibromo-di-µ-methylene-[µ-(tetrahydrofuran)]-
trizinc) which delivered product 39 in 64% yield when applied
in refluxing THF in the presence of TiCl4 as the promoter
(Scheme 8).37
the resulting alcohol 40 with Dess-Martin periodinane40 and
removal of the remaining MOM acetal under slightly acidic
conditions using Dowex AG 50W-X4 resin in MeOH readily
afforded amphidinolide T1 (1) in good overall yield (Scheme
9). We were pleased to find that it was possible to gain access
(38) (a) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey, D.
S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436-6237. (b) For the
preparation and properties of the reagent, see: Noyori, R.; Nishida, I.;
Sakata, J. J. Am. Chem. Soc. 1983, 105, 1598-1608.
(39) The choice of the desilylating agent followed the results obtained in the
model studies depicted below:
Compound 39 represents the common precursor “A” to all
amphidinolides of the T series (except T2). In fact, a selective
cleavage of its TBDPS group can be achieved by means of
[(Me2N)3S][Me3SiF2] in MeCN.38,39 Subsequent oxidation of
(36) (a) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1978,
19, 2417-2420. (b) Okazoe, T.; Hibino, J.; Takai, K.; Nozaki, H.;
Tetrahedron Lett. 1985, 26, 5581-5584. (c) For a highly successful
application in a case where the Wittig reaction had also failed, see: Fu¨rstner,
A.; Guth, O.; Du¨ffels, A.; Seidel, G.; Liebl, M.; Gabor, B.; Mynott, R.
Chem.sEur. J. 2001, 7, 4811-4820.
(37) (a) Tochtermann, W.; Bruhn, S.; Meints, M.; Wolff, C.; Peters, E.-M.;
Peters, K.; von Schnering, H. G. Tetrahedron 1995, 51, 1623-1630. (b)
Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313-315. For recent
applications, see: (c) Clark, J. S.; Marlin, F.; Nay, B.; Wilson, C. Org.
Lett. 2003, 5, 89-92. (d) Tarraga, A.; Molina, P.; Lopez, J. L.; Velasco,
M. D. Tetrahedron Lett. 2001, 42, 8989-8992. (e) Tanaka, M.; Imai, M.;
Fujio, M.; Sakamoto, E.; Takahashi, M.; Eto-Kato, Y.; Wu, X. M.;
Funakoshi, K.; Sakai, K.; Suemune, H. J. Org. Chem. 2000, 65, 5806-
5816.
While the use of Bu4NF or BF3‚Et2O in combination with salicylaldehyde
(Mabic, S.; Lepoittevin, J. P. Synlett 1994, 851) led to the decomposition
of the starting material, HF‚pyridine resulted in formation of the shown
cyclic acetal by participation of the adjacent MOM group. Only the complex
fluorosilicates [(Me2N)3S][Me3SiF2] or [Bu4N][Ph3SiF2] in MeCN gave the
desired alcohol in high yields.
(40) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156. (b)
Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549-7552. (c)
Boeckman, R. K., Jr.; Shao, P.; Mullins, J. J. Org. Synth. 2000, 77, 141-
152.
9
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A R T I C L E S
A¨ıssa et al.
Scheme 10 a
Scheme 11
a Assembly of the RCM precursor for the synthesis of amphidinolide
T3: [a] KHMDS, TBDPSCl, THF, 82%; [b] TsOH, aq MeOH, 87%; [c]
I2, PPh3, imidazole, toluene, 89%; [d] (i) Zn/Cu couple, TMSCl, toluene,
DMA; (ii) 24b, Pd2(dba)3 catalyst, P(2-furyl)3 catalyst, 64% (45:46 ) 3:2).
to amphidinolide T4 (4) by changing the order of events,
although slightly different reagents were necessary in this case.
Specifically, the use of TMSBr (generated in situ from TMSCl
and n-Bu4NBr) led to a selective and high yielding cleavage of
the MOM group without compromising the adjacent silyl ether.
