Selective generation of quaternary all-carbon-centres through Heck-cyclisations: Synthesis of mesembrane

Article abstract of DOI:10.1039/b923175g

Described is an observation that the intramolecular Heck reaction of a trisubstituted alkene proceeds with high regioselectivity and leads to the preferential formation of a quaternary all-carbon-centre. This observation was subsequently applied in a short synthesis of (±)-mesembrane. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b923175g

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Selective generation of quaternary all-carbon-centres through
Heck-cyclisations: synthesis of mesembranew
´
Johannes E. M. N. Klein, Kimberly Geoghegan, Nicolas Meral and Paul Evans*
Received (in Cambridge, UK) 5th November 2009, Accepted 26th November 2009
First published as an Advance Article on the web 14th December 2009
DOI: 10.1039/b923175g
Described is an observation that the intramolecular Heck
reaction of a trisubstituted alkene proceeds with high regio-
selectivity and leads to the preferential formation of a quaternary
all-carbon-centre. This observation was subsequently applied in
a short synthesis of (Æ)-mesembrane.
their seminal palladium-catalysed polyene-cyclisation studies
on route to the synthesis of scopadulcic acid B.6 In terms of an
explanation for the regiochemistry observed we speculate that
this example demonstrates that the alkyl-palladium complex,
formed on carbopalladation, prefers to generate organo-
palladium species 2a, rather than 2b, in which the palladium(II)
fragment is placed in the less-sterically congested position.
Currently we favour this rationale as opposed to the one based
on a subtle electronic disparity in the reactivity of the
differently substituted alkenyl carbon atoms.7
Generally, the preparation of quaternary all-carbon-centres
remains a challenging task.1 In relation to this the intra-
molecular Heck (Heck–Mizoroki) reaction has proven to be
a versatile tool to generate complex structures bearing such
quaternary all-carbon-centres.2 As a rule this has been
achieved through the exo-mode of cyclisation to trisubstituted
double bonds in which regioselectivity is governed by the size
of the forming cycle or/and electronic factors.2 More recently,
an alternative strategy relying on chelation control demonstrated
that similar types of centres may be constructed following
an intermolecular Heck reaction.3 We have considered the
preparation of cyclic sulfonamide containing compounds and
have used the palladium-catalysed intramolecular Heck
reaction for their preparation.4 In relation to this endeavour,
when sulfonamide 15 was submitted to standard Heck conditions
we observed the formation of 3, possessing a quaternary
all-carbon-centre in 90% yield with only trace amounts of
material attributable to its regioisomer 4 (Scheme 1). It is
notable in this example that both isomers 3 and 4 possess an
identical sized ring. Although not as clear cut, due to the more
complex molecular structure and possible conformational
effects, Overman et al. have observed similar selectivity during
Many alkaloids possess
a
cis-3a-aryloctahydroindole
framework 5 and based on their unusual, congested architecture
and interesting biological properties have been the subject of
numerous total syntheses.8 Specific examples of this natural
product class are depicted in Fig. 1 (8 and 9 exhibit a saturated
cyclohexyl ring, whereas a cyclohexenyl ring is present in 10 in
the position indicated).
The unusual regioselectivity observed in the above cyclisation
(1 to 3) led us to pursue the total synthesis of (Æ)-mesembrane
7 to further probe the generality of this selectivity.9
We anticipated that double reduction4 of sulfonamide 16
would allow access to (Æ)-mesembrane 7, while an intra-
molecular Heck reaction of 14 should, in the light of the
regioselectivity discussed above, result in the formation of 15
(Scheme 2). In a forward sense sulfonamide 13 was generated
from amine 11 and 2-bromo-3,4-dimethoxybenzene sulfonyl-
chloride 12.4a Exposure of 13 to I2 in the presence of K2CO3,
according to the protocol reported by Knight et al., resulted in
amino-cyclisation. Subsequent treatment with DBU led to the
formation of hexahydroindole 14 following a regioselective
dehydroiodination.10 Whilst the iodo-cyclisation is reasonably
well described in the literature, the selectivity of the elimina-
tion is not quite as predictable. We reason that E2 elimination
proceeds via the conformer in which the tertiary iodide
occupies the equatorial position such that the only anti-
periplanar proton is part of the 5-membered heterocyclic ring
(see ESIw for more detailed discussion). With the Heck-
cyclisation precursor 14 in hand we turned our attention to
the planned cyclisation. Pleasingly, standard Heck conditions
Scheme 1 Regioselectivity in the intramolecular Heck cyclisation of 1.
