Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis

Article abstract of DOI:10.3762/bjoc.9.131

A successful enone version of an intramolecular aza-[3 + 3] annulation reaction is described here. Use of piperidinium trifluoroacetate salt as the catalyst and toluene as the solvent appears to be critical for a successful annulation. We also demonstrated for the first time that microwave irradiation can accelerate aza-[3 + 3] annulation reactions. An attempt to expand the scope of the enone aza-[3 + 3] annulation was made in the form of propyleine synthesis as a proof of concept. While synthesis of the enone annulation precursor was successfully accomplished, the annulation proved to be challenging and was only modestly successful.

Full text of DOI:10.3762/bjoc.9.131

Establishing the concept of aza-[3 + 3] annulations
using enones as a key expansion of this unified
strategy in alkaloid synthesis
Aleksey I. Gerasyuto, Zhi-Xiong Ma, Grant S. Buchanan
and Richard P. Hsung*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1170–1178.
Division of Pharmaceutical Sciences, School of Pharmacy, and
Department of Chemistry, University of Wisconsin, Madison, WI
53705, USA
doi:10.3762/bjoc.9.131
Received: 02 March 2013
Accepted: 18 April 2013
Published: 18 June 2013
Email:
Richard P. Hsung* - rhsung@wisc.edu
This article is part of the Thematic Series "Transition-metal and
organocatalysis in natural product synthesis".
* Corresponding author
Keywords:
Guest Editors: D. Y.-K. Chen and D. Ma
alkaloids synthesis; catalysis; enones; intramolecular aza-[3 + 3]
annulation; N-heterocycles; natural product; vinylogous amides
© 2013 Gerasyuto et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A successful enone version of an intramolecular aza-[3 + 3] annulation reaction is described here. Use of piperidinium trifluoroac-
etate salt as the catalyst and toluene as the solvent appears to be critical for a successful annulation. We also demonstrated for the
first time that microwave irradiation can accelerate aza-[3 + 3] annulation reactions. An attempt to expand the scope of the enone
aza-[3 + 3] annulation was made in the form of propyleine synthesis as a proof of concept. While synthesis of the enone annulation
precursor was successfully accomplished, the annulation proved to be challenging and was only modestly successful.
Introduction
Throughout the past decade, we have been developing an aza- cycloadditions in constructing piperidines, because the aza-
[3 + 3] annulation reaction as a general and unified strategy in dienes and imines required are not always the most accessible
alkaloid synthesis [1-32]. Our aza-[3 + 3] annulation, which has and/or easily handled substrates given the problems of isomer-
been classified as Type-II [1], with Type-I aza-[3 + 3] annula- ization and hydrolysis (Figure 1) [34-37].
tion being reserved for Robinson’s double Mannich-type
process [33], utilizes readily accessible and easily handled viny- The prevalence of six-membered nitrogen heterocyclic motifs in
logous amides and vinyl iminium salts. It provides a significant alkaloids renders the development of this aza-[3 + 3] annula-
complementary, if not superior, approach to aza-[4 + 2] tion into a powerful strategy a unique opportunity in the field of
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Beilstein J. Org. Chem. 2013, 9, 1170–1178.
Figure 1: An aza-[3 + 3] annulation.
alkaloid synthesis [1-4,8-15]. The intramolecular variant ability to employ enones in aza-[3 + 3] annulations can generate
of this annulation has proven to be particularly valuable a vast array of opportunities, including the case where R is as
for total synthesis [16,26-32]. Specifically, the intramolecular small and simple as a Me group, which would already represent
aza-[3 + 3] annulation of vinylogous amides tethered to a vinyl a facile entry to aza-phenylene alkaloids [30,31,38-45], such as
iminium motif 1a proceeds through a tandem sequence of propyleine [46-48], as well as lycopodium alkaloids that are
N-1,4-addition and C-1,2-addition/β-elimination [16,17], rich in bioactivities [49-51] (Figure 2). In addition, the impor-
effectively leading to a variety of nitrogen heterocyclic motifs, tance of these ventures into an aza-[3 + 3] annulation with
such as 3, which are prevalent among alkaloids (Scheme 1) enones can also be further demonstrated through syntheses of
[16,26-32]. However, there was a significant deficiency tetrahydroisoquinolines and indole alkaloids [52-55] in which
in this annulation: the inability to employ vinylogous amides the R group can constitute a larger functionality of the alka-
tethered to α,β-unsaturated ketones, or enones 1b (R ≠ H) loids, such as that seen in geissoschizine [52-57], and ipecac
(Scheme 1).
