Coupling of alkenes and alkynes: Synthesis of the C1-C11 and C18-C28 fragments of miyakolide

Article abstract of DOI:10.1021/ol800347u

A transition metal-mediated, atom-economical approach toward the crucial A and D rings of miyakolide is described. A Pd-catalyzed alkyne-alkyne coupling/6-endo-dig cyclization is employed to assemble the A ring fragment. The key D ring pyran is constructed utilizing an Ru-catalyzed alkene-alkyne coupling followed by a Pd-catalyzed allylic alkylation to establish the all-cis stereochemistry.

Full text of DOI:10.1021/ol800347u

ORGANIC
LETTERS
2008
Vol. 10, No. 10
1893-1896
Coupling of Alkenes and Alkynes:
Synthesis of the C1-C11 and C18-C28
Fragments of Miyakolide
Barry M. Trost* and Brandon L. Ashfeld
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received February 14, 2008
ABSTRACT
A transition metal-mediated, atom-economical approach toward the crucial A and D rings of miyakolide is described. A Pd-catalyzed alkyne-alkyne
coupling/6-endo-dig cyclization is employed to assemble the A ring fragment. The key D ring pyran is constructed utilizing an Ru-catalyzed
alkene-alkyne coupling followed by a Pd-catalyzed allylic alkylation to establish the all-cis stereochemistry.
As part of a program aimed at isolating biologically active
natural products from marine sponges, Higa and co-workers
in 1992 isolated miyakolide from a sponge of the genus
Polyfibrospongia.1 Bioassay results illustrated potent in vitro
(IC50 17.1 µg/mL against A-549 human lung carcinoma) and
in vivo antitumor activity (T/C 123% at 400 µg/Kg against
B-16 melanoma).2 Aside from its biological activity, miya-
kolide contains a number of intriguing structural features.1,2
Since its isolation, the focus on the pyran A ring has resulted
in an elegant anti-aldol approach by Masamune,3 while the
first enantioselective total synthesis of ent-miyakolide was
reported in 1999 by Evans.4 Our strategy addresses the
synthetic challenges inherent to a macrolide of this complex-
ity and illustrates an efficient, convergent route toward 1.
Immediately, we recognized that the Pd-catalyzed alkyne-
alkyne coupling5 and Ru-catalyzed alkene-alkyne coupling6
strategies developed in our laboratories would be idealy
suited for the rapid construction of the A and D rings of
miyakolide. Retrosynthetic analysis of 1 involves five key
bond disconnections (Scheme 1). First, cleavage of the
macrolide ester and retro-aldol opening of the trans-fused C
and B rings yields intermediate 2. Trione 2 can further be
dissected into fragments 3 and 6 by C11-C12 and C17-C18
cleavage. Alkyne 3 is derived from diyne 4 via a Pd-
catalyzed alkyne-alkyne coupling followed by 6-endo-dig
cyclization, which in turn arises from bis-epoxide 5.7 The
backbone of pyran 6 is constructed utilizing the aforemen-
tioned Ru-catalyzed alkene-alkyne coupling of epoxide 7
and ether 8. Subsequent Pd-catalyzed asymmetric allylic
alkylation effectively closes the critical D ring. In this
manner, the establishment of rings A and D requires
(1) Higa, T.; Tanaka, J.; Komesu, M. J. Am. Chem. Soc. 1992, 114,
7587.
(2) (a) Pettit, G. J. Nat. Prod. 1996, 59, 812. (b) Mutter, R.; Wills, M.
Bioorg. Med. Chem. 2000, 8, 1841.
(3) Takehiko, Y.; Song, J.; Wang, G.-Q.; Masamune, S. J. Org. Chem.
1997, 62, 8978.
(5) Trost, B. M.; Frontier, A. J. J. Am. Chem. Soc. 2000, 122, 11727.
(6) Trost, B. M.; Machacek, M. Angew. Chem., Int. Ed. Engl. 2002, 41,
4693.
(4) Evans, D.; Ripin, D.; Halstead, D.; Campos, K. J. Am. Chem. Soc.
1999, 121, 6816.
(7) Robbins, M. A.; Devine, P. N.; Oh, T. Org. Synth. 1999, 76, 101.
10.1021/ol800347u CCC: $40.75
Published on Web 04/22/2008
2008 American Chemical Society