Centre for Synthesis and Chemical Biology, School of Chemistry and
Chemical Biology, University College Dublin, Dublin 4, Ireland.
E-mail: paul.evans@ucd.ie; Fax: +353-(0)1-7162501;
Tel: +353-(0)1-7162291
w Electronic supplementary information (ESI) available: Details of
synthetic procedures and scanned NMR spectra. CCDC 742478. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b923175g
Fig. 1 Alkaloids possessing the cis-aryloctahydroindole motif.
Chem. Commun., 2010, 46, 937–939 | 937
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resulted in the formation of 18 in 20–25% yield. Interestingly,
although the yield was poor using this reducing agent, under
aprotic conditions, no formation of 17 was detected.
In conclusion, we have reported the formation of quaternary
all-carbon-centres from an unbiased system in terms of the size
of the newly formed cycle. We believe that this selectivity
reflects a preference for the formation of the least sterically
congested organopalladium product of carbopalladation
under our reaction conditions. This observation has been
successfully applied to the synthesis of (Æ)-mesembrane 7.
Further studies to probe the scope of this type of Heck-
cyclisation are underway.
The authors would like to thank University College Dublin
for financial support and the National University of Ireland
for an NUI Travelling Studentship (KG). Dr Helge Muller-
¨
Bunz is thanked for X-ray crystallography and Ms Sine
´
´
Charles (Colaiste Iosagain Stillorgan) for laboratory assistance.
´ ´
Scheme 2 Synthesis of (Æ)-mesembrane 7.
Notes and references
1 Representative reviews regarding the preparation of quaternary
all-carbon-centres: (a) S. F. Martin, Tetrahedron, 1980, 36,
419–460; (b) K. Fuji, Chem. Rev., 1993, 93, 2037–2066;
(c) E. J. Corey and A. Guzman-Perez, Angew. Chem., Int. Ed.,
1998, 37, 388–401; (d) J. Christoffers and A. Mann, Angew. Chem.,
Int. Ed., 2001, 40, 4591–4597; (e) C. J. Douglas and L. E. Overman,
Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5363–5367;
(f) E. A. Peterson and L. E. Overman, Proc. Natl. Acad. Sci.
U. S. A., 2004, 101, 11943–11948; (g) J. Christoffers and A. Baro,
Adv. Synth. Catal., 2005, 347, 1473–1482; (h) B. M. Trost and
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2 For reviews concerning the intramolecular Heck reaction see:
(a) S. E. Gibson and R. Middleton, Contemp. Org. Synth., 1996,
3, 447–471; (b) I. P. Beletskaya and A. V. Cheprakov, Chem. Rev.,
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2006, 106, 4644–4680; (f) J. P. Knowles and A. Whiting, Org.
Biomol. Chem., 2007, 5, 31–44; (g) G. Zeni and R. C. Larock,
Fig. 2 X-Ray crystallographic structure of 15 (diamond representation,
thermal ellipsoids at 50%).
[Pd(OAc)2 (5 mol%), PPh3 (10 mol%) and K2CO3 (2 equiv.) in
DMF at 130 1C] resulted in the formation of 15, bearing the
quaternary all-carbon-centre, in 85% yield as a single diastereo-
isomer and regioisomer.11 Structural confirmation was
achieved by single crystal X-ray crystallography (Fig. 2).12
Subsequent hydrogenation resulted in the formation of the
double reduction precursor 16 (95%). In relation to this
Heck–alkene reduction sequence, a one-pot protocol, leading
directly to 16 from 14 in 43% yield, was realised in which,
following intramolecular Heck cyclisation, the reaction
Chem. Rev., 2006, 106, 4644–4680. For
a monograph see:
The Mizoroki-Heck Reaction, ed. M. Oestreich, Wiley, UK, 2009.