alkaloids such as protoemetine [48,52-55,58-61], emetine [52-
55,58-63], and tubulosine [64]. With the appropriate choice of
Conceptually, employing enals or enones in an aza-[3 + 3] an R group in the synthetic design, a highly convergent and
annulation appears to constitute very little difference, with the expedient strategy can come forth for constructing these alka-
major difference lying in the R group in their respective prod- loids. We report herein our success in achieving intramolecular
ucts 3 and 4. While seemingly an insignificant perturbation, the aza-[3 + 3] annulations of an enone.
Scheme 1: Aza-[3 + 3] annulations with enones.
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Beilstein J. Org. Chem. 2013, 9, 1170–1178.
Figure 2: Possible natural-product targets.
Results and Discussion
this primary amine with 1,3-cyclohexanedione. Oxidation of the
To examine the feasibility of an enone intramolecular aza- secondary allylic alcohol in 9 with MnO2 at ambient tempera-
[3 + 3] annulation, a seven-step synthesis of the annulation sub- ture provided enone 10 in 85% yield. We were poised to
strate 10 commencing from 3-butyn-2-ol (5) was carried out investigate the viability of the enone aza-[3 + 3] annulation.
(Scheme 2). Protection of secondary propargyl alcohol 5 as the
THP-ether followed by alkylation of a lithium acetylide onto Our initial efforts to employ enone substrate 10 met with failure
1,4-dibromobutane afforded bromide 6 in 81% overall yield. when using up to 500 mol % of piperidinium chloride [65] (Ta-
Acid-mediated removal of THP followed by azide formation ble 1, entry 1) or 100 mol % piperidinium acetate salts (Table 1,
using NaN3 afforded alkyl azide 7 in 94% overall yield.
entry 2); even at higher temperatures of 120 °C, these chloride
and acetate salts proved to be ineffective (Table 1, entry 3). We
Preparation of vinylogous amide 9 was then achieved by a two- then explored salts prepared from stronger acids such as (+)-
step sequence: (a) LAH-mediated azide reduction to give a pri- camphorsulfonic acid (CSA) and trifluoroacetic acid, which
mary amine with concomitant reduction of the alkyne revealing should tend to dissociate easier in the reaction medium and lead
the olefin functionality; and (b) dehydrative condensation of to a more reactive vinyl iminium salt intermediate 1b. We were
Scheme 2: Synthesis of the annulation precursor enone 10.
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Beilstein J. Org. Chem. 2013, 9, 1170–1178.
Table 1: Catalyst screening and optimization.
entrya
HX (mol %)
solvent
temp (°C)
time (h)
conv. (%)
yield (%)b
1
2
3
4
5
6
7
8
9
HCl (500)
EtOAc/toluene
EtOAc
100
85
16
12
16
12
7
0
0
–
HOAc (100)
–
HOAc (500)
toluene
120
120
85
0
–
(+)-CSAc (100)
HO2CCF3 (500)
HO2CCF3 (100)
HO2CCF3 (100)
HO2CCF3 (50)
HO2CCF3 (90)
toluene
100
79
100
92
100
94
60
39
50
41
87
65
toluene
toluene
85
5
EtOAc/toluene
toluene
110
150
MWd
4
3
toluene
1.5
aAll reactions run in a sealed tube. Concn = 0.03–0.04 M; 5.0 equiv Na2SO4. bIsolated yields. c(+)-Camphorusulfonic acid. d450-W Microwave.
elated to observe that the use of 100 mol % of piperidinium After establishing the feasibility of the enone version of the
CSA salt in toluene at 120 °C provided 100% conversion with intramolecular aza-[3 + 3] annulation we turned our attention to
60% yield of cycloadduct 11 (Table 1, entry 4). Further opti- propyleine (12) (see Figure 2 and Scheme 3) as a possible target
mizations using trifluoroacetate salt (Table 1, entries 5–8) to showcase the new enone aza-[3 + 3] annulation. Propyleine
revealed that the yield could be improved to 87%, while (12) was isolated in 1972 from Propylaea quatuordecimpunc-
lowering the catalyst loading from 500 mol % to 50 mol %, tata in a continued effort by Tursch and co-workers [46,47] in
although the reaction temperature was raised to 150 °C. Lastly, their isolation of the azaphenalene family of defensive alka-
we also examined the use of microwave irradiation [66,67] and loids from various ladybug beetles [38-45]. Mueller and
observed a distinct rate enhancement (Table 1, entry 9).
