Stereocontrolled access to optically-enriched oxabispidines

Article abstract of DOI:10.1039/c2cc30761h

A range of chiral, optically-enriched bicyclic oxabispidines were prepared from (S)-(-)-2,3-epoxypropylphthalimide using an efficient sequence featuring a stereocontrolled intramolecular Mannich reaction as the key transformation.

Full text of DOI:10.1039/c2cc30761h

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COMMUNICATION
Stereocontrolled access to optically-enriched oxabispidinesw
Heloise Brice,a Duncan M. Gill,z*a Laura Goldie,b Philip S. Keegan,a William J. Kerr*b and
Per H. Svenssoncd
Received 2nd February 2012, Accepted 22nd March 2012
DOI: 10.1039/c2cc30761h
A range of chiral, optically-enriched bicyclic oxabispidines were
prepared from (S)-(-)-2,3-epoxypropylphthalimide using an efficient
sequence featuring a stereocontrolled intramolecular Mannich
reaction as the key transformation.
Over recent years, molecules possessing both the bispidine
(1; X = CH2; Fig. 1) and oxabispidine (1; X = O) unit have
been shown to display a range of biological properties that
Scheme 1 Intramolecular Mannich cyclisation.
have made them attractive targets for the pharmaceutical
industry. For instance bispidines have been employed in
the chiral induction within such asymmetric processes (vide infra).8
aa4b2 nicotinic acetylcholine receptor ligands as potential
neuroprotective agents,1 and the oxabispidine ring system
In contrast, chiral oxabispidines (1; X = O) have been the
focus of significantly less attention as ligands for use in
(1; X = O) has been strategically embedded within molecules
enantioselective organic reactions, despite the potentially
showing a range of potential medicinal applications, including use
similar chiral environment predicting that these species could
as atrial repolarisation-delaying agents in the treatment of cardiac
arrhythmia (AstraZeneca),2 mTOR and PI3 kinase inhibitors
act as effective surrogates for the bispidine-based, sparteine 2.
(Wyeth),3 P2X7 receptor antagonists/interleukin-1b inhibitors
Although some stereoselective routes to oxabispidines have
(AstraZeneca),4 and Factor Xa inhibitors (GlaxoSmithKline).5
emerged recently, the available methods tend to be limited by
The lupine alkaloid, (ꢀ)-sparteine 2,6 also has the bispidine
(i) the requirement for more than one pre-formed chiral substrate,
(ii) relatively lengthy synthetic pathways, and (iii) a lack of
structure (1; X = CH2) at its core, with this natural product
flexibility relating to the substituent groups that can be
introduced around the oxabispidine core.9
having been employed as the key chiral ligand in an extensive
array of enantioselective transformations.7
As part of a search for efficient methods of preparing
oxabispidines,10 we disclosed11 the intramolecular Mannich
cyclisation of oxazine 3 shown in Scheme 1.12,13
Based on this established precedent, we envisaged that
preparation of chiral amine 11 and engagement with a range
of higher aldehydes would potentially open expedient access
to a series of optically-enriched and further functionalised
oxabispidines. According to this strategy and as depicted in
Scheme 2, commercially available (S)-(ꢀ)-2,3-epoxypropyl-
phthalimide 6 provided the key chiral starting material. This
species underwent ring opening with amine 7; following a solvent
swap to toluene and addition of catalytic acid, heating at reflux
Fig. 1 Bridged bicyclic diamines 1 and 2.
Indeed, the rigid and central 3,7-diazabicyclo[3.3.1]nonane
backbone within (ꢀ)-sparteine 2 is believed to be crucial to
a Pharmaceutical Development, AstraZeneca R&D Charnwood,
Bakewell Road, Loughborough LE11 5RH, UK
b Department of Pure and Applied Chemistry,
University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL,
UK. E-mail: w.kerr@strath.ac.uk; Fax: +44 (0)141 548 4822;
Tel: +44 (0)141 548 2959
c Pharmaceutical Development, AstraZeneca R&D Sodertalje,
S-151 85 Sodertalje, Sweden
¨
¨
d Applied Physical Chemistry, Department of Chemistry,
Royal Institute of Technology (KTH), SE-100 44 Stockholm, Sweden
w Electronic supplementary information (ESI) available: experimental
procedures and characterisation data for compounds 8–14 and 16–21.
