Discovery of a multi-bond forming, four-step tandem process: Construction of drug-like polycyclic scaffolds

Article abstract of DOI:10.1039/c2cc33649a

A one-pot tandem process involving an Overman rearrangement, ring closing enyne metathesis and a hydrogen bonding directed Diels-Alder reaction has been developed for the efficient diastereoselective synthesis of functionalised amino substituted tetralin and indene ring systems.

Full text of DOI:10.1039/c2cc33649a

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Discovery of a multi-bond forming, four-step tandem process:
construction of drug-like polycyclic scaffolds†
Mark W. Grafton, Louis J. Farrugia, Hans Martin Senn and Andrew Sutherland*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A
one-pot tandem process involving an Overman
R
NH
H
NC
NH
N
OAc
rearrangement, ring closing enyne metathesis and a hydrogen
bonding directed Diels-Alder reaction has been developed for
the efficient diastereoselective synthesis of functionalised
amino substituted tetralin and indene ring systems.
H
H
N
HN
NH
N
H
n-Bu
Cl
1
0
H
H
O
H
H
A significant challenge facing medicinal chemistry and chemical
biology is the elucidation and development of leadꢀhit
compounds and smallꢀmolecule probes that allow insight into
fundamental and diseaseꢀassociated biological phenomena. To
meet this challenge, a recent trend has been to move away from
50
1
2
3 R= Ph
R= Tol
4
Fig. 1 Biologically active, nitrogenꢀsubstituted indene 1 and tetralin 2ꢀ4
1
2
2
3
3
4
4
5
0
5
0
5
0
5
containing compounds.
2
more traditional sp ꢀrich aromatic and heteroaromatic compounds
3
1
and instead to focus on sp ꢀrich compounds for screening.
Compounds with a higher level of saturation have improved
55
The alkyne derived allylic alcohol substrates required for the
tandem process were easily prepared in three steps from
commercially available 4ꢀpentynꢀ1ꢀol (5) and 5ꢀhexynꢀ1ꢀol (6)
(Scheme 1). Use of a oneꢀpot Swern oxidation and Hornerꢀ
WadsworthꢀEmmons reaction under MasamuneꢀRoush conditions
1
b
solubility, while the threeꢀdimensional nature and higher
complexity of such fragments allows better exploration of
1
c,2
chemical space.
Within this context, saturated and partially
saturated forms of amino substituted indene and tetralin scaffolds 60 gave the corresponding (E)ꢀα,βꢀunsaturated esters 7 and 8 in 95%
10,11
have found widespread application (Fig. 1). These ring systems
are components of natural products such as the antitumour
and 99% yield, respectively.
DIBALꢀH then gave the desired allylic alcohol substrates 9 and
10 in excellent overall yield.
Reduction of 7 and 8 with
3
antibiotic (–)ꢀptilocaulin 1, as well as the antibacterial family of
4
hapalindoles (e.g. hapalindole A 2). New derivatives of nitrogen
n
n
65
substituted tetralin ring systems have also found use in medicinal
i, ii
iii
n
5
,6
chemistry. For example, steroidal analogues such as 3 and 4 are
2
CO Et
6
b
potent antiproliferative agents.
OH
OH
5
6
, n = 0
, n = 1
7, n = 0
8, n = 1
9, n = 0
10, n = 1
While interesting and novel strategies have been developed for
the synthesis of amino substituted indene and tetralin ring
3ꢀ7
systems, these approaches tend to rely on traditional singleꢀstep
transformations. Singleꢀstep reactions require their own set of
reagents, catalysts, solvents and conditions. At the end of the
reaction, timeꢀintensive and yield reducing isolation and
purification of each intermediate is necessary, resulting in
significant waste. In recent years, the limitations of oneꢀstep
transformations for the preparation of polycyclic ring systems
have been overcome using tandem or cascade processes that
permit several chemical reactions and the creation of multiple
Scheme 1 Reagents and conditions: (i) (COCl)
8 °C; (ii) (EtO) P(O)CH CO Et, DBU, LiCl, MeCN, rt, 7 (95%), 8
(99%); (iii) DIBALꢀH, Et O, –78 °C, 9 (93%), 10 (97%).
2 3 2 2
, DMSO, Et N, CH Cl , –
7
2
2
2
7
0
2
(2E)ꢀOctaꢀ2ꢀenꢀ7ꢀynꢀ1ꢀol (10) was initially subjected to the
fourꢀstep tandem process shown in Scheme 2. Conversion to
allylic trichloroacetimidate 11 was followed by an Overman
12
rearrangement under thermal conditions (140 ºC) which gave
75
allylic trichloroacetamide 12. At this stage, Grubbs first
8
,9
bonds in a singleꢀpot operation.
