The Enantioselective Total Synthesis of Exochomine

Article abstract of DOI:10.1002/anie.201604744

Molecules that possess fully substituted chiral centers are often challenging to construct, particularly if those centers connect two seemingly different halves or include a nitrogen atom. Herein, we describe an efficient approach to a molecule that combines both challenges in a single center in the form of exochomine. Failures in direct coupling led to a design fueled by highly specific reaction conditions for several steps and the development of an improved protocol for 1,4-reduction in a hindered context where numerous side reactions were possible. These chemoselective solutions should have value to other problems. Challenges in obtaining matching spectral data for the synthesized natural product are also discussed.

Full text of DOI:10.1002/anie.201604744

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604744
German Edition: DOI: 10.1002/ange.201604744
Natural Product Synthesis
The Enantioselective Total Synthesis of Exochomine
+
+
Alison X. Gao , Tomoaki Hamada , and Scott A. Snyder*
Dedicated to Professor K. C. Nicolaou on the occasion of his 70th birthday
Abstract: Molecules that possess fully substituted chiral centers
are often challenging to construct, particularly if those centers
connect two seemingly different halves or include a nitrogen
atom. Herein, we describe an efficient approach to a molecule
that combines both challenges in a single center in the form of
exochomine. Failures in direct coupling led to a design fueled
by highly specific reaction conditions for several steps and the
development of an improved protocol for 1,4-reduction in
a hindered context where numerous side reactions were
possible. These chemoselective solutions should have value to
other problems. Challenges in obtaining matching spectral data
for the synthesized natural product are also discussed.
O
ne of the key driving forces for new synthetic tactics and
reactions are fully substituted chiral centers. Indeed, the
efficient preparation of such centers often necessitates unique
[1]
designs and novel reactivity considerations. Those chal-
lenges, however, are arguably magnified in those molecules
where nature has placed such fully substituted centers at the
connection point of two seemingly different halves. Com-
[
2]
pounds such as azadirachtin (1, Scheme 1), haplophytine
[
3]
[4]
[5]
(
2), aplyviolene (3), and bionectin A (4) are representa-
tive cases, where years of effort and creative solutions often
based on novel methods were required to generate those
centers marked with a blue asterisk, noting that direct
coupling of the two halves has typically proven impossible
to achieve. Similarly high challenge also exists with a-tertiary
[
6]
[7]
amine centers, such as that found in acutumine (5). We
have recently embarked on a program exploring molecules
that combine both of these challenges within single struc-
[
8]
tures, compounds that include the defensive alkaloids
produced by ladybugs in the form of psylloborine A (6),
the chilicorines (7 and 8), and exochomine (9).
[9]
[
10]
[11,12]
As one
reflection of that challenge, direct couplings of seemingly
[8]
[13]
appropriate monomers, such as the Prins-type addition
shown between 10 and 11, have failed in our hands to deliver
Scheme 1. The challenge of fully substituted chiral center formation,
particularly in cases where two seemingly disparate halves are merged
(
1–4) and when those centers contain nitrogen (5), a problem com-
[
+]
[+]
[
*] A. X. Gao, Dr. T. Hamada, Prof. Dr. S. A. Snyder
bined in the coccinellid alkaloids (6–9).
Dept. of Chemistry, The Scripps Research Institute
130 Scripps Way, Jupiter, FL 33458 (USA)
Prof. Dr. S. A. Snyder
Dept. of Chemistry, University of Chicago
the needed products, necessitating the development of
alternate solutions. Herein, we document a route which can
enantioselectively deliver exochomine (9) in 16 steps, high-
lighting a series of substrate specific steps and unique reaction
conditions whose success in such a hindered context should be
relevant for other synthesis problems.
5735 S. Ellis Avenue, Chicago, IL 60637 (USA)
E-mail: sasnyder@uchicago.edu
Homepage: http://snyder-group.uchicago.edu/
+
[
] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201604744.
