Studies toward the synthesis of spirolide C: Exploration into the formation of the 23-membered all-carbon macrocyclic framework

Article abstract of DOI:10.1021/ol203342e

The synthesis of two complex subunits en route to spirolide C is described. A key alkyllithium addition to an aldehyde joins the fragments, which are advanced in order to investigate a ring-closing metathesis to form the 23-membered all-carbon macrocyclic

Full text of DOI:10.1021/ol203342e

ORGANIC
LETTERS
2012
Vol. 14, No. 3
804–807
Studies toward the Synthesis of
Spirolide C: Exploration into the
Formation of the 23-Membered
All-Carbon Macrocyclic Framework
Craig E. Stivala, Zhenhua Gu, Lindsay L. Smith, and Armen Zakarian*
Department of Chemistry and Biochemistry, University of California, Santa Barbara,
California 93106, United States
zakarian@chem.ucsb.edu
Received December 14, 2011
ABSTRACT
The synthesis of two complex subunits en route to spirolide C is described. A key alkyllithium addition to an aldehyde joins the fragments, which
are advanced in order to investigate a ring-closing metathesis to form the 23-membered all-carbon macrocyclic framework.
The cyclic imine group of marine toxins is an emerging
class of natural products with global distribution in marine
environments.1 After the discovery of the first member of
this family in 1995, the group has grown to include more
than 30 members with complex chemical structures,
including pinnatoxins,2 pteriatoxins,3 spirolides,4 gym-
nodimines,5 and spiro-prorocentrimine.6 Initially, the mode
of action for spirolides, pinnatoxins, and gymnodimine
was attributed to calcium-channel activation,7 which has
been subsequently revised to a potent and selective inhibi-
tion of nicotinic acetylcholine receptors (nAChRs), where
the cyclic imines have been found to be among the most
powerful nonpeptidic antagonists of nAChRs known to
date.8
(1) (a) Cembella, A.; Krock, B. In Seafood and Freshwater Toxins,
2nd ed.; Botana, L. M., Ed.; CRC Press: Boca Raton, 2008; pp 561À580. (b)
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Zheng, S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155–1156. (b) Chou,
T.; Kamo, O.; Uemura, D. Tetrahedron Lett. 1996, 37, 4023–4026. (c)
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1996, 37, 4027–4030.
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3491–3494. (b) Takada, N; Umemura, N.; Suenaga, K.; Uemura, D.
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Commun. 1995, 2159–2161. (b) Hu, T.; Curtis, J. M.; Walter, J. A.;
Wright, J. L. C. Tetrahedron Lett. 1996, 37, 7671–7674. (c) Falk, M.;
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57, 8659–8665. (d) Hu, T.; Burton, I. W.; Cemella, A. D.; Curtis, J. M.;
Quilliam, M. A.; Walter, J. A.; Wright, J. L. C. J. Nat. Prod. 2001, 64,
308–312.
The structure of the spirolides combines the most challeng-
ing aspects within the cyclic imine group of toxins: the char-
acteristic spiroimine subunit, the tetrasubstituted alkene
(6) Lu, C.-K.; Lee, G.-H.; Huang, R.; Chou, H.-N. Tetrahedron Lett.
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(7) See, for example: (a) References 2a and 4a. (b) Gill, S.; Murphy,
M.; Clausen, J.; Richard, D.; Quilliam, M.; MacKinnon, S.; LaBlanc, P.;
Mueller, R.; Pulido, O. Neurotoxicology 2003, 24, 593–604.
(8) (a) Bourne, Y.; Radic, Z.; Araoz, R.; Talley, T. T.; Benoit, E.;
Servent, D.; Taylor, P.; Molgo, J.; Marchot, P. Proc. Natl. Acad. Sci.
2010, 107, 6076–6081. (b) Araoz, R.; Servent, D.; Molgo, J.; Iorga, B. I.;
Fruchart-Gaillard, C.; Benoit, E.; Gu, Z.; Stivala, C. E.; Zakarian, A. J.
Am. Chem. Soc. 2011, 133, 10499–10511.
(5) (a) Seki, T.; Satake, M.; Mackenzie, L.; Kaspar, H.; Yasumoto, T.
Tetrahedron Lett. 1995, 36, 7093–7096. (b) Miles, C. O.; Wilkins, A. L.;
Stirling, D. J.; MacKenzie, A. L. J. Agric. Food Chem. 2000, 48, 1373–
1376. (c) Miles, C. O.; Wilkins, A. L.; Stirling, D. J.; MacKenzie, A. L. J.
Agric. Food Chem. 2003, 51, 4838–4840. For total synthesis, see: (c)
Kong, K.; Romo, D.; Lee, C. Angew. Chem., Int. Ed. 2009, 48, 7402–
7405. (d) Kong, K.; Moussa, Z.; Lee, C.; Romo, D. J. Am. Chem. Soc.
2011, 133, 19844–19856.
r
10.1021/ol203342e
Published on Web 01/19/2012
2012 American Chemical Society