Utilising such processes
13
generation catalyst was added which effected the ring closing
negates the need of handling and isolating intermediates and
results in a substantial reduction in waste generation.
14
enyne metathesis reaction, and this was followed by a Dielsꢀ
Alder reaction with Nꢀphenyl maleimide. After optimisation of
We now report the discovery and development of a novel,
fourꢀstep, multiꢀbond forming tandem process that allows the
diastereoselective synthesis of amino substituted, partially
saturated, indene and tetralin ring systems from readily available
alkyne derived allylic alcohols.
15
each stage (variation of temperature and reaction time), amido
80
substituted tetralin derivative 14 was isolated as a single
diastereomer in 72% yield over the four steps. The relative
stereochemistry of 14 was confirmed by difference NOE
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experiments which showed the synꢀrelationship of the hydrogen
atoms at Cꢀ1, Cꢀ7, Cꢀ8 and Cꢀ8a.
repeating the DielsꢀAlder reaction of diene 13 with Nꢀphenyl
60 maleimide using methanol, rather than toluene as a solvent. In
methanol, a hydrogen bonding directed DielsꢀAlder reaction is
not possible due to competition with the solvent and as a
consequence, a 1:1 mixture of the two endoꢀdiastereomers were
isolated in 87% yield.
16
5
i
ii
HN
O
HN
O
6
7
7
8
8
5
0
5
0
5
OH
CCl3
11
CCl3
12
1
0
n
1
0
i. Cl
3
CCN, DBU, 3 h,
iii
X
n
ii. 140 °C, K CO , 24 h
2
3
X
Y
Y
H
iii. Grubbs I (10 mol%)
5 °C, 48 h
iv. dienophile, 111 °C,
O
NH
CCl
7
OH
8
a
7
1
8
iv
9, n = 0
10, n = 1
3
O
24−312 h
H
14-23
O
NH
NPh
HN
O
15
O
CCl
3
CCl
13
3
1
4
N
O
N
O
Scheme 2 Reagents and conditions: (i) Cl
ii) K CO , 140 ºC, toluene, 24 h; (iii) Grubbs I (10 mol%), 75 ºC, 48 h;
(iv) Nꢀphenyl maleimide, 111 ºC, 48 h, 72% from 10.
3
CCN, DBU, CH
Cl
2 2
, rt, 3 h;
H
H
O
NH
NPh
O
NH
NPh
(
2
3
O
O
20
CCl
3
CCl3
1
4, 72%
15, 75%
Using these optimised conditions, the scope of the fourꢀstep
tandem process was explored using allylic alcohols 9 and 10 and
a range of dienophiles (Scheme 3). This produced a diverse series
of amine substituted, partially saturated indene and tetralin
scaffolds incorporating heteroatoms, quaternary centres as well as
various functional groups in good yields over the fourꢀsteps.
Interestingly, reaction of sixꢀmembered diene 13 with 1,4ꢀ
naphthoquinone as part of the fourꢀstep tandem process gave
oxidised DielsꢀAlder adduct 19, while the analogous reaction
with the cyclopentyl diene gave normal DielsꢀAlder adduct 21.
Confirmation of the structure of 19 was achieved by Xꢀray
crystallography (Fig. 2, see also supporting information†).
Diene 19 crystallises in the triclinic space group P–1 and the
structure clearly shows the sp nature of the Cꢀ7 and Cꢀ8 atoms.
CN
CN
H
H
CN
O
NH NC
O
NH
CO Me
2
25
30
35
40
45
CCl3
CCl3
1
6, 66%
17, 48%
1
7
O
CO Me
2
H
H
O
NH
CCl3
CO
2
Me
O
NH
18
O
CCl
3
2
1
8, 39%
19, 61%
90
O
O
O
H
O
NH
H
O
NH
NPh
O
Cl C
3
3
Cl C
0, 62%a
21, 47%a
2
N
N
H
O
O
O
H
NH
NH
2
CO Me
9
5
NPh
O
3
Cl C
Cl C
3
Fig. 2 Molecular structure of compound 19. Displacement ellipsoids are
drawn at 50% probability level and Hꢀatoms are drawn with spheres of
arbitrary radius.
2
2, 46%a
23, 45%a
a
Scheme 3
The DielsꢀAlder reaction leading to the formation of
compounds 20–23 was performed at 75 °C.
