Total synthesis of lehualide B by allylic alcohol-alkyne reductive cross-coupling

Article abstract of DOI:10.1021/ja104782u

The total synthesis of anticancer marine natural product lehualide B is described. Overall, the synthesis proceeds in just eight steps from a simple γ-pyrone, does not require the use of protecting groups, and delivers each nonconjugated trisubstituted alkene with high levels of stereoselection. The challenging C12-C16 bis-trisubstituted 1,4-diene was installed with a complex reductive cross-coupling reaction between a preformed Ti-alkyne complex and a pyrone-containing allylic alcohol.

Full text of DOI:10.1021/ja104782u

Published on Web 08/03/2010
Total Synthesis of Lehualide B by Allylic Alcohol-Alkyne Reductive
Cross-Coupling
Valer Jeso and Glenn C. Micalizio*
Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458
Received June 1, 2010; E-mail: micalizio@scripps.edu
in the establishment of the trisubstituted alkenes from ketones and
Abstract: The total synthesis of anticancer marine natural product
lehualide B is described. Overall, the synthesis proceeds in just
eight steps from a simple γ-pyrone, does not require the use of
protecting groups, and delivers each nonconjugated trisubstituted
alkene with high levels of stereoselection. The challenging
C12-C16 bis-trisubstituted 1,4-diene was installed with a complex
reductive cross-coupling reaction between a preformed Ti-alkyne
complex and a pyrone-containing allylic alcohol.
difficulties associated with advancing unstable ꢀ,γ-unsaturated
systems, transition metal-catalyzed coupling would be similarly
complex owing to the multistep nature of synthetic pathways to
the required stereodefined coupling partners and the associated
problems with regio- and stereocontrol in the reaction of intermedi-
ate π-allyl complexes. In addition to these difficulties, each alkene
present in the system (from C8-C16) is separated from at least
one other unsaturation by a methylene, a structural feature that both
decreases stability and further complicates any attempted synthesis.
Here, we describe the first total synthesis of any member of the
lehualide class of marine natural products, defining a route to
lehualide B that installs each trisubstituted alkene with high levels
of stereoselectivity and proceeds in just eight steps from a readily
available γ-pyrone.
The lehualides (Figure 1) are a family of pyrone-containing
marine natural products recently isolated from an undescribed
Hawaiian Plakortis sp. that have been shown to possess anticancer
properties in a focused evaluation of ovarian (IGROV-ET) and
leukemia (K562) cell lines.1 Interestingly, subtle differences in
pyrone substitution apparently lead to dramatic differences in
biological properties, as lehualide B (2) serves as a nanomolar
inhibitor of IGROV-ET cell proliferation, while its isomer lehualide
A was not found to have significant growth inhibitory effects in
either IGROV-ET or K562 cells. This differential biological profile
is interesting, especially in light of the close structural homology
between the pyrone ring of lehualide B and the pyridine subunit
shared by the piericidins (3), potent inhibitors of the mitochondrial
electron transport chain protein NADH-ubiquinone reductase
(Complex I).2
Our plan for the synthesis of lehualide B was centered around a
late stage introduction of the C12-C16 bis-trisubstituted skipped
diene by a regio- and stereoselective reductive cross-coupling
reaction of the fully functionalized coupling partner 5 with alkyne
4 (Figure 2).3 While we have previously described the merits of
Figure 2. Retrosynthesis of lehualide B.
Ti-mediated reductive cross-coupling of internal alkynes with allylic
alcohols as a means of preparing skipped dienes, this planned
synthesis of lehualide B presented new challenges to this chemistry
that include investigating the compatibility of this process with a
potentially sensitive γ-pyrone.4 Further, this optimistic bond
construction called for regioselective functionalization of a relatively
simple and sterically unbiased alkyne.5 Moving on, allylic alcohol
5 was thought to derive from 6, via stereoselective Claisen
rearrangement6 and addition of 2-propenylmagnesium chloride to
the resulting aldehyde. Finally, allylic alcohol 6 was reasoned to
be readily available from γ-pyrone 7.
Figure 1. Structure of lehualide A, B, and piericidin B1.
While lehaulide does not possess a single chiral center, the
stereochemistry and substitution of the polyunsaturated tail represent
a significant challenge to modern synthetic organic chemistry.
Perhaps the most complex stereochemical feature is the C12-C16
skipped diene that is composed of two trisubstituted alkenes of (E)-
and (Z)-stereochemistry. The synthesis of such stereodefined
architecture would be difficult with modern synthetic methods based
on carbonyl olefination or transition metal-catalyzed cross-coupling.
While methods based on carbonyl olefination would inevitably be
plagued by challenges associated with the control of stereochemistry
The synthesis of 7 commenced with ꢀ-ketoester 8 (Figure 3).
Iodosobenzene diacetate-mediated oxidation in methanol provided
the R-methoxy-ꢀ-ketoester 9 in 70% yield.7 Next, formation of the
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C O M M U N I C A T I O N S
Figure 3. Synthesis of γ-pyrone 7.
dianion of 9 (LDA, THF), followed by addition of the Weinreb
amide 10, furnished the tricarbonyl 11 as a mixture of isomers.
Stirring this tricarbonyl in neat H2SO4 for 21 h then resulted in the
generation of γ-pyrone 7 in a modest 24% yield (over two steps).
