A telescoped route to 2,6-disubstituted 2,3,4,5-tetrahydropyridines and 2,6-syn-disubstituted piperidines: Total synthesis of (-)-grandisine G

Article abstract of DOI:10.1002/anie.201208118

A grand route to grandisines: A method for the conversion of 6-acyl cyclohexenones into 2,6-disubstituted 2,3,4,5-tetrahydropyridines and, after diastereoselective reduction, 2,6-syn-disubstituted piperidines has been developed. The scope of this process

Full text of DOI:10.1002/anie.201208118

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DOI: 10.1002/anie.201208118
Natural Product Synthesis
A Telescoped Route to 2,6-Disubstituted 2,3,4,5-Tetrahydropyridines
and 2,6-syn-Disubstituted Piperidines: Total Synthesis of (ꢀ)-
Grandisine G**
James D. Cuthbertson and Richard J. K. Taylor*
Nitrogen heterocycles constitute one of the most important
classes of lead compounds in the pharmaceutical and agro-
chemical industries, with pyridines and their reduced ana-
logues occupying a prominent position,[1] particularly in the
case of piperidines.[2] New and efficient routes to such
compounds are always valuable and herein we describe
a remarkable one-pot rearrangement for the conversion of
readily available 6-acyl cyclohexenones 1 into 2,6-disubsti-
tuted 2,3,4,5-tetrahydropyridines 2 and then into 2,6-syn-
disubstituted piperidines 3 after diastereoselective reduction
(Scheme 1). The conceptual novelty of such a telescoped
Initial studies (Scheme 2) were based on the cyclization/
ring-opening of the known diketone 1a,[5] which was readily
prepared from cyclohexenone. The grandisine synthetic
Scheme 1. Novel route to syn-2,6-disubstituted piperidines.
Scheme 2. Initial studies on the rearrangement-hydrogenation
sequence.
approach to reduced pyridines becomes apparent from an
atom mapping analysis: the five carbon atoms in the hetero-
cyclic rings originate from the cyclohexenone ring (4 carbons)
with the 6-acyl carbonyl group providing the fifth carbon
atom.
The sequence shown in Scheme 1 was inspired by
biosynthetic speculation concerning the grandisine alka-
loids,[3] and synthetic studies by our group in the same
area.[4] However, this approach to piperidines has not been
explored, and given the widespread distribution of bioactive
piperidines in nature (from amphibians, insects, plants, and
others), and their importance in pharmaceuticals and agro-
chemicals,[1,2] we decided to explore its potential.
studies had demonstrated that treatment of such diketones
with ammonia resulted in a tandem amination–imination
sequence to generate 5-oxo-2-aza-bicyclo[2.2.2]oct-2-enes
such as 4a.[4,6] However, biosynthetic speculation[3] (and
limited experimental evidence[4b]) indicated that such bicyclic
systems should be susceptible to retro-Dieckmann-like ring-
opening by methanol. Upon treatment with excess 35%
aqueous ammonia in methanol,[4b] rapid consumption of the
starting material was observed giving rise directly to the imine
2a, presumably through the intermediacy of bicycle 4a, in
96% yield (> 90% purity by NMR spectroscopy). Imine 2a
underwent significant decomposition upon chromatography
and was therefore immediately reduced: treatment with Pt/C,
H2 (1 h, RT) gave rise to a single diastereomer 3a, which was
isolated in 90% yield over two steps.[7] Analysis by 1H/
13C NMR spectroscopy, following Lhommetꢀs guidelines,[8]
revealed the product to be syn-2,6-disubstituted piperidine
3a. This stereochemical assignment was subsequently con-
firmed by X-ray analysis on a related compound.[9]
[*] Dr. J. D. Cuthbertson, Prof. R. J. K. Taylor
Department of Chemistry, University of York
Heslington, York, YO10 5DD (UK)
E-mail: richard.taylor@york.ac.uk
Homepage: http://www.york.ac.uk/res/rjkt
[**] We are grateful to the University of York for postdoctoral support
(J.D.C.), and to Andrew A. Godfrey (AstraZeneca, Macclesfield) and
Prof. Peter O’Brien (University of York) for valuable discussions. We
also thank Dr. A. C. Whitwood (University of York) for the X-ray
crystallographic data and Prof. A. R. Carroll (Griffith University,
Brisbane) for comparison NMR spectroscopic data.
