A strategy for complex dimer formation when biomimicry fails: Total synthesis of ten coccinellid alkaloids

Article abstract of DOI:10.1021/ja5045852

Although dimeric natural products can often be synthesized in the laboratory by directly merging advanced monomers, these approaches sometimes fail, leading instead to non-natural architectures via incorrect unions. Such a situation arose during our studies of the coccinellid alkaloids, when attempts to directly dimerize Natures presumed monomeric precursors in a putative biomimetic sequence afforded only a non-natural analogue through improper regiocontrol. Herein, we outline a unique strategy for dimer formation that obviates these difficulties, one which rapidly constructs the coccinellid dimers psylloborine A and isopsylloborine A through a terminating sequence of two reaction cascades that generate five bonds, five rings, and four stereocenters. In addition, a common synthetic intermediate is identified which allows for the rapid, asymmetric formal or complete total syntheses of eight monomeric members of the class.

Full text of DOI:10.1021/ja5045852

Article
pubs.acs.org/JACS
A Strategy for Complex Dimer Formation When Biomimicry Fails:
Total Synthesis of Ten Coccinellid Alkaloids
Trevor C. Sherwood,† Adam H. Trotta,† and Scott A. Snyder*,†,‡
†Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027, United States
‡Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States
S
* Supporting Information
ABSTRACT: Although dimeric natural products can often be synthesized in the laboratory by directly merging advanced
monomers, these approaches sometimes fail, leading instead to non-natural architectures via incorrect unions. Such a situation
arose during our studies of the coccinellid alkaloids, when attempts to directly dimerize Nature’s presumed monomeric
precursors in a putative biomimetic sequence afforded only a non-natural analogue through improper regiocontrol. Herein, we
outline a unique strategy for dimer formation that obviates these difficulties, one which rapidly constructs the coccinellid dimers
psylloborine A and isopsylloborine A through a terminating sequence of two reaction cascades that generate five bonds, five rings,
and four stereocenters. In addition, a common synthetic intermediate is identified which allows for the rapid, asymmetric formal
or complete total syntheses of eight monomeric members of the class.
a single connecting bond to far more complex bond-forming
unions, such as that postulated for the conversion of sorbicillin
(4) into trichodimerol (5) through a series of Michael reactions
and ketalizations.6 In the second dimerization approach,
monomer union occurs at an earlier stage, with subsequent
tandem modifications of each half leading to the final structure
(as in 6 → 7 → 8 and 10 → 11 → 12).7
INTRODUCTION
■
While it is remarkable to consider the sheer wealth and
architectural diversity of natural products that can be produced
from a relatively small set of starting materials, equally striking
is the number of structures within that collection that can be
envisioned to arise via the union of a secondary metabolite with
itself. Indeed, by some estimates, between 15 and 20% of all
natural products likely include a dimerization process at some
point in their biogenesis.1 This analysis includes materials with
obvious symmetry, such as sceptrin (1, Scheme 1),2
compounds with equivalent halves but non-symmetric unions,
such as complanadine A (2),3 and materials whose symmetry
has been partially erased through subsequent structural
modifications like oxidation or decarboxylation, such as CP-
225,917 (3).4 Given the significant energy invested in the
creation of any natural product, the ubiquity of such dimers is
logical, since dimerization enables rapid access to additional
molecular scaffolds without invoking entirely new biosynthetic
pathways. Indeed, with their distinct three-dimensional shapes
and functional group presentations, these new materials may
well afford evolutionary advantages to the producing species.5
Considering only those dimeric natural products that possess
obvious monomer symmetry (i.e., those that have not
undergone extensive modifications, such as 3), Nature appears
to deploy two general strategies to access such materials. The
first and most typical approach forges the dimer in a final
synthetic operation from fully functionalized monomers. Such
processes can range from the simple and direct construction of
During the past several decades, synthetic chemists have
become particularly skilled at utilizing both of these bio-
inspired strategies to access dimeric materials from monomers.8
The first strategy is the most appealing from a retrosynthetic
standpoint, especially if it directly replicates Nature’s synthesis.9
In practice, though, it often requires extensive screening of
conditions to achieve success and sometimes affords only
modest yields of final product. The second approach has
provided the opportunity for further creativity, as dimers
distinct from those deployed by Nature can also be elaborated
in tandem sequences to the final target. This concept was, to
the best of our knowledge, first demonstrated by Stork in the
synthesis of α-onocerin (8) in four steps from 9,10 and used
more recently to great effect by a number of groups,11 including
Boger in his approach to 12.12 It also arguably constitutes the
only general solution for dimer synthesis when direct, final-step
dimerization cannot be achieved, whether due to challenges in
target patterning, monomer reactivity, and/or the absence of
Received: May 7, 2014
© XXXX American Chemical Society
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Scheme 1. Ubiquity of Dimers in Nature and Available
Strategies for Their Formation in Nature and in the
a
Laboratory
Figure 1. Structures of the coccinellid class of alkaloids: unique
monomeric and dimeric frameworks.
a
Dimer linkages are colored in purple.
congested, and stereochemically rich frameworks. To date,
the monomeric members have elicited significant synthetic
interest, with several approaches based on both classical and
modern bond constructions affording every tricycle drawn in
Figure 1.15g,19 Intriguingly, however, it is only within the past
year that the first asymmetric synthesis of any of these members
has been accomplished.19i Equally surprising, no work toward
any higher-order structure has been reported, nor has any
mechanistic hypothesis been advanced to account for dimer
formation in Nature.