carrying a butenolide fragment, the 5,5,6-bispiroketal, and a
highly functionalized 23-membered all-carbon macrocyclic
framework.9 Previously, the groups of Brimble10 and
Ishihara11 described their approaches to solving selected
problems posed by the complexity of spirolides, concen-
trating on the synthesis of the 5,5,6-spirobicyclic ring
system and the construction of the spiroimine subunit.
Herein, we disclose the progress of our own work,12 with a
focus on the formation of the 23-membered macrocyclic
ring by ring-closing metathesis (RCM).
Scheme 2. Synthesis of Intermediate 4
Scheme 1. Synthesis Plan for Spirolide C
Aldol addition of S-ethyl thiopropionate followed by
mesylation with methanesulfonic anhydride and elimina-
tion with DBU afforded 6 as a single stereoisomer in
93% overall yield. Thioester 6 was reduced to the corre-
sponding R,β-unsaturated aldehyde under conditions re-
ported by Fukuyama.14 Soderquist asymmetric allylation
was reproducible on varying scales and provided homo-
allylic alcohol 7 in 76% isolated yield with 5:1 diastereo-
selectivity.15À17 Formation of the tert-butyl carbon-
ate (LiN(SiMe3)2, Boc2O) followed by iodolactonization
(NIS, (CF3)2CHOH)18 and treatment with methanolic
potassium carbonate delivered epoxy alcohol 9 in 69%
yield over the three steps. Treatment of epoxy alcohol 9
with the sulfur ylide generated from trimethylsulfonium
iodide produced the requisite allylic diol19 and was accom-
panied by the removal of the pivalate ester group. Protec-
tion of the 1,3-syn-diol as a p-methoxybenzylidene acetal
An early strategic decision in our plan was to assemble
the 5,5,6-bispiroketal after the construction of the macro-
cyclic framework to ensure the desired stereocontrol in the
ketalization, which would be difficult to achieve in the
acyclic system, in particular with regard to the formation
of the 5,5-ketal, where no anomeric stabilization can be
relied upon to control stereochemistry (Scheme 1).10a,11 An
example of the desired macrocyclic product is compound
2, which could be accessed in a convergent manner from
organolithium reagent 3 and aldehyde 4 followed by RCM
(disconnections along the highlighted bonds at C13ÀC14
and C27ÀC28). Aldehyde 5, previously prepared by a key
diastereoselective IrelandÀClaisen rearrangement, serves
as a precursor to 4.13
The synthesis of intermediate 4 began with a three-step
preparation of thioester 6 from aldehyde 5 (Scheme 2A).
(14) (a) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112,
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(9) For reviews on the synthesis of cyclic imine toxins, see: (a)
Beaumont, S.; Ilardi, E. A.; Tappin, N.; Zakarian, A. Eur. J. Org. Chem.
2010, 30, 5743–5765. (b) O’Connor, P. D.; Brimble, M. A. Nat. Prod.
Rep. 2007, 24, 869–885.
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Furkert, D. P.; Brimble, M. A. Org. Lett. 2002, 4, 3655–3658. (c) Meilert,
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851. (f) Zhang, Y. C.; Furkert, D. P.; Gueret, S. M.; Lombard, F.;
Brimble, M. A. Tetrahedron Lett. 2011, 52, 4896–4898.
(15) (a) Burgos, C. H.; Canales, E.; Matos, K.; Soderquist, J. A. J.
Am. Chem. Soc. 2005, 127, 8044–8049. (b) Canales, E.; Prasad, K. G.;
Soderquist, J. A. J. Am. Chem. Soc. 2005, 127, 11572–11573. (c) Soto-
Cairoli, B.; Soderquist, J. A. Org. Lett. 2009, 11, 401–404.
(16) Brown asymmetric allylation generated homoallylic alcohol 7 in
91% yield as a 10:1 mixture of diastereomers; however, this result was
irreproducible. Jadhav, P. K.; Bhat, K. S.; Perumal, T.; Brown, H. C. J.
Org. Chem. 1986, 51, 432–439.
(17) The separable minor diastereomer could be recycled through an
oxidationÀreduction sequence, providing an additional 7À10% yield
of 7.
(11) Ishihara, J.; Tshizaka, T.; Suzuki, T.; Hatakeyama, S. Tetrahe-
dron Lett. 2004, 45, 7855–7858.
(12) Stivala, C. E.; Zakarian, A. Org. Lett. 2009, 11, 839–842.
(13) (a) Qin, Y.-c.; Stivala, C. E.; Zakarian, A. Angew. Chem., Int. Ed.
2007, 46, 7466–7469. (b) Gu, Z.; Herrmann, A. T.; Stivala, C. E.;
Zakarian, A. Synlett 2010, 1717–1722.
(18) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Org. Lett. 2008, 10,
1727–1730.
(19) Alcaraz, L.; Hartnett, J. J.; Mioskowski, C.; Martel, J. P.; Le
Gall, T.; Shin, D.-S.; Falck, J. R. Tetrahedron Lett. 1994, 35, 5449–5452.
Org. Lett., Vol. 14, No. 3, 2012
805

