Total Synthesis of Leiodermatolide A via Transfer Hydrogenative Allylation, Crotylation, and Propargylation: Polyketide Construction beyond Discrete Allyl- or Allenylmetal Reagents

Article abstract of DOI:10.1021/jacs.1c06062

The total synthesis of leiodermatolide A was accomplished in 13 steps (LLS). Transfer hydrogenative variants of three carbonyl additions that traditionally rely on premetalated reagents (allylation, crotylation, and propargylation) are deployed together i

Full text of DOI:10.1021/jacs.1c06062

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Communication
Total Synthesis of Leiodermatolide A via Transfer Hydrogenative
Allylation, Crotylation, and Propargylation: Polyketide Construction
beyond Discrete Allyl- or Allenylmetal Reagents
Yuk-Ming Siu, James Roane, and Michael J. Krische*
Cite This: J. Am. Chem. Soc. 2021, 143, 10590−10595
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ABSTRACT: The total synthesis of leiodermatolide A was accomplished in 13 steps (LLS). Transfer hydrogenative variants of
three carbonyl additions that traditionally rely on premetalated reagents (allylation, crotylation, and propargylation) are deployed
together in one total synthesis.
atural products that disrupt microtubule dynamics have
1
Nfound broad use as anticancer agents. Leiodermatolide
A is an antimitotic marine macrolide that was isolated in 2008
from crude extracts of a deep sea lithistid sponge of the genus
Leiodermatium found off the Florida coast (Figure 1).2 In a
panel of human cancer cell lines, leiodermatolide A exhibited
potent antiproliferative effects, selectively perturbing tubulin
dynamics at nM concentrations through a novel mechanism:
while incurring abnormal spindle formation at nM concen-
trations in two different cancer cell lines, purified tubulin
remained undisturbed in vitro even at much higher
concentrations.2,3 The scarce supply and compelling biology
of leiodermatolide A has driven efforts toward its de novo
chemical synthesis, resulting in truly impressive total syntheses
by Paterson4 and Furstner5 and substructure syntheses by
̈
Maier.6 The synthesis of leiodermatolide analogues5b,c,6d have
led to additional biological data that reveal mitotic arrest,
micronucleus induction, centrosome amplification, and tubulin
disruption in human U2OS cells without evidence for direct
binding of tubulin in cell-free analyses.5b On the basis of these
data, centrosome declustering was suggested as a possible
mechanism of action.7 Further investigations into leioderma-
tolide’s unique biology have been prohibited due to lack of
material.
The issues surrounding leiodermatolide A are emblematic of
the persistent challenges associated with the construction of
structurally complex secondary metabolites that continue to
evoke innovation across the field of chemical synthesis. In the
specific context of type I polyketides, which are ubiquitous in
human medicine,8 commercial manufacturing routes rarely
exploit de novo chemical synthesis, highlighting the need for
more efficient and process-relevant synthetic methods. Inspired
by the broad use of hydrogenation and transfer hydrogenation
in the production of clinical candidates, we have advanced a
suite of catalytic enantioselective carbonyl reductive couplings
based on alcohol mediated hydrogen transfer.9,10 Using these
methods, an initial (but unsuccessful) campaign toward
leiodermatolide A was undertaken.11 Here, we disclose a
more fruitful approach employing catalytic enantioselective
Figure 1. Structures of leiodermatolides A−C, prior total syntheses,
and retrosynthetic analysis. Longest linear sequence (LLS); total steps
(TS).
Received: June 11, 2021
Published: July 8, 2021
https://doi.org/10.1021/jacs.1c06062
J. Am. Chem. Soc. 2021, 143, 10590−10595
© 2021 American Chemical Society
10590

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Scheme 1. Preparation of Fragment A via Catalytic Enantioselective Transfer Hydrogenative Carbonyl Allylation and
a
Crotylation
a
1
Yields are of material isolated by silica gel chromatography. Diastereoselectivities were determined by H NMR of crude reaction mixtures.