See DOI: 10.1039/c2cc30761h
z Current Address: Department of Chemical and Biological Sciences,
University of Huddersfield, Queensgate, Huddersfield, HD1 3DH,
UK. E-mail: d.m.gill@hud.ac.uk; Fax: +44 (0)1484 472182; Tel:
+44 (0)1484 473337.
Scheme 2 Preparation of amine precursor 11. Reaction Conditions a:
Ethanol, reflux; b: TsOH (10 mol%), toluene, reflux; c: ClCO2Bn,
CH2Cl2, r.t.; d: MeNH2, EtOH, reflux.
c
4836 Chem. Commun., 2012, 48, 4836–4838
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resulted in cyclisation to form acetal 8.14 Prolonged exposure
to these conditions did not result in any further elimination of
methanol to give the oxazine. Consequently, conversion of the
benzylamine to the corresponding CBz protected amines 9 was
secured in a single step by treatment with benzylchloroformate.15
Exposure of 9 to refluxing toluene/catalytic acid resulted in
smooth elimination to deliver oxazine 10 in 67% yield over
4 steps after silica gel chromatography. Whilst deprotection of
the phthalimide with hydrazine16 liberated 11 in an acceptable
70% yield, use of a more practically convenient procedure17 with
the less toxic methylamine delivered this key chiral unit 11 in a
more appreciable 87% yield without recourse to chromatography.
With amine 11 now readily accessible on scale, appropriate
conditions to allow a chemo- and stereoselective annulation
process were investigated.y Initially, the key chiral substrate 11
was coupled with a range of aldehydes to give imines 12,
generally as a single geometric (E) isomer. Following the
screening of a range of Lewis and Brønsted acids, under a
series of conditions, treatment of 12 with 1 molar equivalent of
trifluoromethanesulfonic acid (TfOH) at ꢀ20 1C resulted in
immediate consumption of the imine substrate. Although
isolation and characterisation of intermediate species so
Table 1 Scope of cyclisation and summary of oxabispidines prepared
Entry
R
Methoda
Acetal
Yield
1
2
3
4
5
6
7
8
Ph
A
A
B
A
A
A
A
C
13a
13b
13c
13d
13e
13f
—
92
96
93
76
90
76
0
o-BrC6H4
p-MeOC6H4
o-CF3C6H4
tBu
c-Hex
nBu
nBu
16
75
a
Method A: CF3SO3H, MeOH, CH2Cl2, ꢀ20 1C to r.t.; B: p-TSA
(10 mol%), MeOH, 65 1C; C: CF3SO3H, BtH, CH2Cl2, ꢀ20 1C to r.t.
a feature also observable in the spectra of oxazines 10–12.
Careful assignment of spectra and nOe experiments revealed
that the R-substituent is disposed equatorially, and that the
–OMe group occupies an axial position. Confirmation of these
assignments was provided by a single crystal X-ray diffractogram
of benzyl protected compound 14 (Fig. 2).18 Accordingly, these
outcomes are consistent with a chair-like transition state, as
shown in Scheme 4, in which the imine geometry is conserved,
followed by attack of methanol on the least hindered face of
the iminium ion.
1
formed was not possible, analysis by H NMR spectroscopy
As shown in Table 1, this cyclisation process was applied
successfully to a range of aldehydes. Notably, the imine
derived from electron-rich p-methoxybenzaldehyde did not
react under the standard TfOH conditions, with more forcing
conditions being required to deliver oxabispidine 13c (entry 3).
Additionally, although steric bulk does not appear to compromise
reactivity (entries 5 & 6), aldehydes bearing more than one
a-hydrogen did not work well (entry 7). This is attributable to
the propensity of amine 11 to catalyse competing aldol-type
polymerisation of the aldehyde. This drawback was overcome
by utilising Katritzky’s technique of stabilising reactive aldehydes
as the benzotriazole adduct.19 As shown in Scheme 5, addition of
one equivalent of benzotriazole, followed by the aldehyde, led to
formation of an intermediate with a complex 1H NMR spectrum
assigned as 15. Pleasingly, cyclisation to the oxabispidine acetal
16 occurred smoothly upon treatment with TfOH, although
full conversion required that the reaction be run for 18 h at r.t.