Scheme 1
.
Retrosynthesis of Miyakolide (1)
Scheme 2. Construction of the A Ring Fragment 3
the cross-coupled product 13 in 65% yield. Subsequent
treatment of enoate 13 with PdCl2(MeCN)2 (10 mol %) and
TDMPP (6 mol %) provided the desired cyclization product
14 in a satisfactory yield of 60%. Finally, deprotection of
the alkyne moiety in 14 yielded fragment 3. We found that
if enyne 13 was isolated, and the oxy-palladation cyclization
performed in a discrete second step, the overall yield of the
process was improved. Thus, by isolating intermediate 13,
clean glucal 14 could be produced in a matter of 14–16 h in
40% overall yield, a protocol that was used for subsequent
scale-up efforts.
The ruthenium-catalyzed alkene-alkyne cross-coupling,
in which the 1,4-diene product may be subjected to pal-
ladium-catalyzed allylic substitution without isolation, has
proven to be a valuable tool in accessing heterocycles of
various ring sizes stereoselectively.6,11 We envisioned that
such a sequence would constitute an efficient method to
assemble the carbon framework of the D ring pyran fragment
6. Initially, we targeted alkyne 17, containing a ꢀ-cyano
alcohol functional moiety, as the alkyne substrate (Scheme
3). A regioselective addition of TMS-acetylide to epoxide
substoichiometric quanitites of transition metal catalysts
necessary for the stereoselective bond-forming events.
Overall, this strategy provides a convergent, atom-economi-
cal8 approach toward a particularly challenging natural
product.
Our synthesis commenced with the assembly of intermedi-
ate 3. The focal point of this sequence is a Pd(II)-catalyzed
alkyne-alkyne coupling/cyclization,5 which effectively il-
lustrates how our synthesis addresses key structural issues
inherent to the A ring of 1.4 In particular, this strategy allows
access to either dihydro- or tetrahydropyrans containing an
exocyclic R,ꢀ-unsaturated ester from a terminal alkyne and
suitably functionalized alkynoate. Diyne 4 was synthesized
from bisepoxide 5, which in turn can be obtained in a high-
yielding, five-step sequence from L-dimethyl tartrate (9)
(Scheme 2).7Thus, TMS-acetylide addition to 5 and
subsequent protection of the resulting secondary hydroxyl
as its TBS ether gave epoxide 11.9 Subsequent addition
of methyl propiolate provided the stereochemically pure
diyne 4.
With diyne 4 in hand, our attention turned toward the
crucial alkyne-alkyne cross-coupling with alkyne 12. Previ-
ous reports indicated that the desired glucal could be obtained
directly in a one-pot procedure by treating alkynoate 4 and
alkyne 12 with Pd(OAc)2 in the presence of tris(2,6-
dimethoxyphenyl)phosphine (TDMPP).5 Unfortunately, this
reaction proved to be low yielding and lacked reproducibility.
However, in studies directed toward the synthesis of bry-
ostatin 7, we found that by employing PdCl2(MeCN)2 in the
6-endo-dig cyclization, the ratio of undesired side products
could be suppressed.10 Thus, treatment of 4 and alkyne 12
with Pd(OAc)2 (10 mol %) and TDMPP (5 mol %) afforded
Scheme 3. Synthesis of Alkyne 17
15,12,13 chemoselective tosylation of the resulting diol 16
with Bu2SnO (10 mol %)14 followed by treatment with DBU
(8) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
(9) Boeckman, R. K.; Liu, X. Synthesis 2002, 2138.
(10) Trost, B. M.; Yang, H.; Thiel, O. R.; Frontier, A. J.; Brindle, C. S.
J. Am. Chem. Soc. 2007, 129, 2206.
(11) (a) Trost, B. M.; Indolese, A. F.; Mueller, T. J. J.; Treptow, B.
J. Am. Chem. Soc. 1995, 117, 615. (b) Trost, B. M.; Machacek, M.;
Schnaderbeck, M. J. Org. Lett. 2000, 2, 1761
.
1894
Org. Lett., Vol. 10, No. 10, 2008

