Total synthesis of (-)-18-epi-peloruside A: An alkyne linchpin strategy

Article abstract of DOI:10.1021/ol4024997

A convergent synthetic route toward cytotoxic agent peloruside A that hinges on the use of an alkyne linchpin to assemble the natural product is described. Other highlights of this synthesis include an asymmetric desymmetrization reaction of a 1,3-diol, a one-pot conversion of a dibromoolefin to a stereodefined enone, and a diastereoselective aldol condensation. Misassignment of the absolute stereochemistry of the C18 stereocenter in our synthesis provided the natural product epimeric at the C18 ethyl stereocenter.

Full text of DOI:10.1021/ol4024997

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Total Synthesis of (ꢀ)-18-epi-Peloruside
A: An Alkyne Linchpin Strategy
Barry M. Trost,* David J. Michaelis, and Sushant Malhotra
Department of Chemistry, Stanford University, Stanford, California 94305-5080,
United States
bmtrost@stanford.edu
Received August 30, 2013
ABSTRACT
A convergent synthetic route toward cytotoxic agent peloruside A that hinges on the use of an alkyne linchpin to assemble the natural product is
described. Other highlights of this synthesis include an asymmetric desymmetrization reaction of a 1,3-diol, a one-pot conversion of a
dibromoolefin to a stereodefined enone, and a diastereoselective aldol condensation. Misassignment of the absolute stereochemistry of the C18
stereocenter in our synthesis provided the natural product epimeric at the C18 ethyl stereocenter.
Alkynes are versatile functional groups in organic synthe-
sis due to their ability to undergo catalytic transformations
at the CꢀC triple bond and due to the inherent acidity of
the acetylenic and propargylic CꢀH bonds. Our labora-
toryhastakenadvantageof this broadreactivityof alkynes
in the context of total synthesis to perform alkeneꢀalkyne1
and alkyneꢀalkyne2 coupling reactions, including for
macrolactonizations; for hydrosilylation reactions to gen-
erate stereodefinedtrans olefins;3 for asymmetricadditions
to aldehydes to generate enantioenriched propargylic
alcohols;4 and for metal-catalyzed alcohol additions to
the triple bond to access pyran rings.2,4f In this report, we
capitalize on the latent nucleophilicity of both propargylic
and acetylenic CꢀH bonds and employ an alkyne as a
linchpin for assembling the carbon framework of macro-
lide peloruside A. We then take advantage of the reactivity
of the alkyne triple bond to construct the highly oxyge-
nated pyran ring of the natural product.
Peloruside A (1) is a polyketide natural product isolated
from a marine sponge Mycale hentscheli.5 The impressive
antimitotic activity of peloruside A,6 which includes
microtubule-stabilizing activity that is synergistic with
paclitaxel,7 has made it an attractive target for total
synthesis.8,9 Contained within the pyran ring of peloruside
A is a masked R-hydroxyketone, which we recognized as
an alkyne derivative. This observation forms the basis for
our synthetic strategy, where a simple acetylene linchpin
would enable assembly of the carbon framework.
Our retrosynthetic analysis deconstructs the final target
into aldehyde 2 and alkyne 3, which would allow us to
assemble the right and left-hand portions of peloruside A
via an aldehyde alkynylation reaction (Figure 1). The
alkyne functional group would then enable construction
of the pyran ring via metal-catalyzed alcohol-addition to
the alkyne, followed by oxidation of the resulting vinyl
ether to the fully oxygenated ring. We envisioned accessing
alkyne 3 through a diastereoselective aldol reaction be-
tween enone 4 and aldehyde 5. Enone 4 would be obtained
(1) Trost, B. M.; Amans, D.; Seganish, W. M.; Chung, C. K. J. Am.
Chem. Soc. 2009, 131, 17087.
(2) Trost, B. M.; Dong, G. Nature 2008, 456, 485–488.
(3) (a) Trost, B. M.; Sieber, J. D.; Qian, W.; Dhawan, R.; Ball, Z. T.
Angew. Chem Int. Ed. 2009, 121, 5586–5589. (b) Reference 4c.
