A masked-alkene metathesis-based synthesis of isopulo'upone

Article abstract of DOI:10.1016/j.tetlet.2011.06.082

A metathesis-based formal synthesis of (±)-isopulo'upone has been completed featuring a masked olefin metathesis/elimination sequence followed by an intramolecular Diels-Alder reaction to construct the 5,6-fused bicyclic core.

Full text of DOI:10.1016/j.tetlet.2011.06.082

Tetrahedron Letters 52 (2011) 4494–4496
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A masked-alkene metathesis-based synthesis of isopulo’upone
⇑
Kyle P. Carter, Daniel J. Moser, Jennifer M. Storvick, Gregory W. O’Neil
Department of Chemistry, Western Washington University, Bellingham, WA 98225-9170, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A metathesis-based formal synthesis of ( )-isopulo’upone has been completed featuring a masked olefin
metathesis/elimination sequence followed by an intramolecular Diels–Alder reaction to construct the
5,6-fused bicyclic core.
Received 17 May 2011
Revised 15 June 2011
Accepted 20 June 2011
Available online 28 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Olefin metathesis
b-Acyloxysulfone
Chemoselectivity
Intramolecular Diels–Alder
Natural products
Olefin metathesis has rapidly emerged as one of the most versa-
tile carbon–carbon bond forming reactions used in both organic
and polymer synthesis.1 The introduction of increasingly reactive
and robust catalysts has made it routine to retrosynthetically
envision using metathesis to forge any number of alkenes present
in a wide range of structurally diverse compounds. Care must be
taken, however, when considering metathesis reactions in polyene
systems due to problems associated with chemoselectivity and/or
the possibility of unwanted competing metathesis processes.2 This
has effectively limited metathesis applications in polyene
synthesis to a selected number of typically sterically3 and/or elec-
tronically4 biased arrays. An alternative solution is to ‘mask’ one or
more alkenes as an alkene-precursor, that is, inert to metathesis to
be revealed post-metathesis (Fig. 1).5
Our group has been investigating the use of b-acyloxysulfones,
well known intermediates in the Julia-Lythgoe olefination,6 as
suitably masked alkenes that allow for a metathesis approach to
polyene systems difficult to obtain using standard metathesis tech-
nology. Recently we described an acyloxysulfone cross-metathesis/
reductive-elimination reaction sequence for the preparation of
1,6- and 1,7-dienes, compounds that are particularly challenging
to prepare due to a competing rapid ring closure.7 It was antici-
pated that this general strategy could be extended to the synthesis
of triene subunits. Specifically, compounds of type 1 were expected
to undergo chemoselective cross-metathesis reactions,8 the extent
of selectivity presumably dependent on the nature of R1 and R2
(Scheme 1).9 Post-metathesis reductive elimination of the acyloxy-
sulfone would then afford trienes of type 2.
To test this, several dienyl-acyloxysulfones were prepared by
the addition of the lithium anion of sulfone 310 to an appropriate
aldehyde (Scheme 2). Acylation with either acetyl- or benzoylchlo-
ride gave the corresponding acetyloxy- and benzoyloxysulfones
4–7, respectively.
As outlined in Table 1, a chemoselective cross-metathesis
reaction could be achieved for each of the substrates using the
Grubbs’ second-generation catalyst (8)11 in the presence of cis-
1,4-diacetoxy-2-butene (Scheme 3). Reductive elimination using
12
either Na/Hg or SmI2 then completed our metathesis approach
to the all-trans 1,3,8-trienes 9–12. In general, for R1 – H (entries
4–6) metathesis was only observed at the monosubstituted alkene
irrespective of the nature of R2. Both elimination protocols afforded
the corresponding triene product in comparable yield (compare
entries for 4b). When R1 = H (7), at elevated temperatures a
mixture of products was obtained that included the bis-metathesis
adduct 13. Larger amounts of 13 were observed from the reaction
of the acetyloxysulfone (R2 = CH3) derivative, the larger benzoyl
group (R2 = Ph) presumably affording greater steric deactivation
of the proximal olefin.13 Lowering the reaction temperature and
using benzoyloxysulfone 7b promoted a chemoselective metathe-
sis reaction affording upon reductive elimination triene 12. It
should be noted that this protocol allows for the introduction of
base-sensitive functionality that would otherwise not be tolerated
using standard Julia olefination conditions.14
1,3,8-Trienes represent important intramolecular Diels–Alder
(IMDA) substrates used to generate a variety of fused-5,6-bicyclic
systems.15 As a demonstration of the utility of this sequence in
the context of natural product synthesis, we set out to prepare
isopulo’upone (14),16
a
marine toxin isolated in 1993 from
⇑
Corresponding author. Tel.: +1 360 650 6283; fax: +1 360 650 2826.
E-mail address: oneil@chem.wwu.edu (G.W. O’Neil).
mollusks Navanax inermis and Bulla Gouldiana that has attracted
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.082