ꢀ,γ-unsaturated ester 21, a substrate that was shown to be
quite viable toward the synthesis of bryostatin 7. Thus,
treatment of alkynes 17 and 18 with 21 separately under the
aforementioned conditions, afforded dienes 22c and 22d, in
57% and 93% yield, respectively (entries 3 and 4). Supris-
ingly, concomitant TBS deprotection and acetonide formation
occurred upon alkene-alkyne coupling of 18. Unfortunately,
pyran formation via a subsequent Michael addition to R,ꢀ-
unsaturated ester 22d proved ineffectual. However, the in
situ desilylation-acetonide formation was a pleasant obser-
vation as one can certainly imagine a sequence wherein a
protecting group exchange and carbon-carbon bond forma-
tion, performed in a three step, one-pot tandem operation,
would be synthetically practical.
Table 1. Ruthenium-Catalyzed Alkene-Alkyne Couplinga
Nevertheless, we explored the possibility of installing the
isopropylidene moiety at a later stage via olefin cross-
metathesis.15 To that end, ether 8 was examined, but failed
to provide the corresponding 1,4-dienes in acceptable yield
from reaction with alkynes 17 and 19 (entries 5 and 6). Given
the low catalyst turnover in the presence of the metal
coordinating nitrile and PMB group we next examined diol
16. Treatment with ether 8 did provide 1,4-diene 22g in
which in situ acetonide protection occurred, but in poor yield
(entry 7). However, treatment of epoxide 7 and aryl ether 8
with [CpRu(MeCN)3]PF6 gave the desired diene 22h in a
gratifying 81% yield (entry 8). It should be noted that
although the reaction conditions are Lewis acidic enough to
facilitate desilylation and ketalization with acetone, the
epoxide moiety in 7 remained intact. However, if the acetone
was not freshly distilled just prior to use we observed
formation of acetonide 22g. The synthesis of 22h proved
quite reliable, even on multigram scale, and was subsequently
employed in the synthesis of pyran 6.
a Conditions: all reactions were performed with 1 equiv of alkyne and
1 equiv of alkene. b Only the branched 1,4-diene products were obtained.
c 93% yield based on recovered starting material.
Two distinct observations upon an examination of the
results depicted in Table 1 deserve comment. First, only the
so-called branched isomer is obtained from the productive
alkene-alkyne couplings. This predominant regioselectivity
has previously been observed with TMS-protected alkynes.11b
Second, ester 21 proved to be a better alkene substrate than
ethers 20 and 8 as indicated by entries 2–5 and 7. Both
observations lend insight into the overall process. As
illustrated in Scheme 4, upon formation of intermediate A
by coordination of the alkene and alkyne in a head-to-tail
arrangement, oxidative addition yields ruthenacycle B. At
this stage, ꢀ-hydride elimination gives C followed by
reductive elimination, to the branched 1,4-diene. Our results
seem to indicate that conversion from B to C is the product-
determining step of the catalytic cycle. This would explain
why ester 21 is a better alkene substrate as it would activate
the R-hydrogen (in red) for elimination better than ether 8.
The selectivity for the branched isomer indicates that
formation of ruthenacycle B is preferred, presumably for
steric effects, wherein C-C bond formation preferentially
occurs at the less hindered alkyne carbon.16 Thus, ꢀ-hydride
provided epoxide 7 (89% overall yield). At this stage,
treatment of 7 with Et2AlCN gave nitrile 17 as a latent acetyl
group to be unmasked at a later stage. In an effort to directly
install the trisubstituted olefin in 6, ether 20 was chosen as
the alkene component in the coupling reaction (Table 1, entry
1). Unfortunately, a mixture of nitrile 17, alkene 20 and
[CpRu(MeCN)3]PF6 (10 mol %) returned a near quantitative
yield of both substrates. Thus, we embarked on an examina-
tion of alternative alkene-alkyne coupling substrates.
To determine if the nitrile group was somehow hindering
the reaction, selective monosilylation of diol 16 yielded
alkyne 18. Subsequent treatment with 20 in the presence of
[CpRu(MeCN)3]PF6 failed to provide the desired product
(entry 2). At this stage, we explored the use of the
(12) Gao, Y.; Hanson, R.; Klunder, J.; Ko, S.; Masamune, H.; Sharpless,
K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(13) Suzuki, T.; Saimoto, H.; Tomioka, H.; Oshima, K.; Nozaki, H.
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V. V.; Kosmrlj, B. J. Am. Chem. Soc. 2002, 124, 3578.
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Org. Lett., Vol. 10, No. 10, 2008
1895