Herein, we disclose our efforts to access this entire
compound class. To date, that work has identified a single
common synthetic intermediate capable of rapidly affording
every monomer drawn in Figure 1.20 It has also led to a
biosynthetic proposal for the formation of both psylloborine A
(23) and isopsylloborine A (24), one that, when reduced to
practice, resulted in a non-natural, regioisomeric dimer. This
unexpected result, coupled with observations from other
instances where incorrect dimeric unions have occurred in
biomimetic constructions, has led to the development of a
unique, non-biomimetic strategy for complex dimer synthesis.
As will be described in the ensuing sections, this alternate
strategy has afforded rapid syntheses of both psylloborine A
(23) and isopsylloborine A (24) through sequences involving
some of the most complex condensation/Michael/Mannich
cascade chemistry yet reported.21 Significantly, this approach
suitable enzymes to achieve the needed bond constructions.
Yet, despite their respective advantages, these two approaches
also share a potential limitation: the key step linking the
monomeric materials typically possesses a single reactive
course. Thus, if the needed bond(s) and/or stereocenter(s)
are improperly established in this operation, it is exceedingly
difficult to overcome such results.
Such issues arose during our efforts to synthesize the
coccinellid family of alkaloids, materials secreted by numerous
species of ladybugs as defensive compounds when provoked13
and viewed by some as potential commercial insecticides,
particularly for the control of aphid pest populations.14 Figure 1
provides the structures of eight of the nine monomers within
this class (14−21), tricyclic architectures differing in ring
junction stereochemistry, oxidation state, and olefin place-
ment.15
In addition to these materials, several larger and more
complex compounds are known wherein half of their
framework possesses these monomer cores, such as chilocorine
A (22),16 as well as two other species that structurally reflect
the dimeric combination of these cores in the form of
psylloborine A (23)17 and isopsylloborine A (24).18 The sole
distinction between these latter two natural products is ring-
junction enamine isomerism within their fused, highly
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can likely be applied to other challenging dimerizations and
may, in certain cases, be as efficient and powerful as an overall
synthetic design.
transfer, Mannich reaction, and terminating proton loss to
generate dimers 23 and/or 24.
In total, this proposed direct, final-stage dimerization
sequence would form two new C−C bonds, one ring, and
three stereocenters. The main assumption of this analysis, at
least in terms of a successful laboratory execution, is that pre-
existing chirality within the monomers could dictate the facial
presentation of the reacting partners (i.e., enzymatic
intervention would not be required). Equally critical, but
unclear, were (1) whether one or both dimeric products would
result from such a pathway, and (2) whether only propyleine
(17) would be the active nucleophile, or if its equilibrating and
more dominant enamine isomer, isopropyleine (18), could
participate in addition to, or instead of, 17.
RESULTS AND DISCUSSION
■
1. Possible Biogenesis for Psylloborine A (23) and
Isopsylloborine A (24). Given the absence of any proposal
for how either psylloborine A (23) or isopsylloborine A (24)
might arise in Nature, we began by pondering mechanistic
pathways that could account for their formation from the
known tricyclic coccinellid alkaloids. The idea that ultimately
proved the most attractive is shown in Scheme 2 and was
Scheme 2. Proposed Biogenesis of Psylloborine A (23) and
Isopsylloborine A (24) via Oxidation of Isopropyleine (18)
Despite these concerns, the overall attractiveness of such a
dimerization process prompted us to test its viability. Thus, we
set out to develop synthetic pathways to access 17/18 as well as
26.
2. Initial Retrosynthetic Analysis and Development of
a Family-Level Approach. Scheme 3 provides a retro-
synthetic approach that we hoped could ultimately address the
synthetic challenges posed by the nucleophilic and electrophilic
partners needed to test our proposed dimerization sequence. As
Scheme 3. Global Retrosynthetic Analysis for the
Monomeric Coccinellid Alkaloids from Key Intermediate 31
inspired by a key structural observation among the monomers
depicted in Figure 1. Namely, although three of those
monomers (14−16) have a stable N-oxide counterpart (19−
21, drawn below its respective precursor), propyleine and
isopropyleine (17 and 18, a 1:3 equilibrating mixture in
solution, respectively)15g do not. Thus, perhaps the N-oxides of
17 and/or 18 are unstable and, if generated (25), convert to a
reactive electrophilic species such as 26.22 If this material was
formed in the presence of a molecule of propyleine (17), then
perhaps it could undergo the sequence of events shown in
Scheme 2, involving a vinylogous Mannich reaction, proton
C
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indicated, our goal was to prepare bicyclic intermediate 30
through an intramolecular condensation between the depro-
tected amine variant of 31 and its neighboring carbonyl. Then,
if its thermodynamically favored trisubstituted enamine could
be isomerized to its less stable, exocyclic counterpart and
intramolecularly displace a suitably disposed leaving group,
propyleine (17) would result alongside its equilibrating
enamine isomer, isopropyleine (18). Although isomerization
to the exocyclic enamine isomer is clearly disfavored, we
believed the final ring formation would be an energetically
downhill and essentially irreversible process that would enable
the reaction to be driven to completion.
