Polycyclic alkaloids via transannular Mannich reactions

Article abstract of DOI:10.1039/b822955d

The tricyclic compound 13, representing the framework of the cylindricine 4 and lepadiformine 5 alkaloids, was prepared in a single operation via the first example of a transannular Mannich reaction involving a macrocyclic diketoamine 12.

Full text of DOI:10.1039/b822955d

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Polycyclic alkaloids via transannular Mannich reactionsw
Paulo Vital, Masood Hosseini, M. Sundaram Shanmugham, Charlotte H. Gotfredsen,
Pernille Harris and David Tanner*
Received (in Cambridge, UK) 19th December 2008, Accepted 28th January 2009
First published as an Advance Article on the web 19th February 2009
DOI: 10.1039/b822955d
The tricyclic compound 13, representing the framework of the
cylindricine 4 and lepadiformine 5 alkaloids, was prepared in a
single operation via the first example of a transannular Mannich
reaction involving a macrocyclic diketoamine 12.
diene in 71% yield via a Wittig reaction. Subsequent regio-
selective hydroboration of the exocyclic double bond with
9-BBN, followed by basic H2O2 oxidation, delivered alcohol
8 in good yield (83%).
A Suzuki–Miyaura cross coupling reaction10 with the
9-BBN hydroborated form of N-Boc-allylamine 9 afforded
alcohol 10 in 85% yield, which was then converted to the
corresponding tosylate under standard conditions. The poten-
tially awkward formation of the 8-membered ring11 was
accomplished in high yield (88%) by refluxing the tosylate
with NaH in dilute THF solution, taking advantage of the
conformational constraint provided by the cis endocyclic
double bond. Ozonolysis of bicyclic amine 11 afforded
the crystalline macrocyclic diketoamine 12 in essentially
quantitative yield (see Scheme 2 for X-ray structure).
The feasibility of the proposed TAM reaction could now
be evaluated. Cleavage of the Boc-protecting group was
accomplished under acidic conditions, typically with TFA,
followed by basic work up to trigger the desired TAM
reaction. This procedure reproducibly delivered tricycle 13 in
50–55% yield (based on 11). The TAM reaction presumably
takes place via either the chair-type transition state (TS)
involving the Re face of the Z-enol 14 or the boat-type TS
between the Si face of the E-enol 15 and the iminium ion
(Scheme 3).
Transannular reactions1 can display significant advantages
over their intermolecular and ‘‘conventional’’ intramolecular
counterparts, often proceeding under milder conditions and
with enhanced chemo-, regio- and/or stereoselectivity.
Previous examples of such processes as applied to natural
products synthesis include transannular cycloadditions,2a
aldol reactions,2b radical2c and oxidative2d cyclizations,
Michael additions2e and cycloisomerizations.2f Since the
Mannich reaction, in particular its intramolecular version, is
notable for rapid generation of molecular complexity,3 we
reasoned that a transannular Mannich (TAM) reaction of a
suitable macrocyclic precursor could provide a powerful tool
for constructing complex azapolycyclic frameworks.4 Such a
strategy could thus provide a convenient and general route to
a large number of biologically significant alkaloids.
Hence we decided to investigate the feasibility of such TAM
processes5 and as ‘‘proof of concept’’ the tricyclic skeleton 1,
which constitutes the framework of the cylindricine 4 and
lepadiformine 5 alkaloids (Fig. 1),6 was judiciously chosen as
the target. A simplified retrosynthetic analysis of 1 based on a
key TAM step is shown in Scheme 1. Accordingly, two
simultaneous bond disconnections reveal the 13-membered
macrocycle 2. From a synthetic standpoint, the free amine is
predicted to condense regioselectively with the C-5 ketone to
afford a 5-membered cyclic iminium ion, which would be
intercepted regioselectively by the enol form of the C-11
ketone. The major challenge would then be the synthesis of
the macrocyclic precursor.7 After investigating several possi-
bilities, in particular ring closing metathesis (RCM) of various
substrates,8 we decided that a general method for construction
of macrocycles such as 2 would be via an oxidative ring
fragmentation of [7,8]-bicyclic amines such as 3.