Alcohol 41 (Scheme 9) was oxidized with Dess-Martin
periodinane, and the resulting ketone was desilylated by means
of HF‚pyridine in MeCN to furnish amphidinolide T4 (4). The
analytical and spectroscopic data of the synthetic samples of 1
and 4 are in excellent agreement with those of the natural
products as reported in the literature.4 Since it has previously
been shown that amphidinolide T4 undergoes epimerization at
C14 on treatment with K2CO3 in MeOH to give amphidinolide
T5 (5),4c a formal total synthesis of this only recently discovered
congener has also been achieved.
Total Synthesis of Amphidinolide T3: The Impact of a
Seemingly Minor Change. As outlined in the discussion of
our retrosynthetic plan, a modification of the end game strategy
should lead to the remaining congener amphidinolide T3 (3)
from the common synthetic intermediate 39. Specifically, this
required inversion of the free hydroxyl group in compound 40
to set the proper configuration at C12 followed by a sequence
of oxidation/deprotection steps similar to those outlined above.
Despite considerable efforts, however, we were unable to find
appropriate conditions for the seemingly trivial inversion step.
As a consequence, access to this particular target had to be
secured by a different route. The ease with which the reduction
of ketone 25 can be controlled to give either the (12S)- or the
(12R)-configured alcohols 26 and 27 (cf. Scheme 5 and Table
1) helped to solve this problem. Therefore, we repeated the
assembly of the metathesis precursor using the epimeric series
as shown in Scheme 10. While the elaboration of compound
27 to the corresponding iodide 44a proceeded uneventfully, the
crucial acyl-Negishi coupling28,29 led to a rather surprising
outcome. In addition to the desired ketone 45 and minor amounts
of the reduction product 44b, an additional compound was
isolated from the crude reaction mixture by HPLC. Extensive
NMR investigations allowed us to assign its structure as 46.
This rearranged skeleton is thought to derive from the radical
cascade shown in Scheme 11, triggered by single electron
transfer (s.e.t.) from the Zn/Cu couple to iodide 44a and likely
reflects the conformational peculiarities of this compound.
The radical anion J initially formed on exposure of 44a to
Zn/Cu can evolve along two competing pathways (Scheme 11).
If a rapid second s.e.t. occurs, the desired organozinc derivative
K will be formed which undergoes the palladium catalyzed acyl-
Negishi reaction leading to the expected cross coupling product
45. However, if J expells I- prior to the second s.e.t., the
resulting primary carbon radical L can abstract an anomeric
hydrogen atom from the tetrahydrofuran ring via a formal 1,6-H
shift. The substituents on the carbon backbone obviously enforce
9
15518 J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003

Total Syntheses of Amphidinolide T1, T3, T4, and T5
A R T I C L E S
Scheme 12 a
Scheme 13 a
a [a] (Me3Sn)2 (0.3 equiv), AIBN (0.1 equiv), benzene, reflux, 16 h, 44a:
47 ) 3:1; see text.
a conformation in which these sites are brought into close
vicinity. The resulting radical M undergoes a rapid 5-exo-trig
cyclization leading to the bicyclic intermediate N which delivers
the transposed organozinc derivative O after a second s.e.t..
Interception of this compound by the acid chloride 24b in the
presence of Pd(0) as the catalyst affords the two epimers of
product 46 (diastereomeric ratio, d.r. ) 8:3) which were
unambiguously identified by 2D NMR experiments at 600 MHz.
To lend credence to this scenario, iodide 44a was reacted
with hexamethylditin in the presence of AIBN (Scheme 12).
Under free radical conditions,41 an equilibrium between 44a and
the transposed bicyclic iodide 47 formed by iodine transfer is
established. The latter compound was isolated by preparative
HPLC as a 1:1 mixture of isomers. This control experiment
strongly advocates a radical process triggered by an s.e.t. from
Zn/Cu to the substrate42 as the origin for the observed formation
of compound 46 during the acyl-Negishi coupling step.