K. P. Carter et al. / Tetrahedron Letters 52 (2011) 4494–4496
4495
Figure 2. Isopulo’upone retrosynthesis.
Figure 1. Masked-alkene metathesis.
Scheme 1. Masked-alkene metathesis triene synthesis.
Scheme 3. Chemoselective cross-metathesis.
Scheme 2. Masked triene substrate synthesis.
Table 1
1,3,8-Triene synthesis via Scheme 3
Entry
R1
R2
Metathesis
Elimination
Yielda
(9–12:13)b
4a
4b
4b
5a
5b
6a
6b
7a
7b
7b
Ph
Ph
Ph
n-Pent
n-Pent
CH3
CH3
H
CH3
Ph
Ph
CH3
Ph
CH3
Ph
CH3
Ph
Ph
A
A
A
A
A
A
A
A
A
B
C
D
C
C
D
C
D
C
D
D
74
68
72
83
64
80
70
74
67
65
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
>10:1
65:35
83:17
>10:1
Scheme 4. Reagents and conditions: (1) (a) 3, BuLi, THF; (b) BzCl, pyr., DCM, 80%
(two-steps); (2) crotonaldehyde, 7, then MeMgBr, 84%; (3) (a) Na/Hg, THF/MeOH;
(b) Dess-Martin [O]; (4) PhMe, 110 °C, 36% (three-steps); (5) (a) DDQ, 60%; (b) two-
steps, Ref. 17b.
H
H
Metathesis A: cis-1,4-diacetoxy-2-butene, 8, PhMe, 80 °C; B: cis-1,4-diacetoxy-2-
butene, 8, DCM, rt. Elimination C: Na/Hg, MeOH, rt; D: SmI2, DMPU, À78 °C.
a
Isolated yield for two-steps.
b
Ratios determined by 1H NMR.
provide 19 as the methyl enone intermediate proved sufficiently
sensitive to reductive elimination conditions. In the event,
sodium–mercury mediated elimination followed by Dess–Martin
oxidation gave 19 in sufficient purity that it could be taken directly
into the Diels–Alderreaction withoutadditional purification. Simply
heating a solution of triene 19 in toluene to 110 °C at ambient pres-
sureresultedinasmoothintramolecularDiels–Alderreaction,giving
compound 20 with exclusive endo-selectivity as detectable by 1H
NMR.19 Removal of the PMB-protecting group with DDQ then bi-
sected the route previously described by Evans,17b the synthesis of
( )-isopulo’upone completed in three-steps from 20.
An acyloxysulfone metathesis/elimination reaction sequence
has been extended to include the synthesis of 1,3,8-trienes featur-
ing a chemoselective cross-metathesis reaction. The acyloxysulfone
served to not only mask an internal alkene thereby preventing ring-
closure, but also to sterically deactivate a neighboring olefin toward
metathesis. This approach allowed for the rapid assembly of the
the interest of the synthetic community (Fig. 2).17 It was thought
that our acyloxysulfone metathesis/reductive elimination strategy
might provide rapid entry to a triene of type 15 that could be used
to construct the isopulo’upone core.
Our synthesis began from known PMB-protected aldehyde 1618
asoutlinedinScheme4.Additionofthelithiumanionofsulfone3fol-
lowedbyacylationwith benzoylchloride gavebenzoyloxysulfone17
in 64% yield as a ꢀ1:1 mixture of diastereomers. Benzoyloxysulfone
17 underwent a highly chemoselectivecross-metathesis reaction
with crotonaldehyde affording an intermediate aldehyde that was
immediately treated with methylmagnesium bromide to give com-
pound 18 as a complex mixture of stereoisomers. To complete the
synthesis of 19, it was necessary to first reductively eliminate the
benzoyloxysulfone followed by oxidation of the alcohol to the
desired methyl ketone. Switching the order of these steps failed to