The tricyclic structure of 13 as well as its cylindricine-type
cis-fused 1-azadecalin A–B ring system (as opposed to
lepadiformine’s trans arrangement) was determined by
extensive NMR studies.12 In particular, NOESY experiments
conclusively showed a NOE interaction between the methine
Scheme 1 TAM as the key step in construction of tricycle 1.
The synthesis of the desired macrocyclic diketoamine 12 was
accomplished according to Scheme 2. Treatment of cyclo-
heptanone 6 with PPh3, Br2 and DMF delivered the known
bromoaldehyde 7 in good yield (79%) and in multigram
amounts.9 This was then converted into the corresponding
Department of Chemistry, Technical University of Denmark,
201 Kemitorvet, Lyngby, DK-2800 Kgs., Denmark.
E-mail: dt@kemi.dtu.dk; Fax: +45 45933968
w Electronic supplementary information (ESI) available: Selected
experimental details. CCDC 714338. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b822955d
Fig. 1 Cylindricine 4 and lepadiformine 5 alkaloids.
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Fig. 2 The NOE interaction detected between H-10 and one of the
C-4 bound protons.
Notes and references
1 For a general reference, see: E. L. Eliel and S. H. Wilen, in
Stereochemistry of Organic Compounds, John Wiley & Sons,
New York, 1994.
2 For selected examples see: (a) M. Tortosa, N. A. Yakelis and
W. R. Roush, J. Am. Chem. Soc., 2008, 130, 2722; S. Fortin,
L. Barriault, Y. L. Dory and P. Deslongchamps, J. Am. Chem.
Soc., 2001, 123, 8210; A. Toro, P. Nowak and P. Deslongchamps,
J. Am. Chem. Soc., 2000, 122, 4526; D. A. Evans and J. T. Starr,
Angew. Chem., Int. Ed., 2002, 41, 1787; D. A. Vosburg,
C. D. Vanderwal and E. J. Sorensen, J. Am. Chem. Soc., 2002,
124, 4552; J. D. White, P. R. Blakemore, E. A. Korf and
A. F. T. Yokochi, Org. Lett., 2001, 3, 413; (b) E. M. O’Brien,
B. J. Morgan and M. C. Kozlowski, Angew. Chem., Int. Ed., 2008,
47, 6877; C. L. Chandler and B. List, J. Am. Chem. Soc., 2008, 130,
6737; (c) J. Matsuo, K. Takeuchi and H. Ishibashi, Org. Lett.,
2008, 10, 4049; A. G. Myers and K. R. Condroski, J. Am. Chem.
Soc., 1993, 115, 7926; A. G. Myers and K. R. Condroski, J. Am.
Chem. Soc., 1995, 117, 3057; (d) P. Magnus, M. Giles, R. Bonnert,
G. Johnson, L. McQuire, M. Deluca, A. Merritt, C. S. Kim and
N. Vicker, J. Am. Chem. Soc., 1993, 115, 8116; (e) J. R. Scheerer,
J. F. Lawrence, G. C. Wnag and D. A. Evans, J. Am. Chem. Soc.,
2007, 129, 8968; (f) C. Blaszykowski, Y. H. Harrak, M.-H.
Goncalves, J.-M. Cloarec, A.-L. Dhimane, L. Fensterbank and
M. Malacria, Org. Lett., 2004, 6, 3771; G. T. Sasaki,
K. Kanematsu and A. Kondo, J. Chem. Soc., Perkin Trans. 1,
1976, 2516.
Scheme 2 Preparation of macrocyclic diketoamine 12.
3 For selected general reviews on the Mannich reaction see:
M. Arend, B. Westermann and N. Risch, Angew. Chem., Int.
Ed., 1998, 37, 1044; B. E. Maryanoff, H.-C. Zhang, J. H. Cohen,
I. J. Turchi and C. A. Maryanoff, Chem. Rev., 2004, 104, 1431;
L. E. Overman and D. J. Ricca, in Comprehensive Organic
Synthesis, ed. B. M. Trost and I. Fleming, Pergamon, Oxford,
1991, vol. 2, p. 1007.