More importantly, all the products from this fourꢀstep tandem
process were isolated as single diastereomers, with some
processes forming compounds with up to four contiguous
In order to further explore the cause for the selective formation
5
0
1
00 of 14, we embarked on a computational study using densityꢀ
functional theory at the M06ꢀ2X/def2ꢀTZVP level, including a
polarisable continuum solvent model of toluene. The endo
transition states for both the syn and anti attack of Nꢀphenyl
maleimide onto diene 13 were optimised (Fig. 3; syn/anti
05 designates the approach of the dienophile with respect to the
16
stereogenic centres. Moreover, the tandem processes involving
the nonꢀsymmetrical dienophile, methyl acrylate gave only a
single regioisomer (compounds 17 and 23). We believe these
results are due to the formation of a hydrogen bonding directed
endo transition state between the trichloroacetamide hydrogen
atom and the electronꢀrich atoms present in the sideꢀchain of the
55
1
20
amide substituent of 13). The synꢀTS is stabilised by a hydrogen
bond of 2.10 Å length between the amide NH of 13 and an imide
19
dienophiles. Evidence for such an effect was shown by
2
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oxygen of the dienophile (Fig. 3, bottom transition state). The
Pickett, Drug Discovery Today, 2011, 16, 164. (c) A. W. Hung, A.
Ramek, Y. Wang, T. Kaya, J. A. Wilson, P. A. Clemons and D. W.
Young, Proc. Natl. Acad. Sci. USA, 2011, 108, 6799.
M. Dow, M. Fisher, T. James, F. Marchetti and A. Nelson, Org.
Biomol. Chem., 2012, 10, 17.
A. E. Walts and W. R. Roush, Tetrahedron, 1985, 41, 3463.
R. Bonjouklian, R. E. Moore and G. M. L. Patterson, J. Org. Chem.,
6
6
0
5
calculated reaction Gibbs free energies are –93 (syn) and –85
–
1
(
anti) kJ mol . The synꢀproduct 14 is favoured also on kinetic
2
grounds; the calculated activation Gibbs free energies are 115
–
1 20
5
(syn) and 125 (anti) kJ mol . Assuming that the reaction is
irreversible, and the ratio of syn/antiꢀproduct is entirely under
kinetic control, the difference in activation energy translates into
a syn selectivity of 23:1 at 384 K. This correlates well with what
is observed experimentally for this DielsꢀAlder reaction. Analysis
3
4
1
988, 53, 5866.
5
6
M. P. Kotick, D. L. Leland, J. O. Polazzi, J. F. Howes and A. R.
Bousquet, J. Med. Chem., 1981, 24, 1445.
(a) S. N. Khan, N.ꢀJ. Cho and H.ꢀS. Kim, Tetrahedron Lett., 2007,
48, 5189. (b) Z. Kádár, A. Baji, I. Zupkó, T. Bartók, J. Wölfling and
É. Frank, Org. Biomol. Chem., 2011, 9, 8051.
1
1
0
of the H NMR spectrum of the crude material shows a syn/anti
70
ratio of approximately 20:1.
7
8
(a) S. Wendeborn, A. De Mesmaeker and W. K.ꢀD. Brill, Synlett,
1
998, 865. (b) K. M. Brummond, D. Chen, T. O. Painter, S. Mao and
D. D. Seifried, Synlett, 2008, 759.
7
8
8
9
9
5
0
5
0
5
For general reviews, see: (a) L. F. Tietze, Chem. Rev., 1996, 96, 115.
(b) K. C. Nicolaou, D. J. Edmonds and P. G. Bulger, Angew. Chem.
Int. Ed., 2006, 45, 7134. (c) C. J. Chapman and C. G. Frost,
Synthesis, 2007, 1.
For recent reviews, see: (a) S. W. Youn, Eur. J. Org. Chem., 2009,
2597. (b) J. Poulin, C. M. GriséꢀBard and L. Barriault, Chem. Soc.
Rev., 2009, 38, 3092. (c) J. Zhou, Chem. Asian J., 2010, 5, 422. (d)
M. Ruiz, P. LópezꢀAlvarado, G. Giorgi and J. C. Menéndez, Chem.
Soc. Rev., 2011, 40, 3445.
1
2
2
3
5
0
5
0
9
1
0
R. E. Ireland and D. W. Norbeck, J. Org. Chem., 1985, 50, 2198.
11 M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S.
Masamune, W. R. Roush and T. Sakai, Tetrahedron Lett., 1984, 25,
2
183.
1
1
1
1
2 L. E. Overman and N. E. Carpenter, In Organic Reactions; L. E.
Overman; Ed.; Wiley: Hoboken, NJ, 2005; Vol. 66, 1ꢀ107 and
references therein.