Thompson [48] in 1980 found it interesting that the isomeric
enamine named isopropyleine (14) was not reported in the orig-
The observed reactivity difference of the trifluoroacetate and inal paper [46,47] taking into account that the isolation condi-
camphorsulfonic acid salts, as compared to the chloride and tions involved acid–base extractions. It is conceivable that
acetate salts, can be attributed to the rate at which they promote propyleine (12) and isopropyleine (14) could be intercon-
vinyl iminium ion formation through a “balanced act” [12]. The vertable under acidic conditions via intermediate iminium
difference in reactivity is related to the dissociation capacity of salt 13.
the respective amine salts. Since both “free amine” and “free
acid” are needed in a synergistic manner to generate the vinyl
iminium ion from the corresponding enone, the ability of the
amine salt to dissociate to its “free amine” and “free acid” can
exert an impact on the rate of the iminium formation. The low
reactivity of the chloride salt can be attributed to its higher
resistance toward dissociation, or is simply a tighter ion-pair
compared to the CSA and the trifluoroacetate salt. At the same
time, the formation of vinyl iminium ion from carbonyl systems
Scheme 3: Propyleine-isopropeleine interconversion.
and the “free amine” is also promoted by protonation of the car-
bonyl group via the “free acid”. Consequently, the increased re-
activity of the CSA and trifluoroacetate salt from the acetate salt To investigate this matter, Mueller and Thompson carried out
can be attributed to a higher acidity of the acids.
the first and the only synthesis of propyleine known to date
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Beilstein J. Org. Chem. 2013, 9, 1170–1178.
Scheme 4: Retrosynthesis of propyleine (12).
[48]. They were able to take a mixture of propyleine and Retrosynthetically, we envisioned propyleine (12) to come from
isopropyleine with 1:3 ratio as determined by 1H NMR and the decarboxylation reaction of vinylogous carbamic acid 15
watch two sets of proton resonances collapse into one that [10,28], which could be derived from stereoselective hydro-
corresponds to the iminium salt 13 after addition of TFA. This genation of the endocyclic olefin in tricycle 16 (Scheme 4).
experiment strongly suggested that propyleine (12) and Vinylogous urethane 16 should be accessible via our intramole-
isopropyleine (14) could equilibrate under acidic conditions, cular aza-[3 + 3] annulation of enone 17. Enone 17 could be E
thereby implying that the observed ratio of 12 and 14 repre- or Z with respect to the vinylogous urethane olefin, and cis or
sents a thermodynamic one in favor of the more stable trans with respect to the enone double bond. Thus, from the
isopropyleine [48]. With these experimental findings, Mueller spectroscopic analysis stand point, synthesis of 17 could be
and Thompson concluded that the alkaloid isolated by Tursch messy.
and co-workers [46,47] was in fact a mixture of readily inter-
convertable 12 and 14.
In the forward direction to synthesize 17, we used the approach
developed in our model study for the synthesis of precoc-
We found this controversy in the isolation and total synthesis cinelline, hippodamine and myrrhine alkaloids [30,31]. Specifi-
papers an interesting one that deserves further investigations. cally, TBDPS-protected 3-butyne-2-ol 18 was converted to
Consequently, we performed ab initio calculations on 12 and 14 bromoalkene 19 in two steps involving alkylation with an
to gain insight into their relative thermodynamic stability. excess of dibromopropane and subsequent Lindlar’s hydrogena-
Models of the most stable conformers and their corresponding tion (Scheme 5). Grignard addition to the glutarimide Mg-salt
energies are shown in Figure 3. To our surprise, propyleine (12) 20 followed by reduction of the Mg salt 21 afforded lactam 22
is 2.59 kcal mol−1 more stable than isopropyleine (14), which is as an inseparable 1:1 mixture of two diastereomers in 77%
the opposite of the Mueller–Thompson postulation [48]. Our overall yield [68-70].
