Synthesis of the A-D Ring System of the Gambieric Acids

Article abstract of DOI:10.1021/acs.orglett.5b02093

The A-D fragment of gambieric acids A and C has been synthesized using an asymmetric Tsuji-Trost allylation reaction to couple the two key segments. The A ring fragment has been prepared by a short and highly efficient route involving diastereoselective Lewis acid mediated alkylation of an acetal. Iterative ring-closing metathesis reactions have been used to construct cyclic ethers and assemble the tricyclic B-D fragment.

Full text of DOI:10.1021/acs.orglett.5b02093

Letter
pubs.acs.org/OrgLett
Synthesis of the A−D Ring System of the Gambieric Acids
J. Stephen Clark,*,† Filippo Romiti,† Bora Sieng,† Laura C. Paterson,† Alister Stewart,‡
Subhabrata Chaudhury,† and Lynne H. Thomas†
†WestCHEM, School of Chemistry, Joseph Black Building, University of Glasgow, University Avenue, Glasgow G12 8QQ, United
Kingdom
‡School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom
S
* Supporting Information
ABSTRACT: The A−D fragment of gambieric acids A and C
has been synthesized using an asymmetric Tsuji−Trost
allylation reaction to couple the two key segments. The A
ring fragment has been prepared by a short and highly efficient
route involving diastereoselective Lewis acid mediated
alkylation of an acetal. Iterative ring-closing metathesis
reactions have been used to construct cyclic ethers and
assemble the tricyclic B−D fragment.
he gambieric acids (Figure 1) are polycyclic ethers that
were first isolated by Yasumoto and co-workers from a
Yasumoto and co-workers established the relative stereo-
chemical relationships in the B−J polyether array of the
gambieric acids using two-dimensional NMR methods.1 The
absolute configurations at positions C-3, C-4, and C-48 and in
the side chain ester R2 (C3′) were determined using Mosher’s
method, with or without prior degradation and fragment
functionalization with a chiral anisotropic reagent.1d However,
assignment of the relative stereochemical relationship between
stereogenic centers in the A ring and those in the B−J polyether
array remained tentative until completion of the first total
synthesis of gambieric acid A by Sasaki and co-workers in 2012,3
which permitted unambiguous stereochemical assignments to be
made (Figure 1).1
T
The gambieric acids possess an array of nine trans-fused cyclic
ethers with 6-, 7-, and 9-membered rings forming the typical
laddered structure found in this class of marine natural product.
These natural products also possess an isolated trisubstituted
tetrahydrofuran (the A ring) and a side chain on the J ring
(attached to C-44).
Figure 1. Confirmed structures of gambieric acids A−D.
The immense synthetic challenges presented by the gambieric
acids coupled with their potent bioactivity make them highly
attractive synthetic targets. We have already reported the
syntheses of both the A ring and the F−J fragment of gambieric
acids.4 Herein, we describe a concise synthesis of the A−D
fragment of (−)-gambieric acids A and C that includes a novel,
more efficient, and robust second-generation synthesis of the A
ring system.
At the outset, the stereochemical relationship between the
stereogenic centers in the A ring and those in the B−J fragment
had not been established firmly, and so choice of enantiomer of
the chiral pool starting material for the B−J array was arbitrary.
Sasaki’s synthesis of (+)-gambieric acid A and revision of
culture of the marine dinoflagellate Gambierdiscus toxicus (GII1
strain), the organism responsible for ciguatera poisoning in
humans.1 The gambieric acids possess potent activity against a
variety of filamentous fungi1c and display 2000-fold greater
antifungal activity than amphotericin B in some assays.2
Interestingly, although gambieric acid A inhibits binding of the
brevetoxin B derivative PbTx-3 to site 5 of voltage-gated sodium
channels in excitable membranes, the gambieric acids lack the
potent neurotoxicity that is associated with many other large
fused polyether natural products of marine origin.2 The
significant antifungal activity of the gambieric acids combined
with their moderate toxicity toward mammalian cells makes them
potential lead compounds for the discovery of novel antifungal
agents.1
Received: July 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02093
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Letter
stereochemical assignments was published at a point where our
synthesis of the A−D fragment was well advanced, and at this
stage it became clear that we were preparing the antipode.
