An alkyne strategy for the asymmetric synthesis of natural products: Application to (+)-spirolaxine methyl ether

Article abstract of DOI:10.1002/anie.200702637

(Chemical Equation Presented) Alkyne of magic: An efficient synthesis of (+)-spirolaxine methyl ether (1) was accomplished by using alkynes as versatile synthetic building blocks. Highlights include two ProPhenol-catalyzed asymmetric alkynylations and a P

Full text of DOI:10.1002/anie.200702637

Communications
DOI: 10.1002/anie.200702637
Natural Product Synthesis
An Alkyne Strategy for the Asymmetric Synthesis of Natural Products:
Application to (+)-Spirolaxine Methyl Ether**
Barry M. Trost* and Andrew H. Weiss
The ketone is traditionally regarded as the most useful and
important functional group in organic synthesis.[1] The defin-
ing feature of the reactivity of a ketone is its dual character as
both an inherent electrophile (at the carbonyl carbon atom)
and susceptibility to be rendered nucleophilic by deprotona-
tion (at the a carbon atom). The alkyne functional group
possesses the same bifunctional versatility. The acidity of a
terminal alkyne facilitates its use as a nucleophile (equilib-
rium pKa in dimethyl sulfoxide:[2] phenyl acetylene pKa =
28.7, cyclohexanone pKa = 26.4) when reacting with carbon-
yls, epoxides, and alkylating agents. While not inherently
electrophilic, alkynes can be chemoselectively activated
towards nucleophiles by complexation with a transition
metal.[3] For this reason, alkynes are effective ketone surro-
gates in the context of total synthesis.[4]
methyl ether (1). The spirolaxines were first isolated from
the white-rot fungus Sporotrichum laxum, and tested for
plant-growth inhibition.[8] Since their initial isolation, the
bioactivity of the spirolaxines has been studied for several
therapeutic manifolds, including cholesterol-lowering activ-
ity[9] and cytotoxicity against endothelial cells and several
tumor cell lines (LoVo, HL60).[10] One of the most striking
properties of 1 is its potent activity against Helicobacter pylori
and complete lack of antibacterial activity against a panel of
different microorganisms.[11]
The interesting biological activity and structure has also
attracted others to spirolaxine methyl ether (1), which has
resulted in three total syntheses.[12] The molecule is comprised
of two key portions:a phthalide and a spiroketal, linked by a
five carbon atom chain. Retrosynthetically we envisioned
spiroketal formation through a transition-metal-catalyzed
cyclization of alkyne diol 3 (Scheme 1).
Acetylenes offer many additional advantages over
ketones as synthetic intermediates. Since alkynes are inert
to a wide range of conditions
used in standard organic
transformations, the use of
protecting groups can often
be avoided. Acetylenes can
also be employed in chemo-
selective
carbon–carbon
bond forming reactions that
are unavailable to ketones
such as [2+2+2] cycloaddi-
tions,[5] alkene–alkyne cou-
pling reactions,[6] and reduc-
tive coupling reactions.[7]
To showcase the synthetic
advantage of alkynes, we
devised a synthetic strategy
toward the (+)-spirolaxine
Scheme 1. Retrosynthetic analysis.
We then envisioned a series of three alkyne additions to
stitch together the carbon framework while establishing both
the absolute and relative stereochemistry. The stereochemis-
try of the spiroketal fragment could be derived from (R)-(+)-
propylene oxide and a catalyst-controlled diastereoselective
alkyne addition to the a,b-unsaturated aldehyde 4. The
phthalide portion would be accessed by an enantioselective
alkynylation of 3,5-dimethoxybenzaldehyde. Thus, stereocon-
trolled alkyne additions to unsaturated aldehydes were
considered to be key to access both subunits.
The enantioselective addition of terminal alkynes to
aldehydes is an active field of research and many efficient
and complimentary catalyst systems have been designed.[13]
Our group reported the alkynylation of aromatic and
unsaturated aldehydes[13h] catalyzed by the commercially
available ProPhenol ligand (5). Our alkynylation demon-
[*] Prof. B. M. Trost, A. H. Weiss
Department of Chemistry
Stanford University
Stanford, CA 94305-5080 (USA)
Fax: (+1)650-725-0259
E-mail: bmtrost@stanford.edu
[**] We thank NIH (GM13598) and the National Science Foundation for
the generous support of our programs. A.H.W. thanks Glaxo-
SmithKline (ACS Division of Organic Chemistry Fellowship) and