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Our overall approach was predicated on attempting to
achieve a late-stage coupling of pieces such as 13 and 14,
hoping that an appropriate merger, followed by a selective
afforded homologated ketal 20 in 66% overall yield. From
I
[14]
here, a Cu -promoted allylation afforded the requisite side-
chain with high diastereoselectivity (89:11 d.r.), with subse-
quent oxidative cleavage affording cyclization precursor 21 in
75% overall yield.
1
,4-reduction, could generate 12; if successful, then only
a final ring-closure and minor oxidation state changes would
be left to complete the target. Of note, 13 was designed to
afford maximal flexibility for that merger, both from an
entropic perspective by leaving one ring unclosed as well as by
affording several coupling reaction choices, with the challeng-
ing fully-substituted quaternary center of the target to be pre-
installed as part of 14. That center was hoped to arise through
the facially-selective addition of an appropriate nucleophile
onto the iminium ion (16) derived from enamine 17. In
practice, only a single form of 14 could be accessed, with one
coupling reaction process and a hybrid of existing conditions
for 1,4-reduction proving capable of delivering the exocho-
mine skeleton.
The stage was now set to generate the final tricyclic
framework in a cascade operation. In the event, treatment of
21 with 5.0 equivalents of TFA in 1,2-dichloroethane at 258C
for 1 h, followed by 13 h of heating at 808C, sequentially
effected Boc deprotection, condensation of the resultant
secondary amine onto the ketal and/or ketone to form an
enamine, and finally enamine attack on the pendant aldehyde
to generate the desired conjugated iminium ion tricycle as its
TFA salt. After examining a number of reducing agents (such
[
15a,b]
as DIBAL-H and L-selectride) both Strykerꢀs reagent
and the Hantzsch ester
[15c,d]
afforded full 1,4-selectivity in the
final component of the cascade, providing enamine 17 after
basic work-up. In practice, however, the Hantzsch ester
reduction was used for scale-up as material from this process
proved easier to purify, noting that the key element of this
procedure relative to precedent is that the nitrogen atom of
the intermediate iminium ion was retained in this cyclic
setting rather than being hydrolyzed.
With this material in hand, we then tested its reactivity in
its iminium ion form (16), generated by re-exposure to
3
.3 equivalents of TFA in THF at 258C, with a range of
nucleophiles to see what additions could be achieved and in
what diastereoselectivity. To our surprise, virtually every
[
16]
nucleophile probed, such as tributylvinyl tin,
allyltrime-
[17]
[18]
thylsilane (under Sakurai conditions), Grignard reagents,
vinyl boronic acids (under Petasis-type conditions),
[19]
or
[
20a,b]
[20c,d]
enolates (prepared both in situ
and pre-formed),
failed to deliver any coupling adduct; instead, recovered
starting material or decomposition was observed. Similarly,
radical-based additions, such as those recently developed by
[
21]
[22]
Baran, were also unsucessful. Only a Strecker reaction
Scheme 2. Preparation of key enamine building block 23 and chal-
proved fruitful, affording nitrile 22 in 66% yield (including
the previous cyclization cascade) and 89:11 d.r. when KCN
was used as the quenching agent; that ratio of diastereomers
derives from the stereoselectivity of the preceding allylation.