Scheme 4. Synthesis of Key Intermediate 31 via Two
Different Routes
a
Worth noting is that this sequence, while not fully
biomimetic, is certainly bio-inspired as a disubstituted
piperidine undergoing enamine condensation and subsequent
attack on an intramolecular electrophile has been proposed to
account for the biosynthetic formation of several monomeric
alkaloids in this class.23 Indeed, as shown in the lower half of
Scheme 3, Braekman and co-workers demonstrated that
polyketo-myristic acid (formed from stearic acid through
enzymatic oxidations) is the biosynthetic precursor to coccinel-
line (19) via the proposed intermediacy of 33, a compound
containing a 10-membered ring;23 the intervening steps listed
above each arrow are one proposal for how these net
transformations might specifically occur. Our proposed syn-
thesis of 17/18 is based on a similar, but differently ordered, set
of chemical events involving no individual ring size greater than
six, in which a disubstituted piperidine (34) becomes the
tricyclic system through an enamine condensation and a
terminating C−C bond formation driven by nucleophilic attack
of the enamine moiety.
Assuming success in our proposed synthetic operations
leading to 17/18, attempts to generate electrophile 26 in situ
through N-oxide formation would then begin. As an alternative
approach to access 26, we also considered a de novo preparation
from 32, again proposing enamine equilibration and subsequent
C−C bond formation to close the final ring of its tricyclic
framework. This material, in turn, we believed could also arise
from 31. Given that this proposed key starting material (31)
possesses three reactive domains (highlighted in blue, green,
and orange) with sufficiently distinct and tunable electrophilic
and nucleophilic properties, we also questioned whether every
other monomer configuration (i.e., 14−16 and 19−21) within
the class could be accessed from the same entry point.24 If so,
then a near-universal, family-level solution for the coccinellid
alkaloids would exist, with enantioselective syntheses of all
monomeric members possessing optical activity being achieved,
some for the first time.
a
Reagents and conditions: (a) TBDPSCl (1.05 equiv), imidazole (2.0
equiv), CH2Cl2, 25 °C, 19 h; (b) s-BuLi (1.5 equiv), TMEDA (1.6
equiv), Et2O, −78 to −45 °C, 1 h; CuCN·2LiCl (1.5 equiv), −78 °C,
1 h; 37 (3.0 equiv), −78 to 25 °C, 4 h, 84% over two steps; (c)
PdCl2(PhCN)2 (0.1 equiv), CuCl (1.0 equiv), DMF/H2O (10/1), O2,
60 °C, 6 h, 41%; (d) NaOH (2.0 equiv), i-PrOH, 25 °C, 1 h, 100%;
(e) ATPH (1.5 equiv), CH2Cl2, 0 °C, 20 min; L-Selectride (2.0 equiv),
−78 °C, 1 h, 75%, 15:1 dr; (f) TBAF (2.0 equiv), THF, 25 °C, 2 h,
91%; (g) TBSCl (1.1 equiv), imidazole (2.0 equiv), CH2Cl2, 25 °C, 19
h; (h) same as step b but with 40 (5.0 equiv) instead of 37, 92%; (i)
K2OsO4·2H2O (0.005 equiv), NaIO4 (4.0 equiv), 2,6-lutidine (2.0
equiv), 1,4-dioxane/H2O (3/1), 25 °C, 24 h; (j) 42 (2.2 equiv), THF,
−78 °C, 2.5 h; (k) K2OsO4·2H2O (0.005 equiv), NaIO4 (4.0 equiv),
2,6-lutidine (2.0 equiv), 1,4-dioxane/H2O (3/1), 25 °C, 16 h, 95%; (l)
TFAA (5.0 equiv), pyridine (15 equiv), 4-DMAP (0.1 equiv), CH2Cl2,
0 °C, 1.5 h; (m) DBU (1.5 equiv), CH2Cl2, 0 to 25 °C, 1.5 h, 80% (n)
ATPH (1.5 equiv), CH2Cl2, 0 °C, 30 min; L-Selectride (2.0 equiv),
−78 °C, 1 h; 1 M HCl (10 equiv), MeOH, 25 °C, 1 h, 79%.
analysis.26 With all of the carbons of the final target already in
place, only functional group manipulations and redox adjust-
ments remained. These events began by conversion of 38 into
enone 39 through a modestly yielding and sometimes
capricious Wacker oxidation (41% yield) promoted by
PdCl2(PhCN)2 in DMF/H2O at 60 °C, followed by a nearly
quantitative base-induced (NaOH) olefin isomerization; these
transformations afforded the new alkene with 4:1 selectivity
which we assume to have the structure shown, though we never
explicitly confirmed the process as being E-dominant. Next, we
hoped to set the methyl stereocenter of the target through a
diastereoselective reduction. This step ultimately proved to be
the most challenging of the sequence, with repeated attempts at
substrate-directed hydrogenation using Wilkinson’s or Crab-
tree’s catalysts affording either no diastereoselection or
preference for the undesired methyl epimer on 39 or its
deconjugated enone precursor. Fortunately, use of Yamamoto’s
bulky Lewis acid, aluminum tris(2,6-diphenylphenoxide)
(ATPH),27 in tandem with L-Selectride afforded the desired
stereocenter with a 15:1 diastereomeric ratio (dr) and in 75%
yield.28 A final desilylation using TBAF in THF at 25 °C then
delivered the desired building block (31) in a sequence that was
just seven steps overall (including the two-step preparation of
37).
3. Synthesis of Key Building Block 31. Based on this
plan, our first objective was to devise an efficient synthesis of
our key, common building block (31). As shown in Scheme 4,
we ultimately developed two different routes to accomplish that
goal, both starting from the commercially available N-Boc-(S)-
(−)-piperidine-2-ethanol (36). This material was chosen
because it possessed a key chiral center that we anticipated
would readily encode the remaining stereochemical information
into the final target.
