Pictet-Spengler reactions of oxetan-3-ones and related heterocycles

Article abstract of DOI:10.1016/j.tetlet.2013.11.077

Pictet-Spengler reactions of oxetan-3-ones and azetidin-3-ones with tryptamine and tryptophan derivatives produce spirocyclic tetrahydro-β- carbolines in good yields. Molecular iodine (5 mol %) is an effective catalyst in most cases and high levels of dia

Full text of DOI:10.1016/j.tetlet.2013.11.077

Accepted Manuscript
Pictet-Spengler reactions of oxetan-3-ones and related heterocycles
Benjamin O. Beasley, Abimbola Alli-Balogun, Guy J. Clarkson, Michael
Shipman
PII:
S0040-4039(13)02024-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.077
TETL 43872
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 September 2013
8 November 2013
20 November 2013
Please cite this article as: Beasley, B.O., Alli-Balogun, A., Clarkson, G.J., Shipman, M., Pictet-Spengler reactions
of oxetan-3-ones and related heterocycles, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.11.077
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Benjamin O. Beasley, Abimbola Alli-Balogun, Guy J. Clarkson, Michael Shipman

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Pictet-Spengler reactions of oxetan-3-ones and related heterocycles
Benjamin O. Beasley, Abimbola Alli-Balogun, Guy J. Clarkson, Michael Shipman
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, U.K.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Pictet Spengler reactions of oxetan-3-ones and azetidin-3-ones with tryptamine and tryptophan
derivatives produce spirocyclic tetrahydro-β-carbolines in good yields. Molecular iodine (5
mol%) is an effective catalyst in most cases and high levels of diastereoselectivity are witnessed
using 2-substituted oxetan-3-ones.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Oxetanes
Imines
Catalysis
Spiro compounds
There is much current interest in the use of oxetanes in
medicinal chemistry. Carreira, Rogers-Evans and coworkers have
pioneered their use as bioisosteric replacements for common
functional groups such as gem-dimethyl or carbonyl groups.1
Furthermore, the introduction of an oxetane ring can induce
profoundly beneficial effects on the aqueous solubility,
lipophilicity, metabolic stability and conformational preference
of drug candidates.1 Consequently, there is considerable interest
in exploring the benefits of oxetane introduction into various
privileged drug scaffolds.2 With this in mind, we sought to
examine if practical methods for oxetane introduction into
yield after chromatography. Whilst uncatalysed Pictet Spengler
reactions have been reported using aldehydes,8 we are unaware of
any reports of uncatalyzed reactions using simple ketones.
Presumably the high ring strain associated with the four-
membered ring accelerates the Pictet-Spengler cyclization of the
intermediate ketimine in this instance.
Table 1.
tetrahydro-β-carbolines (THBC) could be realised.
Many
bioactive natural products (e.g. harmicine,3 fumitremorgin C4)
and approved medicines such as tadafil5 contain the THBC
nucleus, and oxetane introduction would be expected to modulate
their physicochemical properties. Since the most direct and
straightforward route to THBCs involves Pictet-Spengler
cyclization,6 we reasoned that oxetane-containing THBCs might
be efficiently made using this chemistry. In this Letter, we report
practical conditions for the synthesis of a range of oxetane-
containing THBCs in high yield and stereoselectivity through
Pictet-Spengler reactions.
Entry
Activator
Solvent
Temp
(°C)
Conversion
(%)a
1
2
3
4
5
6
7
TFA (2 mol%)
TFA (2 mol%)
TFA (1 mol%)
CH2Cl2
MeCN
PhMe
r.t.
82
85
r.t.
40
82
82
4
25
73
0
.
BF3 OEt2 (3 equiv)
CH2Cl2
CH2Cl2
MeCN
MeCN
Yb(OTf)3 (10 mol%)
8
I2 (5 mol%)
-
48b
75b
Initially, a range of Brønsted and Lewis acidic conditions
were explored for the reaction of commercially available oxetan-
3-one (1a) with tryptamine (2a) (Table 1). Modest conversion
into spirocycle 3a was achieved using trifluoroacetic acid (TFA)
at room temperature, with better conversions seen upon heating.
Lewis acids such as boron trifluoride and ytterbium triflate
proved ineffective. Better results were seen using molecular
iodine as the activator7 although intriguingly, the best yield was
achieved in the absence of any activator. Simply heating 1a and
a Determined from 1H NMR using 1,3,5-trimethoxybenzene as an internal
standard. b Isolated yield after chromatography.
Next, we sought to explore the scope of this reaction (Table
2). Using oxetan-3-one (1a), THBCs 3a and 3b were prepared in
good yields without addition of a catalyst (entries 1 and 2).
However, in all other cases, iodine catalysis proved beneficial
(entries 3-8). The reaction tolerates substitution of the indole
2—a —tog—ether in acetonitrile provided THBC 3a in 75% isolated
 Corresponding author. E-mail address: m.shipman@warwick.ac.uk; Fax +44(0)24 76524429