(4) (a) Trost, B. M.; Weiss, A. H. Angew. Chem., Int. Ed. 2007, 46,
7664–7666. (b) Trost, B. M.; Burns, A. C.; Bartlett, M. J.; Tautz, T.;
Weiss, A. H. J. Am. Chem. Soc. 2012, 134, 1474–1477. (c) Trost, B. M.;
Bartlett, M. J. Org. Lett. 2012, 14, 1322–1325. (d) Trost, B. M.;
Quintard, A. Angew. Chem., Int. Ed. 2012, 51, 6704–6708. (e) Trost,
B. M.; Quintard, A. Org. Lett. 2012, 17, 4698–4700. (f) Trost, B. M.; O.
Boyle, B. M.; Hund, D. J. Am. Chem. Soc. 2009, 131, 15061–15074.
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(6) (a) Hood, K. A.; West, L. M.; Rouwe, B.; Northcote, P. T.;
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3356–3360. (b) Gaitanos, T. N.; Buey, R. M.; Diaz, J. F.; Northcote,
P. T.; Teesdale-Spittle, P.; Andreu, J. M.; Miller, J. H. Cancer Res. 2004,
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r
10.1021/ol4024997
XXXX American Chemical Society

Scheme 1. Synthesis of Aldehyde 5
protection of the resulting alcohol as the PMB ether
followed by oxidative cleavage of the olefin gave the
requisite aldehyde 5.
Further elaboration of the left-hand portion of the alkyne
required the synthesis of enone 4 (Scheme 2). Asymmetric
desymmetrization of 1,3-diol 8 using catalytic diethylzinc
(S,S)-ProPhenol generated the enantioenriched mono-
benzoylated product 9 in quantitative yield and high
enantioselectivity.10 Enzymatic desymmetrizations of 8
have proven particularly challenging, and only the (R)-
enantiomer of monoacetylated 8 can be obtained enzy-
matically in high enantioselectivity via monohydrolysis of
the bisacetate substrate.12 Our desymmetrization meth-
od, however, delivers either enantiomer of 9 in good yield
and enantioselectivity simply by switching the enantio-
mer of catalyst. Subsequent oxidation of 9 to the beta-
benzoylaldehyde, followed by immediate treatment with
carbon tetrabromide and triphenylphosphine furnished
dibromoolefin 10 without observable epimerization of
the ethyl stereocenter or byproducts arising from
β-elimination. Our original synthetic studies (see the Sup-
porting Information) led us to believe that the desymme-
trization reaction with (S,S)-ProPhenol generated the
desired (R)-stereochemistry at the ethyl center. However,
when the spectra of our final product did not match those
of the natural product, we then obtained a crystal structure
of dibromide 10, which confirmed that we obtained the (S)-
stereochemistry, as depicted in Scheme 2, leading ultimately
to the epimeric stereocenter to that of the natural product.
Nevertheless, ent-9 (characterized as the dibromide ent-10)
was obtained with the same level of enantioselectivity but
opposite in configuration when (R,R)-ProPhenol was em-
ployed, verifying that the natural product could be obtained
with equal ease through our synthetic route.
Figure 1. Retrosynthetic analysis of (þ)-peloruside A.
by an asymmetric desymmetrization reaction of meso 1,3-
diols previously developed in our laboratory.10 We hy-
pothesized that alkyne 5 could be readily accessed by the
sequential treatment of the dianion of isopropylacetylene
(our alkyne linchpin) with two different electrophiles,
thereby taking advantage of the differential reactivity of
the propargylic and acetylenic anions.
In the forward sense, treatment of commercially avail-
ablealkyne 6with2 equivofn-butyllithium toformthe 1,3-
dilithiated intermediate, followed by sequential trapping
with N,N-dimethylformamide and chlorotriethylsilane, gave
aldehyde 7 in good yield in a single transformation
(Scheme 1). Allylation with (ꢀ)-Ipc2B(allyl)borane pro-
vided the desired alcohol in high enantioselectivity,11 and
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Ho, S. J. Am. Chem. Soc. 2009, 131, 3840. (e) Hoye, T. R.; Jeon, J.; Kopel,
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2010, 49, 6151. (f) McGowan, M. A.; Stevenson, C. P.; Schiffler, M. A.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2010, 49, 6147–6150.
