Diene-transmissive cycloadditions: Control of monocycloaddition by self-assembly on a lewis acid template

Article abstract of DOI:10.1021/ol062869d

The sequential control of diene-transmissive Diels-Alder reactions to expand their versatility for natural product synthesis and the preparation of diversity oriented libraries is described. Self-assembly of the components (trienol 5 and methyl acrylate) via a Lewis acid template proceeds with regio-, diastereo-, and enantioselective [(S)-BINOL added] control to the monoadduct. In contrast, no cycloaddition reaction occurred at 22°C in the absence of catalyst. This protocol obliterates the necessity of tether installation for an intramolecular cyclization.

Full text of DOI:10.1021/ol062869d

ORGANIC
LETTERS
2
007
Vol. 9, No. 4
15-618
Diene-Transmissive Cycloadditions:
Control of Monocycloaddition by
Self-Assembly on a Lewis Acid
Template
6
Michael Santos Souweha, Akram Arab, Megan ApSimon, and Alex G. Fallis*
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie, Ottawa, Ontario,
Canada K1N 6N5
afallis@science.uottawa.ca
Received November 26, 2006
ABSTRACT
The sequential control of diene-transmissive Diels−Alder reactions to expand their versatility for natural product synthesis and the preparation
of diversity oriented libraries is described. Self-assembly of the components (trienol 5 and methyl acrylate) via a Lewis acid template proceeds
with regio-, diastereo-, and enantioselective [(S)-BINOL added] control to the monoadduct. In contrast, no cycloaddition reaction occurred at
22
°
C in the absence of catalyst. This protocol obliterates the necessity of tether installation for an intramolecular cyclization.
3
Cross-conjugated trienes ([3]dendralenes) are versatile pre-
cursors for diene-transmissive (tandem) intermolecular Di-
els-Alder cycloadditions. Sequential cycloadditions can
intermolecular reaction. Another possibility employs dieno-
philes in which the cycloaddition rates differ significantly
4
(Scheme 1, eq b). Schreiber et al. employed a triene
1
afford eight rings directly (quinone, cyclopentadiene).
approach for a library of 29 000 molecules and noted that
chlorine and methyl substitution on the dienophile encour-
aged single cycloadditions.
Substituted [3]dendralenes can be prepared readily from the
exclusive γ addition to carbonyl groups followed by elimina-
tion of water.1 With reactive dienophiles, the tandem
reaction predominates (Scheme 1, eq a).
a,2
Consequently, it is a challenge to control the monoaddition
of different dienophiles in a selective manner when both
cyclizations are intermolecular. One solution is to employ
an intramolecular cycloaddition initially followed by an
Scheme 1. Reaction Pathway for Cross-Conjugated Trienes
([3]Dendralenes)
(
1) (a) Woo, S.; Squires, N.; Fallis, A. G. Org. Lett. 1999, 1, 573-575.
(
b) For [4]dendralene, see: Payne, A. D.; Willis, A. C.; Sherburn, S. J.
Am. Chem. Soc. 2005, 127, 12188-12189. For related examples, see: Hopf,
H. Classics in Hydrocarbon Chemistry; Wiley-VCH: New York, 2000; pp
2
53-260. (c) Miller, N. A; Willis, A. C.; Paddon-Row, M. N.; Sherburn,
M. S. Angew. Chem., Int. Ed. 2006, Early View.
2) Hirashita, T.; Inoue, S.; Yamamura, H.; Kawai, M.; Araki, S. J.
Organomet. Chem. 1997, 549, 305-309.
(
1
0.1021/ol062869d CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/26/2007

