Stable 5-substituted cyclopentadienes for the Diels-Alder cycloaddition and their application to the synthesis of palau'amine

Article abstract of DOI:10.1002/anie.200803344

(Chemical Equation Presented) Putting the brakes on a hydride shift: The incorporation of a 2-silyloxy group increases both the stability and reactivity of 5-substituted cyclopentadienes, thus facilitating their preparation and use (see scheme; Bz=benzyl, TBS=tert-butyldimethylsilyl). This approach has been applied to the synthesis of the E ring in the marine alkaloid palau'amine.

Full text of DOI:10.1002/anie.200803344

Angewandte
Chemie
DOI: 10.1002/anie.200803344
Diels–Alder Reactions
Stable 5-Substituted Cyclopentadienes for the Diels–Alder
Cycloaddition and their Application to the Synthesis of Palauꢀamine**
Jonathan Hudon, Timothy A. Cernak, James A. Ashenhurst, and James L. Gleason*
The Diels–Alder cycloaddition reaction is one of the most
fundamental synthetic transformations and has been the
cornerstone in countless total syntheses. Surprisingly, cyclo-
pentadiene, the most common diene employed in asymmetric
synthesis methods, is used only rarely in total synthesis.
Moreover, substituted variants are almost never used, with
the notable exception of the landmarksynthesis of the
prostaglandins by Corey et al.[1a] Substituted cyclopenta-
dienes, particularly those substituted at the 5 position, are
very attractive substrates as they lead to structures of high
complexity and can provide functional handles for further
Scheme 1. Synthesis of the stable 5-substituted cyclopentadiene 5.
Reagents and conditions: a) HCHO, HCO2H, TsOH; then NaOH
(43%, 55:45 regioisomers); b) 4-acetamido-2,2,6,6-tetramethyl-1-oxopi-
peridinium perchlorate; c) TBSCl, imid; then regioisomer separation
transformation.[2] The main obstacle to their use is the need to
prepare, isolate, and employ the diene at temperatures ꢀ 08C
to prevent a facile [1,5]-sigmatropic shift, which can lead to
mixtures of cycloadducts (e.g. Eq. (1); EWG = electron with-
(45% over 2 steps). imid=imidazole, Tf=trifluoromethanesulfonyl,
Ts =4-toluenesulfonyl.
developed by Bobbitt, and protection of a primary alcohol.[5,6]
Silyl enol ether formation from 4 may be accomplished under
either soft (R3SiOTf, NEt3) or hard (lithium diisopropyl-
amide, R3SiCl) enolization reaction conditions.[7] In this way,
the tert-butyldimethylsilyl (TBS), triethylsilyl, or trimethyl-
silyl enol ethers may be prepared, with the former being
preferred because of the increased hydrolytic stability of the
diene and the subsequent cycloadducts. In all cases, the cross-
conjugated diene is formed exclusively and may be isolated by
a simple extractive workup and used directly in subsequent
cycloaddition reactions.
Diene 5 undergoes a [1,5]-sigmatropic shift of a hydrogen
atom at a considerably slower rate than normal 5-substituted
cyclopentadienes. Monitoring a solution of 5 in [D6]benzene
by 1H NMR spectroscopy demonstrated that it rearranges
with a half-life of 37 hours at 238C, and it was found that 5
could be stored at À208C for up to a month with no significant
rearrangement or dimerization observed. By contrast, 5-
methylcyclopentadiene (8) is reported to rearrange with a
half life of only 1.2 hours at 208C, thus indicating a greater
than 30-fold increase in stability upon incorporation of the 2-
silyloxy group.[8] Although the rearrangement product could
not be separated from 5, its 1H NMR spectrum, the isolation
of enone 7 upon mild acid workup, and its regeneration upon
enolsilylation of 7 were fully consistent with 6 as the major
rearrangement product. The increased stability of 5 undoubt-
edly arises from donation of electron density from the silyloxy
substituent.[9] Density functional calculations at the B3LYP/6-
31G* level showed a reasonable correlation between the
predicted activation enthalpy for a [1,5]-sigmatropic shift and
the electron donor ability of substituents at the 2 position of
the diene (See the Supporting Information for details).[10,11]
drawing group).[1–3] Although this problem may be circum-
vented in certain instances by removing the offending hydro-
gen atom, no direct solution to this long-standing problem has
been reported.[4] Herein, we demonstrate that the incorpo-
ration of a 2-silyloxy group greatly stabilizes 5-substituted
cyclopentadienes toward [1,5]-sigmatropic shifts, for the first
time making their use practical for Diels–Alder cycloaddition
reactions conducted at room temperature. We further dem-
onstrate the potential of this method by applying it to the
synthesis of a key ring in the marine alkaloid palauꢀamine.