Our intention is to construct the full polyether system of the
gambieric acids by union of a tetracyclic A−D fragment with a
pentacyclic F−J fragment followed by closure of the E ring. The
retrosynthetic analysis of the A−D fragment (i) of (−)-gambieric
acids A and C is shown in Scheme 1. Replacement of the C-9
Scheme 2. Synthesis of the A-Ring Fragment 10
Scheme 1. Retrosynthetic Analysis of the A−D Fragment
available allylic silane 8. The trisubstituted tetrahydrofuran 9 was
obtained in excellent yield and with high diastereoselectivity,
mirroring the levels of stereocontrol observed by the groups of
Woerpel and Rainier for Lewis acid mediated reactions of allylic
silanes with closely related acetals.9 Cleavage of the acetate group
was accomplished by treatment of the ester 9 with potassium
carbonate in methanol. The resulting alcohol was converted into
the carbamate 10 by reaction with carbonyl diimidazole. Thus,
the carbamate 10 required for the impending coupling sequence
was prepared from the alcohol 2 in just nine steps and with
excellent overall yield (21%).
Completion of the A ring meant that efforts could be focused
on the preparation of the fused tricyclic B−D fragment (Scheme
3). We had already demonstrated that it is possible to construct
fused polycyclic ethers possessing a variety of ring sizes by
performing highly efficient ring-closing metathesis (RCM)
reactions.4b,9c,10,11 We decided to apply this robust strategy to
the synthesis of the B−D fragment commencing from tri-O-
acetyl-D-glucal (1) (Scheme 3). Treatment of the triacetate 1
with methanol in the presence of boron trifluoride diethyl
etherate resulted in elimination of the allylic acetate group and
concomitant acetal formation.12 Reduction of the acetal with
lithium aluminum hydride12 and protection of the resulting 1,3-
diol as the di-tert-butylsiloxane delivered the enol ether 11 in 63%
yield over three steps. Epoxidation of the enol ether 11 using
dimethyldioxirane followed by addition of allylmagnesium
chloride delivered the alcohol 12 as a diastereomeric mixture.
Swern oxidation and subsequent epimerization delivered the
ketone 13 in 40% yield over four steps.
hydroxyl group with a methylene group and the B-ring hydroxyl
group with an enone reveals the tetracyclic array ii. This system
can now undergo disconnection of the A ring segment iii from
the B−D tricyclic polyether iv at the C-10−C-11 bond, a process
that suggests a Tsuji−Trost allylation reaction in the forward
direction.5,6 Disconnection (C-7−C-8) of tetrahydrofuran iii
reveals the acetal v, and further simplification gives the chiral pool
alcohol vi. Disconnection of the seven-membered ring of the
tricyclic enone iv reveals bicyclic ether vii. Scission of the enol
ether reveals the pyranone viii, which can be prepared from
commercially available tri-O-acetyl-D-glucal (1).
Synthesis of the A ring fragment commenced with
regioselective monosilylation of the commercially available diol
2 (Scheme 2).7 Sequential oxidation of the alcohol and
asymmetric crotylation of the intermediate aldehyde, using the
Z-crotylboronate 3,8 afforded the alcohol 4 with a good level of
diastereocontrol (dr = 4:1−9:1). It should be noted that the
crotylation reaction was completely stereoselective, but the
intermediate aldehyde underwent partial racemization prior to
reaction. The alkene 4 was subjected to cross-metathesis with
vinyl pinacol boronate, mediated by the Hoveyda−Grubbs
second-generation catalyst 5 (10 mol %), to afford the coupled E-
alkene 6 as a single isomer in good yield. Oxidation of the vinylic
boronate by treatment with trimethylamine N-oxide resulted in
aldehyde formation and spontaneous cyclization to produce a
hemiacetal, which was converted into the acetal 7. Stereoselective
installation of the side chain was accomplished by Lewis acid
promoted allylation of the acetal 7 using the commercially
Stereoselective introduction of the ring-junction methyl group
was achieved by treatment of ketone 13 with methylmagnesium
iodide.4b A separable mixture of the tertiary alcohols (dr 4:1) was
obtained in a combined yield of 95% with the required alcohol 14
predominating. Subsequent alkynyl ether formation using
Greene’s procedure13 afforded the enyne 15 in excellent yield.