The nitrile addition itself is likely fully stereoselective
whether under kinetic or thermodynamic control. Indeed,
the established kinetic preference for cyanide addition to
cyclic iminium ions as governed by stereoelectronics should
lenges in effecting additions to iminium ion 16: a) (COCl) (1.5 equiv),
2
DMSO (3.0 equiv), i-Pr NEt (6.3 equiv), CH Cl , ꢀ788C, 3 h; b) 19
2
2
2
(
1.5 equiv), KHMDS (1.2 equiv), PhMe, ꢀ788C, 3 h, 67% over 2
steps); c) H (1 atm), Pt/Al O (5 mol%), EtOAc, 258C, 8 h, 98%;
2
2
3
d) s-BuLi (2.0 equiv), TMEDA (2.0 equiv), ꢀ78!ꢀ458C, 1 h, CuCN·
2
3
LiCl (1.75 equiv), ꢀ788C, 1 h, allyl bromide (5.1 equiv), ꢀ78!258C,
h, 79%, 89:11 d.r.; e) OsO (5 mol%), 2,6-lutidine (2.0 equiv), NaIO
4
4
(
4.0 equiv), 1,4-dioxane/H O (3:1), 258C, 4 h, 95% (~50% ketal
2
deprotection); f) TFA (5.0 equiv), ClCH CH Cl, 258C, 1 h then 808C,
2
2
[
23]
[24]
1
3 h; evaporate solvent; Hantzsch ester (1.5 equiv), CH Cl , 258C, 4 h;
afford 22, while DFT calculations using the B3LYP/6-
31G** level of theory (Jaguar, version 8.8) reveals that the
difference in the Gibbs free energies between 22 and its nitrile
2
2
g) TFA (3.3 equiv), KCN (6.6 equiv), THF, 258C, 66% over 2 steps,
8
1
9:11 ratio of 22 and epimer; h) LiAlH (5.4 equiv), THF, ꢀ508C,
4
0 min, then 258C, 75 min; H SO (41 equiv), 0!258C, 5 h, 91%,
ꢀ1
2
4
epimer favors 22 (9.31 kcalmol ).
single diastereomer. HMDS=hexamethyldisilazane; TMEDA=
N,N,N’,N’-tetramethylethylenediamine; TFA=trifluoroacetic acid.
Nevertheless, the new functional group within this com-
pound proved challenging to reduce, with conventional
reagents such as DIBAL-H and Red-Al giving modest and
variable yields of aldehyde 23. An optimal procedure proved
Scheme 2 presents the developed sequence for the
preparation of generalized azaphenylene coupling partner
to be using LiAlH in THF at ꢀ508C for 10 min, followed by
4
stirring at 258C for ~ 75 min, conditions which allowed for in
1
4 (cf. Scheme 1) in the form of aldehyde 23. Starting from
situ hydrolysis using a final H SO treatment. This one-pot
2
4
chiral alcohol 18, prepared conveniently in just 4 steps from
commercial materials [see Supporting Information (SI) for
details], subsequent Swern oxidation, Julia–Kocienski olefi-
nation, and hydrogenation of the resultant alkene smoothly
process proceeded in 91% yield. To date we have prepared
nearly 1 gram of 23 (~ 250 mg through this route and ~ 700 mg
via a slightly longer route, not shown) and obtained it as
a single diastereomer; the overall scalability is of note relative
2
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[25]
to most efforts towards similarly complex tricyclic amines.
The relative stereochemistry of 23 was verified by X-ray
diffraction of a benzoate derivative of its corresponding
alcohol (see SI).
The synthesis of the pyrrole-based coupling partner
commenced with heterocycle formation using inexpensive,
commercially available l-glutamic acid ethyl ester 24
(
Scheme 3) and 2,5-dimethoxytetrahydrofuran 25. A subse-
quent HBr/AcOH-promoted Friedel–Crafts cyclization
[
26]
smoothly gave the desired acyl pyrrole, and was followed
by dithiolane protection with 1,2-ethanedithiol as promoted
[
27]
by Zn(OTf)2 to give 26 in 37% yield overall for these 3
steps. Homologation to ester 27 was achieved in a further 3-
step sequence involving DIBAL-H reduction of the ester to
an aldehyde, Wittig olefination, and reduction using the
copper hydride formed by premixing Cu(OAc) ·H O, BDP,
2
2
[
28]
and poly(methylhydrosiloxane). The use of standard het-
erogeneous hydrogenation was precluded in the final step as it
also impacted the dithiolane group, noting that this protecting
group proved critical as other alternatives, such as ketals or
protected alcohols, were too fragile. Of note, although the
sequence proceeded through a potentially epimerizable
aldehyde, the enantiopurity was largely retained, being
determined to be 97% ee by chiral HPLC, and 27 could
readily be prepared (> 4 g synthesized). Finally, 27 could also
be converted into cyclized product 28 in 51% yield through
exposure to BBr in CH Cl at 08C for 20 min. This latter
3
2
2
material had been previously prepared racemically by Mein-
[
12]
wald in 5 steps; our overall route, though 2 steps longer, was
asymmetric.