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Taylor, R. E. Org. Lett. 2012, 14, 669–671. (d) Gazaille, J. A.; Abramite,
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The conversion of dibromide 10 to enone ent-4 was
accomplished in a single step using a method developed
by Miyashita and co-workers.13 Treatment of 10 with
dimethyl cuprate led to selective methylation of the less
hindered bromide and formation of a (Z)-vinyl cuprate
intermediate. Quenching with acetyl bromide provided the
desired product. Retaining the geometrical integrity of the
alkene in this process proved quite challenging. Key to its
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J. Can. J. Chem. 1994, 72, 1312–1327. (b) Izquierdo, I.; Plaza, M. T.;
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Chem.;Eur. J. 2008, 14, 7648–7657. (b) Trost, B. M.; Mino, T. J. Am.
Chem. Soc. 2003, 125, 2410–2411.
(11) The assignment of the absolute stereochemistry for the allylation
derives from well-established precedent: Jadhav, P. K.; Bhat, K. S.;
Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986, 51, 432–439. See also:
Trost, B. M.; Dong, G. Nature 2008, 456, 485–488.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Synthesis of Enone ent-4
Scheme 3. Synthesis of Alkyne Partner
ultimate success was a reverse quench procedure where the
intermediate (Z)-vinyl cuprate was added to excess acetyl
bromide at low temperature, providing the enone in >10:1
isomeric purity and 83% isolated yield of pure ent-4. The
use of acetyl bromide in place of acetyl chloride also
enabled reactivity with the vinyl cuprate at lower tempera-
ture, contributing to the success of the reaction.
Scheme 4. Synthesis of Northern Fragment
The union of fragments ent-4 and 5 was next accom-
plished with a diastereoselective aldol reaction (Scheme 3).
The use of zinc chloride as a coordinating Lewis acid was
essential in achieving 1,3-asymmetric induction (74%, 4:1 dr).
The 1,3-trans relationship between the two oxygen cen-
ters was confirmed by formation of the cyclic PMP acetal
via oxidation of the PMB ether with DDQ, then through
NOE correlations (see the Supporting Information). Pro-
duct 11 was then methylated, and a directed reduction of
the carbonyl group with dimethylaluminum chloride and
tributyltin hydride was used to establish the stereochem-
istry of the allylic alcohol with high diastereocontrol.14
The newly created syn 1,3-stereochemistry was verified by
mandelate ester analysis.15 The terminal acetylene was
then deprotected to provide intermediate 12 in prepara-
tion for the aldehyde addition reaction. At this stage, we
found it necessary to remove the benzoyl protecting
group as it interfered with the subsequent alkyne addition
step. Thus, removal of the benzoate with potassium
carbonate in MeOH, followed by selective formation of
the TIPS ether of the primary alcohol8b and PMB protec-
tion of the allylic alcohol provided the necessary alkyne
13 for coupling to aldehyde 2.
The synthesis of the right-hand portion of peloruside A
(2) proceeded through a catalytic asymmetric dihydroxylation
strategy (Scheme 4). Reduction of commercially available
acetal 14, followed by HWE olefination provided the
substrate (15) for dihydroxylation. Osmium-catalyzed
asymmetric dihydroxylation led to diol 16 in good yield
and enantioselectivity with the desired syn stereochemis-
try. Selective protection of the R-hydroxyl group as the
MOM ether, then methylation of the β-hydroxyl group
and hydrolysis of the acetal all proceeded to give aldehyde
17. Allylation with (þ)-Ipc2B(allyl)borane, TES protec-
tion of the resulting alcohol, and oxidative cleavage of the
olefin gave aldehyde 2 in excellent yield (80%) over the
three steps. The stereochemistry of the allylation product
was again verified by mandelate ester analysis.15
The simple coupling of alkyne 13 with aldehyde 2 as-
sembled the entire carbon framework of 18-epi-peloruside
A and introduced the requisite functionality to construct
the highly oxidized pyran ring (Scheme 5). Deprotona-
tion of the terminal acetylene of 13 with n-butyllithium
followed by transmetalation of the lithium acetylide to
magnesium and addition to aldehyde 2 resulted in an 87%
yield of propargylic alcohol 18 (∼2:1 dr). The diastereo-
selectivity of the addition was inconsequential as we found
it necessary to oxidize the propargylic alcohol prior to the
metal-catalyzed alcohol addition to the alkyne. Thus,
oxidation with manganese dioxide and then selective de-
protection of the triethylsilyl ether provided intermediate
19, which was poised to undergo metal-catalyzed cyclization
onto the ynone. As little as 2.5 mol % of a gold(I) catalyst
could facilitate efficient cyclization to form the pyranone
ring (94% yield).16 Final bis-deprotection of both PMB
protecting groups generated the appropriate precursor
(20) for macrolactonization.