The trienes 4 and 5 required for our study were generated
5
from the protected aldehyde 2 followed by pentadienyl
Table 1. Thermal Diels-Alder Reactions of 4 with Chlorine
and Methyl-Substituted Dienophiles
indium addition and elimination of water as illustrated in
Scheme 2.16
Scheme 2. Synthesis of Cross-Conjugated Trienol 5 from
Pentadienyl Indium Condensation with 2
Table 1 summarizes our results with the silyl-protected
triene 4; however, the yields are low to nonexistent (entries
6
2
and 5), and the substitution pattern in the best example
with tetrachloroquinone (entry 1) is not very synthetically
useful.
A significant improvement would be to develop a tem-
porary tether which could also introduce useful functionality
for subsequent transformations and provide a general solution
to eq b in Scheme 1. An attractive possibility involved a
Lewis acid catalyzed and self-assembled Diels-Alder cy-
cloaddition (LACASA-DA) in which magnesium, aluminum,
or a related metal could complex with the unprotected triene
alcohol and the ester dienophile to provide a temporary
template to control the in situ intramolecular Diels-Alder
a
Isolated yields. b Isolated as a mixture of regioisomers.
demonstrate, as anticipated, that the reactions of the silyl-
protected trienol 4 and methyl acrylate were unsatisfactory
with Et AlCl/n-pentanol or MeMgBr/n-pentanol and there
2
was no reaction in the absence of Lewis acid. A blank reac-
tion (entry 3) with 5 and methyl acrylate at 23 °C also failed.
In contrast, the reaction of alcohol 5 with diethylaluminum
chloride and methylmagnesium bromide/n-pentanol7 af-
forded yields of 74% and 85%, respectively (entries 4 and
7
reaction. In addition, this protocol holds promise to control
the chemo-, regio- stereo-, and enantioselectivity of the
reaction.
,8
5
). These latter results demonstrated the utility of this
For silyl ether 4 (Table 2), n-pentanol was added to mimic
the presence of an alkoxide-Lewis acid intermediate and
create conditions similar to the successful cycloadditions
below. The first two examples (entries 1 and 2) in Table 2
approach.
It was also of interest to examine some related dienophiles
to ascertain the selectivity that could be achieved. Examples
of sequential cycloadditions under LACASA conditions with
one equivalent of dienophile afforded concomitant generation
of the lactone 8 or 9 in the case of dimethyl fumarate and
maleic anhydride (Table 3, entries 1 and 2).
(
3) (a) Woo, S.; Legoupy, S.; Parra, S.; Fallis, A. G. Org. Lett. 1999, 1,
1
8
013-1016. (b) Clay, M. D.; Riber, D.; Fallis, A. G. Can. J. Chem. 2005,
3, 559-568.
(4) Kwon, O.; Park, S. B.; Schreiber, S. L. J. Am. Chem. Soc. 2002,
1
24, 13402.
5) Smith, A. B., III; Fox, R. J.; Vanecko, J. A. Org. Lett. 2005, 7, 3099-
102.
Consistent with the examples above, DA reaction of 5 with
dimethyl fumarate afforded lactone 8 with complete chemo-
(
3
(
6) Cebrowski, P., unpublished results.
(
7) For key references on Lewis acid catalyzed and self-assembled Diels-
(8) Addition of n-pentanol has been shown to facilitate cycloadditions
involving dienols, presumably due to the speciation of the Mg(II) salts
formed. See: (a) Coates, G. E.; Ridley, D. J. Chem. Soc., Chem. Commun.
1966, 560-561. (b) Moseley, P. T.; Shearer, H. M. M. J. Chem. Soc., Chem.
Commun. 1968, 279-280.
Alder reactions (LACASA-DA), see: (a) Ward, D. E.; Abaee, M. S. Org.
Lett. 2000, 2, 3937-3940. (b) Ward, D. E.; Souweha, M. S. Org. Lett.
005, 7, 3533-3536. (c) For a templated copper dimerization, see: Heuft,
2
M. A.; Fallis, A. G. Angew. Chem., Int. Ed. 2002, 41, 4520-4523.
616
Org. Lett., Vol. 9, No. 4, 2007