2
Tetrahedron Letters
nitrogen atom (entry 4), or substituents on the aromatic ring
is racemic. NOE experiments were used to establish that the same
(entries 2 and 6). High yields were obtained using L-tryptophan
ethyl ester (2c) as the amine component (entries 3 and 7). Chiral
shift NMR analysis using Pirkle’s reagent9 confirmed that no
measurable racemization occurred during the Pictet-Spengler
cyclization to form 3c (see Supplementary Information). Using
oxetanes 1b and 1c bearing substituents on the ring, the reactions
proceeded in a highly diastereoselective manner. For example,
reaction of 1b with 2a provided 3e in 65% yield as a single
sense of stereochemical induction had occurred in spirocycles 3g-
i.11
diastereoisomer.
The relative stereochemistry of 3e was
unambiguously determined by X-ray crystallography on a crystal
grown from CH2Cl2/pentane (Figure 1).10 This product must
arise from nucleophilic attack of the indole nucleus to the least
hindered face of the intermediate iminium ion, i.e., the face
opposite the phenethyl group on the oxetane ring. The reaction
of 1b with 2c produced near equal quantities of two
diastereomers, 3g and 3h (ca. 1.1:1), because the starting ketone
Figure 1. ORTEP representation of the X-ray crystal structure of 3e
Table 2. Scope of Pictet-Spengler reactions involving oxetan-3-ones
Entry
1
Ketone
Amine
Catalyst
-
Product
Yield (%)a
75
1a
2a
3a
2
3
1a
1a
2b
2c
-
85
3b
I2 (5 mol%)
89
≥95%eeb
3c
4
1a
2d
I2 (5 mol%)
52
3d
5
6
1b
1b
2a
2b
I2 (5 mol%)
I2 (5 mol%)
65
3e
72
3f
7
1b
2c
I2 (5 mol%)
72
3g
ca. 1.1 : 1
3h

