An Efficient approach to the securinega alkaloids empowered by cooperative n-heterocyclic carbene/lewis acid catalysis

Article abstract of DOI:10.1002/anie.201301849

Folding it all together: Most of the syntheses developed for the securinega alkaloid class require lengthy sequences to create their bridging butenolide domains. A novel approach uses N-heterocyclic carbenes (NHCs) and Lewis acids to forge the entire domain in a single step from appropriate precursors, showing that ynal-derived homoenolates can participate as nucleophiles in intramolecular settings (see scheme). Copyright

Full text of DOI:10.1002/anie.201301849

Angewandte
Chemie
DOI: 10.1002/anie.201301849
Cooperative Catalysis
An Efficient Approach to the Securinega Alkaloids Empowered by
Cooperative N-Heterocyclic Carbene/Lewis Acid Catalysis**
Adel M. ElSohly, Daniel A. Wespe, Tyler J. Poore, and Scott A. Snyder*
Dedicated to Professor Ronald Breslow on the occasion of his 82nd birthday
Plants of the Euphorbiaceae family are sources of several
important collections of secondary metabolites, one being the
securinega alkaloids (1–5[2] and 7, Scheme 1).[1] These materi-
als possess unique frameworks typically characterized by
a bridged, tetracyclic substructure bearing a strained a,b,g,d-
unsaturated lactone motif (as in 1–5), though rearranged
variants of such domains (such as in 7)[3] also exist. They also
display intriguing biological activity;[4] for instance, securinine
(1), the most abundant member of the family, is a potent
GABA antagonist. Given these attributes, it is unsurprising
that the synthetic community has devoted significant atten-
tion to this collection of compounds,[5] particularly to the
challenges posed by the key shared domains within 1–5.
Indeed, since the inaugural total synthesis of securinine (1) by
Horii in 1966,[5a] several other successful and highly creative
approaches for forging their fused bicyclic butenolide
domains have been disclosed, efforts that include selenoxide
eliminations,[5b,e,f,h,i,r] intramolecular Wittig olefinations,[5e,-
Our generalized approach to quickly fashion the buteno-
lide domains of the securinega class is shown in the lower half
of Scheme 1, using target 6 for purposes of illustration. As
indicated, we envisioned that this entire key motif could be
accessed from an appropriate linear enynal precursor (8)
through an intramolecular NHC-catalyzed homoenolate
addition onto the lone ketone followed by lactonization.
ring-closing metatheses,[5j–p,s,x] and alkylation of allylic
f,o,p,t–v]
bromides or mesylates.[5a,h,i–m,q,t–v,x] However, most of these
strategies require multiple steps to execute, typically con-
stituting the longest (and least efficient) portion of the overall
route. Here, we disclose a new disconnection for this critical
domain, one that uses a simple, acyclic starting material and
a novel N-heterocyclic carbene (NHC)-catalyzed reaction[6,7]
to forge the entire butenolide system in a single step. We
highlight its utility through a concise and efficient synthesis of
3-deshydroxy-secuꢀamamine A (6, an analog of 5[2] and
a structural isomer of 1) as well as the core framework of 1–
3, and indicate preliminary results of the components
necessary for its successful application in other contexts.
[*] Dr. A. M. ElSohly, Dr. D. A. Wespe,[+] T. J. Poore,[+]
Prof. Dr. S. A. Snyder
Department of Chemistry, Columbia University
Havemeyer Hall, 3000 Broadway, New York, NY 10027 (USA)
E-mail: sas2197@columbia.edu
Homepage: http://www.columbia.edu/cu/chemistry/groups/
snyder/
[+] These authors contributed equally to this work.
[**] We thank the NSF (CHE-0619638) for an X-ray diffractometer and
Prof. Gerard Parkin and Aaron Sattler for performing our crystallo-
graphic analysis. Financial support was provided by Columbia
University, the NSF (Predoctoral Fellowship to A.M.E.), and the
Swiss Benevolent Society of New York (Predoctoral Fellowship to
D.A.W.). S.A.S. is a Fellow of the Sloan Foundation and a Cottrell
Scholar of the Research Corporation for Science Advancement.
