Stereoselective approaches to 2,3,6-trisubstituted piperidines. An enantiospecific synthesis of quinolizidine (-)-217A

Article abstract of DOI:10.1039/c1cc13048j

The enantiospecific and diastereocontrolled total synthesis of alkaloid (-)-217A is described that employs a stepwise [3+3] annelation strategy and a piperidine 2,3-cyclopropanation-ring opening reaction as the key steps.

Full text of DOI:10.1039/c1cc13048j

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COMMUNICATION
Stereoselective approaches to 2,3,6-trisubstituted piperidines.
An enantiospecific synthesis of quinolizidine (ꢀ)-217Aw
Nicole C. Mancey,a Nicolas Sandon,a Anne-Laure Auvinet,a Roger J. Butlin,b
Werngard Czechtizkyc and Joseph P. A. Harrity*a
Received 24th May 2011, Accepted 20th July 2011
DOI: 10.1039/c1cc13048j
The enantiospecific and diastereocontrolled total synthesis of
alkaloid (ꢀ)-217A is described that employs a stepwise [3+3]
annelation strategy and a piperidine 2,3-cyclopropanation–ring
opening reaction as the key steps.
Our underlying strategy was to develop a stereoselective
synthesis of the 2,3,6-trisubstituted core of (ꢀ)-217A 1 thereby
ensuring relatively simple closing steps towards the natural
product. As outlined in Scheme 1, the synthesis of key
piperidine 2 relied on the successful diastereoselective function-
alisation of exo-olefin containing 3, or tetrahydropyridine 4.
We envisaged that heterocyclic intermediates 3 and 4 would
each be accessible by [3+3] annelations developed in our labs.7
Our first goal was to devise an efficient route to the key
aziridine required for both [3+3] annelation approaches. We
chose to employ an enantiospecific synthesis starting from
commercially available dimethyl aspartate 5, and our route is
shown in Scheme 2. Amine tosylation followed by LiBH4
reduction proceeded smoothly to furnish diol 6 in high yield.
Cyclisation of the diol to the corresponding aziridine took
place selectively under Mitsunobu conditions and the remaining
hydroxyl-group was protected as a TBDPS-ether to furnish 7.
This four step sequence took place in 53% overall yield and
provided multigram quantities of the key aziridine 7 for the
[3+3] annelation studies.
Quinolizidine alkaloid (ꢀ)-217A was isolated from the
Madagascan frog Mantellabaroni in 1993 by Daly and
co-workers,1 and is a member of a wider class of alkaloids
possessing a broad range of biological activities.2 As amphi-
bian sources generally provide only small quantities of such
compounds, there has been widespread interest in the develop-
ment of efficient synthetic routes to this family of alkaloid
natural products. With specific regard to quinolizidine 217A,
Pearson reported the first total synthesis of this compound in
1998.3 Although a racemic synthesis, this study provided
confirmation of the relative stereochemistry of this natural
product. Since that time, three approaches to (ꢀ)-217A have
been reported by the groups of Panek4 and Danheiser,5 with
the most recent disclosure in 2010 by Lhommet et al.6
Recent studies in our laboratory have focused on the use of
aziridines as three-atom components in a series of [3+3]
annelation processes7 for the stereoselective synthesis of
piperidines.8 During our methodology development, we have
had the opportunity to test these strategies in the synthesis
of alkaloid natural products,9 and this has provided much
impetus to develop new and more general variants of this
unusual ring forming approach.10 With regard to the present
study, investigations into the synthesis of alkaloid (ꢀ)-217A
have provided a further platform for investigating stereo-
selective functionalisation of olefin containing piperidines.
We report herein the realisation of an enamide cyclopropanation—
ring opening strategy for the diastereoselective synthesis of
2,3,6-trisubstituted piperidines and the application of this
method in the synthesis of (ꢀ)-217A.