The unexpected results of the zinc-induced fragment coupling
process augured for possible difficulties during the ring closure
of diene 45 by RCM. In line with the notion that the anti-syn
stereotriad in the C12-C14 region of this compound might be
far from optimal for the macrocyclization, this compound was
found to react much more reluctantly than its syn-syn config-
ured counterpart 33.43 Good conversion could only be attained
by exchanging the solvent from CH2Cl2 to toluene44 and
increasing the reaction temperature to 110 °C.45 Although
ruthenium carbene complexes are known to be fairly labile
under such forcing conditions,46 the desired ring closure was
faster than the decomposition of the catalyst, thus delivering
a Completion of the total synthesis of amphidinolide T3 (3). [a] catalyst
34b (20 mol %), toluene, 110 °C, 82%; [b] H2 (1 atm), Pd/C, EtOAc, 99%;
[c] Nysted’s reagent 38, TiCl4, THF, reflux, 54%; [d] Dess-Martin
periodinane, CH2Cl2, 88%; [e] HF‚pyridine, MeCN, 55%.
cycloalkene 48 in a respectable 82% isolated yield. The mixture
of isomers (E:Z ) 2:1) was hydrogenated under standard
conditions to give product 49 (Scheme 13).
The conformational constraints imposed on all compounds
of this series by the -OTBDPS group at C12 and the eclipsed
MOM acetal in an anti arrangement at C13 are particularly
pronounced in cycloalkene 48 and the saturated derivative 49
derived thereof. Specifically, the NMR spectra of 48 and 49
show exceptional line broadening due to severely restricted
rotations in this part of the molecule when recorded using the
programs of the standard NMR pulse library at ambient
temperature. This effect is so strong that the -OCH2O- entity
of the MOM group is seemingly absent, and even its -OMe
part is very strongly affected; the corresponding signals are
clearly visible only upon recording the spectra at +80 °C (cf.
the Supporting Information). All other spectroscopic data (IR,
MS, HRMS) confirm that the MOM acetal is fully intact and
preserved until after the olefination step.
Furthermore, it is noteworthy that the relative configuration
at C12/C13 of the cyclization precursor determines the stereo-
chemical course of the RCM reaction. This can be deduced from
a comparison of the E/Z ratios produced in the cyclizations of
dienes 33 and 45, which differ only in the configuration of the
remote C12 chiral center. While cycloalkene 35 derived from
33 is formed with an appreciable selectivity in favor of the (E)-
isomer (E:Z ) 6:1), the corresponding E:Z ratio for its congener
48 was only 2:1. Assuming that the reactions using the highly
active “second generation” catalyst 34 at elevated temperatures
are reversible and therefore likely under thermodynamic control
as previously shown in other cases,47 this outcome should reflect
the relative stability of the geometrical isomers.48 In fact,
(41) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc. 1989, 111, 6265-
6276.
(42) It has been previously shown that the formation of organozinc derivatives
under similar reaction conditions likely involves radical intermediates; cf.:
(a) Crandall, J. K. Ayers, T. A. Organometallics 1992, 11, 473-477. (b)
Luche, J. L.; Allavena, C.; Petrier, C.; Dupuy, C. Tetrahedron Lett. 1988,
29, 5373-5374. (c) Pradhan, S. K.; Kolhe, J. N.; Mistry, J. S. Tetrahedron
Lett. 1982, 23, 4481-4484. (d) Samat, A.; Vacher, B.; Chanon, M. J. Org.
Chem. 1991, 56, 3524-3530 and literature cited therein.
(43) For previous examples showing that small changes at remote sites of a
given substrate can have a strong impact on the outcome of RCM-based
macrocyclizations, see ref 12 and the following: (a) Fu¨rstner, A.; Thiel,
O. R.; Blanda, G. Org. Lett. 2000, 2, 3731-3734. (b) Fu¨rstner, A.; Dierkes,
T.; Thiel, O. R.; Blanda, G. Chem.sEur. J. 2001, 7, 5286-5298. (c)
Fu¨rstner, A.; Schlede, M. AdV. Synth. Catal. 2002, 344, 657-665. (d) Meng,
D.; Su, D.-S.; Balog, A.; Bertinato, P.; Sorensen, E. J.; Danishefsky, S. J.;
Zeng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. J. Am. Chem. Soc. 1997,
119, 2733-2734.