Scheme 1. Structures of selected members of the securinega family of
natural products and an approach for the rapid assembly of the core
polycyclic domain of the targets.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301849.
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These steps constitute a net [3+2]-addition of an ynal onto
a ketone to afford what could be formally viewed as a hetero
Pauson–Khand[8] product (12), without any need for the
functional group interconversions, protecting groups, and/or
redox adjustments typical of past approaches.
catalysts for our reaction.[12] We hoped that such an additive
could: 1) activate the aldehyde for attack by the carbene,
2) activate the ketone for nucleophilic attack by the homo-
enolate, and 3) coordinate both the ketone and the presumed
Breslow intermediate[13] (i.e. 9, cf. Scheme 1) to organize the
substrate for a productive reaction. However, all examples of
using such co-catalysts in the literature have also required the
presence of an exogenous base, a species seemingly incom-
patible with our starting material based on our initial
explorations (see above). Our hope was that a Lewis acid
such as Ti(OiPr)4 might circumvent the need for an added
base, hopefully providing enough activation and attendant
basicity to promote the desired reaction.
Despite its attractiveness on paper, there was little
precedent indicating that such an approach would be
successful in the laboratory. To the best of our knowledge,
there are no examples of an ynal participating as a conven-
tional nucleophile (i.e. not as a base) in a homoenolate
setting; in fact, the few explorations utilizing ynals as
substrates demonstrate instead that facile redox transfer
through protonation of their derived homoenolates is the
preferred reaction pathway.[9] Only one report detailing enal-
derived homoenolates as nucleophiles toward unactivated
ketones under NHC catalysis is known,[10] and in this case,
good yields were realized only when non-enolizable ketones
were deployed. Moreover, for our preferred substrates (i.e. 8),
we were concerned not only that the ynal motif itself might
not be stable, but also that it might undergo non-productive
intramolecular Michael addition with an enol or enolate
derived from its ketone.[10] With additional conjugation to the
ynal domain present, we were also cognizant of the possibility
of further complications through homo-homoenolate reac-
tivity. Nevertheless, we sought to test its viability, in that if
such a transformation could be achieved, rapid access to the
core of the securinega alkaloids would be obtained while
concomitantly increasing the substrate scope and overall
power of NHC catalysis.
Our explorations began with compound 13, the corre-
sponding diol of which is readily accessible in multi-gram
quantities (see Supporting Information). Given its instability
to bases such as Et3N, we elected to start our explorations with
amine-free conditions similar to those reported by Bode an
co-workers for asymmetric Claisen rearrangements using
NHC catalysts.[3c] Specifically, compound 13 was treated with
NHC precatalyst 14[11] in CDCl3 and heated to 508C in an
NMR tube. After 14 h, 1H NMR analysis of the reaction
mixture revealed ca. 5% conversion to a new compound.
Following purification of the reaction mixture and subsequent
X-ray crystallographic analysis, we confirmed that the new
material was 15, indicating that the desired cyclization had
occurred [Eq. (1)]. Despite this initial hit, efforts to optimize
the efficiency of the process through standard modifications
(solvent, temperature, catalyst structure, and catalyst counter-
ion) failed to provide isolated yields of 15 beyond 10%. All
variants proved sluggish and, if the reaction was left for
prolonged periods, significant decomposition was observed
with no increase in the yield of 15.
Pleasingly, treatment of 13 with 2.0 equivalents of Ti-
(OiPr)4 and 20 mol% of precatalyst 14 in CH2Cl2 at 238C for
12 h not only led to full consumption of the starting material,
but also provided the desired tricyclic product in a markedly
improved yield (37%, Table 1, entry 1). Highlights from our
Table 1: Initial optimization of the NHC/Lewis acid-catalyzed cyclization
of 13.