and oxidation of the primary hydroxy group under Swern
conditions20 completed the synthesis of intermediate 4.
During the development of the synthetic route to 4
described above, we explored the synthesis of the desired
1,3-syn-diol acetal based on the recently developed Recat-
alyzed transposition of allylic alcohols directed by hydroxy
groups.21 To this end, diol 10 was prepared from 7 by
cross-metathesis with (Z)-2-butene-1,4-diol diacetate fol-
lowedbymethanolysis(97% over two steps, Scheme 2B).22
However, only a small amount of 11 could be detected, and
generally decomposition was observed under a variety of
conditions.
primary hydroxy group, addition of vinylmagnesium bro-
mide generated an inconsequential ∼1:1 mixture of dia-
stereomers. Protection of the resulting secondary alcohol
as its triethylsilyl ether completed the synthesis of the key
intermediate 3 (Scheme 3).
Scheme 3. Synthesis of Intermediate 3
The synthesis of the bispiroketal precursor fragment (3)
was initiated by methylation of lithium acetylide gener-
ated from 1223 followed by hydrozirconationÀiodination24
to form the corresponding (E)-iodoalkene. Palladium-
catalyzed cross-coupling of the iodide and the alkylzinc
halide 13 afforded trisubstituted alkene 14 (57% over three
steps).25 Hydrolysis of the acetonide, epoxide formation,26
and alkylation of lithiated sulfone 15 with the epoxide
afforded 16 in excellent yield. Introduction of the exo-
methylene group was accomplished by a Julia-type process
after protection of the secondary hydroxyl group as a
triethylsilyl ether.27
Sharpless asymmetric dihydroxylation28 of diene 17
took place at the trisubstituted double bond, selectively
affording the desired diol in 57% yield (85% based on re-
covered 17). Oxidation by the ParikhÀDoering method29
cleanly afforded hydroxy ketone 18. Removal of the tri-
ethylsilyl ether with concomitant ketalization afforded
the sensitive methyl ketal 19 in 91% yield. Attempts to
form the triethylsilyl ether at the tertiary hydroxy group
(TESOSO2CF3, 2,6-lutidine; TESCl, ImH, DMF, 40 °C,
12 h) were thwarted by a facile elimination of the ketal
methoxy group, affording the exocyclic vinyl ether. On the
other hand, silylation of 19 with chlorotrimethylsilane in
DMF at 40 °C efficiently delivered the desired monosily-
lated product after treatment with potassium carbonate in
methanol. Iododehydroxylation of the primary alcohol
delivered 20 in 89% yield over three steps.
The fragment coupling was accomplished as planned by
a direct addition of the functionalized alkyllithium reagent
3-Li generated by lithum-iodine exchange from iodide 3
with aldehyde 4 in 98% yield (Scheme 4).30 DessÀMartin
oxidation and desilylation delivered substrate 22 for key
RCM studies.31
We carried out extensive studies on ring-closing metath-
esis of tetraene 22, the results of which are summarized in
Table 1. In all cases, the HGII catalyst provided cleaner
reactions than the GII catalyst. Although the formation of
Careful oxidative removal of the p-methoxybenzyl ether
with DDQ followed by a Swern oxidation of the resulting
(20) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660.
(21) Herrmann, A. T.; Saito, T; Stivala, C. E.; Tom, J.; Zakarian, A.
J. Am. Chem. Soc. 2010, 132, 5962–5963.
(22) Cluzeau, J.; Capdevielle, P.; Cossy, J. Tetrahedron Lett. 2005, 46,
6945–6948.
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P. Tetrahedron 1999, 55, 4655–4684.
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Baba, S.; Negishi, E. J. Am. Chem. Soc. 1976, 98, 6729–6731.
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M. D.; Boldi, A. M.; Moser, W. H.; Murase, N.; Nakayama, K.;
Sobukawa, M. Angew. Chem., Int. Ed. 2001, 40, 191–195. (b) Julia,
M.; Paris, J. M. Tetrahedron Lett. 1973, 4833–4836.
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Chem. 2003, 681, 210–214.
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(b) Boeckman, R. K.; Shao, P.; Mullins, J. J. Org. Synth. 2000, 77, 141–
152.
(32) See the Supporting Information for the structure of the ketone.
(a) Gurjar, M. K.; Yakambram, P. Tetrahedron Lett. 2001, 42, 3633–
3636. (b) Renzulli, M. L.; Rocheblave, L.; Avramova, S. I.; Galletti, E.;
Castagnolo, D.; Tafi, A.; Corelli, F.; Botta, M. Tetrahedron 2007, 63,
497–509. (c) Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 169–171.
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806
Org. Lett., Vol. 14, No. 3, 2012