Additionally, within this revised protocol we discovered that
the liberated benzotriazole was a competent nucleophile,
leading to direct formation of the stable adduct 16.
indicated that neither the imine, nor the oxazine olefinic
protons were present at this stage. Accordingly, addition of
1 molar equivalent of methanol resulted in formation of the
oxabispidine hemiaminal ether 13 (Scheme 3; Table 1), as a
single diastereomer in generally good to excellent yields.
Scheme 3 Formation of imines 12 and Mannich cyclisation to give
oxabispidine acetals 13.
The 1H NMR spectrum of 13a (which is typical of the series)
gives the appearance of a mixture of two isomers; variable
temperature studies showed that this is, in fact, due to
restricted rotation between stable conformations of the carbamate,
With a view to accessing compounds of this class which
would have application in asymmetric synthesis, the further
functional manipulation of the product oxabispidines was
targeted. In this regard and as shown in Scheme 6, compounds
13a, c, and e, and 16 were treated with benzyl chloroformate,
followed by LAH to give the corresponding N,N0-dimethyl
Fig. 2 The molecular structure of 14 with the thermal displacement
ellipsoids set at 50% probability and hydrogen atoms as spheres of
arbitrary radius.
Scheme 4 Postulated mechanistic pathway.
Scheme 5 Preparation of oxabispidines from an aliphatic aldehyde.
Chem. Commun., 2012, 48, 4836–4838 4837
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Notes and references
y During initial investigations, amine 11 readily performed double
alkylation processes when exposed to conditions similar to those
shown in Scheme 1.
1 A. Mazurov, L. Miao, Y.-D. Xiao, P. S. Hammond, C. H. Miller,
S. R. Akireddy, V. S. Murthy, R. C. Whitaker, S. R. Breining and
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PCT Int. Appl., 2006, Application: WO 2006-SE688 20060612.
3 A. Zask, J. A. Kaplan, J. C. Verheijen, K. J. Curran, D. J. Richard
and S. Ayral-Kaloustian, U.S. Pat. Appl. Publ., 2009, Application:
US 2008-251712 20081015.
Scheme 6 Conversion of oxabispidine acetals to diamines 18.
4 M. Furber, L. Alcaraz, J. E. Bent, A. Beyerbach, K. Bowers,
M. Braddock, M. V. Caffrey, D. Cladingboel, J. Collington,
D. K. Donald, M. Fagura, F. Ince, E. C. Kinchin, C. Laurent,
M. Lawson, T. J. Luker, M. M. P. Mortimore, A. D. Pimm,
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R. Weaver, P. Webborn and P. Willis, J. Med. Chem., 2007,
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5 C. Chan, J. N. Hamblin, H. A. Kelly, N. P. King, A. M. Mason,
V. K. Patel, S. Senger, G. P. Shah, N. S. Watson, H. E. Weston,
C. Whitworth and R. J. Young, PCT Int. Appl., 2002, Application:
WO 2002-GB2586 20020606.
6 D. Hoppe and T. Hense, Angew. Chem. Int. Ed., 1997, 36,
2282; O. Chuzel and O. Riant, Top. Organomet. Chem., 2005,
15, 59.
7 For examples of the use of (ꢀ)-sparteine and (+)-sparteine as
chiral ligands, see: P. O’Brien, Chem. Commun., 2008, 655.
8 M. J. Dearden, C. R. Firkin, J.-P. R. Hermet and P. O’Brien,
J. Am. Chem. Soc., 2002, 124, 11870; A. J. Dixon, M. J. McGrath
and P. O’Brien, Org. Synth., 2006, 83, 141.
9 M. Breuning and M. Steiner, Synthesis, 2007, 1702; M. Breuning
and M. Steiner, Tetrahedron: Asymmetry, 2008, 19, 1978;
M. Breuning, M. Steiner, C. Mehler, A. Paasche and D. Hein,
J. Org. Chem., 2008, 74, 1407.
10 L. Cheema, D. Cladingboel and R. Sinclair, PCT Int. Appl., 2002,
Application: WO 2002-08360; L. Cheema and D. Cladingboel,
PCT Int. Appl., 2002, Application: WO 2002-083691; D. Cladingboel,
PCT Int. Appl., 2004, Application: WO 2004-035592.