Entry
Base
(15 mol%)
Lewis acid
(equiv)
Solvent
Yield
[%][a]
1
2
3
4
5
none
none
DBU
DBU
DBU
Ti(OiPr)4 (2 equiv)
Ti(OiPr)4 (1 equiv)
Ti(OiPr)4 (2 equiv)
Ti(OiPr)4 (1 equiv)
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
37
30
38
37
12
[a] Yields were determined by NMR analysis of the crude mixture using
biphenyl as an internal standard.
extensive set of screening experiments to build on this new hit
are presented in Table 1. Intriguingly, the inclusion of an
amine base in substoichiometric quantities relative to the
NHC precatalyst prior to addition of the starting material was
tolerated and allowed the Lewis acid loading to be reduced to
1.0 equivalent, although no yield improvement was observed
(Table 1, entry 4). Importantly, the use of base in the absence
of the Lewis acid was much less efficient, with product formed
in only 12% yield (Table 1, entry 5). Additionally, no other
common Lewis acid was able to improve upon the results
within Table 1. Indeed, many common Lewis acids known to
promote NHC/Lewis acid cooperative catalysis, such as LiCl,
Mg(OtBu)2, Sc(OTf)3, and Mg(OTf)2, were completely inef-
fective in delivering product, while for titanium-based
systems, the efficiency of the reaction was found to be
highly sensitive to the ligand environment around the TiIV
center. For example, exchange of the isopropoxide ligands
with tert-butoxide led to a decrease in yield while replacement
of a single isopropoxide with chloride failed to deliver any
detectable amount of product (see the Supporting Informa-
Given this state of affairs, recent reports by Scheidt and
co-workers prompted us to consider using Lewis acid co-
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tion for a tabulation of some of these results). As such,
Ti(OiPr)4 was used for the remainder of our studies.[14]
The key to the next level of improvement resided in our
observation during these optimization studies that crude mass
recoveries were consistently low and consisted only of
product after simple filtration through a small pad of silica
gel. We ultimately learned that while the product itself was
stable to Ti(OiPr)4 and the overall reaction conditions, the
starting material underwent Lewis acid-mediated decompo-
sition. A concentration screen (Table 2) then suggested that
ring system would be tolerated in our critical NHC-induced
cascade assembly of the butenolide domain. Thus, as shown in
Scheme 2, Boc- and ketal-protected piperidone 16 was
subjected to sequential deprotonation/alkylation[18] to estab-
lish the 2,6-trans-stereochemistry of the piperidine ring within
17 in good overall stereoselectivity (> 8:1). Installation of the
requisite enyne moiety in 18 proceeded through a two-step
protocol involving Stork–Wittig olefination[19] of the aldehyde
Table 2: Concentration screen for the conversion of 13 to 15.[a]
Entry
Conc.
[m]
Solvent
Yield
[%][b]
1
2
3
4
0.1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
38
0.05
0.01
0.005
49
41[c]
[a] All reactions were conducted at 238C with 20 mol% 14, 15 mol%
DBU, and 1 equiv Ti(OiPr)4 for 18 h. [b] Yields were determined by NMR
analysis of the crude mixture using biphenyl as an internal standard.
[c] At 97% conversion.
the decomposition was likely intermolecular in nature, with
a concentration of 0.01m proving optimal if all the starting
material was initially present with the full amount of the
Lewis acid (Table 2, entry 3). As an alternative method, we
also found that the starting material could be introduced to
the reaction via slow addition over the course of 4 h; although
a 49% yield was obtained in both cases, the final reaction
concentration could be increased to 0.04m with the latter
protocol.[16]
Given the marked improvement of our slow addition
protocol, we elected to re-examine the choice of reaction
solvent. To our delight, changing the solvent from CH2Cl2 to
toluene in this procedure proved beneficial. Further screening
of the catalyst loading provided a superior protocol: slow
addition of starting material 13 as a toluene solution to
a suspension of 0.4 equivalents of 14 and 2.0 equivalents of
Ti(OiPr)4 in toluene to reach a final concentration of 0.03m.