3
8
1c
2a
I2 (5 mol%)
23
3i
a Full experimental procedures and characterization data in Supplementary data. b Determined using chiral shift NMR employing Pirkle’s alcohol.
54, 3094. (d) Beasley, B. O.; Clarkson, G. J.; Shipman, M.
Tetrahedron Lett. 2012, 53, 2951. (e) Stepan, A. F.; Karki, K.;
McDonald, W. S.; Dorff, P. H.; Dutra, J. K.; DiRico, K. J.; Won,
The chemistry can be extended to azetidin-3-ones. For
example, spirocycle 5 can be made in 65% yield from N-tosyl
azetidin-3-one (4) and tryptamine (2a) using TFA as the catalyst
(Scheme 1). Lower yields (44%) were observed using iodine (5
mol%) in MeCN. Using L-tryptophan ethyl ester (2c), compound
6 was produced in good yield without detectable racemization.
A.; Subramanyam, C.; Efremov, I. V.; O’Donnell, C. J.; Nolan, C.
E.; Becker, S. L.; Pustilnik, L. R., Sneed, B.; Sun, H.; Lu, Y.;
Robshaw, A. E.; Riddell, D.; O’Sullivan, T. J.; Sibley, E.; Capetta,
S.; Atchison, K.; Hallgren, A. J.; Miller, E.; Wood, A.; Obach, R.
S. J. Med. Chem. 2011, 54, 7772. (f) Vigo, D.; Stasi, L.; Gagliardi,
S. Tetrahedron Lett. 2011, 52, 565. (g) Burkhard, J. A.; Guérot,
C.; Knust, H.; Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2010,
12, 1944. (h) Wuitschik, G.; Rogers-Evans, M.; Buckl, A.;
Bernasconi, M.; Märki, M.; Godel, T.; Fischer, H.; Wagner, B.;
Parilla, I.; Schuler, F.; Schneider, J.; Alker, A.; Schweizer, W. B.;
Müller, K.; Carreira, E. M. Angew. Chem. Int. Ed. 2008, 47, 4512.
(i) Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fischer, H.;
Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew.
Chem. Int. Ed. 2006, 45, 7736.
3. Kam T.-S.; Sim, K.-M. Phytochemistry 1998, 47, 145.
4. Rabindran, S. K.; Ross, D. D.; Doyle, L. A.; Yang, W.;
Greenberger, L. M. Cancer Res. 2000, 60, 47.
5. (a) Daugan, A.; Grondin, P.; Ruault, C.; Le Monnier de Gouville,
A.-C.; Coste, H.; Kirilovsky, J.; Hyafil, F.; Labaudinière, R. J.
Med. Chem. 2003, 46, 4525; (b) Daugan, A.; Grondin, P.; Ruault,
C.; Le Monnier de Gouville, A.-C.; Coste, H.; Linget, J.-M.;
Kirilovsky, J.; Hyafil, F.; Labaudinière, R. J. Med. Chem. 2003,
46, 4533.
Scheme 1
6. For reviews, see: Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95,
1797. (b) Stöckigt, J.; Antonchick, A. P.; Wu, F. R.; Waldmann,
H. Angew. Chem. Int. Ed., 2011, 50, 8538.
7. (a) Lingam, Y.; Rao, D. M.; Bhowmik, D. R.; Santu, P. S.; Rao, K.
R.; Islam, A. Tetrahedron Lett., 2007, 48, 7243. (b) Prajapati, D.;
Gohain, M. Synth. Commun., 2008, 38, 4426.
8. See, for example: Soerens, D.; Sandrin, J.; Ungemach, F.; Mokry,
P.; Wu, G. S.; Yamanaka, E.; Hutchins, L.; DiPierro, M.; Cook, J.
M. J. Org. Chem. 1979, 44, 535.
9. Pirkle, W. H.; Hoover, D. J. Topics Stereochem. 1982, 13, 263.
10. Crystallographic data (excluding structure factors) for 3e (CCDC
961012) have been deposited with the Cambridge Crystallographic
Data Centre. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.
11. The structural assignment for 3e deduced by X-ray (Figure 1) was
also confirmed by NOE experiments. Specifically, reciprocal
NOE enhancements were seen between the indole NH and two
oxetane ring hydrogens attached to different ring carbons. These
and other relevant NOEs were also seen in 3g, 3h and 3i. These
observations are consistent with the oxetane substituent being anti
to the new C–C bond in all cases.
In conclusion, we have developed simple methodology for the
synthesis of oxetane- and azetidine-containing tetrahydro--
carbolines through application of Pictet-Spengler cyclizations.
Iodine catalysis proved effective in most cases and the reactions
exhibited high diastereofacial selectivity. In the course of this
work, we have unearthed what we believe to be the first
examples of uncatalysed Pictet-Spengler reactions involving
simple ketones. Work to explore the benefits of oxetane
introduction into THBCs and other drug-like scaffolds is
continuing in our laboratory.
Acknowledgements
This work was supported by the University of Warwick and
the Engineering and Physical Sciences Research Council
(EPSRC). N-Tosyl azetidin-3-one was kindly provided by
Nicola Powell. The Oxford Diffraction Gemini XRD system was
obtained, through the Science City Advanced Materials project:
Creating and Characterizing Next Generation Advanced
Materials, with support from Advantage West Midlands.
Supplementary Materials
Supplementary material associated with this article can be
found, in the online version, at ******
References and notes
1. For reviews, see: (a) Wuitschik, G.; Carreira, E. M.; Wagner, B.;
Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Müller, K.
J. Med. Chem. 2010, 53, 3227. (b) Burkhard, J. A.; Wuitschik, G.;
Rogers-Evans, M.; Müller, K.; Carreira, E. M. Angew. Chem. Int.
Ed. 2010, 49, 9052.
2. (a) Burkhard, J. A.; Wuitschik, G.; Plancher, J.-M.; Rogers-Evans,
M.; Carreira, E. M. Org. Lett. 2013, 15, 4312. (b) Fujishima, T.;
Nozaki, T.; Suenga, T. Bioorg. Med. Chem. 2013, 21, 5209. (c)
Nassoy, A.-C.; Raubo, P.; Harrity, J. P. A. Tetrahedron Lett. 2013,