Our successful advance of γ-pyrone 7 to lehualide B is illustrated
in Figure 4. Metalation of 7, followed by addition to the R-phe-
nylseleno aldehyde 12, provided pyrone 13 in 78% yield. Subse-
quent oxidation and syn-elimination then furnished allylic alcohol
6 in 94% yield. Conversion to the stereodefined γ,δ-unsaturated
aldehyde 14 proceeded uneventfully and with the anticipated levels
of stereoselectivity typically seen for Claisen rearrangement of
related allylic alcohols (90% yield over two steps; E:Z ) 10:1).8
Chemoselective nucleophilic addition of 2-propenylmagnesium
bromide then delivered allylic alcohol 5 in 59% yield, suitably
functionalized for the planned reductive cross-coupling reaction.
In light of the unexpectedly high reactivity of the pyrone’s
carbonyl group toward nucleophiles, we opted to access the requisite
alkoxide for Ti-mediated reductive cross-coupling by using 2.5
equiv of LiHMDS to simultaneously mask the pyrone as a γ-enolate.
As depicted in Figure 5, exposure of the Li-dianion of 5 (17),
generated by exposure to LiHMDS in THF, to the Ti-alkyne
complex 18 (derived from reaction of 4 with ClTi(Oi-Pr)3 and
c-C5H9MgCl) resulted in the formation of coupled products in 50%
yield, presumably by a sequence of events that includes (1) rapid
and reversible ligand exchange (17 + 18 h 19), (2) intramolecular
carbometalation (via 20), and (3) syn-elimination (via 21).9 While
lehualide B was produced by this C-C bond process, regiochemical
control in the functionalization of 4 was poor, leading to the
Figure 5. Empirical model for allylic alcohol-alkyne coupling.
formation of a 1.3:1 mixture of isomeric products.5 To circumvent
this problem, we pursued reductive cross-coupling of TMS-propyne
(15) with allylic alcohol 5. Preformation of a Ti-alkyne complex
of 15 (by exposure to the combination of ClTi(Oi-Pr)3 and
c-C5H9MgCl, -78 to -40 °C) was followed by cannula transfer
to a -78 °C solution of the Li-dianion of 5, followed by slow
warming to 0 °C. After aqueous quench of this reaction, we were
delighted to find that reductive cross-coupling was successful and
furnished the stereodefined vinylsilane 16 in 61% yield (Z:E )
7:1; rs g 20:1). Interestingly, no evidence was found for competitive
functionalization of the pendant pyrone.
Next, conversion of the stereodefined vinylsilane to the corre-
sponding vinyliodide was straightforward (NIS, ClCH2CN,
EtOAc),10 and subsequent Pd-catalyzed cross-coupling with ben-
zylzinc bromide furnished lehualide B in 63% yield (over two
steps).
Overall, we report the first total synthesis of the marine natural
product lehualide B. The shortest synthetic pathway proceeds in
just six steps from γ-pyrone 7, yet delivers an inseparable mixture
of regioisomeric products. An alternative sequence was established
that delivers lehualide B in just eight steps from pyrone 7 and
establishes the complex polyunsaturated tail with high levels of
stereocontrol. The orthogonality of Claisen rearrangement and Ti-
Figure 4. Synthesis of lehualide B.
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C O M M U N I C A T I O N S
Nakamaru-Ogiso, E.; Yagi, T.; Boger, D. L. J. Am. Chem. Soc. 2006, 128,
11799–11807.
(3) Kolundzic, F.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, 15112–15113.
(4) For an example of the use of allylic alcohol-alkyne coupling in a recent
total synthesis, see: Macklin, T. K.; Micalizio, G. C. J. Am. Chem. Soc.
2009, 131, 1392–1393.
(5) For a recent review of regioselective reductive cross-coupling reactions of
unsymmetrical alkynes, see: Reichard, H. A.; McLaughlin, M.; Chen, M. Z.;
Micalizio, G. C. Eur. J. Org. Chem. 2010, 391–409.
(6) For a recent review of the Claisen rearrangement, see: Hiersemann, M.,
Nubbemeyer, U., Eds. The Claisen Rearrangement: Methods and Applica-
tions; Wiley-VCH: Weinheim, 2007; p 571.
(7) The procedure employed is a variation of that reported: Moriarty, R. M.;
Vaid, R. K.; Ravikumar, V. T.; Vaid, B. K.; Hopkins, T. E. Tetrahedron
1988, 44, 1603–1607.
(8) For an early example, see: Johnson, W. S.; Werthem, A. L.; Bartlett, W. R.;
Brocksom, T. J.; Li, T. T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem.
Soc. 1970, 92, 741–743.
(9) While our standard reaction conditions for allylic alcohol-alkyne reductive
cross-coupling start with preformation of a Ti-alkyne complex (followed
by addition of the allylic alkoxide), during the study of this reaction we
found that premixing the coupling partners prior to addition of Ti(IV)
alkoxide and Grignard reagent provided higher yields of the coupled
product.
mediated reductive cross-coupling reaction is notable for the
elaboration of the intermediate allylic alcohols 6 and 5. Finally,
the success of the reductive cross-coupling reaction in advancing
pyrone 5 speaks to the chemoselectivity possible in this type of
bimolecular C-C bond forming process and further supports the
role that this and related Ti-mediated convergent coupling reactions
can play in complex molecule synthesis.
Acknowledgment. We gratefully acknowledge financial support
of this work by the American Cancer Society (RSG-06-117-01)
and the National Institutes of Health-NIGMS (GM80266).
Supporting Information Available: Experimental procedures and
tabulated spectroscopic data for new compounds (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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(2) For a recent total synthesis of piericidin B1 and discussion of structure-
activity relationships, see: Schnermann, M. J.; Romero, F. A.; Hwang, I.;
(10) Stamos, D. P.; Taylor, A. G.; Kishi, Y. Tetrahedron Lett. 1996, 37,
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