As shown in Equation (2), this procedure led to product 15 in
91% isolated yield (0.2 mmol scale reaction). Importantly, the
use of catalyst loadings higher or lower than 20 mol% with
CH2Cl2 as solvent provided an inferior yield. Though the
reason for this yield improvement is not fully understood, the
near insolubility of precatalyst 14 in toluene[17] could further
reduce the concentration of reactive species in solution,
resulting in an improved yield.
Scheme 2. Synthesis of 6-deshydroxy-secu’amamine A (6): a) sBuLi
(1.4m in cyclohexane, 1.5 equiv), TMEDA (1.6 equiv), Et2O, ꢀ78!
ꢀ408C, 1 h; CuCN·2LiCl (1.5 equiv), THF, ꢀ788C, then allyl bromide
(5.0 equiv), ꢀ78!238C, 12 h, 65% (unoptimized); b) sBuLi (1.4m in
cyclohexane, 1.8 equiv), TMEDA (2.2 equiv), Et2O, ꢀ78!ꢀ408C, 1 h,
then DMF (10 equiv), ꢀ78!ꢀ408C, 1.5 h, 60% (unoptimized);
c) NaHMDS (1.0m in THF, 1.2 equiv), ICH2PPh3I (1.25 equiv), THF/
HMPA (10:1), ꢀ788C, 1 h, 80%; d) CuI (14 mol%), PdCl2(NCPh)2
(7 mol%), propargyl alcohol (3 equiv) THF/piperidine (2:1), 238C,
24 h, 86%; e) PPTS (1.5 equiv), tBuOH/H2O (5:1), 758C, 15 h, 78%;
f) Dess–Martin periodinane (1.25 equiv), CH2Cl2, 238C, 1 h, >98%;
g) 14 (40 mol%), Ti(OiPr)4 (2 equiv), toluene, 508C, slow addition over
8 h, 8 h additional stirring, 47%; h) DIAB (5.0 equiv), THF, ꢀ25!
108C over 2 h; aq. NaBO3, 238C, 4.5 h, 72%; i) MsCl (2.0 equiv), Et3N
(3.0 equiv), CH2Cl2, 12 h, then TFA, 08C, 1 h, 92%. DIAB=disiamyl-
borane, DMF=dimethylformamide, HMDS=hexamethyldisilazide,
HMPA=hexamethylphosphoramide, Ms=methanesulfonyl,
PPTS=pyridinium p-toluenesulfonate, TFA=trifluoroacetic acid,
THF=tetrahydrofuran, TMEDA=N,N,N’,N’-tetramethylethylene-
diamine.
With this success in hand, we then embarked on a synthesis
of natural product analog 3-deshydroxy-secuꢀamamine A (6)
to determine if additional substituents on the core piperidone
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and subsequent Sonogashira coupling in 69% overall yield.
Importantly, no epimerization of the aldehyde was observed
during the olefination step (see Supporting Information for
full details). Next, deprotection of the ketal with PPTS in
tBuOH/H2O (5:1) at 758C furnished the desired ketone in
78% yield without any observable alkene isomerization,
while subsequent oxidation of the primary alcohol with Dess–
Martin periodinane[20] furnished enynal 19 in excellent yield
(> 98%), setting the stage for our key cyclization event.
Pleasingly, slow addition of a solution of 19 to a suspension
of Ti(OiPr)4 and precatalyst 14 in toluene using our previously
optimized conditions (0.03m) was effective in delivering the
desired tricyclic compound (20); however, the yield of 20
(28%) was much lower than in our previous model study.
Fortunately, lowering the final concentration to 0.02m led to
an increase in yield to 35%. The diminished yields for 20
relative to our model (15) suggests that substrate 13 may
possess a conformational bias that facilitates the reaction
given that carbamate-protected piperidines generally prefer
an axial orientation of C2 substituents when monosubsti-
tuted.[18] In 19, however, the presence of 2,6-trans-disubstitu-
tion likely induces a conformational equilibrium in which the
desired enynal only resides in the axial orientation intermit-
tently (Scheme 3). In line with that supposition, heating of the
Scheme 4. Synthesis and NHC-induced cyclization of 25 to deliver the
[3.2.1]-bicyclic core (26) found in various securinega alkaloids:
a) TMSCHN2 (2.0m in toluene, 1.1 equiv), THF/MeOH (10:1) ꢀ78!