controlled rather than substrate controlled reaction.5 It should
be noted that employing [Pd(η-C3-C3H5)Cl]2 as the catalyst
or switching to DBU as the base resulted in poor cis/trans
selectivity. This would imply that as the rate of the
cyclization was increased, a substantial amount of substrate
22e underwent allylic alkylation unchecked by the presence
of ligand (S,S)-L.
Scheme 4
.
Proposed Mechanism of the Alkene-Alkyne
Coupling
The final assembly of pyran 6 involved chemoselective
epoxidation of the vinylsilane in pyran 2318 and subsequent
cleavage with periodic acid yielding pyranone 24.19 Reduc-
tion with NaBH4, TBS protection, and subsequent methyl-
cerium addition to the nitrile moiety gave ketone 25.20
Isopropylidene installation via olefin cross-metathesis in the
presence of Grubbs’ second-generation catalyst yielded pyran
6 in quantitative yield.21 This route effectively completes
the A ring fragment en route toward the title compound,
miyakolide.
In summary, an efficient, convergent approach toward
miyakolide has been examined. Through the use of atom-
economical transformations, the rapid assembly of advanced
intermediates with high levels of enantio- and diastereocon-
trol are discussed. The use of transition metal-mediated
addition reactions to provide more structurally complex
intermediates is just one of the highlights in the synthetic
design. Examination of the ruthenium-catalyzed alkene-alkyne
coupling highlight some important aspects of the transforma-
tion, in particular, the ability to exploit the latent Lewis
acidity of the catalyst to initiate in situ deprotection-protection
sequences, as well as lending insight into the catalytic
process.
elimination occurs at a faster rate, thereby leading to the
observed product distribution.
With a practical route toward diene 22h in hand, our
pursuit of pyran 6 continued with an addition of Et2AlCN
to epoxide 22h to yield the allylic alkylation precursor 22e
(Scheme 5).17 Treatment of allyl ether 22e with Pd2(dba)3·
Scheme 5. Final Assembly of Pyran 6
Acknowledgment. We thank the National Institutes of
Health (GM33049) and the Ruth L. Kirschstein postdoctoral
fellowship program (B.L.A.) for their generous support of
our programs. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of Califor-
nia–San Francisco, supported by the NIH Division of
Research Resources.
Supporting Information Available: Experimental pro-
1
cedures and copies of H NMR spectra are provided for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL800347U
(18) Trost, B. M.; Yang, H.; Wuitschik, G. Org. Lett. 2005, 7, 4761.
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Marcos, I. S.; Pedrero, A. B.; Sexmero, M. J.; Diez, D.; Basabe, P.; Garcia,
N.; Moro, R. F.; Broughton, H. B.; Mollinedo, F.; Urones, J. G. J. Org.
Chem. 2003, 68, 7496.
CHCl3 (2 mol %) in the presence of (S,S)-L and Hunig’s
base effectively closed the pyran ring with excellent dias-
tereoselectivity (15:1) favoring cis isomer 23 in a catalyst
(20) Gaunt, M. J.; Jessiman, A. S.; Orsini, P.; Tanner, H. R.; Hook,
D. F.; Ley, S. V. Org. Lett. 2003, 5, 4819.
(17) Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Org. Chem. 1987,
52, 667.
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