Ruthenium-catalyzed alkene-alkyne coupling: Synthesis of the proposed structure of amphidinolide A

Article abstract of DOI:10.1021/ja027883+

The ruthenium-catalyzed alkene-alkyne coupling provides a powerful method for the synthesis of 1,4 dienes and a way to simplify synthetic strategy. The latter potential is explored in the context of a synthesis of the assigned structure of amphidinolide A

Full text of DOI:10.1021/ja027883+

Published on Web 09/27/2002
Ruthenium-Catalyzed Alkene-Alkyne Coupling: Synthesis of the Proposed
Structure of Amphidinolide A
Barry M. Trost,* John D. Chisholm, Stephen T. Wrobleski, and Michael Jung
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received July 26, 2002
The ruthenium-catalyzed additions of alkynes and alkenes
provide an atom economic strategy for carbon-carbon bond
formation.1-3 An intramolecular version of this process constitutes
a cycloisomerization. While cyclizations to form “normal” ring sizes
proceed with CpRu(MeCN)3PF6,3 a key question that arises is its
suitability to form macrocycles.4 As part of an effort to explore
this aspect, we chose to consider amphidinolide A,5,6 whose
proposed structure indicated it to be an ideal target. This highly
unsaturated macrocycle contains the exact structural features nicely
accessed by this methodology - the two disconnections being the
C6-C7 and C15-C16 bonds which lead to subunits 2-4 (Figure
1). In this paper, we report the first example of a macrocycloisom-
erization using the ruthenium-catalyzed alkyne-alkene addition
which culminated in the total synthesis of the presumed structure
of amphidinolide A. During the course of our studies, two other
groups have succeeded in the total synthesis of structure 1.7,8
Julia sulfone was based upon the palladium asymmetric allylic
alkylation (AAA) involving sulfone ester 8 and carbonate 9 (see
Scheme 2).14 This resulted in a 1:1 mixture of diastereomers, which
were then convergently decarboxylated. Hydrogenation of the olefin
provided the tetrazole sulfone 12 in 90% ee, as determined by chiral
HPLC analysis.
Scheme 2. Synthesis of Asymmetric Sulfone for Julia Olefinationa
a (a) Methyl bromoacetate, NaOMe, MeOH, 85%. (b) MCPBA, CH2Cl2,
82%. (c) Pd2(dba)3 (1.5 mol %), Cs2CO3, ligand 10 (6 mol %), carbonate
9 (1.5 equiv), CH2Cl2, 84%. (d) NaCl, DMSO, 150 °C 64%. (e) H2,
Pd(OH)2/C, EtOH/AcOH, 68%.
The synthesis of the aldehyde partner for the Julia olefination is
based upon opening of an oxetane, a functional group that is often
overlooked in synthesis, with an acetylide (see Scheme 3). After
some protecting group manipulations, alcohol 16 is oxidized to the
corresponding aldehyde and coupled with sulfone 12 to provide
the desired olefin with >20:1 trans:cis selectivity. Because of the
uncertainty with the structure of the natural product, the epoxidation
was then performed nonselectively with MCPBA.
Scheme 3. Synthesis of C16-C25 Subunit 3a
Figure 1. Retrosynthetic analysis.
The C1-C6 portion was efficiently accessed as shown in Scheme
1. 2-Butynoic acid was esterified under acidic conditions with
9-fluorenylmethanol. Addition of the allylcopper species of Lip-
shutz9,10 gave the desired olefin in excellent yield and geometric
purity. The fmoc ester was chosen after screening a number of
protecting groups and was unique in its ability to be removed in
good yield without significant isomerization of the unsaturated ester.
a (a) 1 equiv of NaH, PMBCl THF, room temperature, 53%. (b) Sharpless
epoxidation, 71% (84% ee). (c) Me2CuLi, then NaIO4, THF-H2O, room
temperature, 68%. (d) TsCl, pyridine. (e) NaH, THF, ether, -50 to -20
°C, 82% (two steps). (f) Lithium trimethylsilyl acetylide, BF3-OEt2, THF,
-78°, 62%. (g) TBSCl, imidazole, 93%. (h) DDQ, 93%. (i) Dess-Martin.
(j) KHMDS, 12, 72% (two steps). (k) TBAF, THF, 92%. (l) MCPBA, 41%
+ 37% of the diastereomeric epoxide.
Scheme 1. Synthesis of C1-C6 Subunit 2a
a (a) 9-Fluorenylmethanol, CSA (10 mol %), toluene, Dean-Stark, 71%.
(b) Allyltributyltin, BuLi, CuI, THF, -78 °C, 97%.
The synthesis of the protected tetraol fragment relies upon the
Sharpless asymmetric dihydroxylation as delineated in Scheme 4.15