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¨
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5 For the preparation of 1 see ESIw.
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7 For an example of similar regioselectivity following the carbo-
mixture was cooled before stirring under
a hydrogen
atmosphere.13 Based on our earlier work the double reduction
was effected using lithium in liquid NH3. Previous studies
using lithium in liquid NH3 have been reported to result in the
partial loss of the methoxy-group in the para-position to the
sulfonamide moiety.4a,14 Thus, when we subjected sulfon-
amide 16 to Li (8.5 equivalents) in liquid NH3 we isolated,
following aqueous work-up, a 1 : 1 mixture of mono- and
dimethoxy substituted secondary amines. After conversion
into their carbamate derivatives (17 and 18) these compounds
proved separable by flash column chromatography. Treatment
of 18 with lithium aluminium hydride gave mesembrane 7 with
data in accord with those reported.9 Alternative means to
achieve the double reduction were also briefly investigated.
For example, use of sodium, or lithium naphthalenide radical
palladation of
a trisubstituted alkene see: S. A. Godleski,
K. B. Gundlach and R. S. Valpey, Organometallics, 1985, 4,
296–302.
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comprehensive coverage of Amaryllidiceae and Sceletium alkaloids
see: Z. Yin, Nat. Prod. Rep., 2009, 26, 363–381; (d) for Elwesine
see: H. Ishibashi, T. S. So, K. Okochi, T. Sato, N. Nakamura,
H. Nakatani and M. Ikeda, J. Org. Chem., 1991, 56, 95–102.
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3263–3270; (c) M. Saito, J. Matsuo and H. Ishibashi, Tetrahedron,
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B. Liu and T. Wu, J. Org. Chem., 2001, 66, 3119–3128;
(e) W. H. Pearson, D. P. Szura and M. J. Postich, J. Am. Chem.
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However, the formation of the hydrodehalogenation product was
also observed.
12 X-Ray crystallographic data for compound 15: C16H19NO4S; M =
321.38; monoclinic, P21/n; unit cell parameters: a = 9.8281(12) A;
b = 14.6214(18) A; c = 10.9381(14) A; U = 1471.8(3) A3; T =
10 (a) A. D. Jones, D. W. Knight and D. E. Hibbs, J. Chem. Soc.,
Perkin Trans. 1, 2001, 1182–1203. For related halo-cyclisations via
5-endo-trig mode of similar cyclohexenes see: (b) M. C. Marcotullio,
V. Campagna, S. Sternativo, F. Costantino and M. Curini,
100(2) K; Z = 4; 10 783 reflections collected, 2600 unique (Rint
0.0280); the final wR2 was 0.1109 (all data). CCDC 742478.
=
13 This type of process has some precedent and has been termed
‘‘a multi-task’’ catalytic method. For a recent example see:
M. L. Kantam, R. Chakravarti, V. R. Chintareddy, B. Sreedhar
and S. Bhargava, Adv. Synth. Catal., 2008, 350, 2544–2550 and
literature cited within.
Synthesis, 2006, 2760–2766; (c) J. E. M. N. Klein, H. Muller-Bunz
and P. Evans, Org. Biomol. Chem., 2009, 7, 986–995.
¨
11 The same reaction using 10 mol% Pd(OAc)2 and 20 mol% PPh3 at
110 1C led to only partial conversion. Using 10 mol% Pd(OAc)2
and 20 mol% PPh3 at 130 1C resulted in full conversion.
14 For an additional example regarding the loss of a p-methoxy-group
see: W. Zeng and S. R. Chemler, J. Org. Chem., 2008, 73, 6045–6047.
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