Our first route began with silylation of the alcohol and was
followed by a copper-mediated allylation with branched
bromide 37,25 itself available in two steps from propargyl
alcohol (see Supporting Information for synthesis). These
operations led to trans-disposed intermediate 38 in 84% overall
1
yield and with >19:1 diastereoselectivity based on H NMR
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Concurrent with these efforts, especially in light of the low-
yielding Wacker oxidation step, we developed an additional
sequence to 31. Though slightly longer at eight steps, it proved
to be operationally simpler and higher yielding overall. It began
similarly from 36, with a two-step sequence of silyl protection
of the alcohol (this time as a TBS ether) and a copper-mediated
addition using allylic bromide 40 that proceeded in 92% overall
yield. Subsequent oxidative cleavage of the new alkene,
mediated by K2OsO4 and NaIO4,29 afforded methyl ketone
41. The remaining carbon atoms of the target were then
installed via nucleophilic addition of Grignard reagent 42, with
a second oxidative cleavage then generating the ketone within
43 in 95% yield over three steps. Formation of the desired
enone was accomplished via trifluoroacetate formation and
DBU-induced elimination in 80% yield over two steps. Finally,
this transformation was followed by the same facially selective
hydride delivery, with a terminating in situ deprotection upon
quenching of the [1,4]-reduction product with HCl, completing
the synthesis of 31 in 79% yield and in 8:1 dr.
Scheme 5. Asymmetric Formal and Total Synthesis of Eight
Monomeric Coccinellid Alkaloids
a
Worth noting is that both routes contributed substantively to
the delivery of material for subsequent studies, with each being
performed on relatively large scales. Indeed, the first route was
able to deliver 2.68 g of 31 in a single campaign, while the
second afforded 3.02 g of this key intermediate.
4. Synthesis of the Monomeric Coccinellid Alkaloids
and Exploration of Dimerization Pathways to Psyllo-
borine A (23) and Isopsylloborine A (24). With compound
31 in hand, our efforts to synthesize the monomeric members
of the coccinellid class began in earnest. Starting with
propyleine and isopropyleine (17 and 18, Scheme 5), we first
converted the alcohol within 31 to a reactive bromide (44)
through the intermediacy of its N-deprotected TFA salt (TFA;
PBr3, one-pot operation). We then dissolved this material (44)
in i-PrOH and treated it with Et3N in hopes that its enamine
could be isomerized to its less stable, exocyclic counterpart
(45) as noted earlier, thereby inducing a terminating
cyclization. Pleasingly, this conjecture proved true, affording
(−)-propyleine (17) and (−)-isopropyleine (18) as an
equilibrating 1:3 mixture in 43% yield. This nine-step sequence
(using the step count of the shorter route to 31) is the first
asymmetric solution for these targets and the shortest route to
date. In addition, the levorotatory rotation of the final synthetic
materials matched that of the natural isolates, confirming the
absolute configuration of these compounds for the first time as
based on the initial assignment of 36 (cf. Scheme 4).
From here, subsequent reduction of a portion of these
natural products with NaBH(OAc)3 led to a 3.7:1 mixture of
precoccinelline (14) and hippodamine (15, Scheme 5). Due to
the trans-ring fusions of these materials, it was difficult to
predict the outcome of this reaction a priori. However, given
the observed facial bias, we presume that if the top ring (as
drawn in the two-dimensional depiction of 46) were to adopt a
twist-boat orientation, as indicated by the three-dimensional
representation of imine 46 in Scheme 5, then hydride delivery
from the bottom face would appear to be preferred, forming
precoccinelline (14). If true, then hippodamine (15) would
have resulted from hydride delivery onto the other side of the
structure. Presumably, delivery from the top face, forming
hippodamine, forces the methyl group into an unfavorable 1,3-
diaxial relationship with the incoming hydride in the transition
state, whereas delivery from the opposite face produces no such
interaction. From the standpoint of synthesis, however, as
precoccinelline (14) has previously been readily converted into
a
Reagents and conditions: (a) TFA/CH2Cl2 (1:1), 0 °C, 1 h; solvent
removal, PBr3 (5.0 equiv), Et2O, 70 °C, 5 h; (b) Et3N (1.0 equiv), i-
PrOH (cat.), CH2Cl2, 25 °C, 13 h, 43% yield over two steps; (c)
NaBH(OAc)3 (5.0 equiv), CH2Cl2, 0 °C, 3 h, 80%, 3.7:1 dr; (d)
BzONHMe·HCl (1.0 equiv), DMSO, 25 °C, 2 d, 62%; (e) TFA/
CH2Cl2 (1:1), 0 °C, 1 h; concentrate, PBr3 (5.0 equiv), Et2O, 70 °C, 5
h; (f) Et3N (0.77 equiv), i-PrOH (0.91 equiv), CH2Cl2, 40 °C, 4 h;
concentrate, aq NaOH (10 equiv), MeOH, 65 °C, 6 h, 46% over two
steps, 1:1.2 dr, recyclable.
its N-oxide congener coccinelline (19, cf. Figure 1),19g its
preparation allowed us to claim a formal synthesis of this
oxidized monomer as well.
Alternatively, α-oxidation of common intermediate 31 with
BzONHMe·HCl,30 followed by the same general steps already
described (TFA; PBr3 in one pot then Et3N, i-PrOH; NaOH)
generated oxidized skeleton 48 by way of 47 as a mixture of
recyclable diastereomers about the new, highlighted chiral
center.31,32 This compound (48) has previously been advanced
by Mueller to hippodamine and hippocasine (15 and 16,
respectively) as well as their N-oxides (20 and 21, cf. Figure
1),15g,33 thus completing total and/or formal syntheses of all
eight monomers drawn in Scheme 1, all starting from a single
starting material (i.e., 31).