5-Substituted cyclopentadiene 5 is easily prepared by
enolsilylation of 4-substituted cyclopentenone 4 (Scheme 1).
The latter is prepared from cyclopentadiene by an easily
scalable, three-step procedure involving a Prins reaction with
formaldehyde, selective allylic oxidation with the reagent
[*] J. Hudon, T. A. Cernak, J. A. Ashenhurst, Prof. J. L. Gleason
Department of Chemistry
McGill University
801 Sherbrooke St. West, Montreal, QC, H3A 2K6 (Canada)
Fax: (+1)514-398-3797
E-mail: jim.gleason@mcgill.ca
[**] This work was supported by the NSERC. J.H. thanks the NSERC and
the FQRNT for predoctoral fellowships. T.A.C. thanks the FQRNT for
a predoctoral fellowship. J.A.A. thanks the Walter C. Sumner
Foundation for a predoctoral fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803344.
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Diene 5 proved to be highly competent in Diels–Alder
approach of the dienophile is from the face opposite to the 5-
silyloxymethyl group, and provided endo/exo ratios compa-
rable to those observed with cyclopentadiene.[12]
Diene 5 is compatible with the use of mild Lewis acids.
The cycloaddition of 5 with methacrolein proceeded very
slowly at room temperature, and afforded only a 35% yield of
isolated 10i after 43 hours (Scheme 2). However, the use of
6% Eu(fod)3 as a catalyst allowed the reaction to proceed to
completion in just 3.5 hours at 238C, and gave the cycloadduct
10i in 74% yield as a 4:1 mixture of exo/endo isomers.[13]
cycloadditions with a wide variety of dienophiles under very
mild reaction conditions ([5] = 0.5m, [dienophile] = 1.5m,
CH2Cl2, 238C; Table 1). The cycloadducts were isolated as
the versatile silyl enol ethers after chromatography on neutral
alumina (Brockman Grade IV). Cycloaddition reactions were
rapid with dienophiles such as benzoquinone (Table 1,
Table 1: Diels–Alder cycloaddition reactions of cyclopentadiene 5.[a]
Entry Dienophile
Product
t [h]
Yield [%][b] endo/exo
1
0.15
66
79
>95:5
>95:5
2
0.5
Scheme 2. Lewis acid catalysis with diene 5. fod=6,6,7,7,8,8,8-hepta-
fluoro-2,2-dimethyl 3,5-octanedionate.
3
4
0.75
2
79
71
–
Diene 5 offers an additional advantage over simple 5-
substituted cyclopentadienes in that it is chiral and, as can be
seen in Table 1, it provides excellent regioselectivity and
diastereofacial control with respect to both the 2- and 5-
substituents. Diene 5 may be prepared in an enantiomerically
enriched form from 11 (94 Æ 1% ee; Scheme 3), which is
available from the procedure developed by Hodgson et al.,[14]
by using selective allylic oxidation and silylation.[6] Cyclo-
addition of enantiomerically enriched 5 with N-methylmalei-
mide and subsequent selective desilylation of the enol ether
afforded ketone 12 as a single diastereomer in 95 Æ 1% ee,
thus indicating that the diene does not racemize during
formation nor during successive reversible [1,5]-sigmatropic
shifts.