238C over 1 h, 99%; b) TBSCl (1.3 equiv), imidazole (1.8 equiv),
CH2Cl2, 238C, 12 h, 98% over 2 steps); c) DIBAL-H (1.0m in toluene,
2.5 equiv), THF, ꢀ788C, 45 min, then 238C, 10 min, 98%; d) SO3·pyr
(3.0 equiv), Et3N (4.0 equiv), DMSO/CH2Cl2 (2:1), 0!238C, 45 min,
90–97%; e) NaHMDS (1.0m in THF, 1.2 equiv), ICH2PPh3I
(1.25 equiv), THF/HMPA (10:1), ꢀ78!ꢀ408C, 1 h, 50%; f) CuI
(14 mol%), PdCl2(NCPh)2 (7 mol%), propargyl alcohol (3 equiv) THF/
piperidine (2:1), 238C, 24 h, 78%; g) TBAF (1.0m in THF, 1.5 equiv),
THF, 238C, 14 h, 94%; h) Dess–Martin periodinane (2.5 equiv),
CH2Cl2, 238C, 1.5 h, >95%; i) 14 (40 mol%), Ti(OiPr)4 (2 equiv),
toluene, slow addition over 4 h, 508C, 12 h, 31%. TMS=trimethylsilyl,
DIBAL-H=diisobutylaluminum hydride.
508C.[24] This outcome highlights that several variants of the
butenolide core found within the family can be accessed using
this general approach in a number of different contexts. At
present, work to apply these reactions to fully functionalized
materials capable of accessing natural products is underway,
as is the exploration of the full substrate scope of this reaction.
Immediately clear is that the conformational bias provided by
the N-Boc protecting group within 13 is essential for deliver-
ing high yields, as its fully carbogenic congener is much less
efficient. Furthermore, the alkene moiety appears to provide
a further benefit in restricting the degrees of rotational
freedom available to the side chain. Thus, it appears that this
reaction manifold is highly sensitive to the conformation
adopted by the various substrates, and those substrates that
are suitably oriented to facilitate the desired reaction through
either conformational locking or restriction of rotational
degrees of freedom have a greater chance for success.
In conclusion, we have developed and applied a novel and
efficient NHC/Ti(OiPr)4 cascade reaction to the synthesis of
the tricyclic framework of the securinega alkaloids. This
reaction has enabled access to 6 and compound 26 in only 9
linear steps from commercial materials, a length which
compares favorably to past approaches,[22] and has demon-
strated the viability of ynal-derived homoenolates as nucle-
Scheme 3. Important conformational dynamics in 13 and 19 leading to
observed differences in yield of the key reaction.
reaction mixture to 508C during the slow addition process
provided a notable yield increase to 47%. From here,
butenolide 20 was thus taken forward with a chemoselective
hydroboration/oxidation sequence[21] furnishing the desired
primary alcohol in 72% yield, with 6 then accessed in 92%
yield by a one-pot methane sulfonate ester formation/N-Boc
deprotection/cyclization sequence.
As a final study, we wanted to examine the ability of this
NHC/Lewis acid reaction to forge bridging butenolide cores
within [3.2.1]-bicycles as well, a motif found within a large
number of securinega alkaloids such as securinine (1) and
norsecurinine (3). Thus, we prepared compound 25 through
the route delineated in Scheme 4 (drawing from many of the
lessons learned in the context of Scheme 2) and, to our
delight, found that our protocol could deliver the desired
[3.2.1]-bicyclic framework of 26 in 31% yield when heated to
4
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synthesis of 6 outlined in this work is redox economic,[23]
enabled by our key NHC/Lewis acid transformation. Thus, we
anticipate that these studies will provide opportunities for the
development of further NHC-catalyzed reactions using ynals
as nucleophilic homoenolate precursors,[25] as well as efficient
syntheses of natural product members of the securinega
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Received: March 5, 2013
Published online: && &&, &&&&
Keywords: alkaloid · cascade reaction · natural product ·
.