We have shown that functionalised enantiopure piperidines
can be prepared by the addition of Pd-trimethylenemethane
(Pd-TMM)7a,b or functionalised organomagnesium reagents7c,d
to aziridines. We therefore decided to examine each of these
methods for the transformation of 7 into an enantiopure
functionalised piperidine, our results are highlighted in
Scheme 3. Use of Trost’s conjunctive reagent 811 in the
presence of a Pd-catalyst resulted in formation of piperidine
9 in good yield. Unfortunately however, this reaction was
found to be highly capricious and efficient cycloaddition
a Department of Chemistry, University of Sheffield, Sheffield, S3 7HF,
UK. E-mail: j.harrity@sheffield.ac.uk
b Research and Development, AstraZeneca, Alderley Park,
Macclesfield, SK10 4TG, UK
c Research and Development, Sanofi-Aventis, Industrial Park Hoechst,
D-65926, Frankfurt am Main, Germany
w Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data for all new compounds. See DOI:
10.1039/c1cc13048j
Scheme 1 Retrosynthetic analysis of quinolizidine (ꢀ)-217A
c
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The successful elaboration of 11 to an appropriate
piperidine precursor for the synthesis of (ꢀ)-217A hinged
upon a diastereoselective functionalisation of the enamide that
provided efficient installation of the C-1 Me-group and the
hydrocarbon chain for assembly of the quinolizidine moiety.
We began our studies towards this end by investigating a
sequence involving enamide epoxidation followed by Lewis
acid catalysed allylation. As outlined in Scheme 5, treatment
of 11 with DMDO followed by BF3ꢁOEt2 mediated allylation
of the crude epoxide provided 2,3,6-trisubstituted piperidine in
high yield as a single diastereoisomer. The product was
accompanied by a small amount of silyl ether hydrolysis
product 16b, which showed identical relative stereochemistry
as evidenced by TBAF desilylation of 16a. The high levels of
stereocontrol exhibited in this sequence was intriguing and a
rationale is put forward in models I, II in Scheme 5. The
propensity for 6-alkyltetrahydropyridines to adopt an axial
orientation13 may encourage reagent addition onto the olefin
face opposite to the alkyl group (I). Lewis acid catalysed
opening then forms an iminium (II) that will undergo
stereoelectronically controlled addition syn-to the 6-alkyl
group. Indeed, Rutjes and Blaauw have highlighted a similar
diastereoselective functionalisation sequence in the synthesis
of 5-hydroxypipecolic acid derivatives.14
Scheme 2 Reagents and conditions: (a) TsCl, Et3N, THF, 84%.
(b) LiBH4, THF, 87%. (c) PBu3, ADDP, toluene, 81%. (d) TBDPSCl,
imidazole, THF, 90%. ADDP: 1,10-(azodicarbonyl)dipiperidine.
Scheme 3 Reagents and conditions: (a) 8, 10% Pd(OAc)2, 60% P(OPri)3,
20% BuLi, THF, reflux, 16 h, 65%. (b) (i) CH2QC(Me)CH2OH, BuLi
(2.1 eq.), TMEDA (2.1 eq.), Et2O, 16 h; (ii) MgBr2 (2.1 eq.), THF, r.t.,
85%. (c) 10% Pd(OAc)2, 40% PPh3, 4 A M.S., tol., reflux, 16 h, 84%.
(d) 10, 25% CuBrꢁDMS, THF, r.t., 16 h, 80%. (e) TFA, acetone, r.t.,
20 h, 88%.
proved to be irreproducible. We therefore turned our attention
to a stepwise annelation process (conditions b, Scheme 3)
which provided 9 reproducibly in 72% yield over two steps.
Finally, we prepared piperidine 11 through an alternative
The studies outlined in Scheme 5 demonstrated that piper-
idine 11 could be elaborated to an appropriately substituted
intermediate with correct stereochemistry for the synthesis of
(ꢀ)-217A 1. However further modification of compound 16a
to install the C-1 Me-group raised the prospect of engineering
further diastereocontrol within any given synthetic sequence.
Much more attractive, was the notion of using a similar
paradigm but exploiting a cyclopropane linchpin rather than
an epoxide. This strategy would require the analogous ring
opening of a piperidine 2,3-cyclopropane. Such processes are
relatively rare and generally require the use of an activated
cyclopropyl ester,15 although non-activated systems have also been
exploited.16 With specific regard to heteroatom promoted cyclo-
propane ring opening—nucleophile addition, significantly more
precedent is available in the pyran series. In this regard, cyclo-
propane haloetherification seemed potentially very attractive.17
In the event, cyclopropanation of enamide 11 proceeded in
excellent yield to provide 17 as a single diastereoisomer. Upon
treatment with NBS however, we were disappointed to find
that vicinal-dibromide 18 was formed, albeit in good yield.
