A concise Diels–Alder strategy leading to congeners of the ABC ring system of the marine alkaloid ‘upenamide

Article abstract of DOI:10.1016/j.tetlet.2016.05.102

A second-generation approach to the BC spirocycle of ‘upenamide is reported. Central to the synthesis is an endo selective Diels–Alder reaction between 1-(t-butyldimethylsiloxy)-1,3-butadiene and bromomaleic anhydride followed by a radical mediated allylation of the ring fusion bromide. Functional group manipulation provides three (9–11) advanced synthetic intermediates ready for coupling with the remaining half (DE bicycle) of ‘upenamide.

Full text of DOI:10.1016/j.tetlet.2016.05.102

Accepted Manuscript
A concise Diels-Alder strategy leading to congeners of the ABC ring system of
the marine alkaloid ‘upenamide
Marta E. Wenzler, Bruce J. Melancon, Gary A. Sulikowski
PII:
S0040-4039(16)30645-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.102
TETL 47721
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
11 May 2016
27 May 2016
Please cite this article as: Wenzler, M.E., Melancon, B.J., Sulikowski, G.A., A concise Diels-Alder strategy leading
to congeners of the ABC ring system of the marine alkaloid ‘upenamide, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.05.102
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A concise Diels-Alder strategy leading to
congeners of the ABC ring system of the
marine alkaloid upenamide
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Marta E. Wenzler, Bruce J. Melancon and Gary A. Sulikowski*

1
Tetrahedron Letters
A concise Diels-Alder strategy leading to congeners of the ABC ring system of the
marine alkaloid ‘upenamide
Marta E. Wenzler, Bruce J. Melancon and Gary A. Sulikowski*
Department of Chemistry, Institute of Chemical Biology, Vanderbilt University, Nashville, TN 77842–3012, U.S.A
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A second-generation approach to the BC spirocycle of ‘upenamide is reported. Central to the
synthesis is an endo selective Diels-Alder reaction between 1-(t-butyldimethylsiloxy)-1,3-
butadiene and bromomaleic anhydride followed by a radical mediated allylation of the ring
fusion bromide. Functional group manipulation provides three (9-11) advanced synthetic
intermediates ready for coupling with the remaining half (DE bicycle) of ‘upenamide.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Diels-Alder
quaternary stereocenter
Stereocontrol
hemiaminal
Staudinger reaction
In 2000 Scheuer and co-workers described the isolation and
structure elucidation of ‘upenamide, a unique macrocylic alkaloid
from the Indonesian sponge Echinochalina sp.1 The structure of
‘upenamide features a tricyclic and a bicyclic hemiaminal ring
system connected by an unsaturated macrocyclic core (Figure 1).
While a biosynthetic pathway leading to ‘upenamide can be
conceived based on comparison to structurally similar 3-
alkylpiperidine marine natural products such as the manzamines
and haliclonacyclamines, complete structural assignment of
‘upenamide awaits clarification by total synthesis.2,3
appropriately substituted cyclohexene (C ring) intermediates
(Scheme 1). As summarized in Scheme 1 our group used the
cycloadduct derived
from 1-(t-butyldimethylsiloxy)-1,3-
butadiene and 2-bromo-5-(methoxy)furan-2(5H)-one to access
aldehyde II by way of a six-step reaction sequence and vinyl
iodide III by way of the Takai olefination of II (Scheme 1).4b
The Taylor group produced aldehyde V, differing only silyl
protecting group relative to II, starting from cyclohexene IV.5c,d
Overall, a 12-step reaction sequence was required to advance IV
to imine VI.
Figure 1. Structure of ‘upenamide and advanced synthetic intermediates.
Our group4 and the Taylor3,5 group have developed synthetic
routes to key intermediates leading to an ABC tricyclic ring
system progenitor and DE bicyclic ring system.6 In assembling
the former structure, both our group and Taylor’s group took
advantage of stereocontrolled Diels-Alder reactions leading to
Scheme 1. Synthetic routes to upenamide BC spirocycle.
Common strengths of ours and Taylor’s synthetic routes are
the use of endo selective Diels-Alder reactions followed by