With azaphenylene aldehyde 23 in hand, as well as two
potential coupling partners (27 and 28), studies were under-
taken to bring the two halves together. Using these pieces and
a range of other compounds (not shown), that process initially
proved challenging, with approaches based on metathesis,
[
29]
Horner–Wadsworth–Emmons olefinations,
and Nozaki–
[30]
Hiyama–Kishi couplings all failing.
Our first success was registered with a titanium-mediated
[
31]
aldol condensation
between ketone 28 and aldehyde 23
Scheme 3. Completion of the total synthesis of exochomine: a) 25
(
2
CH
3
1.05 equiv), ClCH CH Cl, 658C, 4 h, 80%; b) HBr (2 equiv), AcOH,
which delivered 30, albeit in low and variable yields due
principally to the instability of ketone 28 under the reaction
conditions. Pleasingly, after much optimization, we found that
a milder coupling could be achieved by using the more
conformationally flexible ester 27. In the event, LDA-
mediated enolization and aldol addition with 23 (0.9 equiv)
in THF at ꢀ788C for 2 h provided 29 (any warming led to
retro-aldol reactions); this intermediate was then treated with
p-TsOH in situ, with subsequent solvent evaporation, resus-
pension in benzene, and heating at 608C for 4 h effecting
dehydration and Friedel–Crafts cyclization in one pot,
delivering 30 in 32% yield. No intermediates were character-
izable, so the exact order of steps is unknown, and though this
outcome is not numerically high, 3 steps were achieved
overall, with the likely culprit for throughput being the
Friedel–Crafts reaction given the observed yield (51%) in the
conversion of 27 into 28. Also worth noting is that the same
conditions (as well as other protocols) did not lead to coupling
products when 28 was the enolate partner, likely because
2 2
58C, 3 h, 60%; c) 1,2-ethanedithiol (1.3 equiv), Zn(OTf) (1.3 equiv),
2
2
Cl
2
, 258C, 12 h, 78%; d) DIBAL-H (1.05 equiv), CH
2
Cl
2
, ꢀ788C,
0 min; e) PPh CHCO Me (1.1 equiv), CH Cl , 0!258C, 12 h, 81%
3
2
2
2
over 2 steps; f) Cu(OAc) ·H O (5 mol%), BDP (0.5 mol%), PMHS
(
(2.5 equiv), CH Cl , 08C, 20 min, 51%; h) LDA (1.5 equiv), 23
2
2
2.0 equiv), t-BuOH (2.0 equiv), toluene, 258C, 8 h, 90%; g) BBr3
2
2
(0.9 equiv), THF, ꢀ788C, 2 h; pTsOH·H
O (5.0 equiv), ꢀ78!258C;
2
evaporate; benzene, 608C, 4 h, 32%; i) TiCl (2.0 equiv), Et N
4
3
(
(
2.1 equiv), CH Cl , ꢀ788C, 2 h, 19%; j) Mn(dpm) (2.2 equiv), MeSi-
2
2
3
OEt) H (5.0 equiv), i-PrOH/CH Cl (8:1), 258C, 16 h, 48%, 10:1 d.r.;
2
2
2
k) MeLi (2.0 equiv), THF, ꢀ78!ꢀ308C, 30 min, pTsOH·H O
2
(
5 equiv), ꢀ30!258C, 4% 9 and 65% protected 9; l) PhI(OAc)
2
(1.3 equiv), CH CN/CH Cl /H O (5:1:1), ꢀ108C, 10 min, 31%, 23%
3
2
2
2
from 31; p) HCl (1.0m in Et
O, 1.5 equiv), EtOAc, 258C, 30 min, 70%.