Enantioselectivities were determined by chiral stationary phase HPLC analysis. TTMPP = Tris(2,4,6-trimethoxyphenyl)phosphine. See Supporting
Information for experimental details.
transfer hydrogenative allylation,12a,b crotylation,12c−e and
propargylation12f,13 that has resulted in a 13 step longest
linear sequence (LLS) total synthesis of leiodermatolide A,
constituting the most concise route to this compound
reported, to date.
methane,21 and silylzinc-mediated regio- and stereospecific
copper-catalyzed allylic substitution, as described by Oester-
eich.22 Aldehyde 8 is prepared through transfer hydrogenative
crotylation of acetylenic aldehyde 512c−e followed by
Mitsunobu inversion-saponification23 to furnish 1,5-enyne 7.
Conversion of 7 to the TOM ether (iPr3SiOCH2)24 followed
by ozonolysis delivers aldehyde 8. With allyl silane 4 and
aldehyde 8 in hand, Hosomi−Sakurai reaction14 was
attempted. Upon evaluation of different Lewis acids,11 it was
found that chelation-controlled addition could be achieved in
62% yield using AlEtCl2 (250 mol%). Exhaustive deprotection
of the Hosomi−Sakurai product delivers Fragment A.
Retrosynthetically, leiodermatolide A was envisioned to arise
through a polyconvergent assembly of Fragments A, B, and C
(Figure 1). Fragment A is accessible through the Hosomi−
Sakurai reaction14 of aldehyde 8 (prepared by catalytic
enantioselective transfer hydrogenative crotylation of acety-
lentic aldehyde 5),12e with allylsilane 4 (prepared by
enantioselective transfer hydrogenative allylation of tiglic
aldehyde 1).11,12a−c Fragment B is generated via transfer
hydrogenative carbonyl propargylation employing an enyne
pronucleophile.12f,13 Finally, Fragment C is prepared by
Mukaiyama aldol reaction of phenyl acrylate 11 with propanal
12 to give the anti-aldol15,16 followed by kinetic resolution via
asymmetric acetylation using Birman’s catalyst,17 and then
Dieckmann condensation-ketone allylboration.5b,18
Fragment B is prepared via iridium-catalyzed enyne-
mediated propargylation of dienol 10 (eq 1),12f,13 which is a
known compound accessible in 2 steps from crotonaldehyde.25
The synthesis of Fragment A begins with the conversion of
tiglic aldehyde 1 to allyl silane 4 (Scheme 1).11 Using 1.25 mol
% loadings of the π-allyliridium-C,O-benzoate modified by (S)-
BINAP, 2-propanol-mediated reductive coupling of tiglic
aldehyde 1 with allyl acetate delivers the homoallylic alcohol
2 in 78% yield and 92% ee.12a,b As shown, the chromato-
graphically stable iridium catalyst could be recovered in 39%
yield and recycled without erosion in performance. Conversion
of alcohol 2 to aldehyde 3 is achieved via benzoylation of
secondary alcohol followed by chemoselective anti-Markovni-
kov Wacker oxidation19 of the less substituted olefin. Aldehyde
3 is transformed to allyl silane 4 via Pinnick oxidation,20
treatment of the resulting carboxylic acid with TMS-diazo-
The reported method for propargylation utilized an enyne
substituted by (TIPSO)Me2C. However, it was anticipated
that the δ-lactone of leiodermatolide A would not tolerate
conditions required for deprotection of this group (which
involves base-mediated elimination of acetone). Hence, the
indicated triisopropylsilyl terminated enyne 9 was used and, to
our delight, good levels of diastereo- and enantioselectivity
were observed.
The synthesis of Fragment C, which incorporates the δ-
lactone of leiodermatolide A, is accomplished in 5 steps
(Scheme 2). The δ-lactone of leiodermatolide A was previously
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Communication
allylation used to form Fragment C represents the mismatched
case.