Partial hydrogenation using Lindlar catalyst produced vinyl ether
B
DOI: 10.1021/acs.orglett.5b02093
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Scheme 3. Synthesis of the Bicyclic CD Fragment 18
Scheme 4. Synthesis of the Tricyclic B−D Fragment 25
Scheme 5. Stereoselective Palladium-Catalyzed Coupling of
the A and B−D Fragments To Give the A−D Ring System
16, and this compound was subjected to RCM in the presence of
the Grubbs second-generation catalyst 17 (5 mol %) to give the
cyclic enol ether 18 in 95% yield.10c,14
Construction of the B ring commenced with stereoselective
epoxidation (dr >9:1) of the cyclic enol ether 18 using
dimethyldioxirane (Scheme 4). Zinc(II) chloride promoted
opening of the epoxide with sodium acetylide15 afforded the
alcohol 19 in 55% yield over two steps. Partial hydrogenation of
the alkyne in the presence of Lindlar catalyst gave the alkene 20
in high yield.
Inversion of configuration at the hydroxyl-bearing stereogenic
center of the alcohol 20 was necessary at this stage and was
accomplished by sequential Dess−Martin oxidation and ketone
reduction with sodium borohydride. The resulting alcohol 21
was converted into the RCM precursor 24 by etherification with
3-chloro-2-oxopropylidene triphenylphosphorane (22) and
reaction of the resulting phosphonium ylide 23 with form-
aldehyde under buffered conditions.16 The RCM reaction of the
diene 24 was performed using the Grubbs second-generation
catalyst 17 (5 mol %) to provide the crystalline enone 25 in 85%
yield. The structure of this tricyclic enone and the stereochemical
assignments were confirmed by X-ray crystallography.17
Both key fragments were available in sufficient quantities, and
so the stage was set for attempted stereoselective fragment
coupling of the A ring 10 to the tricyclic B−D segment 25 using
the asymmetric Tsuji−Trost allylation reaction5 developed by
Stoltz and co-workers (Scheme 5).6 Formation of the required
enol carbonate 26 proved to be extremely challenging, but under
optimized conditions the required compound was obtained in
48% yield (Scheme 5). Furthermore, the enol carbonate was
found to be prone to decomposition and had to be used
immediately in the subsequent asymmetric palladium-catalyzed
rearrangement reaction. Pleasingly, asymmetric allylation using
Pd(PPh3)4 (10 mol %) in the presence of the chiral ligand (S)-t-
BuPHOX (27, 12.5 mol %) afforded substituted enone 28 as a
single diastereomer in 81% yield.18 Subsequent Luche reduction
of the ketone 2819 delivered the alcohol 29 in excellent yield and
with high diastereoselectivity.
In summary, the tetracyclic alcohol 29 corresponding to the
A−D fragment of the gambieric acids A and C was prepared from
commercially available tri-O-acetyl-D-glucal (1) in 23 steps
(longest linear sequence) and 1.45% overall yield. The
tetrahydrofuran in the A ring segment was prepared by
C
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(10) (a) Clark, J. S.; Hamelin, O. Angew. Chem., Int. Ed. 2000, 39, 372−
374. (b) Clark, J. S.; Elustondo, F.; Kimber, M. C. Chem. Commun. 2004,
2470−2471. (c) Clark, J. S. Chem. Commun. 2006, 3571−3581.