2
Ts =tosyl; BDP=1,2-bis(diphenylphosphino)benzene; PMHS=
poly(methylhydrosiloxane).
retro-aldol pathways might be favored due to its more rigid
framework.
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Table 1: Key optimization studies for the selective 1,4-reduction of enone 30.
sought to alter the acid content by
titration with HCl as well as elim-
inate water content in the sample,
[35]
there were always subtle discrepan-
cies from the isolation data without
specific patterning. Pleasingly, how-
ever, X-ray diffraction of a suitably
grown crystal of synthetic 32
obtained from slow evaporation in
CH Cl /EtOAc was able to confirm
its structure. We are not completely
sure of the source of the variances
in the respective NMR spectra
between the synthetic and natural
material, but believe that water
content is the likely culprit and
should be considered as an addi-
2
2
Entry
Conditions
Product
Yield of
[
a]
31 [%]
1
2
3
4
5
6
7
8
9
Cu(OAc) ·H O, BDP, PMHS
n.r.
n.r.
0
0
2
2
[CuH(PPh )]6
3
[
b]
Cu(OAc) ·H O, P(Oi-Pr) , MeSi(OEt) H
31 + 1,6-reduction
33 + 31 + 1,6-reduction
n.r.
33
33
n.r.
n.r.
n.r.
<20
2
2
3
2
[
b]
SmI , t-BuOH, THF
<20
2
Pd(PPh ) , ZnCl , n-Bu SnH
0
0
0
0
0
0
0
25
40
52
3
4
2
3
catecholborane
DIBAL-H
RedAl, CuBr, BF ·OEt2
tional point of concern for such
3
[36]
compounds;
counterion impuri-
CuBr·Me S, t-BuLi, DIBAL-H, THF/HMPA
2
ties could also be at play as the
exact procedure by which the iso-
lation team obtained their HCl salt
from the crude extract is not
10
11
12
13
14
NBSH, Et N
3
TsNHNH , NaOAc, THF/H O
n.r.
2
2
Mn(dpm) , PhSiH , TBHP
31 + deprotection
31
31
3
3
Mn(dpm) , PhSiH3
3
[
37]
Mn(dpm) , MeSi(OEt) H
3
2
defined.
In conclusion, we have com-
[a] A very small amount of isomer at the newly formed chiral center was also observed in these
reductions, but was separated and is not part of these yield calculations; [b] Isolated yield, but includes pleted the first enantioselective
some minor inseparable contaminants.
total synthesis of the coccinellid
alkaloid exochomine (9) in 16
linear steps. The key a-tertiary
From here, only a few operations remained to complete
the target, with the next, selective conjugate enone reduction
of 30 to give 31, proving highly challenging to effect as the
dithiolane group, benzylic ketone, and acyl pyrrole all proved
prone to reduction (leading to products such as 33). As shown
in Table 1, copper hydride-based approaches gave sluggish
reactions and, when products were observed, typically the
major adduct was 1,6-reduction across the pyrrole ring
amine center linking the two disparate halves was constructed
using a highly diastereoselective Strecker reaction from an
iminium precursor, with the key linking CꢀC bond formed
convergently using an aldol reaction from two advanced
intermediates in a cascade where a Friedel–Crafts cyclization
proceeded in the same pot. Flexibility in coupling partners
was key to its success. In addition, selective 1,4-reduction
III
conditions based on the combination of Mn and a unique
(
entries 1–3). Radical-based methods such as SmI2 also
hydride source succeeded on a reactive and sterically
encumbered system where other tools failed, and should be
of use for other challenging systems. Current efforts seek to
deploy the strategies and methodological advances from this
synthesis to other challenging targets.
afforded predominantly 1,6-reduction (entry 4), while a vari-
ety of other standard protocols for conjugate enone reduction
did not provide promising results (entries 5–11). Only Mn -
mediated conditions as reported by Shenvi (entry 12) and
Magnus
III
[32]
[
33]
(entry 13) provided encouraging selectivity and
yield, with the use of the same hydride source from entry 3,
that is, MeSi(OEt) H, providing the best overall outcome for Acknowledgements
2
this transformation in 52% isolated yield (entry 14). The
identity and absolute configuration of 31 was confirmed by X-
ray analysis.