With syntheses of our targeted monomers complete, our
attention now turned to dimerization. Although our proposed
nucleophilic partner was already available from the synthesis of
propyleine and isopropyleine (17 and 18), efforts to generate a
reactive electrophile directly from these materials through N-
oxidation were unsuccessful. As such, we sought an alternate
and potentially more controlled path to the needed electro-
philic dimerization precursor in the form of cross-conjugated
diene 49 (Scheme 6). Our hope was that, upon exposure to an
appropriate proton source, iminium electrophile 26 (Schemes 2
and 7) could be generated in situ, and then we could expose
that species to the appropriate nucleophilic partners. Our initial
route to access this compound sought to dehydrate 51, itself
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Scheme 6. Preparation of Key Dimerization Precursor 49
from Key Intermediate 31
Scheme 7. Attempts at Direct, Late-Stage Dimerization Led
to a Non-natural Dimeric Analogue (54) with Incorrect
Regiocontrol
a
a
a
Reagents and conditions: (a) (COCl)2 (1.6 equiv), DMSO (3.2
equiv), Et3N (6.0 equiv), CH2Cl2, −78 to 0 °C, 90 min, 94%; (b)
TFA/CH2Cl2 (1/1), 0 °C, 1 h, carried forward crude; (c) RuO2·xH2O
(0.10 equiv), NaIO4 (4.0 equiv), acetone/H2O (1:1), 0 °C, 90 min,
77%; (d) p-nitrophenol (1.2 equiv), DCC (1.2 equiv), 4-DMAP (0.10
equiv), 25 °C, 20 h; filter, solvent removal, TFA/CH2Cl2 (1:1), 0 °C,
1 h; (e) i-PrOH (cat.), CH2Cl2, 40 °C, 18 h, 31% over two steps; (f)
DIBAL-H (2.5 equiv), THF/1,4-dioxane (4:1), 25 °C, 4 min.
readily prepared from 31 in just two steps via oxidation and a
one-pot TFA-promoted deprotection/condensation/Mannich
reaction sequence. Unfortunately, no conditions were found
that could reliably afford 49 from this intermediate. As such, an
alternate, slightly longer four-step pathway was developed as
shown in the lower half of Scheme 6.34 The key operation was
the final step involving DIBAL-H-mediated reduction of
vinylogous amide 53. This step proceeded in ∼45% conversion
a
Reagents and conditions: (a) TFA (1.0 equiv based on vinylogous
amide 53), 25 °C, 2 min; 17 and 18 (1:3, 1.07 equiv combined based
on vinylogous amide 53), 25 °C, 2 h, 21% over two steps.
1
(based on crude H NMR of samples accounting for full mass
recovery) to afford 49 along with the [1,4]-reduced counterpart
of 53. As this critical compound proved unstable and difficult to
purify, it was carried forward directly into dimerization studies
once formed.
Following extensive experimentation with acid source and
solvent, we found that electrophile 26 (Scheme 7) could be
obtained when 49 was taken up in CD2Cl2 (to enable close
monitoring by NMR analysis) and exposed to TFA at 25 °C.
When propyleine and isopropyleine (17 and 18) were then
added as a CD2Cl2 solution to this electrophile 2 min later, a
new dimeric material was formed over the course of 2 h in 21%
overall yield from 53. Unfortunately, this material did not
match the spectral data for either 23 or 24.17,18 Extensive NMR
analysis (1H, 13C, COSY, TOCSY, NOESY, HSQC, and
HMBC; see Supporting Information for full details) ultimately
revealed that this dimer was non-natural, resulting from
incorrect regiocontrol in the union of the two building blocks,
as noted by the highlighted carbons within their frameworks.
This result meant that isopropyleine (18), not propyleine (17),
served as the nucleophilic partner. We have elected to give this
new dimeric material, compound 54, the name “psylloborine
B”, should it ever prove to be a natural isolate.
As indicated in Figure 2, extensive molecular modeling
employing hand-held model kits has provided a rationale as to
why this outcome may have occurred. Critically, we believe it is
the result of kinetic control based on the stereoelectronic and
conformational demands of the lone desymmetrizing methyl
group within nucleophiles 17 and 18, not the ratio of these two
components in solution. In theory, there are a total of four
possible reactive pathways: either propyleine or isopropyleine
serving as a nucleophile (with the nucleophilic carbons colored
to match that of Scheme 7), with approach of the electrophile
Figure 2. Possible basis for the observed dimerization result based on
transition-state models for electrophile addition (i.e., 26) using either
the propyleine (17) or isopropyleine (18) enamines as nucleophile.
occurring from either the top or bottom face. These
possibilities are drawn in Figure 2 as transition states A−D,
all viewed from the perspective of looking down the C−N bond
of the enamine, with the nitrogen atom located behind the
circle of the Newman projection.