Apparently, the iminium intermediate III undergoes loss of a
proton and a second bromination reaction. We repeated the
reaction with alcohol 19 in the hope that the alcohol would
cyclise onto the iminium and preclude the formation of
enamide IV, unfortunately this approach failed to obviate
the formation of 18 (Scheme 6).
stepwise sequence involving addition of Buchi Grignard 10
¨
to 7 followed by acid catalysed cyclisation.
We anticipated that piperidine 9 would be most appropriate
for elaboration to (ꢀ)-217A as the exomethylene moiety
appeared to be well placed to install the Me-group at C-1
of the natural product. Accordingly, we carried out the
Rh-catalysed isomerisation of
9 towards enamide 12
(Scheme 4). Whilst this process was poorly selective, isomers
12 and 13 could be separated allowing desired enamide 12 to
be isolated in 66% yield. Treatment of 12 with NaOMe,
bromine resulted in the formation of bicycle 14 in high yield.12
Subjection of bromide 14 to efficient Sn-mediated debromina-
tion provided compound 15 as a single diastereoisomer, that
provided suitable crystals for X-ray analysis. Disappointingly
however, these showed that the undesired endo-Me stereo-
chemistry had been produced. Whilst compound 15 represents
a useful intermediate for the synthesis of all-cis 2,3,6-trisub-
stituted piperidines, this particular stereochemical outcome
coupled with the inefficient olefin isomerisation step prompted
us to explore an alternative synthesis of (ꢀ)-217A from 11.
Scheme 4 Reagents and conditions: (a) 10% RhCl(PPh3)3, DBU, 4 A
M.S., EtOH, 100%, 12 : 13 : 2 : 1; (b) NaOMe, Br2, 95%; (c) Bu3SnH,
AIBN, C6H6, reflux, 16 h, 90%.
Scheme 5 Reagents and conditions: (a) DMDO, CH2Cl2; (b) BF3ꢁOEt2,
CH2QCHCH2SiMe3, 80% over two steps, 16a :16b: 7:1.
c
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enoate moiety to provide 23, followed by removal of the
Ts-group and cyclization. Hydrolysis of the silyl ether 25
proceeded without incident to provide alcohol 26, that was
elaborated to the natural product according to previously
described methods4,6 to provide 1. Our sample exhibited
identical spectroscopic data to that reported in previous
structural and synthetic studies in (ꢀ)-217 A (Scheme 8).
In conclusion, [3+3] annelation strategies offer a convenient
and stereoselective method for the synthesis of piperidines.
This method has successfully delivered alkaloid (ꢀ)-217 A.
We are grateful to AstraZeneca, sanofi-aventis and the
EPSRC for financial support.
Scheme 6 Reagents and conditions: (a) CH2I2, Et2Zn, toluene, 85%
(495 : 5 d.r.); (b) NBS (7 equiv), MeOH, 91%; (c) TBAF, THF, 99%;
(d) NBS (1 equiv), MeOH, 40% (50% borsm).
NIS has also been employed in heteroatom promoted
cyclopropane cleavage reactions. We proposed that the larger
iodonium ion may reduce the rate of the second halogenation
step and therefore set about exploring the haloetherification
under these conditions. To our delight, cyclopropane 17
underwent smooth ring opening to provide aminal 20.
Compound 20 proved to be extremely sensitive to decomposi-
tion on silica gel, or by warming above ambient temperature
so we decided to explore the subsequent steps on the crude
material. In the event, reduction of the iodide followed by
allylation with ketene acetal 21 provided the desired piperidine
intermediate 22 as a single diastereoisomer in good yield over
three steps (Scheme 7).
Notes and references
1 P. Jain, H. M. Garraffo, H. Yeh, T. F. Spande, J. W. Daly,
N. R. Andriamaharavo and M. Andriantsiferana, J. Nat. Prod.,
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2 J. P. Michael, Nat. Prod. Rep., 2004, 21, 625.
3 W. H. Pearson and H. Suga, J. Org. Chem., 1998, 63, 9910.
4 H. Huang, T. F. Spande and J. S. Panek, J. Am. Chem. Soc., 2003,
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5 K. M. Maloney and R. L. Danheiser, Org. Lett., 2005, 7, 3115.