Unfortunately, attempts to dihydroxylate both olefins of 19
simultaneously resulted in unusable mixtures of diastereomers.
Epoxide 3 is readily available from the corresponding trans olefin,
which derives from a Julia olefination.11-13 The synthesis of the
* To whom correspondence should be addressed. E-mail: bmtrost@stanford.edu.
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10.1021/ja027883+ CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Synthesis of C7-C15 Subunit 4a
however, provided the desired ester with virtually no isomerization.
Gratifyingly, intramolecular cycloisomerization to form the C15-
C16 bond proceeded laudably in 58% yield. Deprotection of the
cyclopentylidene acetals then yielded the macrocycle 1, [R]23
D
+55.8 (c ) 0.2, CH2Cl2). Spectral data for our synthetic compound
are identical to those of Pattenden and Maleczka, further confirming
the structure of the synthetic material and its differences with the
isolated material. Thus, as noted by Pattenden, this structure does
not correspond to the natural product, which he concluded is a
diastereomer.
The successful synthesis of macrolide 1 using the Ru-catalyzed
alkene-alkyne coupling twice, once inter- and once intramolecularly,
demonstrates the power of this method. The ability to obtain
synthetically useful yields of pentaene 24 indicates the exceptional
chemoselectivity exhibited. It also provides the first report of its
applicability for macrocyclization. Furthermore, this macrocycliza-
tion proceeded in higher yields than those reported by Pattenden7
(Pd cross-coupling) and Maleczka8 (Ru metathesis). Also, this
synthesis differs in that the stereochemistry ultimately derives from
catalytic asymmetric processes and no building blocks came from
the “chiral pool”. Thus, either enantiomer as well as diastereomers
are available by this route and offer the opportunity to ascertain
which diastereomer corresponds to the natural product, a task that
is currently underway.
a (a) (i) BuLi; (ii) ethyl formate. (b) Red-Al 61% (two steps). (c) TBSCl,
imidazole, 89%. (d) Sharpless AD, 79%. (e) Cyclopentanone dimethyl acetal,
10 mol % TsOH. (f) TBAF, 94% (two steps). (g) Dess-Martin, 91%. (h)
Sharpless AD. (i) Cyclopentanone dimethyl acetal, 10 mol % TsOH, 88%
(two steps). (j) TMSCH2MgBr. (k) KHMDS, 72% (two steps). (l) DDQ,
83%. (m) 1 equiv of NaH, TBSCl, 80%. (n) (i) Tf2O, pyridine; (ii) lithium
trimethylsilylacetylide. (o) TBAF, THF/AcOH, 96% (two steps). (p) 2 mol
% Pd/CaCO3/Pb, quinoline, H2, 96%. (q) Moffatt-Swern oxidation. (r)
(MeO)2P(O)CHN2, NaHMDS, 84% (two steps).
Suitably high selectivity could be obtained when the reactions were
performed in a stepwise manner. Diol 22 was obtained diastereo-
and enantiomerically pure.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health (GM-33049) for their generous
support of our programs. J.D.C. and S.T.W. were supported by NIH
postdoctoral fellowships. Mass spectra were provided by the Mass
Spectrometry Facility, University of San Francisco, supported by
the NIH Division of Research Resources. We thank Professor
Robert Maleczka and Professor Gerald Pattenden for sharing their
spectral data and unpublished results.
While one could imagine forming either the C6-C7 or the C15-
C16 bond in an intra- or intermolecular event, the only successful
path is presented here, with the other route to be discussed
elsewhere. To override the effect of propargylic oxygens to favor
the linear product, the Cp*Ru(MeCN)3PF616 catalyst was employed
(see Scheme 5). This catalyst provided the product in a 46% yield
(76% yield brsm) as a 3.5:1 mixture of separable branched and
linear isomers, with approximately 30% of the starting alkyne also
recovered.
Supporting Information Available: Experimental procedures and
characterization data for 1-6, 8, 11, 12, 14-17, 19-25 (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
Scheme 5. Assembly of the Subunitsa
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basic conditions. Esterification with the powerful method of Kita,17
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