Total Synthesis of Swinholide A: An Exposition in Hydrogen-Mediated C-C Bond Formation

Article abstract of DOI:10.1021/jacs.6b10645

Diverse hydrogen-mediated C-C couplings enable construction of the actin-binding marine polyketide swinholide A in only 15 steps (longest linear sequence), roughly half the steps required in two prior total syntheses. The redox-economy, chemo- and stereos

Full text of DOI:10.1021/jacs.6b10645

Communication
pubs.acs.org/JACS
Total Synthesis of Swinholide A: An Exposition in Hydrogen-
Mediated C−C Bond Formation
Inji Shin,† Suckchang Hong,† and Michael J. Krische*
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: Diverse hydrogen-mediated C−C couplings
enable construction of the actin-binding marine polyketide
swinholide A in only 15 steps (longest linear sequence),
roughly half the steps required in two prior total syntheses.
The redox-economy, chemo- and stereoselectivity em-
bodied by this new class of C−C couplings are shown to
evoke a step-change in efficiency.
atural products that modulate microtubule dynamics in the
Ncourse of cell division have emerged as an important class
of anti-cancer compounds.1 Paclitaxel (taxol), docetaxel
(taxotere), ixabepilone (ixempra), and eribulin mesylate
(halaven) represent FDA-approved members of this compound
class. Consequently, the prospect of utilizing actin-binding
marine polyketides in cancer therapy has garnered increasing
interest.2 Swinholide A, first isolated from the Okinawan marine
sponge Theonella swinhoei in 1985,3,4 dimerizes actin (Kd ≈ 50
nM).5a A highly resolved X-ray crystal structure of swinholide A
affixed to two actin molecules has been acquired.5c The ability of
swinholide A to disrupt the carefully regulated assembly of actin
cytoskeletal constructs5 confers cytotoxicity in the ng/mL range
against diverse tumor cell lines,6 making it the most potent
member of its class (Figure 1).7−9 Due to its well-understood
mode of binding and potency, simplified functional analogues of
Figure 1. Structure of swinholide A, related secondary metabolites, and
swinholide A might serve as molecular probes or as starting
points for the design of clinical candidates.2 However, while
analogues of other actin-binding natural products have been
prepared,10 synthetic congeners of swinholide A have nota fact
that may be attributed to the daunting structural complexity of
swinholide A and that high levels of potency require preservation
of the symmetric 44-membered macrodiolide ring.11 Indeed,
despite numerous synthetic studies,12 to date, only two total
syntheses of swinholide A have been accomplished in the
laboratories of Paterson (1994)13 and Nicolaou (1996).14,15
Additionally, a total synthesis of preswinholide A was reported by
Nakata (1996).16
The original paradigm for polyketide construction, which
encompasses prior syntheses of swinholide A, relies largely on
C−C bond formations mediated by pre-formed organometallic
C-nucleophiles. We have developed a broad, new family of
catalytic carbonyl reductive couplings induced via hydrogenation
or hydrogen auto-transfer.17a,b These processes bypass pre-
metalated reagents and streamline the synthesis of polyketide
natural products by merging redox and C−C bond construction
events (redox-economy).17c,18 Additionally, by virtue of their
highly chemo- and stereoselective nature, enantioselective C−C
analysis of prior total syntheses of swinholide A. For graphical
summaries of prior total syntheses, see Supporting Information (SI).
LLS, longest linear sequence; TS, total steps. Only transformations in
the LLS are considered in the analysis of reaction type.
coupling can be achieved in the absence of protecting groups.19
Collectively, these attributes contribute to a step-change in
efficiency.17b,c Here, using diverse hydrogen-mediated C−C
couplings, we report a 15-step (longest linear sequence, or LLS)
total synthesis of swinholide Aa route roughly half the length
of the two previous total syntheses.