2
Tetrahedron
stereoselective alkylation reactions to install the three
contiguous stereocenters contained within the C ring of
‘upenamide including the central quaternary carbon. We
identified two significant problems in our approach to BC
spirocycle (II and III), namely the propensity of the C15
aldehyde to undergo epimerization (partly due to electrostatic
interaction with the C10 amide carbonyl) and, second, the
required adjustment of oxidation state of the C10 carbon. We
desired access to the equivalent of a differentiated bis-aldehyde
intermediate (cf. Figure 1, ABC tricyle precursor). With these
objectives in mind, we describe herein a simplified and expedient
approach to ABC tricycle precursors starting with a Diels-Alder
reaction between 1-(t-butyldimethylsiloxy)-1,3-butadiene and
bromomaleic anhydride.
Scheme 3. Synthesis of BC spirocycle and ABC tryicycle precursors 9-11.
In conclusion, we described a concise route leading to
advanced synthetic intermediates ready to serve as progenitors to
the ABC tricycle within the context of an‘upenamide total
synthesis. When compared to our earlier synthetic efforts the
described 9 to 11 step reaction sequence leading to intermediates
9-11 compare favorably.
Scheme 2. Synthesis of diol 5.
Acknowledgments
To our surprise bromomaleic anhydride (2) has found limited
utility in natural product synthesis (Scheme 1).7 We found the
Diels-Alder reaction between 1 and 2 to be quite facile to
affording crystalline adduct 3 in 76-80% yield as a single (endo)
This research was supported by the National Science
Foundation (CHE-1464864).
References and notes
isomer.
Radical
mediated
allylation
of
3
with
allyltributylstannane (AIBN, toluene, 90 °C, W, 45 min)8
provided desired 4a and 4b in 65 and 23% yield, respectively.9
Reduction of anhydride 4a to diol 5 was examined using a
variety of reducing reagents. Reduction of anhydride 4 with
lithium aluminum hydride produced triol 6 in 65-70% yield
accompanied by diol 5 (9% yield).10 Optimal conditions for
production of TBS ether 5 employed L-Selectride as the
reductant in THF at 0 °C to provide 5 in 43% yield without
observation of triol 6.
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Orthogonal protection of diol
5
allowed controlled
functionalization that was accomplished by tritylation of the less
hindered alcohol (Ph3Cl, Et3N, DMAP, DMF, 97%) followed by
acetylation (Ac2O, pyridine, 86%) of the remaining primary
alcohol to afford orthogonally protected triol 7. Hydroboration-
oxidation of the terminal alkene afforded a hydroxyl group
available for conversion to azide 8. The desired functional group
interconversion was readily achieved using diphenylphosrphoryl
azide and DBU. Removal of the acetate group released the
internal alcohol which following oxidation under Parikh-Doering
conditions gave aldehyde 9 in 72% yield. The key Staudinger
cyclization was affected using trimethylphosphine to give imine
10 in 98% yield. Removal of the trityl protecting group released
the remaining primary alcohol resulting in subsequent cyclization
to give aminal 11. Notably, advanced intermediates 9, 10 and 11
(Scheme 3) are of utility in advancing a total synthesis of
‘upenamide (cf. Figure 1).
7. Apponyi, M. A.; Bowie, J. H.; Skelton, B. W.; White, A. H. Aust. J. Chem.
2002, 55, 343-348.
8. Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829-5831.
9. Stereochemistry assigned based on nOe analysis of 4a and 4b.
10. For examples of loss of silyl protecting groups during LAH reduction,
see: (a) Wender, P. A.; Bi, F. C.; Brodney, M. A.; Gosselin, F. Org. Lett.
2001, 3, 2105-2108. (b) de Vries, E. F. J.; Brussee, J.; van der Gen, A. J.
Org. Chem. 1994, 59, 7133-7137.

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