Scheme 2. Preparation of Fragment C via Kinetic
Resolution of anti-Aldol 13 Using Birman’s Catalyst
a
With Fragments A, B and C in hand, the total synthesis of
leiodermatolide A was undertaken (Scheme 3). The union of
Fragment B and C is achieved via cross-metathesis using the
second generation Hoveyda−Grubbs catalyst. The alkyne
moiety present in Fragment B made this transformation
challenging, yet dienyne 15 could be formed in 47% yield
along with a dimer derived from Fragment C (that could be
subjected to cross-metathesis with Fragment B to provide 15
in comparable yield). Conversion of 15 to the cis-vinyl iodide
16 was accomplished in a three step sequence involving silyl-
deprotection of the TIPS alkyne, NIS-mediated iodination of
the resulting terminal alkyne,26 and diimide reduction of the
acetylenic iodide to the cis-vinyl iodide 16 using NBSH.27
Sonogashira coupling of equimolar quantities of cis-vinyl iodide
16 and Fragment A occurred in the presence of the free
carboxylic acid28 to deliver the conjugated enyne 17 in 60%
yield. Yamaguchi lactonization29 of compound 17 occurred in
remarkably high yield despite the presence of multiple
unprotected hydroxyl groups. Several methods for semi-
hydrogenation of the macrocyclic enyne were explored,
a
Diastereoselectivities were determined by 1H NMR of crude reaction
mixtures. Enantioselectivities were determined by chiral stationary
phase HPLC analysis.
including Zn(Cu/Ag) amalgam as described by Fu
̈
rstner.4 In
prepared by Furstner using a chiral enolate modified by Evan’s
̈
auxiliary.5 Direct catalytic enantioselective aldol addition of a
propionate ester such as 11 with propanal 12 would avoid
manipulations associated with the preparation, installation, and
removal of an auxiliary, yet aldol additions of this type remain
an unmet challenge. Kinetic resolution of the racemic aldol rac-
13, which is accessible via anti-diastereoselective Mukaiyama
aldol addition,15,16 was deemed an attractive alternative, as the
resulting acetate could be directly subjected to Dieckmann
condensation to deliver the cyclic β-ketoester 14. Using
Birman’s catalyst,17 (R)-HBTM, formation of the acetate was
realized with useful levels of selectivity and, therefrom,
enantiomerically enriched β-ketoester 14 was made. BINOL-
catalyzed allylboration of β-ketoester 145b,18 completes the
synthesis of Fragment C. Upon use of racemic BINOL as
catalyst, a 1:3 diastereomeric ratio was observed in favor of the
opposite stereoisomer, indicating that the asymmetric
our hands, these methods were problematic due to over-
reduction accompanied by isomerization of the initially formed
cis,cis-diene. We eventually found that semihydrogenation
using a cationic rhodium catalyst provided the most reliable
results.30,31 It should be noted that our cis,cis-diene is identical
with material prepared by Paterson, who found that treatment
of the C7,C9-diol with Cl3CC(O)NCO resulted in a 4:1 ratio
of the C7 and C9 carbamates (favoring the undesired isomer).5
In a model system, we found the regioselectivity of
carbamoylation could be inverted upon pretreatment with 9-
BBN (eq 2).32 This effect was less pronounced in the
carbamoylation en route to leiodermatolide A, but still availed
an improvement relative to the intrinsic bias of the system,
enabling access to leiodermatolide A in 13 steps (LLS)the
most concise synthesis of leiodermatolide A reported, to date.
a
Scheme 3. Union of Fragments A, B, and C and Total Synthesis of Leiodermatolide A
a
Yields are of material isolated by silica gel chromatography. See Supporting Information for experimental details.
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C.; Jordan, M. A. Microtubule-Binding Agents: A Dynamic Field of
Cancer Therapeutics. Nat. Rev. Drug Discovery 2010, 9, 790−803.
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(2) For isolation and partial structure determination of leioderma-
tolides A and B, see: (a) Wright, A. E.; Reed, J. K.; Roberts, J.;
Longley, R. E. Antiproliferative Activity of The Leiodermatolide Class
of Macrolides. U. S. Pat. Appl. Publ. US 20080033035 A1 20080207,
2008. (b) Paterson, I.; Dalby, S. M.; Roberts, J. C.; Naylor, G. J.;
Guzmán, E. A.; Isbrucker, R.; Pitts, T. P.; Linley, P.; Divlianska, D.;
Reed, J. K.; Wright, A. E. Leiodermatolide, a Potent Antimitotic
Macrolide from The Marine Sponge Leiodermatium sp. Angew.