Bristol–Myers Squibb (for a graduate fellowship). Mass spectra
were provided by the Mass Spectrometry Regional Center of the
University of California, San Francisco, which is supported by the
NIH Division of Research Resources. Palladium salts were gen-
erously supplied by Johnson–Matthey.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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strates broad scope with respect to both the aldehyde and the
alkyne, thus giving access to adducts that present challenges
to other alkynylation procedures. We questioned whether we
could use this empowering method twice in our route to build
up the carbon framework while controlling the stereochem-
istry on each side of the molecule.
In a forward sense, the ProPhenol-catalyzed addition of 4-
(tert-butyldimethylsilyloxy)-1-butyne to 3,5-dimethoxyben-
zaldehyde reproducibly led to high yield and enantiomeric
excess of the desired propargylic alcohol 6 (82% yield, 89–
90% ee) on a 6.5 mmol scale (Scheme 2). All of these
reagents were commercially available and used directly. The
absolute configuration was assigned by analogy to other
aromatic alkynylations with the ProPhenol catalyst.[13h]
ethyl acetate furnished the saturated alkane without reduc-
tion of the benzylic alcohol observed with Pd/C (Scheme 3).
Directed ortho-lithiation of the benzyl alcohol and subse-
quent trapping with CO2 would be the most direct route to
phthalide 8. Unfortunately, this lithiation suffered from poor
regioselectivity, a result also observed[18] with similar sub-
strates. In stark contrast, bromination proved to be an
extremely regioselective route to activation of the dimethoxy
aromatic ring, and provided phthalide precursor 7 in nearly
quantitative yield. From bromo alcohol 7, there were two
routes to the desired phthalide:Pd-catalyzed carbonylation [19]
or lithium-halogen exchange with CO2 trapping. Pd-catalyzed
carbonylation to access phthalide 8 was largely unsuccess-
ful,[20] with only trace product formed. Our initial examination
of the anionic route was initially frustrated by debrominated
product (presumably from rapid lithium-halogen exchange
and internal proton transfer).[18] This setback could be
mitigated by treating 7 with nBuLi (2.2 equiv) at À788C for
only one minute, then rapidly flushing the reaction with CO2
gas to trap the aryl lithium species. After acidic workup,
phthalide 8 was isolated with concomitant silyl group cleavage
in high yield (90%). Oxidation of the primary alcohol 8 and
homologation using Wittig olefination gave access to enal 4.
With the phthalide portion complete, our attention turned
to the synthesis of the spiroketal portion of the molecule. A
second ProPhenol-catalyzed asymmetric alkynylation was
employed to set the stereochemistry of the distal stereogenic
center and to construct the carbon skeleton (Scheme 4).
Catalyst-controlled diastereoselective alkynylation of enal 4
Scheme 2. ProPhenol-catalyzed enantioselective alkynylation.
TBS=tert-butyldimethylsilyl.
With direct access to homochiral propargylic alcohol 6,
our attention turned to the elaboration of phthalide 4
(Scheme 3). Acetylenes, although at the ketone oxidation
state, are excellent synthons for alkanes (-CH2CH2R), Z ole-
fins (through Lindlar reduction[14]), and E olefins (by dissolv-
ing metal reductions[15] or trans-hydrosilylation chemistry[16]).
Mild hydrogenation of alkyne 6 with the Adams catalyst[17] in
Scheme 3. Phthalide synthesis. a) (R,R)-5 (10 mol%), Me2Zn, 4-(tert-
butyldimethylsilyloxy)-1-butyne, toluene, 82%, 90% ee (determined by
HPLC on a chiral stationary phase); b) H2, PtO2, EtOAc, quant.;
c) NBS, CHCl3, 99%; d) nBuLi (1 min), THF, À788C then CO2, HCl/
H2O, 90%; e) TEMPO (5 mol%), bisacetoxyiodobenzene, 84%; f) (tri-
phenylphosphoranylidene)acetaldehyde, benzene, 808C, 56%.
NBS=N-bromosuccinimide, TEMPO=2,2,6,6-tetramethylpiperidin-1-
yloxyl.
Scheme 4. Spiroketal synthesis. a) 4,4-diethoxybut-1-yne, Me2Zn, (S,S)-
5 (10 mol%), toluene, 52%, 5:1 d.r. (d.r. and absolute configuration
determined by formation of methyl mandelate); b) TBSCl, imidazole,
CH2Cl2, 71%; c) H2, PtO2, 91%; d) PPTS, wet acetone, 98%; e) Ohira–
Bestmann, K2CO3, MeOH, 75%; f) nBuLi, BF3·Et2O, (R)-(+)-propylene
oxide. g) HCl/H2O, 51% (2 steps); h) [PdCl2(PhCN)2], THF/CH3CN
3:1, 79%. PPTS=pyridinium toluene-para-sulfonate.
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7665