Intermediate 20 closely resembles an intermediate from
the synthesis of peloruside A reported by the Taylor
(14) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am.
Chem. Soc. 2001, 123, 10840–10852.
(15) The 1,3-syn relationship of the oxygen centers was confirmed via
formation of the (R)- and (S)-O-methylmandelate esters and then by
analysis of the 1H NMR spectra (see the Supporting Information).
(16) Forareviewongold(I)-catalyzedCꢀX bond formation, see: Corma,
ꢀ
A.; Leyva-Perez, A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657–1712.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 5. Alkyne Addition for Assembly of 2 and 3
Scheme 6. Completion of (ꢀ)-18-epi-Peloruside A
laboratory,17,8b and thus, our final sequence of reactions
closely follows their reported route. We found it particu-
larly troublesome to liberate the free acid by hydrolysis of
the methyl ester without epimerizing the R center. Success-
ful cleavage was accomplished using excess trimethyltin
hydroxide at elevated temperatures.18
Our strategy takes advantage of the latent nucleophi-
licity of both propargylic and acetylenic CꢀH bonds to
perform key carbonꢀcarbon bond-forming reactions. The
utilization of the alkyne for metal-catalyzed intramolecu-
lar hydration and later oxidation to the R-hydroxy ketone
further demonstrate the utility of the alkyne functional
group in the context of total synthesis. While our end game
strategy closely follows the sequence reported by the Taylor
laboratory,8b our alkyne strategy allowed us to arrive at the
required pyranone intermediate (20) in a significantly re-
duced number of steps. Interestingly, the efficiency of our
prophenol-catalyzed diol desymmetrization proves to be
significantly better than the reported enzymatic methods.11
Although a misassignment of the absolute configuration of
the product obtained in our desymmetrization reaction led to
the synthesis of (ꢀ)-18-epi-peloruside A, the epimer corre-
sponding to the natural product should also be accessed
simply by preparation of 4 rather than ent-4, which we
established can be done. Thus, this route readily supplies
epimers of the natural product itself, which is of value to
establish structureꢀactivity relationships. This and addi-
tional synthetic studies will be reported in due course.
Our efforts toward macrolactonization were only suc-
cessful under Yamaguchi conditions, and after extensive
optimization we were able to obtain macrolactone 21 in a
respectable yield (57%, 2 steps) (Scheme 6). Accessing 18-
epi-peloruside A from intermediate 21 was most easily
accomplished by performing the final four steps without
intermediate characterization. Thus, reduction of the en-
one in 21 with sodium borohydride and cerium trichloride,
followed by directed oxidation of the enol ether with
m-CPBA, gave 22.19 Selective methylation of the equatorial
hydroxyl group6a and global deprotection provided
18-epi-pelosuride A in an average of 70% yield per step over
the final four steps. Very small discrepancies in the NMR
spectra and the opposite sign of the optical rotation of our
final compound from that of the natural product led us to
question the stereoselectivity of our desymmetrization reac-
tion since the stereochemistries of the other stereocenters were
independently verified. The studies described above con-
firmed the identity of our product as (ꢀ)-18-epi-peloruside A.
In conclusion, we have demonstrated that our alkyne
linchpin strategy is an efficient method for assembling the
carbon framework and oxidized pyran ring of peloruside A.
Acknowledgment. Funding was provided by the National
Institutes of Health (GM033049). We thank the NSF for their
generous support of our programs. D.J.M. wishes to thank
the NIH for a postdoctoral fellowship (F32 GM093467).
(17) Protection of 21 as the MOM ether allowed us to intercept an
intermediate from the Taylor synthesis. Spectroscopic data from our
product did not match what was previously reported, suggesting that a
stereocenter formed previous to the final sequence of four reactions was
incorrect (see the Supporting Information).
(18) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina,
B. S. Angew. Chem., Int. Ed. 2005, 44, 1378–1382.
(19) The small coupling constant (2.5 Hz) between the C8 and C7
hydrogens on the pyran ring of (ꢀ)-18-epi-peloruside A confirms that
the 1,2-syn stereochemistry was obtained in the reduction/directed
oxidation sequence from 21 to generate 22. See ref 5.
Supporting Information Available. Experimental proce-
dures, characterization data, and copies of 1H NMR and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
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