4496
K. P. Carter et al. / Tetrahedron Letters 52 (2011) 4494–4496
Fürstner, A.; Nevado, C.; Waser, M.; Tremblay, M.; Chevrier, C.; Teply, F.; Aissa,
C.; Moulin, E.; Mueller, O. J. Am. Chem. Soc. 2007, 129, 9150–9161.
3. Bouzbouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6, 3465–3467.
4. (a) Funk, T. W.; Efskind, J.; Grubbs, R. H. Org. Lett. 2005, 7, 187–190; (b) Ferrié,
L.; Amans, D.; Reymond, S.; Bellosta, V.; Capdeville, P.; Cossy, J. J. Organomet.
Chem. 2006, 691, 5456–5465.
core of the natural product isopulo’upone. Ongoing efforts are
aimed at highlighting the utility of an acyloxysulfone metathesis/
elimination strategy for the preparation of a range of polyene
systems with applications in natural product synthesis.
5. For examples of masked alkene metathesis in synthesis see: (a) Barluenga, S.;
Dakas, P.-Y.; Ferandin, Y.; Meijer, L.; Winssinger, N. Angew. Chem., Int. Ed. 2006,
45, 3951–3954; (b) Baird, L. J.; Timmer, M. S. M.; Teesdale-Spittle, P. H.; Harvey,
J. E. J. Org. Chem. 2009, 74, 2271–2277.
6. Dumeunier, R.; Markó, I. E. The Julia Reaction. In Modern Carbonyl Olefination;
Takeshi, T., Ed.; Wiley-VCH: Weinheim, 2004.
7. O’Neil, G. W.; Moser, D. J.; Volz, E. O. Tetrahedron Lett. 2009, 50, 7355–7357.
8. For a recent review see: Nolan, S. P.; Clavier, H. Chem. Soc. Rev. 2010, 39, 3305–
3316.
9. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360–11370.
Acknowledgments
Financial support from Western Washington University, M.J
Murdock Charitable Trust and Research Corporation departmental
development grant, and the Petroleum Research Fund adminis-
tered by the American Chemical Society (49499-UNI) is gratefully
acknowledged.
10. Yang, H.; Carter, R. G. Org. Lett. 2010, 12, 3108–3111.
11. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29.
12. (a) Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60, 3194–3204;
(b) Marko, I. E.; Murphy, F.; Kumps, L.; Ates, A.; Touillaux, R.; Craig, D.;
Carballares, S.; Dolan, S. Tetrahedron 2001, 57, 2609–2619.
13. Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1, 1123–1125.
14. For additional examples see Ref. 7.
15. For a recent review see: Juhl, M.; Tanner, D. Chem. Soc. Rev. 2009, 38, 2983–
2992.
Supplementary data
Supplementary data (complete analytical data and experimen-
tal procedures for new compounds 9–12, 17, 19, 20 are provided)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.06.082.
16. Spinella, A.; Alvarez, L. A.; Cimino, G. Tetrahedron 1993, 49, 3203–3210.
17. (a) Matikainan, J.; Kaltia, S.; Hase, T. Synth. Commun. 1995, 25, 195–201; (b)
Evans, D. A.; Johnson, J. S. J. Org. Chem. 1997, 62, 786–787.
18. Nanda, S. Tetrahedron Lett. 2005, 46, 3661–3663.
References and notes
1. (a) Ivin, K. J.; Mol, J. C. Olefin Metathesis and Metathesis Polymerization;
Academic Press: San Diego, 1997; Alkene Metathesis in Organic Synthesis;
Fürstner, A., Ed.; Springer: Berlin, 1998.
19. See Supplementary data for details.
2. For select applications in natural product synthesis see: (a) Mitton-Fry, M. J.;
Cullen, A. J.; Sammakia, T. Angew. Chem., Int. Ed. 2007, 46, 1066–1070; (b)