(a) P. Schwab, M. B. France, J. W. Ziller and R. H. Grubbs, Angew.
Chem. Int. Ed., 1995, 34, 2039. (b) P. Schwab, R. H. Grubbs and J.
W. Ziller, J. Am. Chem. Soc., 1996, 118, 100.
4 (a) C. S. Poulsen and R. Madsen, Synthesis, 2003, 1. (b) S. T. Diver
and A. J. Giessert, Chem. Rev., 2004, 104, 1317. (c) H. Villar, M.
Frings and C. Bolm, Chem. Soc. Rev., 2007, 36, 55.
5 (a) M. D. Swift and A. Sutherland, Org. Lett., 2007, 9, 5239. (b) F. I.
McGonagle, L. Brown, A. Cooke and A. Sutherland, Org. Biomol.
Chem., 2010, 8, 3418. (c) S. Ahmad, M. D. Swift, L. J. Farrugia, H.
M. Senn and A. Sutherland, Org. Biomol. Chem., 2012, 10, 3937.
6 See supporting information for NOE experiments for compounds 14ꢀ
3
1
1
1
1
1
1
00
05
10
15
20
25
3
5
Fig. 3. DFTꢀoptimised anti (top) and syn (bottom) transition states for the
attack of Nꢀphenyl maleimide onto 13. Selected distances are given in Å.
1
1
2
3†.
7 The DielsꢀAlder products formed from the reaction of 5ꢀmembered
dienes and naphthoquinones are more stable than the analogous
products from sixꢀmembered dienes and require slightly more forcing
conditions to oxidise than just air or an excess of quinone: (a) S.
Kotha, M. Meshram and A. Tiwari, Chem. Soc. Rev., 2009, 38, 2065
and references therein. (b) B. Köhler, T.ꢀL. Su, T.ꢀC. Chou, X.ꢀJ.
Jiang and K. A. Watanabe, J. Org. Chem., 1993, 58, 1680. (c) D. M.
Gelman, P. A. Mayes, R. Mulder and P. Perlmutter, Tetrahedron:
Asymmetry, 2006, 17, 3341.
In summary, a fourꢀstep tandem process that allows the rapid
formation of multiple bonds and the generation of significant
molecular complexity has been developed. The final step of the
tandem process involving a DielsꢀAlder reaction was shown to
proceed via a hydrogen bonding directed endo transition state
forming compounds with up to four stereogenic centres in
excellent diastereoselectivity. Current studies are underway to
investigate the extension of this approach for the preparation of
natural products and medicinally important agents.
4
0
1
8 Crystallographic data for 19: C20
3 3
H16Cl NO , M = 424.69, triclinic, a
4
5
= 9.2312(3), b = 9.9744(4), c = 10.6797(4) Å, α = 74.0757(16), β =
3
7
9.2214(18), γ = 74.1904(19)°, V = 903.11(6) Å , T = 100 K, space
Financial support from the University of Glasgow (University
Scholarship to M.W.G.) is gratefully acknowledged.
group P–1, Z = 2, 40097 reflections measured, 5178 unique (Rint
=
0
wR
.061) which were used in all calculations. The final R
1
(F) = 0.0517,
2
2
(F ) = 0.122 (all data). The structure has been deposited with the
Notes and references
Cambridge Crystallographic Data Centre, with code CCDC 876917.
9 For a recent study of hydrogen bonding directed DielsꢀAlder
reactions: S. Agopcan, N. ÇelebiꢀÖlçüm, M. N. Üçisik, A. Sanyal
and V. Aviyente, Org. Biomol. Chem., 2011, 9, 8079 and references
therein.
0 For full details on computational modelling, see supplementary
information†. ∆G values are calculated at 384 K, 100 kPa, relative to
free reactants. Interestingly, the preference for synꢀdiastereomer 14
appears to be entropically favoured rather than enthalpic stabilisation
1
2
WestCHEM, School of Chemistry, The Joseph Black Building, University
of Glasgow, Glasgow G12 8QQ, UK. Fax: +44 141 330 4888; Tel: +44
5
5
0
5
1
41 330 5936; E-mail: Andrew.Sutherland@glasgow.ac.uk
†
Electronic Supplementary Information (ESI) available: Full
experimental/computational procedures, spectroscopic data, NMR spectra
for all compounds synthesised. CIF file for compound 19. CCDC 876917.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b000000x/.
(see Table S1).
1
(a) F. Lovering, J. Bikker and C. Humblet, J. Med. Chem., 2009, 52,
752. (b) T. J. Ritchie, S. J. F. MacDonald, R. J. Young and S. D.
6
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