Finally, a one-pot methyl addition, elimination, and
ketone deprotection from 31 afforded a small amount of
exochomine (9) alongside its protected form in 4% and 65%
We thank Dr. HaJeung Park (Scripps) for a preliminary X-ray
structure of a derivative of 23 and Dr. Alexander Filatov
(Chicago) for X-ray structures of 31 and 32. The latter was
obtained at Argonne National Labs; ChemMatCARS Sector
15 is principally supported by the Divisions of Chemistry
(CHE) and Materials Research (DMR), National Science
Foundation, under grant number NSF/CHE-1346572. Use of
the Advanced Photon Source, an Office of Science User
Facility operated for the U.S. Department of Energy (DOE)
Office of Science by Argonne National Laboratory, was
supported by the U.S. DOE under Contract No. DE-AC02-
06CH11357. We also thank Dr. Xiangming Kong (Scripps) for
NMR assistance and Dr. Jun-Yong Choi (Scripps) for help
yield, respectively. The use of PhI(OAc) in a 5:1:1 mixture of
2
CH CN/CH Cl /H O converted any remaining protected
3
2
2
2
[
34]
intermediate into the final compound (i.e. 9). As NMR
data for the free base form of the target was not available,
synthetic exochomine was converted into its corresponding
HCl salt (i.e. 32) and purified by preparative TLC. However,
1
13
upon comparison of both its H and C NMR data to that
reported by the isolation team, including experiments which
4
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Angewandte
Communications
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with calculations. Financial support came from TSRI, the
University of Chicago, and Daiichi-Sankyo (to T.H.).
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group (without Cu), see: d) P. Beak, W.-K. Lee, Tetrahedron
Lett. 1989, 30, 1197; e) P. Beak, W. K. Lee, J. Org. Chem. 1993,
5
8, 1109.
Keywords: 1,4-reduction · alkaloid · azaphenylene · coccinellid ·
total synthesis
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[34] CH
Cl was necessary to dissolve the substrate. Other depro-
2
2
tections, such as metal-mediated protocols (Hg, Tl, Ag),
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Communications
Chemie
alkylating agents (MeI, EtI) and oxidizing agents [IBX, PhI-
CO CF ) ], failed.
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(
2
3 2
[
35] We thank Prof. J.-C. Braekman and Prof. D. Daloze for
providing copies of their original spectra of 32; these data
included sets not originally referenced that show variation,
potentially due to water content, as one is noted to have water
present and the other does not.
[
36] For recent alkaloid syntheses that point to similar challenges,
such as needing to titrate acid to obtain matching spectra, see:
a) R. A. Altman, B. L. Nilsson, L. E. Overman, J. R. de Alaniz,
Received: May 15, 2016
Published online: && &&, &&&&
6
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Communications
Natural Product Synthesis
Challenging chirality: Use of a distinct
synthetic strategy to address the chal-
lenges in merging two different halves
bearing a chiral center at their merger
point has enabled access to the alkaloid
exochomine in 16 steps. Key operations
include the functionalization of a hin-
dered iminium precursor, a unique aldol-
based coupling cascade, and a robust
protocol for 1,4-reduction in a hindered
context where numerous side-reactions
can occur.
A. X. Gao, T. Hamada,
S. A. Snyder*
&&&& — &&&&
The Enantioselective Total Synthesis of
Exochomine
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7
These are not the final page numbers!