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To conclude, the synthetic challenges posed by the
structural complexity of polyketide natural products have
evoked numerous advances in acyclic stereocontrol, especially
in the context of carbonyl addition. Whereas the initial lexicon
of asymmetric methods that emerged focused on the use of
premetalated C-nucleophiles and chiral auxiliaries, we aim to
advance a suite of catalytic enantioselective C−C couplings
that bypass discrete organometallic reagents and stoichiometric
chiral inducing elements. The present total synthesis of
leiodermatolide A, which exploits asymmetric alcohol-medi-
ated allylation, crotylation, and propargylation, exemplifies how
time-honored transformations that have traditionally relied on
premetalated reagents can now be conducted catalytically from
tractable π-unsaturated pronucleophiles.
(4) For work on leiodermatolide from the Paterson laboratory, see:
(a) Paterson, I.; Paquet, T.; Dalby, S. M. Synthesis of the Macrocyclic
Core of Leiodermatolide. Org. Lett. 2011, 13, 4398−4401.
(b) Paterson, I.; Ng, K. K.-H.; Williams, S.; Millican, D. C.; Dalby,
S. M. Total Synthesis of the Antimitotic Marine Macrolide
(−)-Leiodermatolide. Angew. Chem., Int. Ed. 2014, 53, 2692−2695.
(c) Paterson, I.; Williams, S. Strategy Evolution in the Total Synthesis
of (−)-Leiodermatolide. Isr. J. Chem. 2017, 57, 192−201.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c06062.
■
sı
Graphical summaries of prior total syntheses, exper-
imental procedures, and spectral data for all new
compounds (PDF)
(5) For work on leiodermatolide from the Fu
(a) Willwacher, J.; Kausch-Busies, N.; Furstner, A. Divergent Total
̈
rstner laboratory, see:
̈
AUTHOR INFORMATION
Corresponding Author
Michael J. Krische − Department of Chemistry, University of
Texas at Austin, Austin, Texas 78712, United States;
orcid.org/0000-0001-8418-9709; Email: mkrische@
mail.utexas.edu
Synthesis of the Antimitotic Agent Leiodermatolide. Angew. Chem.,
Int. Ed. 2012, 51, 12041−12046. (b) Mailhol, D.; Willwacher, J.;
Kausch-Busies, N.; Rubitski, E. E.; Sobol, Z.; Schuler, M.; Lam, M.-
■
H.; Musto, S.; Loganzo, F.; Maderna, A.; Furstner, A. Synthesis,
̈
Molecular Editing, and Biological Assessment of the Potent Cytotoxin
Leiodermatolide. J. Am. Chem. Soc. 2014, 136, 15719−15729.
(c) Furstner, A.; Mailhol, D.; Willwacher, J. Leiodermatolide
̈
Derivatives and Their Use. Eur. Pat. Appl. EP 3012257 A1
20160427, 2016.
Authors
Yuk-Ming Siu − Department of Chemistry, University of Texas
at Austin, Austin, Texas 78712, United States
James Roane − Department of Chemistry, University of Texas
at Austin, Austin, Texas 78712, United States
(6) For work on leiodermatolide from the Maier laboratory, see:
(a) Navickas, V.; Rink, C.; Maier, M. E. Synthetic Studies towards
Leiodermatolide: Rapid Stereoselective Syntheses of Key Fragments.
Synlett 2011, 2011, 191−194. (b) Rink, C.; Navickas, V.; Maier, M. E.
An Approach to the Core Structure of Leiodermatolide. Org. Lett.
2011, 13, 2334−2337. (c) Reiss, A.; Maier, M. E. Toward
Leiodermatolide: Synthesis of the Core Structure. Org. Lett. 2016,
18, 3146−3149. (d) Reiss, A.; Maier, M. E. Synthesis of a
Leiodermatolide Analogue with a Dienyl Side Chain. Eur. J. Org.
Chem. 2018, 2018, 4246−4255.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c06062
Notes
The authors declare no competing financial interest.
(7) For reviews on the relationship between centrosomes and
cancer, see: (a) Gonczy, P. Centrosomes and Cancer: Revisiting a
Long-Standing Relationship. Nat. Rev. Cancer 2015, 15, 639−652.
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ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038), and the NIH-
NIGMS (R01 GM093905, 1 S10 OD021508-01) are acknowl-
edged for financial support. We thank Dr. Julian Wippich and
Dr. Stephen D. Ramgren for efforts toward our first-generation
route to leiodermatolide A (ref 11).
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