Table 2. Trial Diels-Alder Reactions of 4 or 5 with Methyl
Acrylate
Table 3. Monocyclization via LACASA Reactions of 5 with
Various Dienophiles
yield
entry
1
diene
conditions
(%)a
4
Et2AlCl, n-pentanol
2
3 °C, 2 d
MeMgBr, n-pentanol
3 °C, 2 d
10
0
2
4
2
b
3
4
5
5
23 °C, 2 d
Et2AlCl
0
2
3 °C, 1 d
MeMgBr, n-pentanol
3 °C, 1 d
74
85
5
5
2
a
Isolated yields. b Only starting material detected in the crude H NMR
1
spectrum.
and stereoselectivity. The yield with maleic anhydride is
poor, but the cycloaddition afforded a single adduct. The
reversal in chemoselectivity (i.e., 10:11) observed for entries
3
and 4 was not anticipated but provides additional experi-
mental support for the importance of the Lewis acid complex
and its promotion of the initial cycloaddition. Consequently,
minor variation of the experimental conditions expands the
synthetic utility of this protocol. The tetracyclic structure of
9
adduct 11 was confirmed by X-ray analysis (Figure 1).
The scope of this procedure would be enhanced if the
LACASA-DA reaction of 5 with methyl acrylate could be
rendered enantioselective. These results are summarized in
a
Isolated yields.
Scheme 2, and clearly, trimethyl aluminum by itself is not a
suitable catalyst. The cycloaddition became enantioselective
with the addition of (S)-BINOL (1 equiv) in the presence of
Me
3
Al to afford 80% yield of 7 with a modest ee of 75%
(Scheme 3). The presence of (S)-BINOL accelerates the
reaction, but the factors responsible are still unclear.
Recently, several synthetic examples or studies toward a
target utilized a stereoselective Lewis acid tethered Diels-
Alder reaction as an important step for natural product
10
11
construction. These include Abyssomicin C, Penostatin F,
Scheme 3. Enantioselective LACASA-DA Reaction of 5 with
Methyl Acrylate to Lactone 7
Figure 1. X-ray structures of adducts 11, 12a, and 12b.
Org. Lett., Vol. 9, No. 4, 2007
617

maleimide provided the tetracyclic heterocycle 12 in 93%
yield with good diastereoselectivity (dr ) 7:1) (Scheme 4).
These results were confirmed by X-ray analysis (Figure 1)9
and revealed the bowl-shaped motif of the minor isomer
Scheme 4. Sequential Double Diels-Alder of
Cross-Conjugated Trienol 5 with Methyl Acrylate and
N-Methylmaleimide
1
2b.
In summary, the application of an initial mono-LACASA-
DA reaction in a controlled, stepwise, sequential cycload-
dition sequence expands the potential of this triene chemistry
for the preparation of complex polycyclic frameworks.
Currently, we are applying this chemistry toward a variety
of synthetic objectives.
and Vinigrol.12 Another interesting and synthetically useful
variant is to follow the initial mono-LACASA-DA reaction
with a second intramolecular [4+2] cycloaddition for a more
complex natural product skeleton. In addition, the monocy-
cloaddition adduct may now be employed in a double Diels-
Alder reaction from the cross-conjugated triene 5 in a
stepwise fashion. Thus, exposure of lactone 7 to N-methyl-
Acknowledgment. We are grateful to the Natural Sci-
ences and Engineering Research Council of Canada (NSERC)
for financial support of this research and to I. Korobkov
(University of Ottawa) for X-ray analysis.
Supporting Information Available: Experimental de-
tails, spectral characterization, and CIF data files for these
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
9) CCDC 633006-633008 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
OL062869D
(10) (a) Nicolaou, K. C.; Harrison, S. T. J. Am. Chem. Soc. 2007, 129,
429-440. (b) Nicolaou, K. C.; Harrison, S. T. Angew. Chem., Int. Ed. 2006,
45, 3256-3260. (c) Zografos, A. L.; Yiotakis, A.; Georgiadis, D. Org. Lett.
2005, 7, 4515-4518. (d) Rath, J.-P.; Kinast, S.; Maier, M. E. Org. Lett.
2005, 7, 3089-3092.
(11) Barriault, L.; Ang, P. J. A.; Lavigne, R. M. A. Org. Lett. 2004, 6,
1317-1319.
(12) Morency, L.; Barriault, L. J. Org. Chem. 2005, 70, 8841-8853.
618
Org. Lett., Vol. 9, No. 4, 2007