6 M. Fellah, M. Santarem, G. Lhommet and V. Mouries-Mansuy,
J. Org. Chem., 2010, 75, 7803.
7 (a) S. J. Hedley, W. J. Moran, A. H. G. P. Prenzel, D. A. Price and
J. P. A. Harrity, Synlett, 2001, 1596; (b) S. J. Hedley, W. J. Moran,
D. A. Price and J. P. A. Harrity, J. Org. Chem., 2003, 68, 4286;
(c) K. M. Goodenough, P. Raubo and J. P. A. Harrity, Org. Lett.,
2005, 7, 2993; (d) L. C. Pattenden, R. A. J. Wybrow, S. A. Smith
and J. P. A. Harrity, Org. Lett., 2006, 8, 3089.
8 For recent reviews of synthetic routes to piperidines see:
(a) P. R. Girling, T. Kiyoi and A. Whiting, Org. Biomol. Chem.,
2011, 9, 3105; (b) J. P. A. Harrity and O. Provoost, Org. Biomol.
Chem., 2005, 3, 1349; (c) M. G. P. Buffat, Tetrahedron, 2004,
60, 1701; (d) F.-X. Felpin and J. Lebreton, Eur. J. Org. Chem.,
2003, 3693; (e) P. M. Weintraub, J. S. Sabol, J. M. Kane and
D. R. Borcherding, Tetrahedron, 2003, 59, 2953; (f) S. Laschat and
T. Dickner, Synthesis, 2000, 1781.
With a stereoselective route to the key 2,3,6-trisubstituted
piperidine 22 in hand, we turned our attention to the elabora-
tion of this advanced intermediate towards the target
compound. Firstly, we successfully assembled the remaining
ring of the quinolizidine core by a two-step reduction of the
9 (a) W. J. Moran, K. M. Goodenough, P. Raubo and J. P. A.
Harrity, Org. Lett., 2003, 5, 3427; (b) K. M. Goodenough,
W. J. Moran, P. Raubo and J. P. A. Harrity, J. Org. Chem.,
2005, 70, 207; (c) O. Y. Provoost, S. J. Hedley, A. J. Hazelwood
and J. P. A. Harrity, Tetrahedron Lett., 2006, 47, 331;
(d) O. Y. Provoost, A. J. Hazelwood and J. P. A. Harrity, Beilstein
J. Org. Chem., 2007, 3, 8.
10 For an overview of alternative [3+3] annelations see:
(a) R. P. Hsung, A. V. Kurdyumov and N. Sydorenko, Eur. J.
Org. Chem., 2005, 23; (b) G. S. Buchanan, J. B. Feltenberger and
R. P. Hsung, Curr. Org. Synth., 2010, 7, 363.
Scheme 7 Reagents and conditions: (a) NIS, MeOH; (b) Bu3SnH,
AIBN, toluene; (c) 21, BF3ꢁOEt2, CH2Cl2, 59% over three steps.
11 B. M. Trost, Angew. Chem., Int. Ed. Engl., 1986, 25, 1.
12 The stereochemistry of compound 14 was not determined.
13 (a) L. C. Pattenden, H. Adams, S. A. Smith and J. P. A. Harrity,
Tetrahedron, 2008, 64, 2951; (b) D. Craig, R. McCague,
G. A. Potter and M. R. V. Williams, Synlett, 1998, 55.
14 P. N. M. Botman, F. J. Dommerholt, R. de Gelder, Q. B.
Broxterman, H. E. Schoemaker, F. P. J. T. Rutjes and R. Blaauw,
Org. Lett., 2004, 6, 4941.
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Chem., 2005, 4654.
17 (a) P. Bertinato, E. J. Sorensen, D. Meng and S. J. Danishefsky,
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Scheme 8 Reagents and conditions: (a) 10% Pd/C, H-Cubet, EtOAc,
93%; (b) LAH, THF, 100%; (c) Na, C10H10, DME, 79%; (d) PPh3, I2,
imidazole, CH2Cl2, 79%; (e) TBAF, THF, 100%.
c
9806 Chem. Commun., 2011, 47, 9804–9806
This journal is The Royal Society of Chemistry 2011