calculations suggest that the ratio obtained from the
Mueller–Thompson study was likely determined by the kinetics Vinylogous amide 23 was prepared by O-methylation of lactam
(kB versus kR) in the deprotonation step or the tautormerization 22 with freshly distilled MeOTf followed by condensation with
process from the iminium salt 13, and not by thermodynamics Meldrum’s acid in the presence of Ni(acac)2. Treatment of 23
as originally proposed. Resolving this interesting literature with MeONa in MeOH under reflux gave vinylogous urethane
controversy added extra incentive for us to pursue propyleine. 24. It is noteworthy that the geometry of the vinylogous
urethane double bond exclusively favored Z, presumably due to
the internal hydrogen bonding. Cleavage of the TBDPS group
with TBAF provided allylic alcohol 25 in 79% from 23.
However, submission of 25 to the standard MnO2 oxidation
procedure did not lead to enone 17, with only the starting ma-
terial being recovered (Table 2). After extensive screening of
various oxidation protocols, we succeeded with the
Doering–Parikh conditions [71], and the cis geometry of the
enone olefin was preserved under these conditions.
With enone 17-cis in hand, we studied its intramolecular aza-
[3 + 3] annulation reaction utilizing piperidinium salts
(Table 3). When compound 17-cis was treated with the acetate
Figure 3: Relative stabilities of propyleine and isopropyleine.
salt in EtOAc at rt, no reaction was observed after 18 h
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Beilstein J. Org. Chem. 2013, 9, 1170–1178.
Scheme 5: Synthesis of allyl alcohol 25.
tion of the desired annulation product 16 (Table 3, entry 2). The
inefficiency of the piperidinium acetate salt in the intramolec-
ular aza-[3 + 3] annulation of enones was consistent with our
previous findings (see Table 1). We were also not successful in
converting enone 17-cis to the desired tricycle 16 using the
more reactive trifluoroacetate salt and EtOAc as the solvent. In
this case also only isomerization to trans-enone was detected
(Table 3, entry 3). Heating this reaction to 130 °C led to even-
tual decomposition of the starting material (Table 3, entry 4).
Table 2: Synthesis of the annulation precursor 17.
entry
oxidants
solvent
yield (%)
However, when enone 17-cis was heated in toluene at 100 °C,
complete consumption of starting material was observed after
5 h (Table 3, entry 5). Even though the reaction was relatively
messy, the formation of the desired cycloadduct 16 was
confirmed by the presence of characteristic signals in the 1H
NMR spectra of the crude mixture. Unfortunately, attempts to
isolate the annulation product in pure form were not successful,
probably due to the high instability of the electron-rich dihy-
dropyridine moiety in 16. Based on our previous experience
with precarious annulation products, in situ hydrogenation was
1
2
3
4
5
6
7
8
MnO2
MnO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
no rxn (rt)
decomp (40 °C)
no rxn
BaMnO4
DMP
slow decomp
decomp
PCC
TEMPO/oxone
TPAP/NMO
Pyr-SO3/DMSO
no rxn
decomp
85%
(Table 3, entry 1). Heating this reaction mixture at 85 °C for then carried out, and we managed to track down ~30% of the
12 h only led to slow isomerization of cis-enone 17 to the ther- desired reduced aza-annulation product 26, although stereose-
modynamically more stable trans-isomer again with no forma- lectivity for the reduction was modest. We ultimately elected
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Beilstein J. Org. Chem. 2013, 9, 1170–1178.
Table 3: Aza-[3 + 3] annulations of 17-cis.
entrya
HX (1.0 equiv)
solvent
temp (°C)
time (h)
yield (%)b
1
2
3
4
5
HOAc
EtOAc
EtOAc
EtOAc
EtOAc
toluene
25
85
18
12
12
12
5
–
HOAc
17-trans
17-trans
decomp
30% of 26
HO2CCF3
HO2CCF3
HO2CCF3
55
130
100
aAll reactions run in a sealed tube. Concn = 0.03–0.04 M; 5.0 equiv Na2SO4. bIsolated yields.
not to force our way toward propyleine using the enone aza- Acknowledgements
[3 + 3] annulation, as we succeeded in total syntheses of other Authors thank NIH [NS38049] for financial support.
members of the azaphenalene alkaloid family through annula-
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