N-heterocyclic carbene · securinega
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14 (a catalyst designed to prefer homoenolate addition) was no
more effective than 14 in our reactions.
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subsequent disclosures and
a review of NHC/Lewis acid
cooperative catalysis, see Ref. [6i], and references therein.
[13] R. Breslow, J. Am. Chem. Soc. 1958, 80, 3719 – 3726.
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[14] To the best of our knowledge, this reaction represents the first
example of NHC/Lewis acid co-catalysis in the absence of
common exogenous bases to generate the active carbene.
Although we have no evidence that the alkoxide ligands are
directly involved in generation of the carbene species, the fact
that the reaction does proceed in the absence of any exogenous
base or Lewis acid [see Eq. (1)] suggests that weakly basic
species can still promote generation of the active carbene.
Hence, Ti(OiPr)4 is likely basic enough to facilitate the
generation of the active carbene. Use of the more basic and
related Zr(OiPr)4·iPrOH complex led to rapid MPV-type
reduction of the aldehyde. For a discussion of some factors
contributing to the Lewis acidity/basicity of TiIV species, see: M.
Reetz, Top. Curr. Chem. 1982, 106, 1 – 54. For a discussion of the
moderate Lewis basicity of ZrIV alkoxides, see: S. Yamasaki, M.
Kanai, M. Shibasaki, Chem. Eur. J. 2001, 7, 4066 – 4072.
Interestingly, imidazolium pre-catalysts were ineffective in the
absence of an exogenous base.
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[21] This procedure has been used for hydroboration of a related
substrate: a) P. Magnus, J. Rꢄdriguez-Lꢄpez, K. Mulholland, I.
Matthews, J. Am. Chem. Soc. 1992, 114, 383 – 385; b) P. Magnus,
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1993, 49, 8059 – 8072.
[22] The only published synthesis of 5 required 18 steps from
commercial materials; see Ref. [5r].
[23] N. Z. Burns, P. S. Baran, R. W. Hoffmann, Angew. Chem. 2009,
121, 2896 – 2910; Angew. Chem. Int. Ed. 2009, 48, 2854 – 2867.
[24] While the turnover number en route to compounds 6 and 26 are
indeed close to (or even less than) 1, the reaction achieves
greater than 2 turnovers in the conversion of 13 to 15, thus
prompting us to believe that catalytic activity is maintained. The
low turnover number in the former cases is likely due to
competing pathways that lead to nonspecific decomposition of
the starting material.
[25] During the review of this manuscript, a related NHC/Lewis acid
catalyst system for the intermolecular homoenolate addition of
an ynal to non-enolizable a-keto esters was reported: J. Qi, X.
Xie, R. Han, D. Ma, J. Yang, X. She, Chem. Eur. J. 2013, 19,
4146 – 4150.
[15] Variations in aqueous work-up and extraction procedure also
failed to improve the overall yield of the desired product.
[16] Neither decreasing the final concentration nor increasing the
time of addition provided any additional benefit.
[17] In fact, the final step in the preparation of precatalyst 14 involves
recrystallization from toluene; see Ref. [11].
6
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Angewandte
Chemie
Communications
Cooperative Catalysis
Folding it all together: Most of the
syntheses developed for the securinega
alkaloid class require lengthy sequences
to create their bridging butenolide
A. M. ElSohly, D. A. Wespe, T. J. Poore,
S. A. Snyder*
&&&& — &&&&
domains. A novel approach uses N-
heterocyclic carbenes (NHCs) and Lewis
acids to forge the entire domain in
a single step from appropriate precur-
sors, showing that ynal-derived homo-
enolates can participate as nucleophiles
in intramolecular settings (see scheme).
An Efficient Approach to the Securinega
Alkaloids Empowered by Cooperative N-
Heterocyclic Carbene/Lewis Acid
Catalysis
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These are not the final page numbers!