1.6:1
5
4
67
2:1
6
7
3.5
73
68
3.2:1
1.2:1
20
The concept of stabilization by a silyloxy group is not
limited to diene 5. Diene 6, produced cleanly by enolsilylation
of enone 7, is even more stable than 5 to [1,5]-sigmatropic
shifts (Scheme 4).[15] Exposure of 6 to N-methlymaleimide for
30 minutes under our standard cycloaddition reaction con-
ditions afforded endo cycloadduct 13 in 68% yield as a single
regio- and diastereomer. Presumably, this silyloxy stabiliza-
tion can be incorporated in other diene substitution patterns.
As a demonstration of the synthetic utility of 5, we applied
it to the significant synthetic challenge presented by the
oroidin alkaloid palauꢀamine.[16] This marine alkaloid pos-
8
24
65
2.3:1
[a] Reactions were carried out with excess dienophile (3 equiv) in CH2Cl2
with a diene concentration of 0.5m at 238C. [b] Overall yields of isolated
products (endo + exo) starting from enone 4.
entry 1), N-methylmaleimide (entry 2), and dimethylacety-
lene dicarboxylate (entry 3), as well as being highly endo
selective in the first two cases. Cycloaddition reactions with
slightly less reactive dienophiles such as acrolein (entry 4),
methyl vinyl ketone (entry 5), and chloroacrylonitrile
(entry 6) also proceeded efficiently at room temperature in
just 2–4 hours. Finally, the reaction of 5 with acrylonitrile
(entry 7) and methyl acrylate (entry 8) also afforded cyclo-
adducts in good yields at room temperature, even with
extended reaction times (20–24 h): these reaction conditions
would clearly be unsuitable for simple 5-substituted cyclo-
pentadienes. In all cases, the cycloaddition reactions pro-
ceeded with excellent diastereofacial selectivity, where the
Scheme 3. The preparation and use of the enantioenriched diene 5.
TFA=trifluoroacetic acid.
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Scheme 4. 2,4-Disubstituted cyclopentadiene 6 in a Diels–Alder cyclo-
addition reaction.
sesses a hexacyclic structure containing two guanidine-
containing rings and a densely functionalized E ring, the
configuration about which has been a matter of significant
debate.[17] The original structure assignment suggested that
the D/E ring junction was cis fused and that the chlorine
substituent of the E ring was on the a face (14a).[16] Several
groups have recently proposed that the D/E ring junction is
trans fused and that the chlorine substituent is on the b face
(14b).[18] Both of these stereoarrays represent demanding
synthetic challenges. Despite significant efforts by many
research groups, the original all-cis E ring stereoarray of the
originally reported structure has only recently been synthe-
sized.[19]
Scheme 5. Application of 5 to the synthesis of the E ring of palau’amine.
Bz=benzyl.
regio- and diastereocontrol with no loss of enantiopurity. It is
expected that this versatile new diene will find application in
the synthesis of complex molecules.[23]
Received: July 9, 2008
Published online: October 15, 2008
Keywords: cycloaddition · Diels–Alder reaction ·
.
sigmatropic shift · synthetic methods
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of the original structure is through the cycloaddition of a 5-
substituted cyclopentadiene with a b-chlorodehydroalanine
derivative and subsequent oxidative ring-opening of the
cycloadduct.[20,21] We found that the cycloaddition of 5 with
chloromethyleneoxazolone 15[22] proceeds rapidly in
dichloromethane at room temperature (Scheme 5). The
resulting 1:1 mixture of cycloadducts was not stable to
chromatography and therefore was treated directly with
dimethyldioxirane (DMDO) and subsequent methanolysis
of the oxazolone afforded hydroxy ketones 17a and 17b in
52% yield over three steps. Subsequent cleavage of the
hydroxy ketone of 17a with lead tetraacetate in methanol
afforded the hexasubstituted cyclopentane 18, which pos-
sesses the same configuration as the E ring in 14a. This is a
successful preparation of the E ring of palau’amine with the
all-cis configuration.
In conclusion, we have shown that 2-silyloxy substitution
markedly stabilizes 5-substituted cyclopentadienes towards
[1,5]-sigmatropic shifts, thus allowing the facile preparation
and efficient use of this important class of diene. Furthermore,
the diene may be easily prepared in enantiomerically
enriched form and undergoes cycloaddition with excellent
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Communications
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