Based on the analysis provided earlier in the context of
Scheme 2, the requisite pathway to psylloborine A (23) or
isopsylloborine A (24) would require nucleophilic attack by
propyleine (transition states A and/or B). In transition state A,
a favorable pseudochair-like transition state can be achieved,
but it incurs a significant steric penalty by requiring the
incoming electrophile to approach syn to the pendant methyl
group. In transition state B, addition from the bottom face is
now anti to the pendant methyl group, but it seems to require a
pseudoboat-like orientation to proceed, with a number of
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destabilizing flagpole and eclipsing interactions resulting as
indicated. By contrast, when isopropyleine (18) is the enamine
nucleophile (transition states C and D), there are no proximal
substituents that can destabilize the approach of the electro-
phile as in pathway A or B. Therefore, the lowest energy
pathway is likely to proceed through these transition states, and
thus 54 results.35
5. Development and Execution of an Alternate
Dimerization Strategy. Given this experimental outcome, a
new synthetic approach was needed for psylloborine A (23)
and/or isopsylloborine A (24). Ultimately, it was careful
consideration of this, as well as other cases where direct
dimerization had also failed,36 which led to the revised
retrosynthesis as drawn in Scheme 8. This analysis is based
complete the targets. Initiation of the first cascade required
the ability to differentiate selectively between the protecting
groups on the two piperidine rings in 59 to reach 58 via a
condensation and Michael closure. The second cascade would
utilize an added electron-withdrawing group (EWG, colored in
blue) on one of the pendant methyl groups of the final target to
dictate the correct order of bond constructions through
condensation, enamine-based Michael attack to form the
tricyclic ring system, and a terminating Mannich ring-closure
to complete the carbon framework. Collectively, these two
cascades would forge five new bonds, five new rings, and four
stereogenic centers, assuming again that pre-existing chirality
within 59 could govern the incorporation of the remaining
chiral elements. If successful, then a terminating excision of the
EWG in cascade product 57 would complete the synthesis of
23 and/or 24.
On initial inspection, this approach appears contrary to the
general tenets of retrosynthetic analysis,39 since an arguably
more complex precursor and set of terminating events are
required than those needed for the two dimerization strategies
presented in Scheme 1. However, given the failure of direct
dimerization and the likely inapplicability of tandem elaboration
to a non-symmetric dimer, we required a distinct strategy. One
potential and logical benefit of this new approach is that the
final stitching operations appear to take advantage of
biosynthetic efficiency through the use of cascades that
resemble Nature’s synthesis of the monomeric frameworks.
Indeed, apart from the linkage within 59, the portions of this
material colored in Scheme 8 match very closely the analogous
portions of structures 55 and 56, moving only one bond
colored in black and changing the positioning and identity of
the functional groups colored in blue. Moreover, we anticipated
that this synthetic sequence would not be much longer than the
failed direct dimerization strategy. Indeed, key test substrate 59
was expected to readily arise from a Horner−Wadsworth−
Emmons coupling between phosphonate 60, a material we
anticipated could be readily synthesized, and aldehyde 50, the
oxidized version of our key common intermediate for monomer
synthesis which was already available on gram scale (cf. Scheme
6). For maximal flexibility in EWG selection, the incorporation
of this group would be attempted once most of 59 had been
assembled to afford opportunities to probe different variants as
needed to successfully induce the designed cascades.
Scheme 8. “Intramolecular Dimerization”: An Approach to
Consider Deploying When Direct Monomer Coupling Fails
to Provide Necessary Unions and/or Stereocenters
As shown in Scheme 9, the key elements of this new
“dimerization” precursor were indeed synthesized quite readily,
starting once again from piperidine 36, the same material used
earlier to commence our monomer syntheses. Its core elements
closely mirror the synthetic pathways described earlier in the
context of Scheme 4, differing only in terms of the fragments
coupled, and thus will not be discussed in detail (Scheme 9).
Pleasingly, after phosphonate 60 was accessed in just six steps
from 36, the Masamune−Roush variant of the Horner−
Wadsworth−Emmons reaction (LiCl, i-Pr2NEt in CH3CN at
25 °C) coupled it with aldehyde 50 to afford 65, with the
previously inaccessible intermolecular dimerization linkage now
in place (highlighted in purple in Scheme 9).
on a conceptually different approach for dimer synthesis from
those posited within the confines of Scheme 1 and centered on
the long-established principle that intramolecular linking can
potentially overcome those factors governing intermolecular
reactivity.37 Specifically, rather than combine advanced
materials in a final step or merge simpler materials earlier
and then elaborate in tandem,38 instead (1) link two simpler
precursors at an appropriate site to ensure proper regiocontrol
and (2) embed enough chiral information and reactivity within
the overall structure to establish the remaining rings and
stereocenters as well as forge any remaining bonds between the
two halves.
From here, treatment of 65 (Scheme 10) with TFA at −78
°C differentiated the two Boc-protected piperidine ring systems
by taking advantage of neighboring group participation,
selectively transforming the upper ring Boc group (as drawn)
into a base-labile carbamate through cyclization onto the enone
while leaving the lower ring Boc group intact. Although this
operation afforded no stereocontrol at the highlighted center
We term this approach “intramolecular dimerization,” and
compound 59 was designed for the coccinellid alkaloids on the
basis of its general concepts, outfitted with one of the requisite
dimer linkages (highlighted in purple in Scheme 8) that could
not be forged from direct, advanced monomer coupling. From
here, two cascades were envisioned to forge the remaining
rings, stereocenters, and final dimeric linkage needed to
G
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Article
oxidizing the alcohol and performing a Horner−Wadsworth−
Emmons coupling with an aryl sulfone-containing phosphonate
[either Ph-, 3,5-(CF3)2Ph-, or 4-NO2Ph-, vide infra].40
Scheme 9. Synthesis of Key Linking Bond as a Prelude to
Testing the Designed Closure Cascades for Psylloborine A
and Isopsylloborine A Synthesis
a
The stage was now set for the first critical cascade. Pleasingly,
treatment of all three of these variants of 66 with 1,1,3,3-
tetramethylguanidine (TMG) in a 9:1 mixture of toluene/i-
PrOH effected the desired reaction sequence of carbamate
cleavage, enone regeneration, condensation, enamine equilibra-
tion to the exocyclic isomer, and a terminating Michael
addition. However, despite the high control in bond
construction events, the highlighted chiral center within 68
was generated in a 1:1.2 dr favoring the undesired, undrawn
epimer. Exploration of various conditions revealed that this
outcome could not be improved, with several alternatives
affording inferior stereoselection. While not optimal, it was
certainly an improvement on the direct dimerization approach
where that center could not be forged correctly to any degree.