Retrosynthetically, we envisioned access to swinholide A
through a direct macrodiolide formation via successive cross-
metathesis (CM)−ring-closing metathesis (RCM) of fragment
C or a protected congener thereof (Scheme 1).20 The two prior
syntheses of swinholide A installed the macrodiolide ring
through stepwise formation of ester/lactone linkages. The
possibility that fragment C would engage in RCM (without
initial CM) leading to formation of hemiswinholide rendered the
Received: October 11, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b10645
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Journal of the American Chemical Society
Communication
Scheme 1. Retrosynthetic Analysis of Swinholide A via C−C Bond-Forming Hydrogenation and Transfer Hydrogenation
a
Scheme 2. Synthesis of Fragment A
Scheme 3. Synthesis of Fragment B via Catalyst-Directed
a
Diastereoselective and Site-Selective Allylation of Diol 8
a
Enantioselectivity was determined by chiral stationary phase HPLC
analysis. See SI for further experimental details.
outcome of this approach uncertain. The planned synthesis of
fragment C is highly convergent and involves the use of methyl
vinyl ketone (MVK) as a doubly nucleophilic aldol lynchpin for
the union of fragments A and B. Specifically, hydrogen-mediated
reductive aldol reaction21 of MVK with fragment A is followed by
Mukaiyama aldol reaction22 of the resulting methyl ketone with
fragment B. This strategy requires exceptional chemoselectivity,
as rhodium-catalyzed hydrogenation of MVK in the presence of
fragment A must induce reductive coupling rather than
conventional hydrogenation of the C2−C5 diene and C10−
C11 olefin. Fragment A is prepared using one transfer
hydrogenative alcohol C−H allylation23 to form the C12−C13
carbon−carbon bond. As established in preliminary studies on
the synthesis of the C19−C32 substructure of swinholide A,24
fragment B is accessible through CM of the vinyl pyran 11 with
iodo ether 14. Vinyl pyran 11 is prepared through stereo- and
site-selective allylation of commercially available (S)-1,3-butane
diol 8.25 The iodo ether 14 is prepared from the pseudo-C2-
symmetric diol 13, which, in turn, is obtained directly from 2-
a
(R,R)-ligand = (1R,2R)-(+)-1,2-diaminocyclohexane-N,N′-bis(2-
diphenylphosphinobenzoyl). See SI for further experimental details.
Scheme 4. Synthesis of Iodo Ether 14 via Diastereo- and
Enantioselective Double anti-Crotylation of Diol 12
a
a
Enantioselectivity was determined by chiral stationary phase HPLC
analysis. See SI for further experimental details.
B
DOI: 10.1021/jacs.6b10645
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Journal of the American Chemical Society
Communication
The synthesis of fragment B begins with catalyst-directed
diastereo- and site-selective allylation of commercially available
(S)-1,3-butanediol 8 (Scheme 3).24,25 The homoallylic alcohol 9,
which forms as a single diastereomer, is then subjected to CM
with cis-1,4-diacetoxy-2-butene to provide the allylic acetate 10 as
a 5:1 (E:Z)-mixture of olefin stereoisomers. Exposure of 10 to
the indicated chiral palladium catalyst results in Tsuji−Trost
cyclization to form the 2,6-trans-disubstituted pyran in 90% yield
as a 4:1 mixture of diastereomers. Diastereoselectivity is
independent of the olefin geometry of 10. Subsequent O-
methylation provides 11. Cross-metathesis of 11 with iodoether
14, previously prepared in our laboratory (Scheme 4),26 was
challenging due to competing alkene isomerization of 14. Using
the second-generation Grubbs−Hoveyda catalyst with 1,4-
benzoquinone,31 the desired metathesis product 15 was obtained
in 52% yield. Diimide reduction32 of the C25−C26 double bond,
Bernet−Vasella cleavage33 of the iodoether followed by TBS
protection of the alcohol with subsequent oxidative removal of
the PMB-ether provides 16. Alkene oxidative cleavage and
acryloylation of the β-hydroxy aldehyde converts 16 to fragment
B in 10 steps (LLS).