Communications
with 4,4-diethoxybut-1-yne[21] gave access to the desired
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propargylic alcohol 9 without disturbing the relatively sensi-
tive phthalide group. The diastereomeric ratio and absolute
configuration of this new stereocenter were determined by
formation of the methyl mandelate ester (see the Supporting
Information). Our initial plan was to forego the TBS group
(Scheme 4, omit step b) to access the hydroxy aldehyde 11 (in
the hemiacetal tautomer). Subjection of 11 to TMS-diazo-
methane and subsequent trapping with propylene oxide did
not give alkyne diol 3 directly as planned because of a
competitive destruction of the phthalide lactone with TMS-
diazomethane. For this reason, alcohol 9 was silylated,
followed by global reduction to the fully saturated chain.
Acid hydrolysis of the diethyl acetal furnished the silyl-
protected alkoxy aldehyde 10. Homologation of aldehyde 10
to the terminal alkyne without destruction of the phthalide
was accomplish by the mild Ohira–Bestmann[22] alkynylation.
Spiroketal precursor 3 was accessed in two steps from
alkyne 12. Addition of the alkyne to R-(+)-propylene oxide
assisted by a Lewis acid gave the corresponding homopro-
pargylic alcohol. Subsequent treatment with HCl effectively
removed the TBS group to provide diol 3.
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In natural product synthesis, spiroketals are most com-
monly accessed by the alkoxylation of a ketone with pendant
alcohols. While this method is generally effective (and has
been used in all of the previous syntheses of spirolaxine), the
ketone diol precursor comes with the inherent chemoselec-
tivity issues associated with ketones. A complimentary alkyne
diol precursor (such as 3) would be inert to many of the
standard synthetic operations that would be incompatible
with a ketone. This type of spiroketalization of an alkyne was
first demonstrated by Utimoto.[23] Since its discovery, it has
been relatively underused in total synthesis[24] and methodo-
logical exploration.[25] We carried out the spiroketalization of
3 promoted by [PdCl2(PhCN)2] to give (+)-spirolaxine methyl
ether (1) in 79% yield. All spectroscopic data were in
agreement with the reported data.[8,12]
In conclusion, we have synthesized (+)-spirolaxine methyl
ether in 13 total steps using an alkyne-based strategy. The
stereochemistry in both the phthalide portion and the
spiroketal portion were established by ProPhenol catalyst-
controlled asymmetric alkynylation chemistry. The carbon
framework was constructed using terminal alkynes as nucle-
ophiles, and the spiroketal was formed using an internal
alkyne as an electrophilic ketone surrogate. This type of
alkyne strategy will help alleviate chemoselectivity issues of
ketones, and should be widely applicable to complex natural
product syntheses.
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Received:June 15, 2007
Published online:August 23, 2007
Keywords: alkynes · asymmetric synthesis · natural products ·
.
spiro compounds · total synthesis
[25] B. Liu, J. K. De Brabander, Org. Lett. 2006, 8, 4907.
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