Pressing forward with both diastereomers (as they could not
be separated at this stage when the EWG was an aryl sulfone),
treatment of 68 with TFA in CH2Cl2 at 0 °C for 1 h removed
the remaining Boc group to unveil the free amine needed to
initiate the second cascade. Subsequent dissolution in benzene-
d6 (to monitor the reaction) and heating at 65 °C then initiated
that cascade sequence: condensation to 69, Michael closure to
70, and a terminating Mannich reaction to complete the
synthesis of 72. As long as the aryl sulfone was sufficiently
electron-deficient [i.e., Ar = 3,5-(CF3)2Ph- or 4-NO2Ph-], these
operations proceeded in the order designed. However, when
the unsubstituted phenyl sulfone was used, a large portion of
the material appeared to undergo Mannich reaction prior to
Michael addition to afford materials believed to have structure
71.41 Despite various attempts, these compounds could not be
converted into 72. Thus, the more electron-withdrawing aryl
sulfones seem to have enabled the sequence to succeed by
ensuring that Michael reaction preceded Mannich closure.
Taken together, these two cascade events arguably constitute
the most complex use of condensation/Michael/Mannich
a
Reagents and conditions: (a) TBSCl (1.1 equiv), imidazole (2.0
equiv), CH2Cl2, 25 °C, 19 h; (b) sec-BuLi (1.5 equiv), TMEDA (1.6
equiv), Et2O, −78 to −45 °C, 1 h; CuCN·2LiCl (1.5 equiv), −78 °C,
1 h; allyl bromide (5.0 equiv), −78 to 25 °C, 2 h, 91% over two steps;
(c) K2OsO4·2H2O (0.005 equiv), NaIO4 (4.0 equiv), 2,6-lutidine (2.0
equiv), 1,4-dioxane/H2O (3/1), 25 °C, 2.5 h; (d) 62 (1.22 equiv),
CH2Cl2, 25 °C, 14 h, 84% over two steps; (e) Pd/C (10%, 0.06 equiv),
H2, MeOH/EtOAc (3/1), −78 to 25 °C, 20 h, 97%; (f) 64 (2.0
equiv), THF, −78 to −45 °C, 1.5 h, 87%; (g) LiCl (4.0 equiv), i-
Pr2NEt (2.0 equiv), 25 °C, 30 min; 50 (1.0 equiv), 25 °C, 4 h; HCl
(6.0 equiv), MeOH, 0 °C, 25 min, 79%.
within 66, that outcome was of no consequence, as this chiral
center would be subsequently destroyed. The synthesis of the
key precursor (in protected form as 66) was then completed by
a
Scheme 10. Total Synthesis of Psylloborine A (23) and Isopsylloborine A (24) via the “Intramolecular Dimerization” Strategy
a
Reagents and conditions: (a) 10% v/v TFA in CH2Cl2 (10 equiv), CH2Cl2, −78 °C, 2 h, 89%, 2:1 dr; (b) oxalyl chloride (1.6 equiv), DMSO (3.2
equiv), Et3N (6.0 equiv), −78 °C, 30 min; 0 °C, 1 h; (c) phosphonate (Ar = 3,5-(CF3)2C6H3, 1.0 equiv), LiCl (2.0 equiv), i-Pr2NEt (2.0 equiv),
CH3CN, 25 °C, 30 min; substrate (1.0 equiv), CH3CN, 25 °C, 2 h, 67% over two steps (all ensuing yields are for when Ar = 3,5-(CF3)2C6H3); (d)
TMG (1.0 equiv), toluene/i-PrOH (9:1), 25 °C, 5.5 h, 1:1.2 dr; (e) TFA/CH2Cl2, 0 °C, 1 h; (f) C6D6, 65 °C, 3 h, 15% yield over three steps (79%
yield per transformation); (g) 5 wt % Na/Hg (276 equiv), i-PrOH, 25 °C, 30 min, 46%; (h) TFA (2.0 equiv), ClCH2CH2Cl, 75 °C, 30 min, ∼75%.
H
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Journal of the American Chemical Society
Article
chemistry yet described, given that they involve a total of seven
distinct chemical events that forged three C−C bonds, two C−
N bonds, five rings, and four stereocenters; the overall yield
obtained for the 3,5-(CF3)2Ph variant, at 15%, reflects a
throughput of 79% per chemical transformation. Finally,
exposure of the 3,5-(CF3)2Ph derivative of 72 to Na/Hg
amalgam42 transformed it into psylloborine A (23), a material
identical in all respects to the natural isolate, thereby
completing the first total synthesis of this molecule as well as
that of any dimeric coccinellid alkaloid.43 As a final experiment,
heating this material with TFA in ClCH2CH2Cl at 75 °C
afforded isopsylloborine A (24), completing the first total
synthesis of this dimer as well as establishing 23 as a viable
biosynthetic precursor to 24.44 In total, the route to 23 required
16 linear steps, only four steps more than the original direct
dimerization approach that failed to deliver the target, thus
highlighting the efficiency of this alternate dimerization
strategy.