Having confirmed the viability of the proposed sequence
for the preparation of heterocycles 2 and 3, the scope of the
reaction was investigated using a range of readily available
1,3-diketones 1. As can be seen from Table 1 (entries 1–3),
unsubstituted cyclohexenone substrates bearing phenyl, het-
erocyclic and aliphatic ketones 1a–c gave the corresponding
piperidines 3a–c in good to excellent yield over the two step
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208118.
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Table 1: Conversion of cyclohexenones 1.[a]
of cyclohexyl piperidine 3c proved to be crystalline, and
single crystal X-ray analysis confirmed the syn-stereochem-
istry of the side chains.[9]
We next moved on to examine the effect of substituents on
the cyclohexenone ring (entries 4–7). In the case of
2-methylcyclohexenone 1d, 3-methyl- 1e, and 4,4-dimethyl-
cyclohexenone 1 f the expected 2,3,4,5-tetrahydropyridines
2d,e,f and 2,6-disubstituted piperidines 3d,e,f were formed,
but extended reaction times were required for the ammon-
olysis/ring-opening sequence (8–36 h as opposed to 3 h for the
unsubstituted examples). With 6-methylcyclohexenone 1g
(entry 7), the ammonia addition reaction was unsuccessful,
presumably because of the fact that epimerization at the C6
center is now precluded.
Entry Cyclohexenone 2,3,4,5-Tetrahydropyridine[b]
Piperidine[c]
1
Much more surprising, however, was the observation that
the bicyclo[2.2.2]oct-2-enes derived from 5-methyl-substi-
tuted cyclohexenones were completely stable to methanolic
ring-opening (Scheme 3). So, when cyclohexenone 1h was
2
3
4
5
6
Scheme 3. Conditions for 5-methylcyclohexenones.
treated with methanolic ammonia under the normal con-
ditions for 3 h only the bicycle 4h was isolated, and even after
96 h only a trace of the ring-opened tetrahydropyridine 2h
was observed. Other 5-methyl-substituted cyclohexenones
behaved in a similar manner. It would therefore appear that it
is the presence of the 5-methyl substituent that dramatically
inhibits the ring-opening of 5-oxo-2-aza-bicyclo[2.2.2]oct-2-
enes such as 4h. There are a number of possible rationales for
this observation, but further studies are needed to provide
a definitive explanation. However, with bicycle 4h in hand,
more forcing conditions for the base-induced methanolic ring-
opening process to give 2,3,4,5-tetrahydropyridine 2h were
examined. Eventually, it was found that the use of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in methanol at reflux
resulted in complete conversion into methyl ester 2h after
6 h; when the reaction was repeated in the microwave at
808C, the reaction time could be reduced to 2 h. X-ray
crystallography confirmed the structure of compound 2h[9]
(Scheme 3).
no
reaction
no
reaction
7
[a] Reaction conditions: Unless otherwise stated, all reactions were
performed on a 0.500 mmol scale with 1) MeOH (4 mL), 35% aq. NH3
(2 mL), 08C for 30 min, then RT for 3 h; 2) MeOH (5 mL), Pt/C
(2.5 mol%), H2, RT for 1 h. Chromatographic purification was used for
all products except 3a and 3c. [b] The identity of imines 2 was confirmed
by NMR analysis of the unpurified product and the crude material was
then reduced before chromatographic purification. [c] Yield of isolated
product over 2 steps; in all cases, apart from 3e, only the cis
diastereoisomer of the piperidine was observed, according to the
1H NMR spectrum of the unpurified product. [d] Standard conditions,
but a longer reaction time was required for the ammonolysis/rear-
rangement (2d, 36 h; 2e, 16 h; 2 f, 8 h).
Using the same two-step procedure, the corresponding
5-methyl-substituted cyclohexenone compounds were con-
verted into cyclohexyl- and cyclohexenyl-substituted tetrahy-
dropyridines 2i and 2j, respectively. So either directly, or by
process. In all cases, the identity of imines 2 was confirmed by
NMR analysis of the unpurified products and the crude
material was then reduced to give piperidines 3. The HCl salt
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a two-step procedure, a new route for the preparation of
tetrahydropyridines 2 and piperidines 3 had been developed.
To demonstrate the utility of this novel sequence, the
conversion of cyclohexenone into cis-2-methoxycarbonyl-
(methyl)-6-pentylpiperidine (3k), a natural product isolated
from ladybirds of the species Calvia guttata,[10] was inves-
tigated (Scheme 4). The readily obtained diketone 1k under-
went ammonia addition/imine formation/methanolysis under
standard conditions and then syn-hydrogenation to give the
natural product 3k in 90% yield from compound 1k (68%
from cyclohexenone).
use of the DBU/MeOH microwave reaction for 7 h gave the
ring-opened product (ꢀ)-grandisine G (8) in 63% yield after
column chromatography.