(44) The “second generation” catalyst 34 is known to be inherently more reactive
in toluene than in CH2Cl2. This effect is not merely a consequence of the
higher reaction temperature that can be reached but reflects a real solvent
effect. For a discussion see ref 33d and the following reference: Fu¨rstner,
A.; Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann, C. W.; Mynott, R.;
Stelzer, F.; Thiel, O. R. Chem.sEur. J. 2001, 7, 3236-3253.
(45) For recent precedence on the use of very high temperatures in RCM, see:
Yamamoto, K.; Biswas, K.; Gaul, C.; Danishefsky, S. J. Tetrahedron Lett.
2003, 44, 3297-3299.
(46) For studies on the decomposition of ruthenium carbene complexes, see:
(a) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 6543-6554. (b) Amoroso, D.; Yap, G. P. A.; Fogg, D. E. Organo-
metallics 2002, 21, 3335-3343.
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A R T I C L E S
A¨ıssa et al.
semiempirical calculations indicate that (E)-35 is considerably
more stable than its (Z)-counterpart (∼8 kcal mol-1), whereas
the geometrical isomers of 48 are much closer in energy,
they showcase how seemingly small changes in the substrates
can have a major impact on the course and efficiency of a given
transformation. This is evident from the RCM experiments
which are strongly affected by the chosen stereochemical setting
of the substrate. Likewise, the configuration of a remote
stereocenter determines whether a radical manifold can ef-
fectively compete with the organometallic pathway during an
acyl-Negishi reaction used for fragment coupling. Therefore,
these results bear witness to the eminent importance of control-
ling the conformational space populated by acyclic molecules,
an aspect that is likely gaining further relevance as the
complexity of the target structures continues to increase.
favoring the (E)-cycloalkene by only ∼1.2 kcal mol-1 35
.
Product 49 was then subjected to olefination using Nysted’s
reagent 38 in combination with TiCl4.37 Not only did this
reaction install the exo-methylene group but also was ac-
companied by a cleavage of the MOM acetal during the workup.
Since this protecting group had to be removed anyway, product
50 was directly amenable to oxidation with Dess-Martin
periodinane.40 Cleavage of the remaining silyl group in 51
completed the total synthesis of amphidinolide T3 (3) in
excellent overall yield.
Acknowledgment. Generous financial support by the Deut-
sche Forschungsgemeinschaft (Leibniz award to A.F.) and the
Fonds der Chemischen Industrie is acknowledged with gratitude.
We thank Mr. A. Deege and his crew for performing the HPLC
separations and Dr. C. W. Lehmann for solving the X-ray
structure of compound 11 as well as Dr. R. Mynott and C. Wirtz
for their help with the unambiguous structure assignment of
the rearranged product 46.
Conclusions
A concise, modular, and high yielding entry into the amphi-
dinolide T family has been described. The syntheses of these
bioactive macrolides of marine origin highlight the outstanding
performance and excellent application profile of modern orga-
nometallic chemistry and catalysis. At the same time, however,
Supporting Information Available: Full experimental details,
spectroscopic and analytical data of all new compounds, and
copies of the spectra of compounds 1, 3, 4, 39, 46, 47, and 49
as well as crystallographic data concerning compound 11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(47) See the following for leading references: (a) Smith, A. B.; Adams, C. M.;
Kozmin, S. A. J. Am. Chem. Soc. 2001, 123, 990-991. (b) Fu¨rstner, A.;
Thiel, O. R.; Ackermann, L. Org. Lett. 2001, 3, 449-451. (c) 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, 10302-10316. (d) Paquette,
L. A.; Basu, K.; Eppich, J. C.; Hofferberth, J. E. HelV. Chim. Acta 2002,
85, 3033-3051.
(48) For a detailed discussion and an example showing how to use kinetic versus
thermodynamic control over RCM in synthesis, see: Fu¨rstner, A.; Rad-
kowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C. W.; Mynott, R. J. Am.
Chem. Soc. 2002, 124, 7061-7069.
JA038216Z
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15520 J. AM. CHEM. SOC. VOL. 125, NO. 50, 2003