Table 1. RCM Studies of 22 and Its Derivativesa
Scheme 4. Fragment Coupling
the 23-membered all-carbon macrocycle was found to be
rather challenging, we succeeded in forming the desired
product, albeit in low yield (entries 1À4). NMR studies
have shown conclusively that the RCM process is initiated
at the C14 terminal alkene selectively. The main bypro-
duct was the C15 methyl ketone, presumably arising by
fragmentation of the intermediate ruthenium carbene at
C14.32 Various attempts to minimize side reactions using
additives such as 1,4-benzoquinone33 or 2,6-lutidine34
proved to be unproductive. To our delight, in no case
was a RCM observed between the olefins at C13 or C14
and C24.35
time (h),
entry
R; X
H; H, OH
solvent
temp (°C) conversion, %
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
C2H4Cl2
1, 40
10
H; H, OH
H; H, OH
H; H, OH
H; O
18, 40
18, 20
12, 40
7 d, 40
24, 85
24, 40
24, 90
24, 90
10
20
17b
5 (95 brsm)
H; O
0
SiMe3; H, OSiEt3 CH2Cl2
SiMe3; H, OSiEt3 PhMe
SiMe3; H, OSiEt3 C2H4Cl2
0
10 (90 brsm)
0
a All reactions were carried out under an inert atmosphere of argon in
degassed solvents. Reactions were performed on scales of 1À2 mg with a
concentration of 0.005 M. Percent conversions were determined by
NMR spectroscpy. b Isolated yield.
Ring-closing metathesis with the C13 enone, prepared by
oxidation of the C13 hydroxyl, was substantially cleaner,
although slower (∼5% conversion after 7 days), and pre-
vented formation of C13 methyl ketone (entry 5). Increasing
the reaction temperature from 40 to 85 °C resulted in
complete decomposition (entry 6). Finally, fully silylated
diol 22 was also more stable and resistant to the methyl
ketone formation, but also exhibited low reactivity (entry 8).
To conclude our study on the key formation of the
23-membered macrocyclic framework en route to the
spirolides, we tested the hypothesis that a more compact
substrate such as spiroketal 23 would be a superior
substrate for RCM (Scheme 5). Intermediate 23 could
be readily prepared from diol 22 in one step in a nearly
quantitative yield. Indeed, when 23 was subjected
to optimized conditions for RCM (GII 30 mol %, 1,2-
dichloroethane, 60 °C, 24 h), a clean reaction ensued
affording the anticipated macrocyclic product (25% iso-
lated yield) and the recovered starting material (54%
isolated yield).
In closing, we report the successful fragment coupl-
ing and extensive studies on RCM reactions of the 23-
membered all-carbon macrocyclic ring system en route to
the spirolides. While these studies revealed that the RCM is
no doubt challenging, the powerful reaction was successful
in forming the expected compounds and provided suffi-
cient amounts of the macrocyclic products to enable key
spiroketalization studies central to our approach in the
synthesis of spirolides.
Scheme 5. RCM with Spiroketal 23
Acknowledgment. Financial support was provided by
the National Institutes of Health, National Institute of
GeneralMedical Sciences (R01GM077379), and kind gifts
from Amgen and Eli Lilly. C.E.S. is supported by a
Tobacco-Related Disease Research Program Dissertation
Award and the UCSB Graduate Research Mentorship
Fellowship. We are grateful to Dr. Hongjun Zhou (UC
Santa Barbara) for continued assistance with NMR
spectroscopy.
Supporting Information Available. Experimental pro-
1
cedures and copies of H and 13C NMR spectra. This
(34) 2,6-Lutidine was used to avoid possible fragmentation of the
sensitive methyl ketal.
(35) For a similar problen in the synthesis of pinnatoxins, see: (a)
Stivala, C. E.; Zakarian, A. J. Am. Chem. Soc. 2008, 130, 3774–3776. (b)
Reference 8b.
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
807