11 D. M. Gill, PCT Int. Appl., 2003, Application: WO 2003-045956;
D. M. Gill, H. Holness and P. S. Keegan, Abstracts of Papers,
232nd ACS National Meeting, San Francisco, 2006.
12 For other examples of such cyclisation reactions, see C. Chan,
S. Zheng, B. Zhou, J. Guo, R. M. Heid, B. J. D. Wright and
S. Danishefsky, Angew. Chem., Int. Ed., 2006, 45, 1749;
K. C. Nicolaou, B. S. Safina, M. Zak, S. H. Lee, M. Nevalainen,
M. Bella, A. A. Estrada, C. Funke, F. J. Zecri and S. Bulat, J. Am.
Chem. Soc., 2005, 127, 11159.
13 For intermolecular reactions of oxazines with electrophiles, see:
L. Eberson, M. Malmberg and K. Nyberg, Acta Chem. Scand., Ser.
B, 1984, 38b, 345.
Scheme 7 Elaboration of 13a to deliver an array of amine substitution.
Reaction Conditions a: LAH, Et2O, 20, 72%; b: (i) MeI, K2CO3, CH2Cl2,
73%; (ii) H2, Pd/C, MeOH, 21, 92%.
oxabispidines 18a, c, e, and g (R = Ph; p-MeOC6H4; tBu; and
nBu, respectively) in good yields over two steps.
Compound 13a was chosen as a vehicle to demonstrate the
inherent flexibility of this class of intermediate and, as shown
in Scheme 7, was efficiently converted to bis-2y amine 19, and
both complementary monomethyl compounds 20 and 21.
Having now established an efficient route to optically-
enriched oxabispidine structures, the relationship of these
species with sparteine-type molecular architectures is worthy
of note. As recently shown by O’Brien, sparteine surrogates
(without the D ring unit) are superior to the full sparteine
structure within certain asymmetric applications.20 However,
access to (ꢀ)-sparteine surrogates is not presently available. In
relation to this, structures 13/16 map directly onto the B/C
rings within (ꢀ)-sparteine 2, whilst providing functionality to
allow further structural manipulations. Furthermore, employ-
ment of the commercially available enantiomeric (R)-glycidyl
phthalimide, (R)-6, will deliver the opposite chiral oxabispidine
series, equivalent to the known (+)-sparteine surrogates.7
These features add further to the preparative flexibility and
utility of the routes developed here.
14 H. Ito, Y. Ikeuchi, T. Taguchi, Y. Hanzawa and M. Shiro, J. Am.
Chem. Soc., 1994, 116, 5469.
In summary, a range of C-substituted oxabispidines have
been prepared from a commercially available chiral building
block, using a novel stereoselective intramolecular Mannich
reaction. The route is highly modular and amenable to creation
of a wide range of analogues where diversity is incorporated late
in the synthetic sequence. Further studies directed towards the
stereoselective synthesis of other classes of bridged heterobicyclic
compounds with potential pharmaceutical and catalytic appli-
cations are ongoing within our laboratories.
15 A. Commercon and G. Ponsinet, Tetrahedron Lett., 1985, 26, 4093.
16 T. Sasaki, K. Minamoto and H. Itoh, J. Org. Chem., 1978,
43, 2320.
17 S. E. Sen and S. L. Roach, Synthesis, 1995, 756.
18 Crystallographic data for the compound reported in this paper
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication CCDC 835119. Copies of
the data can be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44) 1223-336-033;
email: deposit@ccdc.cam.ac.uk). Further crystallographic infor-
mation is available within the ESI.
19 A. R. Katritzky, Tetrahedron, 1991, 47, 2683.
We thank Ms T. Weber and Mr K. Munro (Univ. of
Strathclyde) and Drs A. R. Burns and J. Pavey (AZ) for additional
contributions, and the EPSRC Mass Spectrometry Service,
Univ. of Wales, Swansea, and H. Pancholi (AZ) for analyses.
20 G. Carbone, P. O’Brien, K. R. Campos, I. Coldham and
A. Sanderson, J. Am. Chem. Soc., 2010, 132, 7260; D. Stead,
G. Carbone, P. O’Brien and G. Hilmersson, J. Am. Chem. Soc.,
2010, 132, 15445.
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4838 Chem. Commun., 2012, 48, 4836–4838
This journal is The Royal Society of Chemistry 2012