Scheme 5. Hydrogen-Mediated Reductive Aldol Couplings of
Methyl Vinyl Ketone
a
The union of fragments A and B using MVK as a doubly
nucleophilic aldol lynchpin begins with the hydrogen-mediated
reductive aldol coupling21 of fragment A. Tolerance of multiple
olefinic functional groups, including a terminal diene, to the
conditions of rhodium-catalyzed hydrogenation could not be
assumed. Hence, the reaction of model aldehydes 17 and 19 was
initially explored (Scheme 5). To our delight, the respective
adducts 18 and 20 were formed in good yields without
competing hydrogenation of the alkene functional groups.
Good selectivity with respect to discrimination of the diastereo-
topic aldehyde π-faces was accompanied by complete aldol syn-
diastereoselectivity. Encouraged by these results, fragment A was
exposed to conditions for hydrogen-mediated reductive aldol
coupling. The requisite aldol 21 was formed in 68% yield.
To complete the synthesis of swinholide A, aldol 21 was
methylated to form 22, which was converted to the enol silane
and treated with fragment B in the presence of BF3-etherate
(Scheme 6). The product of Mukaiyama aldol addition 23 is
formed in 72% yield as a single diastereomer, as predicted by the
Felkin−Anh and Cram−Reetz models.30 Hydroxy-directed
reduction of the ketone34 followed by removal of silyl protecting
groups provides the acrylic ester 24. Exposure of 24 to the
second-generation Grubbs−Hoveyda catalyst provides the
product of successive CM-RCM, swinholide A, in 25% yield
along with the product of RCM, hemiswinholide, in 43% yield.
The CM-RCM pathway appears critically dependent on
preorganization derived from the internal network of hydroxyl
a
See SI for further experimental details.
methyl-1,3-propanediol 12 via double diastereo- and enantio-
selective diol C−H anti-crotylation.26
The synthesis of fragment A begins with enantioselective
iridium-catalyzed alcohol C-allylation23 of the commercially
available alcohol 1 (Scheme 2). The homoallylic alcohol 2 is
formed in 83% yield and 93% enantiomeric excess. The iridium
catalyst is readily recovered and recycled in a second round of
allylation to provide additional quantities of alcohol 2. Cross-
metathesis with acrolein followed by treatment of the resulting
enal with allyltrimethylsilane results in allylation of a transient
cyclic oxacarbenium ion to provide the trans-2,6-disubstituted
pyran 3 with good levels of diastereocontrol.27 Chemoselective
oxidative cleavage28 of the terminal olefin of pyran 3 delivers
aldehyde 4. In close analogy to the work of Paterson,13c exposure
of aldehyde 4 to BF3-etherate in the presence of silyl dienol ether
529 triggers vinylogous Mukaiyama aldol addition to provide enal
6. As predicted by the Cram−Reetz model,30 good levels of 1,3-
stereoinduction are observed. Protection of the alcohol as the
TBS ether with subsequent addition of DDQ provides enal 7.
The resulting enal 7 was subjected to Wittig methylenation to
form the C2−C5 diene. This sequence avoids problematic PMB
deprotection in the presence of the diene. Finally, Dess−Martin
oxidation of the C15 alcohol delivers fragment A in 8 steps
(LLS).
a
Scheme 6. Total Synthesis of Swinholide A via Successive Cross-Metathesis−Ring-Closing Metathesis
a
See SI for further experimental details.
C
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Journal of the American Chemical Society
Communication
(8) Preswinholide A (swinholide A seco acid): Todd, J. S.; Alvi, K. A.;
Crews, P. Tetrahedron Lett. 1992, 33, 441.
hydrogen bonds, as the silyl-protected precursors to 24
exclusively form RCM products under metathesis conditions.