(d) Clark, J. S.; Grainger, D. M.; Ehkirch, A. A.-C.; Blake, A. J.;
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Blake, A. J. Org. Lett. 2007, 9, 2091−2094.
diastereoselective Lewis acid mediated alkylation of an acetal.
The iterative ring-closing metathesis strategy developed by our
group was successfully applied to the construction of the tricyclic
B−D fragment. Coupling of the A-ring fragment 10 to the
tricyclic B−D fragment 25 was accomplished using a highly
stereoselective Tsuji−Trost allylation reaction. The synthesis of
the natural enantiomer of the A−D fragment and its attachment
to the F−J fragment is currently in progress, and results of these
synthetic studies will be reported in due course.
(11) For other important contributions involving the preparation of
polyethers using RCM reactions, see: (a) Delgado, M.; Martín, J. D.
Tetrahedron Lett. 1997, 38, 6299−6300. (b) Crimmins, M. T.; Choy, A.
L. J. Org. Chem. 1997, 62, 7548−7549. (c) Rainier, J. D.; Allwein, S. P. J.
Org. Chem. 1998, 63, 5310−5311. (d) Delgado, M.; Martín, J. D. J. Org.
Chem. 1999, 64, 4798−4816. (e) Rainier, J. D.; Cox, J. M.; Allwein, S. P.
Tetrahedron Lett. 2001, 42, 179−181. (f) Crimmins, M. T.; Ellis, J. M.;
Emmitte, K. A.; Haile, P. A.; McDougall, P. J.; Parrish, J. D.; Zuccarello, J.
L. Chem. - Eur. J. 2009, 15, 9223−9234.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02093.
(12) Lesimple, P.; Beau, J.-M.; Jaurand, G.; Sinay, P. Tetrahedron Lett.
̈
1986, 27, 6201−6204.
X-ray data for enone 25 (CIF)
(13) Moyano, A.; Charbonnier, F.; Greene, A. E. J. Org. Chem. 1987,
52, 2919−2922.
Experimental details plus spectroscopic and other data for
compounds 2, 4−7, 9−16, 18−21, 23−25, 28, and 29
(PDF)
(14) (a) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 123−126.
(b) Clark, J. S.; Kettle, J. G. Tetrahedron 1999, 55, 8231−8248.
(c) Sturino, C. F.; Wong, J. C. Y. Tetrahedron Lett. 1998, 39, 9623−9626.
(15) (a) Leeuwenburgh, M. A.; Timmers, C. M.; van der Marel, G. A.;
AUTHOR INFORMATION
Corresponding Author
■
van Boom, J. H.; Mallet, J.-M.; Sinay, P. G. Tetrahedron Lett. 1997, 38,
̈
6251−6254. (b) Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, H.
*E-mail: stephen.clark@glasgow.ac.uk.
W. B.; Rainier, J. D. Tetrahedron 2002, 58, 1997−2009.
(16) (a) Hudson, R. F.; Chopard, P. A. J. Org. Chem. 1963, 28, 2446−
2447. (b) Cossy, J.; Taillier, C.; Bellosta, V. Tetrahedron Lett. 2002, 43,
7263−7266.
Notes
The authors declare no competing financial interest.
(17) X-ray data (CIF files) for the enone 25 can be found in the
Supporting Information. Data have been deposited with the Cambridge
Crystallographic Data Centre (CCDC 1413202) and can be obtained
free of charge from CCDC via www.ccdc.cam.ac.uk.
(18) The presence of ligand 27 was essential for high levels of
diastereocontrol. In model studies performed using the simple allyl
carbonate analogue of carbonate 26, a low level of diastereocontrol was
obtained in the absence of a chiral ligand.
ACKNOWLEDGMENTS
The authors gratefully acknowledge EPSRC (grant EP/
F031505/1) and the University of Glasgow for funding.
■
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