This is the first reported total synthesis of grandisine G (8)
and the characterization data was fully consistent with the
assigned structure: for example, 13C NMR (CDCl3, 100 MHz)
173.1 (ester), 164.0 (imine). Although no optical rotation data
was reported for grandisine G (8),[3b] the synthetic material
gave [a]D = ꢀ82.2 (c = 0.60, CHCl3). Treatment of the free
base 8 with trifluoroacetic acid (TFA) allowed comparison
with the NMR spectroscopic data reported by Carroll and co-
workers.[3b] Full details are given in the Supporting Informa-
tion, but an excellent agreement was observed between the
NMR spectroscopic data for (8)2·TFA and the published
values: for example, 13C NMR ([D6]DMSO, 100 MHz): d =
172.0, 162.9, 135.7, and 127.1 ppm; published values:[3b]
13C NMR ([D6]DMSO, 125 MHz): d = 172.0, 163.0, 135.2,
and 127.0 ppm.
In summary, we have developed and evaluated the scope
of a novel, bio-inspired method for the conversion of 6-acyl
cyclohexenones into 2,6-disubstituted 2,3,4,5-tetrahydropyr-
idines and, after diastereoselective reduction, 2,6-syn-disub-
stituted piperidines. The potential of the piperidine synthesis
has been demonstrated by a short synthesis of cis-2-methox-
ycarbonylmethyl-6-pentylpiperidine (3k, isolated from lady-
birds of the species Calvia guttata). Furthermore, the first
total synthesis of (ꢀ)-grandisine G (8) has been accom-
plished. Applications of this new method for the synthesis of
more complex piperidine alkaloids are the subject of current
investigations.
Scheme 4. Reagents and conditions: a) 1) LDA, ꢀ788C, THF then
RCHO, THF, ꢀ788C; 2) TFAA, DMSO, Et3N, CH2Cl2, ꢀ788C, 76%
yield over 2 steps; b) 1) 35% aq. NH3, MeOH, 08C!RT; 2) Pt/C, H2,
MeOH, RT, 90% yield over 2 steps. LDA=lithium diisopropylamine,
TFAA=trifluoroacetic anhydride.
Finally, the value of this new procedure as a means of
preparing 2,3,4,5-tetrahydropyridines was exemplified by
application to the first total synthesis of (ꢀ)-grandisine G
(8), a compound isolated by Carroll et al. from an extract
obtained from the Australian rainforest tree Elaeocarpus
grandis and shown to display human d-opioid receptor
binding affinity.[3b] Thus (Scheme 5), (+)-grandisine D (6)
Received: October 9, 2012
Published online: December 12, 2012
Keywords: grandisines · nitrogen heterocycles · piperidines ·
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rearrangement · total synthesis
[1] a) Comprehensive Heterocyclic Chemistry III (Eds.: A. R.
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Scheme 5. Reagents and conditions: a) 35% aq. NH3, 1m aq. HCl,
08C!RT, 72%; b) DBU, MeOH, 808C (microwave), 63%. DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene.
[3] a) A. R. Carroll, G. Arumugan, R. J. Quinn, J. Redburn, G.
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[5] See Ref. [4b] and J. M. Duffault, Synlett 1998, 33 – 34.
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was prepared from a commercially-available l-proline deriv-
ative 5 using the procedure previously reported by our
group,[4a] and then subjected to the tandem amination-
imination conditions to generate (ꢀ)-grandisine B (7).[4a,6]
We were now in a position to test the base-induced
methanolysis of compound 7; given the presence of the
5-methyl substituent it was not surprising to find that no ring-
opening was observed at room temperature under the original
conditions. However, we were delighted to observe that the
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[7] Reduction using sodium borohydride in methanol gave a mixture
(ca. 3:1) of the cis/trans-isomers of the disubstituted piperidine
3a.
[8] D. Bacos, J. P. Cꢁlꢁrier, E. Marx, S. Rosset, G. Lhommet, J.
Heterocycl. Chem. 1990, 27, 1387 – 1392.
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Pasteels, V. Plasman, S. Wang, Eur. J. Org. Chem. 1999, 1749 –
1755; b) S. Calvet-Vitale, C. Vanucci-Bacquꢁ, M. C. Fargeau-
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and references therein.
[9] CCDC 899115 (3c) and 901364 (2h) contain the supplementary
crystallographic data for this paper. These data can be obtained
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