In summary, by merging the characteristics of hydrogenation
and carbonyl addition, we have unlocked a broad, new family of
catalytic C−C couplings that streamline chemical synthesis by
virtue of their redox-economy, chemo- and stereoselectivity. As
illustrated in the present synthesis of swinholide A, wherein 10
C−C bonds are formed by hydrogenative coupling, the target
compound is made in 15 steps (LLS), roughly half the steps
required in two prior total syntheses. A comparable step-change
in efficiency is evident in other polyketide total syntheses
utilizing our methods.17c Future work will focus on expanding
the lexicon of hydrogen-mediated C−C bond formations,
including the use of α-olefins as pronucleophiles.
(9) The misakinolides (bistheonellides) and scytophycin C are
structurally related to swinholide A. See literature cited in ref 24.
(10) Analogues of reidispongiolide, rhizopodin, and bistramide:
(a) Perrins, R. D.; Cecere, G.; Paterson, I.; Marriott, G. Chem. Biol.
2008, 15, 287. (b) Herkommer, D.; Dreisigacker, S.; Sergeev, G.; Sasse,
F.; Gohlke, H.; Menche, D. ChemMedChem 2015, 10, 470.
(11) Isoswinholide A, an isomeric 46-membered macrodiolide, is
significantly less potent.
(12) For a summary of synthetic studies, see literature cited in ref 24.
(13) (a) Paterson, I.; Yeung, K.-S.; Ward, R. A.; Cumming, J. G.; Smith,
J. D. J. Am. Chem. Soc. 1994, 116, 9391. (b) Paterson, I.; Cumming, J. G.;
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(14) (a) Nicolaou, K. C.; Ajito, K.; Patron, A. P.; Khatuya, H.; Richter,
P. K.; Bertinato, P. J. Am. Chem. Soc. 1996, 118, 3059. (b) Nicolaou, K.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b10645.
Experimental procedures and spectral data (PDF)
(16) (a) Nakata, T.; Komatsu, T.; Nagasawa, K. Chem. Pharm. Bull.
1994, 42, 2403. (b) Nakata, T.; Komatsu, T.; Nagasawa, K.; Yamada, H.;
Takahashi, T. Tetrahedron Lett. 1994, 35, 8225. (c) Nagasawa, K.;
Shimizu, I.; Nakata, T. Tetrahedron Lett. 1996, 37, 6881. (d) Nagasawa,
K.; Shimizu, I.; Nakata, T. Tetrahedron Lett. 1996, 37, 6885.
(17) Selected reviews on hydrogen-mediated C−C bond formation:
(a) Hassan, A.; Krische, M. J. Org. Process Res. Dev. 2011, 15, 1236.
(b) Ketcham, J. M.; Shin, I.; Montgomery, T. P.; Krische, M. J. Angew.
Chem., Int. Ed. 2014, 53, 9142. (c) Feng, J.; Kasun, Z. A.; Krische, M. J. J.
Am. Chem. Soc. 2016, 138, 5467.
AUTHOR INFORMATION
Corresponding Author
*mkrische@mail.utexas.edu
■
Author Contributions
†I.S. and S.H. contributed equally to this work.
Notes
The authors declare no competing financial interest.
(18) Review on redox-economy: Burns, N. Z.; Baran, P. S.; Hoffmann,
R. W. Angew. Chem., Int. Ed. 2009, 48, 2854.
ACKNOWLEDGMENTS
■
The Welch Foundation (F-0038), the NIH-NIGMS (RO1-
GM093905), and the National Research Foundation of Korea,
funded by the Ministry of Education (2014058834, S.H.
postdoctoral fellowship), are acknowledged for partial support
of this research.
(19) Review on protecting group-free synthesis: (a) Saicic, R. N.
Tetrahedron 2014, 70, 8183;(b) Tetrahedron 2015, 71, 2777.
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(a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4490. (b) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006,
45, 6086.
(21) Bee, C.; Han, S. B.; Hassan, A.; Iida, H.; Krische, M. J. J. Am. Chem.
Soc. 2008, 130, 2746.
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D
DOI: 10.1021/jacs.6b10645
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