4 TAM processes have been previously considered in the synthesis of
azapolycyclic alkaloids but were not implemented, see:
C. H. Heathcock, E. Kleinman and E. Binkley, J. Am. Chem.
Soc., 1982, 104, 1054.
5 There is precedent for TAM processes in the form of a tandem
cationic aza-Cope/Mannich cyclization involving a macrocyclic
intermediate, see: L. E. Overman, M. Sworin and R. M. Burk,
J. Org. Chem., 1983, 48, 2685.
6 For a recent review concerning total syntheses of the cylindricines
and lepadiformine alkaloids, see: S. M. Weinreb, Chem. Rev., 2006,
106, 2531; See also: T. Shibuguchi, H. Mihara, A. Kuramochi,
S. Sakuraba, T. Ohshima and M. Shibasaki, Angew. Chem., Int.
Ed., 2006, 45, 4635.
Scheme 3 Preparation of tricycle 13 via a TAM reaction.
proton at C-10 and one of the protons at C-4, which is possible
only for the cis arrangement (Fig. 2).13
In conclusion, the first example of a TAM reaction on a
macrocyclic diketoamine was used as the key step to accom-
plish an expeditious synthesis of tricyclic pyrroloquinoline
derivative 13.14 This methodology represents a new entry to
the construction of complex polycyclic alkaloids from readily
available macrocycle precursors; this powerful strategy is
currently being applied to the enantioselective total synthesis
of related target molecules.
This work was supported by the Portuguese Foundation for
Science and Technology and by the Lundbeck Foundation.
The spectra at 800 MHz were obtained on the Bruker Avance
800 spectrometer of the Danish Instrument Center for NMR
Spectroscopy of Biological Macromolecules.
7 For selected reviews on macrocyclizations, see: C. Roxburgh,
Tetrahedron, 1995, 51, 9767; I. Paterson and R. D. Norcross,
Chem. Rev., 1995, 95, 2041; A. S. Williams, Synthesis, 1999, 10,
1707.
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8 An alternative approach for the preparation of macrocycle 12
based on RCM of dienes 17 and 18 was initially pursued. These
results were presented at the 5th International Symposium on
Transition Metals in Organic Synthesis, Glasgow, 2004, Poster
no. 54.
solvent. The 1H and 13C spectra were referenced to this solvent
with resonances at dH = 7.16 ppm and dC = 128.39 ppm,
respectively. The resonance assignments were obtained using 1D
1H and 13C spectra in combination with 2D DQF-COSY, gHSQC,
gH2BC and gHMBC spectra. 2D NOESY spectra were used for
the assignment of the stereochemistry
9 N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Satoh and
A. Suzuki, J. Am. Chem. Soc., 1989, 111, 314.
10 For selected reviews on the Suzuki–Miyaura cross-coupling, see:
N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457;
S. R. Chemler, D. Trauner and S. J. Danishefsky, Angew. Chem.,
Int. Ed., 2001, 40, 4544.
11 For a leading reference concerning synthetic approaches to
8-membered rings, see: N. A. Petasis and M. A. Patane, Tetrahedron,
1992, 48, 5757.
12 In addition, the tricyclic structure of ketoamine 13 was confirmed
by X-ray crystallography of the corresponding picrate but the
relative stereochemistry could not be securely assigned by this
method due to the twinned nature of the crystals.
13 All spectra were acquired on a Bruker Avance 800 MHz spectro-
meter using standard pulse sequences. Benzene-d6 was used as the
14 Evans and Scheerer have reported attempts on a similar TAM
reaction to access the alkaloid clavolonine, see: D. A. Evans and
J. R. Scheerer, Angew. Chem., Int. Ed., 2005, 44, 6038.
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This journal is The Royal Society of Chemistry 2009
1890 | Chem. Commun., 2009, 1888–1890