Scheme 12. Possible Rationale for Cascade Arrest Following
Formation of 75
Finally, it is worth noting that while only the 3,5-
(CF3)2PhSO2- group afforded complete success for the entire
sequence, EWGs other than sulfones were also probed for the
final cascades. As shown in Scheme 11, use of the same
involving finely tuned and highly reactive intermediates coupled
with a new synthetic logic for the formation of dimeric natural
products where biomimetic, direct dimerization approaches
have failed to control regio- and stereoselectivity. We anticipate
that this unique design for dimerization is applicable to a
number of other natural product compound classes, foremost
of which may be the myrmicarin alkaloids for which available
approaches have failed. Work is ongoing to verify that assertion,
as are biochemical studies of the synthesized materials and
efforts to prepare other molecules in the class.
Scheme 11. Additional Late-Stage Ring Closures: Subtleties
a
in EWG Choice for the Michael System
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures, copies of all spectral data,
and full characterization. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
a
Reagents and conditions: (a) TFA/CH2Cl2, 0 °C, 1 h; (b) TMG (2.0
equiv), i-PrOH, 25 °C, 1 h; (c) i-PrOH, 60 °C, 2.5 h, 38% yield over
three steps; (d) TFA/CH2Cl2, 0 °C, 1 h; (e) i-PrOH, 80 °C, 2 h, 56%
yield over two steps.
AUTHOR INFORMATION
Corresponding Author
ssnyder@scripps.edu
Notes
■
sequence with a simple methyl ketone (i.e., 73, X = Me)
proceeded in similar overall yield (79% per transformation for
the steps shown; see Supporting Information) to generate the
full heptacyclic core of the dimeric coccinellid alkaloids (74).
However, no approach could be discovered to convert the
methyl ketone to the final pendant methyl of the target natural
products. By contrast, use of a simple methyl ester (i.e., 73, X =
OMe), a far easier group to potentially remove, arrested at
compound 75 with Mannich closure preceding Michael
addition in the second cascade, just as a simple vinyl phenyl
sulfone had putatively done (69 → 71, Ar = Ph).
Scheme 12 provides a possible graphical explanation for
sequence arrest, with steric clashing likely being the basis for
the failed terminating ring-closure.45 Collectively, these findings
reveal overall that, while there is some flexibility in the groups
that can allow the key elements of this cascade chemistry to
proceed, careful control of electronics is required to fully
orchestrate the designed sequences.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. John Decatur and Dr. Yasuhiro Itagaki of
Columbia University for NMR spectroscopic and mass
spectrometric assistance, respectively, Ms. Tara Pesce for the
preparation of some early intermediates, and Dr. Adel ElSohly
for helpful discussions. We also thank Dr. F. Schroder (Cornell
̈
University) for generously providing us with physical copies of
the spectral data for natural psylloborine A (23). Financial
support for this work was provided by Columbia University,
Bristol-Myers Squibb, Eli Lilly, Amgen, the NSF (Predoctoral
Fellowship to T.C.S.), and the National Institutes of Health
(R01-GM84994). A.H.T. is a recent recipient of an NSF
Predoctoral Fellowship.
REFERENCES
■
CONCLUSION
■
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Journal of the American Chemical Society
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that the chiral center which would reveal that initial facial preference
has been destroyed in the final dimer (i.e., 54, “psylloborine B”).
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̈
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(38) A tandem strategy, while elegant, is less applicable to these
coccinellid dimers, as they are pseudosymmetric and the monomeric
components are of differing oxidation state. Some initial attempts were
made to investigate pseudo-tandem closure cascades on fully
deprotected analogues of 66 and close structural congeners; however,
these efforts were unsuccessful in delivering materials resembling 72,
thereby strengthening the need to utilize an alternative approach
delineated with stepwise polycycle constructions.
(39) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; John
Wiley & Sons: New York, 1995; p 436.
(40) Bournaud, C.; Marchal, E.; Quintard, A.; Sulzer-Mosse,
́
S.;
Alexakis, A. Tetrahedron: Asymmetry 2010, 21, 1666.
(41) Trace amounts of 72 did form. The structure assignment of 71,
as noted, is tentative, with its instability precluding full character-
ization. However, the data obtained are of high homology to the fully
characterized 75 introduced in the context of Scheme 11. We also note
that the undesired diastereomer of 68 which was carried into this final
cascade sequence formed uncharacterized products that were
separated from the desired polycycles once those operations were
complete.
(42) Alonso, D. A.; Najera, C. Org. React. 2008, 72, 367.
(43) The 4-NO2PhSO2 variant of 72 (formed in 12% yield from 66,
77% yield per transformation) formed the aniline first, and then
decomposed under more forcing reaction conditions.
(44) The spectra of psylloborine A (23) were compared directly to
physical spectra of the natural source. Efforts to obtain similar spectra
for 24 were not successful. Notably, it appears that 24 was originally
characterized (ref 18) as a partial salt with an unspecified
stoichiometry of TFA added to the sample. We have attempted to
reproduce these conditions and have also fully characterized the
mono-TFA salt of 24 via 2D NMR spectroscopy. See the Supporting
Information for full details.
(45) The EWG handles do undergo Michael additions on simpler
systems, bolstering the idea that in this more complex system the
cascade electronics must be finely tuned.
K
dx.doi.org/10.1021/ja5045852 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX