(1R)-(+)-camphor and acetone derived α′-hydroxy enones in asymmetric diels-alder reaction: Catalytic activation by Lewis and bronsted acids, substrate scope, applications in syntheses, and mechanistic studies

Article abstract of DOI:10.1021/jo9023039

Chemical Equation Presented The Diels-Alder reaction constitutes one of the most powerful and convergent C-C bond-forming transformations and continues to be the privileged route to access cyclohexene substructures, which are widespread within natural products and bioactive constituents. Over the recent years, asymmetric catalytic Diels-Alder methodologies have experienced a tremendous advance, but still inherently difficult diene-dienophile combinations prevail, such as those involving dienes less reactive than cyclopentadiene or dienophiles like β-substituted acrylates and equivalents. Here the main features of a'-hydroxy enones as reaction partners of the Diels-Alder reaction are shown, with especial focus on their potentials and limitations in solving the above difficult cases. α'-Hydroxy enones are able to bind reversibly to both Lewis acids and Bronsted acids, forming 1,4-coordinated species that are shown to efficiently engage in these inherently difficult Diels-Alder reactions. On these bases, a convenient control of the reaction stereocontrol can be achieved using a camphor-derived chiral α'-hydroxy enone model (substrate-controlled asymmetric induction) and either Lewis acid or Bronsted acid catalysis. Complementing this approach, highly enantio- and diastereoselective Diels-Alder reactions can also be carried out by using simple achiral α'-hydroxy enones in combination with Evans' chiral Cu(II)BOX complexes (catalyst-controlled asymmetric induction). Of importance, α'-hydroxy enones showed improved reactivity profiles and levels of stereoselectivity (endo/exo and facial selectivity) as compared with other prototypical dienophiles in the reactions involving dienes less reactive than cyclopentadiene. A rationale of some of these results is provided based on both kinetic experiments and quantum calculations. Thus, kinetic measurements of Bronsted acid promoted Diels-Alder reactions of α'-hydroxy enones show a first-order rate with respect to both enone and Bronsted acid promoter. Quantum calculations also support this trend and provide a rational explanation of the observed stereochemical outcome of the reactions. Finally, these fundamental studies are complemented with applications in natural products synthesis. More specifically, a nonracemic synthesis of (-)-nicolaioidesin C is described wherein a Brαnsted acid catalyzed Diels-Alder reaction involving a α'-hydroxy enone substrate is the key step toward the hitherto challenging tri substituted cyclohexene subunit.

Full text of DOI:10.1021/jo9023039

pubs.acs.org/joc
(1R)-(þ)-Camphor and Acetone Derived r0-Hydroxy Enones in
Asymmetric Diels-Alder Reaction: Catalytic Activation by Lewis and
Brønsted Acids, Substrate Scope, Applications in Syntheses, and
Mechanistic Studies
‡
Patricia Banuelos, Jesus M. Garcıa, Enrique Gomez-Bengoa, Ada Herrero,
‡
†
‡
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Jose M. Odriozola, Mikel Oiarbide, Claudio Palomo,* and Jesus Razkin
ꢀ
ꢀ
‡
†
,†
‡
ꢀ
ꢀ
†
´
ꢀ
´
Contribution from Departamento de Quımica Organica I, Facultad de Quımica, Universidad del Paıs Vasco,
Apdo. 1072, 20080 San Sebastian, Spain and Departamento de Quımica Aplicada, Universidad Publica de
´
ꢀ
‡
ꢀ
´
´
Navarra, Campus de Arrosadıa, 31006 Pamplona, Spain
claudio.palomo@ehu.es-
Received November 10, 2009
The Diels-Alder reaction constitutes one of the most powerful and convergent C-C bond-forming
transformations and continues to be the privileged route to access cyclohexene substructures, which are
widespread within natural products and bioactive constituents. Over the recent years, asymmetric
catalytic Diels-Alder methodologies have experienced a tremendous advance, but still inherently
difficult diene-dienophile combinations prevail, such as those involving dienes less reactive than
cyclopentadiene or dienophiles like β-substituted acrylates and equivalents. Here the main features of
R0-hydroxy enones as reaction partners of the Diels-Alder reaction are shown, with especial focus on
their potentials and limitations in solving the above difficult cases. R0-Hydroxy enones are able to bind
reversibly to both Lewis acids and Brønsted acids, forming 1,4-coordinated species that are shown to
efficiently engage in these inherently difficult Diels-Alder reactions. On these bases, a convenient
control of the reaction stereocontrol can be achieved using a camphor-derived chiral R0-hydroxy enone
model (substrate-controlled asymmetric induction) and either Lewis acid or Brønsted acid catalysis.
Complementing this approach, highly enantio- and diastereoselective Diels-Alder reactions can also
be carried out by using simple achiral R0-hydroxy enones in combination with Evans’ chiral Cu(II)-
BOX complexes (catalyst-controlled asymmetric induction). Of importance, R0-hydroxy enones
showed improved reactivity profiles and levels of stereoselectivity (endo/exo and facial selectivity) as
compared with other prototypical dienophiles in the reactions involving dienes less reactive than
cyclopentadiene. A rationale of some of these results is provided based on both kinetic experiments and
quantum calculations. Thus, kinetic measurements of Brønsted acid promoted Diels-Alder reactions
of R0-hydroxy enones show a first-order rate with respect to both enone and Brønsted acid promoter.
Quantum calculations also support this trend and provide a rational explanation of the observed
stereochemical outcome of the reactions. Finally, these fundamental studies are complemented with
applications in natural products synthesis. More specifically, a nonracemic synthesis of (-)-nicolaioi-
desin C is described wherein a Brønsted acid catalyzed Diels-Alder reaction involving a R0-hydroxy
enone substrate is the key step toward the hitherto challenging trisubstituted cyclohexene subunit.
Introduction
component), is among the most powerful bond construction
processes in organic synthesis.1 Not only does this transfor-
mation establish two new carbon-carbon bonds in a single
The Diels-Alder reaction, that is, the [4 þ 2] cyclo-
addition involving a diene and an alkene (the dienophile
1458 J. Org. Chem. 2010, 75, 1458–1473
Published on Web 02/02/2010
DOI: 10.1021/jo9023039
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Banuelos et al.
JOCArticle
synthetic operation and provide functionalized cyclohexenes
with up to four new stereogenic centers, it also plays a pivotal
strategic role in the synthesis of numerous complex natural
products.2 Its relevance and versatility in synthesis is due in
part to the wide variety of both diene and dienophile
components that nicely engage in the cycloaddition process.
As a logical consequence, both activation of the reaction and
control of its stereochemical outcome have been and con-
tinue to be the subjects of intensive research activity, and to
date a number of effective chiral reagents as well as catalysts
have been demonstrated to be effective for the purpose.3,4
For years, the dominant strategy for substrate activation
has relied on lowering the energy of LUMO of the dienophile
component by coordination with a Lewis acid. Concomitant
stereocontrol can be effected by either a covalently bound
chiral auxiliary (stoichiometric amount of chiral inductor) or
chiral ligands coordinated to the Lewis acid metal center
(substoichiometric amount of chiral inductor). As a result
several Lewis acid catalyzed diastereo-1,3 and enantioselec-
tive2,4 Diels-Alder methodologies have been developed.5
Complementing Lewis acid mediated methods, organocata-
lytic methods have recently emerged as a plausible strategy,
with chiral amines and Brønsted acids being the most useful
organocatalysts. Amines can act by LUMO-lowering of
the respective unsaturated aldehyde or ketone dienophile
FIGURE 1. R-Hydroxy enone templates derived from camphor
and acetone as acrylate equivalents.
through iminium ion formation,6 whereas Brønsted acids
activate the dienophile by hydrogen bonding.7,8
All of these tools combined offer a powerful platform for
carrying out many individual Diels-Alder reactions with
remarkable levels of efficiency and selectivity. The fact is,
however, that difficult diene-dienophile combinations per-
sist for which known methods are not suitable or perform
less satisfactorily, a notable deficiency that hampers a more
general use of this reaction. In particular, dienes less reactive
than cyclopentadiene, which has become the benchmark
diene in the field, require more forcing conditions that lead
to diminished stereoselectivity in most cases. Similarly, β-
substituted enoyl derivatives are often less competent dieno-
philes than the corresponding β-unsubstituted (acryloyl)
counterparts. Accordingly, the search for new methodolo-
gies (chiral reagents, catalysts, and templates) to address
these persistent limitations is of considerable current interest.
Recently our laboratory introduced two new subtypes of
R0-hydroxy enones as acrylate equivalents, Figure 1, showing
their potential as dienophile components of the Diels-Alder
reaction. On the one hand, chiral R0-hydroxy enone 1, readily
accessible from commodity chemicals, nicely engages in
Brønsted acid promoted Diels-Alder reactions with a vari-
ety of dienes.9 On the other hand, simple achiral R0-hydroxy
enone 2 behaves remarkably as dienophile in enantioselec-
tive Diels-Alder reactions catalyzed by Cu-bis(oxazoline)
chiral complexes.10 From these preliminary results it was
apparent that the R0-hydroxy carbonyl moiety played a key
role for the Diels-Alder reactions to proceed satisfactorily.
The present investigation provides full details of our studies
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(9) Palomo, C.; Oiarbide, M.; Garcıa, J. M.; Gonzalez, A.; Lecumberri,
A.; Linden, A. J. Am. Chem. Soc. 2002, 124, 10288–10289.
ꢀ
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SCHEME 1. Masamune’s Self-Immolative Chiral Dienophile
Approach for Asymmetric Diels-Alder Reactions11
FIGURE 2. Proposed stereomodels showing the shielding capacity
of the camphor skeleton in R0-hydroxy enone 1.
SCHEME 2. “Acetate” Aldol and Mannich Reactions from
Camphor-Based Methyl Ketone Reagent 6
in this area that reveal R0-hydroxy enones as robust bidentate
substrates, well-suited for appropriate activation/chirality
transfer events that might also be applicable beyond the
confines of the Diels-Alder reaction.
Results and Discussion
Early r0-Hydroxy Enone Models in Asymmetric
Diels-Alder Reactions. The first illustration of the potential
of R0-hydroxy enones in Diels-Alder reactions was reported
by Masamune and co-workers,11 who have documented the
capability of these templates to react with cyclopentadiene
without the need of external catalysts or promoters. Both the
high reactivity and selectivity of enones 3, Scheme 1, were
attributed to the formation of an internal hydrogen bond
between hydroxyl and carbonyl group, which freezes the free
rotation along the bond that links the carbonyl and the
carbinol carbons. The same group subsequently found that
chiral auxiliary from the reaction adducts (8) affords the
products along with camphor, the stoichiometric source
of chiral information that can be reused without loss of
efficiency. Of practical and conceptual significance, all
carbon atoms employed in the entire process, including
acetylene as the source of acetyl, are integrated in the final
products 9.
On the basis of these results, we were intrigued by the
possibility of using camphor-derived R0-hydroxy enone 1 as a
new non-self-inmolative dienophile reagent in asymmetric
Diels-Alder reactions. For this concept to be successful, the
new enone model represented by 1 needed to fulfill the
requirements of chemical and stereochemical efficiency.
The subjacent hypothesis was that 1 might adopt a rigid
enough coplanar cisoid conformation, as in Figure 2, with
strongly biased front and rear half spaces while still eliciting
proper reactivity against dienes. Accordingly, the prepara-
tion of 1 and of the β-substituted congeners needed for the
study was pursued.
A convenient route for preparing gram quantities of
compound 1 in a straightforward manner from (1R)-(þ)-
camphor was developed, which consists of the addition of
lithium methoxyallene to the camphor carbonyl followed by
mild acid hydrolysis (workup) of the resulting intermediate
10 (Scheme 3). The overall process took place in 75% yield at
a 10 g scale, after chromatographic purification of the solid
product. For comparative purposes, enone 11 was also
prepared via methylation reaction of 10 using NaH and
iodomethane in DMF and subsequent acid hydrolysis with
5% H2SO4. In their turn, several alternate protocols for the
preparation of β-substituted analogs 12 from either 6 or 1
were also established. Thus Heck reaction or olefin metath-
esis applied to 1 provided the corresponding enones 12 with
β-aryl or β-alkyl substituents, respectively, in good yields.
Optionally, direct aldol condensation of methyl ketone 6
with aromatic aldehydes also led to the desired enones 12.
Using these procedures, one may routinely obtain β-aryl-
and alkyl-substituted R0-hydroxy enones in yields ranging
some Lewis acids, particularly ZnCl2 and BF3 OEt2, en-
3
hance the reaction speed and also selectivity, although these
studies were essentially limited to reactive dienes such as
cyclopentadiene, the very active diacetoxybutadiene, and
Cbz-protected aminobutadiene. Chemical elaboration of
the resulting cycloadducts 4, to furnish the corresponding
carboxylic acid 5, implies oxidative scission of the ketol C-C
bond by treatment with sodium metaperiodate, a step that
causes destruction of the source of chiral information
(stoichiometric) that cannot be recovered and reused.
Background and Working Hypothesis. Prior reports from
our laboratories12 have documented the utility of methyl
ketone reagent 6, derived from (1R)-(þ)-camphor and acety-
lene, two raw materials available in bulk, for the asymmetric
lithium enolate mediated “acetate” aldol and Mannich
reactions (Scheme 2). The high level of diastereofacial con-
trol imparted during the reactions was explained on the
basis of formation of lithium-centered chelate 7, which
shows strongly biased front and rear faces with respect to
the enolate π plane. Interestingly, oxidative removal of the
(11) (a) Reed, L. A., III.; Choy, W.; Masamune, S. J. Org. Chem. 1983,
48, 1137–1139. (b) Masamune, S.; Reed, L. A. III; Davis, J. T.; Choy, W.
J. Org. Chem. 1983, 48, 4441–4444.
ꢀ
(12) (a) Palomo, C.; Gonzalez, A.; Garcıa, J. M.; Landa, C.; Oiarbide, M.;
Rodrıguez, S.; Linden, A. Angew. Chem., Int. Ed. 1998, 37, 180–182. (b)
ꢀ
Palomo, C.; Oiarbide, M.; Aizpurua, J. M.; Gonzalez, A.; Garcıa, J. M.;
Landa, C.; Odriozola, I.; Linden, A. J. Org. Chem. 1999, 64, 8193–8200. (c)
ꢀ
Palomo, C.; Oiarbide, M.; Gonzalez-Rego, M. C.; Sharma, A. K.; Garcıa, J.
M.; Gonzalez, A.; Landa, C.; Linden, A. Angew. Chem., Int. Ed. 2000, 39,
ꢀ
ꢀ
1063–1065. (d) Palomo, C.; Oiarbide, M.; Landa, A.; Gonzalez-Rego, M. C.;
Garcıa, J. M.; Gonzalez, A.; Odriozola, J. M.; Martın-Pastor, M.; Linden, A.
ꢀ
J. Am. Chem. Soc. 2002, 124, 8637–8643.
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SCHEME 3. Preparation of Camphor-Derived R0-Hydroxy Enones 1, 11, and 12
TABLE 1. Uncatalyzed Diels-Alder Reaction of Enone 1 with Cyclo-
Concomitant with the above experiments, attempted un-
catalyzed reaction of enone 11 with cyclopentadiene failed,
the unreacted starting materials being recovered. The lack of
reactivity of enone 11, which presents its hydroxyl group
blocked in the form of its methyl ether, strongly supports the
internal hydrogen bonding activation model, previously
disclosed by Masamune for enones 3.
pentadienea
As expected, the uncatalyzed D-A reaction of enone 1
with dienes less reactive than cyclopentadiene proceeded
much more slowly. For instance, with 2,3-dimethylbutadiene
(Table 2, entry 1), 3 days at room temperature were required
for substantial (96%) conversion, and the reaction turned
impractical at 0 °C. Accordingly, the reaction between 1 and
2,3-dimethylbutadiene was selected as convenient case study
in order to evaluate the effect of added Lewis acids on the
reaction outcome. Among others, Mg(OTf)2, Zn(OTf)2,
entry solvent T, °C t, h conv, % yield, % endo:exo
dr
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2 -25
CHCl3
toluene
Et2O
THF
EtOH
20
0
12
12
24
12
12
12
12
24
>99
>99
>99
>99
>99
50
90
82
90
80
94
ND
95
92:8
93:7
94:6
90:10
90:10
90:10
88:12
91:9
96:4
97:3
98:2
96:4
0
0
0
20
94:6
83:17
84:16
73:27
>99
>99
-25
87
aYields after purification of the crude reaction mixture. ND: not
determined.
Cu(OTf)2, (CuOTf)2 Tol, SnCl4, and SnCl2 salts were tested
3
for the reaction at 0 °C using a 10 mol % loading of the
catalyst. From the survey, Cu(OTf)2 clearly arose as the most
effective Lewis acid catalyst for this reaction.13 Other Cu(II)
and Cu(I) species also demonstrated acceleration of the
reaction but to a lesser extent, whereas Mg(OTf)2, Zn(OTf)2,
or Sn species showed almost no appreciable catalytic effect.
Encouraged by these observations, the reactivity of 1 against
other dienes with attenuated reactivity under Cu(OTf)2
catalysis was examined, and the results are summarized in
Table 2. The catalytic effect by added 10 mol % Cu(OTf)2
was observed in all cases studied. Importantly, this Lewis
acid also improved the selectivity. For example, the reaction
of 1 with 2,3-dimethylbutadiene at 0 °C was complete after
16 h, with an increase of the diastereoselectivity from 96:4 to
greater than 98:2 (entries 1 and 2). A similar trend was
observed in the reactions with isoprene and cyclohexa-
diene, respectively, in this latter case with more pronounced
catalytic effect. Thus, while no reaction was observed
between 1 and cyclohexadiene at 20 °C in the absence of
from 80% to 90%. It is worth noting that all of these enones
are bench-stable compounds and could be safely stored for
weeks at room temperature or even months at -30 °C
without detectable decomposition.
Uncatalyzed and Lewis Acid Catalyzed Diels-Alder Reac-
tions. For initial evaluation of the capability of enone 1 as a
dienophile, its reaction with cyclopentadiene was studied
first. The results in Table 1 correspond to the uncatalyzed
reaction between 1 and cyclopentadiene carried out in dif-
ferent solvents and temperatures. In most of the cases full
conversion was obtained after 12 h at 0 °C (24 h at -25 °C,
entry 3) regardless of the solvent employed. The endo/exo
selectivity also was quite invariant (around 90:10 in favor of
the endo isomer) with respect to the nature of the solvent or
temperature used. Facial selectivity (dr) was the most de-
pendent parameter. The highest dr values (equal or higher
than 95:5) were attained with poorly coordinating solvents
such as CH2Cl2, CHCl3, or toluene (entries 1-5), whereas
lower dr values were obtained in more polar solvents such as
Et2O, THF, or alcohols (entries 6-8).
(13) For a review on copper-catalyzed Diels-Alder reactions, see:
Reymond, S.; Cossy, J. Chem. Rev. 2008, 108, 5359–5406.
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TABLE 2. Diene Survey for the Cu(OTf)2-Catalyzed Diels-Alder Reaction with Enone 1a
aReactions conducted at 1 mmol scale in CH2Cl2. Molar ratio of diene/enone = 5:1, and 10 mol % of Cu(OTf)2 was used. bendo:exo or regioisomer
ratio, as applicable, determined by HPLC or 13C NMR. cDiastereomeric ratio of the endo or major regioisomer (as applicable) determined by 13C NMR.
catalyst (entry 5), full conversion of starting material and
formation of cycloadduct with excellent yield, endo/exo
selectivity, and diastereoselectivity was observed in its pre-
sence (entry 6). These representative examples demonstrate
that enone 1 in combination with Cu(OTf)2 constitutes a
powerful dienophile-catalyst combination set, suitable for
highly stereoselective Diels-Alder reactions involving less
reactive diene counterparts.
Next, we turned our attention to the Diels-Alder reaction
involving the corresponding β-substituted R0-hydroxy en-
ones 12, which expectedly resulted to be more challenging
substrates. Indeed, camphor-derived enones 12 in combina-
tion with Cu(OTf)2 were essentially unreactive toward dienes
less reactive than cyclopentadiene. However, with cyclopen-
tadiene useful reactivity and selectivity could be attained
even in the absence of catalyst. As eq 1 illustrates, the
reaction between 12a and cyclopentadiene provided adduct
17 in good endo:exo and diastereomeric ratio.
and hence contribute to both acceleration of the reaction and
enhancement of the stereochemical control. Accordingly, the
effect of a series of Brønsted acids on the reaction between 1
and some representative dienes was surveyed in CH2Cl2 as
solvent (Table 3). The studies revealed that both triflic acid
(TfOH) and trifluoroacetic acid (TFA) did indeed promote the
reactions to completion, affording the cycloadducts with high
regio- and stereoselectivity. In general, TfOH was more active
than TFA, allowing for shorter reaction times15,16 and smaller
catalyst loading. However, TfOH required lower temperatures
(-78 °C) for clean reaction, since at temperatures higher than
about -25 °C increasing amounts of decomposition products
were detectable. For instance, the reaction of 1 and 2,3-
dimethylbutadiene was over after 3 h of stirring at -78 °C
with 10 mol % TfOH (16 h at -25 °C with 30 mol % TFA),
and the product 14 was obtained as a single isomer in 98%
isolated yield (75% for the TFA-catalyzed reaction, entries 3,
4). Other acids tested, among them CH3CO2H, BrCH2CO2H,
Br2CHCO2H, Cl2CHCO2H, and HCO2H, led to inferior
results regardless of the temperature applied. On the other
hand, while essentially the same trend was observed when
toluene was employed as solvent, in solvents such as Et2O or
THF the unchanged starting materials were recovered what-
ever was the acid employed. The poor results obtained with
ethereal solvents might be ascribed to competition for protons
because of the Lewis basicity of the ether oxygen.
We next investigated the suitability and scope of the TfOH-
catalyzed Diels-Alder reaction for the more challenging
β-substituted acrylate substrates 12a-g. As the results in
Table 4 show, the reaction tolerates substrates with β-alkyl
substituents of variable size (entries 1-10), as well as β-aryl
substituents of electron-neutral (entries 11-13), electron-
rich (entries 14, 15), or electron-poor (entry 16) character,
which reacted smoothly with cyclopentadiene, and with less
reactive dienes such as cyclohexadiene, isoprene, and 2,3-
dimethylbutadiene, giving excellent stereoselectivity (endo/
exo g 150:1; facial selectivity g98:2). Under the above
Brønsted Acid Catalyzed Diels-Alder Reactions. While
catalysis of the Diels-Alder reaction has largely relied on
the use of Lewis acids, less attention has been paid to the
complementary Brønsted acid catalyzed Diels-Alder meth-
odologies. In the late 1940s pioneering work by Wasser-
mann14 underscored the ability of Brønsted acids to
accelerate Diels-Alder reactions in organic solvents, thus
setting the principles of a metal-free Diels-Alder methodol-
ogy. However, despite the elapsed time since then, only a few
reports that have appeared relatively recently have docu-
mented diastereo- and enantioselective Diels-Alder reac-
tions mediated by Brønsted acid catalysts.7,8 Given the
inherent reactivity demonstrated by R0-hydroxy enone 1
and the fact that the most plausible activation model involves
an internal hydrogen bond, it was argued that external
Brønsted acids might engage in hydrogen bonding networks
(15) The relationship between the pKa of the added acid and the reaction
acceleration has been previously documented for the case of Diels-Alder
reaction between several acrylates or methyl vinyl ketone and cyclopenta-
diene using a series of acetic acids: (a) Kasper, F.; Zobel, H. J. Prak. Chem.
1975, 317, 510–514. (b) Kasper, F.; Bischoff, St. J. Prak. Chem. 1986, 328,
449–453.
(16) For Diels-Alder reactions catalyzed by trimethylsilyl bis-
(trifluoromethanesulfonyl)imide, see: Mathieu, B.; Ghosez, L. Tetrahedron
2002, 58, 8219–8226.
(14) (a) Wassermann, A. J. Chem. Soc. 1942, 618–622. (b) Wassermann,
A. J. Chem. Soc. 1942, 623–627.
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TABLE 3. Brønsted Acid Catalyzed Diels-Alder Reactions of Acrylate Equivalent 1a
aReactions conducted on a 1 mmol scale in CH2Cl2; ratio diene/1 = 5:1. bYield of isolated pure major diastereomer after column chromatography.
cDetermined by HPLC. dDiastereomeric ratio of the endo or major regioisomer (as applicable) determined by 13C NMR.
conditions, β-aryl-substituted acrylate equivalents usually
took longer reaction times, which could be consistently re-
duced by slightly increasing catalyst loading. Remarkably,
even enones bearing bulky substitution at β-position, such as
cyclohexyl- and tert-butyl-substituted enones 12b (entries
5-8) and 12c (entries 9, 10), were able to react with these
representativeless reactivedienestofurnishthe corresponding
adducts 22-24 and 26, respectively, in acceptable yields and
with essentially total stereocontrol.
diastereoselectivity. This is so far the first reported asym-
metric Diels-Alder reaction involving dienyl phosphates
as dienes.19,20
From this study it becomes clear that Brønsted acid
catalysis of the Diels-Alder reaction involving R0-hydroxy
enones is more efficient than Cu(II) Lewis acid catalysis17
and provides an efficient entry to nontrivial substituted
cyclohexene systems, such as those often encountered in
natural products, vide infra. A significant exception to the
above preference is the Diels-Alder reaction involving acid-
sensitive diene or dienophile counterparts, a reaction sub-
type where the utility of strong Brønsted acids, e.g., TfOH,
may be somewhat limited. For example (eq 2), dienyl phos-
phates constitute an attractive class of dienes for Diels-
Alder reactions owing to the synthetic possibilities of the
resulting vinyl phosphate products.18 In addition, they have
been shown to be more stable than the corresponding
silyloxy and alkoxy dienes.19 However, treatment of dienyl
phosphate 33 with TfOH and 1 led to polymeric products
only. In cases like this, the alternative Cu(OTf)2-catalyzed
reaction provided a useful compromise. Thus, treatment
of 1 with 33 under the presence of 30 mol % Cu(OTf)2 gave
rise to adduct 34 in 89% yield and essentially complete
Catalyst-Controlled Enantioselective Diels-Alder Reac-
tions with Achiral r0-Hydroxy Enones. The above results
based on the camphor-derived R0-hydroxy enones 1 and 12
could be ascribed to the capability of these dienophiles for
acting as bidentate substrates susceptible to coordination to
either selected Lewis acids, particularly Cu(II) salts, or
hydrogen donors (Brønsted acid). Under the reported con-
ditions, the formed complexes apparently are rigid enough to
allow the camphor skeleton to impart efficient steric shield-
ing in the transition state, thus resulting in almost perfect
transfer of chiral information to the forming cycloadducts.
At this stage, the question was whether development of an
enantioselective, catalyst-controlled variant of the reaction
would be feasible. The realization of this objective would
involve simple achiral R0-hydroxy enones and a chiral cata-
lyst acting in a concerted manner.21 However, at the outset it
(20) For non-asymmetric Diels-Alder reactions involving O-dienyl
phosphate esters, see: (a) Skowronska, A.; Dybowsky, P.; Koprowski, M.;
Crawczyc, E. Tetrahedron Lett. 1995, 36, 8133–8136. (b) Tatsuta, K.; Inukai,
T.; Itoh, S.; Kawarasaki, M.; Nakano, Y. J. Antibiot. 2002, 55, 1076–1080. (c)
Koprowski, M.; Skowornska, A.; Glowka, M. L.; Fruzunski, A. Tetrahedron
2007, 63, 1211–1228.
(17) A reversal in chemical efficiency has been observed in the reaction
of azachalcone dienophiles with cyclopentadiene. See: Mubofu, E. B.;
Engberts, J. B. F. N. J. Phys. Org. Chem. 2004, 17, 180–186.
(18) Review on the chemistry of enol phosphates: Linchtenthaler, F. W.
Chem. Rev. 1961, 61, 607–649. Enol phosphates in cross-coupling reactions:
(a) Miller, J. A. Tetrahedron Lett. 2002, 43, 7111–7114. (b) Cahiez, G.; Gager,
O.; Habiak, V. Synthesis 2008, 2636–2644. (c) Guo, J.; Harling, J. D.; Steel, P.
G.; Woods, T. M. Org. Biomol. Chem. 2008, 6, 4053–4058. Also, see:. (d)
(21) For selected examples of bidentate dienophiles, see the following. N-
Hydroxyacrylamides: (a) Corminboeuf, O.; Renaud, P. Org. Lett. 2002, 4,
1735–1738. R,β-Unsaturated 2-acylimidazoles: (b) Evans, D. A.; Fandrick,
K. R.; Soug, H. J.; Scheidt, K. A.; Xu, R. J. Am. Chem. Soc. 2007, 129,
10029–10041. (c) Boersma, A. J.; Feringa, B. L.; Roelfes, G. Org. Lett. 2007,
9, 3647–3650. (d) Ishihara, K.; Fushimi, M. Org. Lett. 2006, 8, 1921–1924.
R,β-Unsaturated N-acylpyrazolidinones: (e) Sibi, M. P.; Stanley, L. M.; Nie,
X.; Venkatraman, L.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 2007, 129,
395–405. (f) Zhou, J.; Tang, Y. Org. Biomol. Chem. 2004, 2, 429-433.
Alkylidenemalonates: (g) Yamauchi, M.; Aoki, T.; Li, M.-Z.; Honda, Y. Tetra-
hedron Asymmetry 2001, 12, 3113–3118. R0-Arylsulfonyl enones: (h) Barroso,
ꢀ
Skowronska, A.; Koprowski, M.; Krawczyk, E. Phosphorus, Sulfur Silicon
2002, 177, 1877–1880. In R-hydroxyl ketone synthesis: (e) Krawczyk, E.;
ꢀ
Koprowski, M.; Skowronska, A.; Luczak, J. Tetrahedron: Asymmetry 2004,
15, 2599–2602.
(19) Liu, H. J.; Feng, W. M.; Kim, J. B.; Browne, E. N. C. Can. J. Chem.
1994, 72, 2163–2175.
~
S.; Blay, G.; Al-Midfa, L.; Munoz, M. C.; Pedro, J. R. J. Org. Chem. 2007, 129,
395–405 and also ref 13.
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TABLE 4. Diels-Alder Reaction of Representative β-Alkyl- and β-Aryl-Substituted Acrylate Equivalents 12 with Dienes Catalyzed by TfOHa
aReactions conducted at 1 mmol scale in CH2Cl2 at -78 °C. Molar ratio of diene/enone/TfOH = 5:1:0.1, except for branched chain enones 12b, 12c,
which was 5:1:0.5. bIn every applicable single cases, endo:exo ratio of g150:1, determined by 13C NMR and/or HPLC. In every case dr g98:2. cReaction
performed with 30 mol % TfOH. dReaction performed at -50 °C.
was not clear whether chirality transfer from the catalyst chiral
structure would be effective as the intramolecular chirality
transfer involved in the Diels-Alder reactions described in the
previous section. In pursuing this idea we found inspiration
from the previous seminal work by Evans, who developed
N-acyl oxazolidinones as efficient dienophile components of
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SCHEME 4. Performance of Acrylate Equivalents Based on the
Ketol and the N-Acyloxazolidinone Template, Respectively, in
35-Catalyzed Diels-Alder Reaction with 2,3-Dimethylbutadiene
FIGURE 3. N-Enoyl oxazolidinones and their 1,5-metal binding
complexes as useful dienophiles for Diels-Alder reactions devel-
oped by the Evans group. Active complex A formed from chiral
oxazolidinone and achiral ML2 catalyst; active complex B formed
from achiral oxazolidinone and chiral ML*2 catalyst.
the Diels-Alder reaction in its substrate-controlled, diaster-
eoselective version,22 first, and the catalyst-controlled, enan-
tioselective version later (Figure 3).5a-c,23,24
Oxidative Cleavage of Ketol Moiety in Adducts. Access to
aldehydes, ketones, and carboxylic acids. After determination
of the most favorable conditions for Diels-Alder reactions
with a survey of representative diene/dienophile combina-
tions, reliable protocols were established for the removal of
the auxiliary group from the adducts. It was found that by
following standard methods for the oxidative C-C bond
scission of ketols, the corresponding aldehydes, ketones, and
carboxylic acids can be obtained in good yields and without
compromising the configurational integrity of the products.
The alternate paths shown in Scheme 5 represent two of such
well-established protocols, which furnish, respectively, the
corresponding carboxylic acid or ketone products. For
instance, treatment of adducts 13/27 with ceric ammonium
nitrate (CAN) in a mixture of acetonitrile and water
smoothly afforded the corresponding carboxylic acids 50/
51 in high yield and in essentially enantiopure form. For
adducts with limited solubility in acetonitrile/water, the
oxidation could be carried out with equal efficiency by
treatment with either periodic acid in THF (or diethyl ether)
or sodium metaperiodate in a mixture of methanol and
water. It is important to note that camphor, the accompany-
ing byproduct delivered in these reactions, could be almost
fully recovered and reused without loss of efficiency. As a
consequence, all carbon atoms employed in the cycloaddi-
tion reaction are integrated in the final target compounds, an
aspect of the approach that bears practical interest. Likewise,
when the same conditions were applied to adducts such as 38
and 47, which arise from the catalyst-controlled enantiose-
lective Diels-Alder reaction, carboxylic acids such as 52 and
53 were afforded in high yield along with acetone, the
accompanying organic byproduct concomitantly formed
during these reactions. As evidenced by the opposite abso-
lute configuration of products 50/51 with respect to 52/53,
either enantiomer of the final carboxylic acid is accessible by
proper choice among the two optional approaches, namely,
the camphor-based (substrate-controlled) approach or the
catalyst-controlled enantioselective approach.
Since previous observations indicated Cu(OTf)2 as the best-
suited Lewis acid catalyst for the D-A reaction with camphor-
derived enones 1 and 12, we set out to test the behavior of
achiral R0-hydroxy enone 2incombinationwithEvans’Cu(II)-
bis(oxazoline) chiral catalysts.5a,b,23 Initial experiments with
this enone/catalyst system proved instructive. For example,
Scheme 4, the reaction of 2 with 2,3-dimethyl butadiene in the
presence of 10 mol % 35b at -20 °C provided 36 with 80%
yield and remarkable enantioselectivity (94% ee), whereas the
parent reaction using N-acryloyl oxazolidinone afforded the
respective adduct 37 in 78% yield, but only 65% ee.5b
The results from the reaction of 2 with a range of dienes,
Table 5, demonstrated that (Cu(BOX))(OTf)2 35a and the
related complex 35b are indeed excellent catalysts for these
transformations. Adducts 38 and 39, from cyclopentadiene
and cyclohexadiene, were formed in high yield and almost
perfect enantiocontrol (entries 1, 2). Although piperylene
provided 40 as an isomeric cis/trans mixture, the major cis
isomer was also formed with essentially complete enantios-
electivity (entry 4). Again, enone 2 reacted with isoprene in
the presence of catalyst 35b to afford the expected adduct 41
with good yield and 94% ee (entry 5), while the analogous
reaction with N-acryloyl oxazolidinone provided the corre-
sponding cycloadduct in only 59% ee.5b
As previously observed in the context of the camphor-
derived enones, substitution at Cβ position of the R0-hydroxy
enone with alkyl or aryl groups diminished their reactivity
considerably. In fact, enones 42-45 resulted unsuitable
dienophiles for the D-A reaction involving challenging
dienes under the conditions tested. Still, such enones25
reacted satisfactorily with cyclopentadiene, affording ad-
ducts 46-49 in almost complete enantioselectivity (Table 6).
(22) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1984,
106, 4261–4263. (b) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem.
Soc. 1985, 106, 4261–4263. (c) Evans, D. A.; Chapman, K. T.; Bisaha, J. J.
Am. Chem. Soc. 1988, 110, 1238–1256.
(23) (a) Evans, D. A.; Miller, S. J.; Lectka, T J. Am. Chem. Soc. 1993, 115,
6460–6461. (b) Evans, D. A.; Murry, J. A.; von Matt, P.; Norcross, R. D.;
Miller, S. J. Angew. Chem., Int. Ed. 1995, 34, 798–800. Reaction scope and
applications to synthesis: (c) Evans, D. A.; Ripin, D. H. B.; Johnson, J. S.;
Shaugnessy, E. A. Angew. Chem., Int. Ed. 1997, 36, 2119–2121. (d) Evans, D.
A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von Matt, T.; Miller, S. J.;
Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos, K. R. J. Am.
Chem. Soc. 1999, 121, 7582–7594.
(24) (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325–335.
For a recent review on bis(oxazolidine) ligands, see: (b) Desimoni, G.; Faita,
G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561–3651.
(25) The starting enones may be easily prepared in multigram quantity
from commercially available materials in a manner similar to that employed
for camphor-based enones 12. For details, see Supporting Information.
Complementing the direct oxidative scission of adducts to
carboxylic acids, a two-step process involving initial treat-
ment with an alkyllithium and subsequent oxidation of
the resulting carbonyl addition intermediate with CAN26
gave rise to the corresponding ketones, such as 54-57.
(26) For adducts bearing acid-sensitive groups, like acetals, or showing
limited solubility in the acetonitrile/water system, the scission step could be
carried out with improved results by using alternative oxidants like lead
tetraacetate in benzene or sodium periodate in diethyl ether.
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TABLE 5. Reactions of Acrylate Equivalent 2 with Representative Dienes Catalyzed by 35a and 35ba
aReactions conducted at 0.5 mmol scale in CH2Cl2. Molar ratio of enone/diene/catalyst = 1:5:0.1. bRatio of regio- or cis/trans isomers, as applicable,
determined by 13C NMR. cDetermined by 13C NMR. dEnantiomeric excess of the major regio- or diastereoisomer, as applicable, determined by HPLC.
TABLE 6. Diels-Alder Reaction of β-Substituted Acrylate Equivalents 42-45 with Cyclopentadiene Catalyzed by 35b
entry
enone
R
T (°C)
t (h)
endo:exoa
product
yield (%)
ee (%)b
1
2
3
4
42
43
44
45
Et
Ph
-78
21
14
2.5
24
>98:2
94:6
95:5
46
47
48
49
90
86
85
94
>99
>99
>99
>99
0
0
0
4-ClC6H4
4-MeOC6H4
c
94:6
aDetermined by 13C NMR. bDetermined by HPLC. cUsing 10 equiv of diene.
SCHEME 5. Ketol C-C Bond Scission with Liberation of the Auxiliary
Again, the product ketones with preserved stereochemis-
try were obtained in yields from good to excellent, with
liberation of camphor or acetone as the only organic side
product formed, which could easily be separated and re-
cycled. By this two-step sequence, cyclohexenes formally
derived from a Diels-Alder reaction of simple monodentate
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SCHEME 6. TfOH-Promoted Asymmetric Diels-Alder
Reaction of R0-Hydroxy Enone 59 Documented by Philips in His
Synthesis of (þ)-Cyanthiwigin U
enones are obtained, a process that also bears considerable
challenge.27
Alternatively, a two-step sequence for the removal of the
auxiliary group from the cycloadducts can yield the corre-
sponding aldehyde products. For instance, aldehyde 58 was
smoothly obtained from the corresponding cycloadduct 28
by reduction with LiAlH4 and subsequent oxidation with
CAN in 78% overall yield. It should be noted that attempted
Diels-Alder reaction of cinnamaldehyde and cyclohexane-
diene to afford 58 using MacMillan’s iminium activation
methodology under a variety of conditions failed, and
unreacted materials were recovered.28
FIGURE 4. Representative “condensed” chalcones isolated from
natural sources and the hypothetical Diels-Alder pathway for their
biogenesis. Absolute configuration of (-)-panduratin A according
to the assignment by Yoshikawa.33
families, isolated from natural sources.30 Despite the wide
variety of biological activities displayed by extracts of these
constituents, data for most of these substances about the
specific activity of each enantiomeric form remain awaited.
On the other hand, while A can be considered to be biogen-
etically derived from a Diels-Alder-type cyclization be-
tween the respective chalcone and monoterpenoid diene,
realization of this transformation in the laboratory has been
demonstrated to be challenging.31 In this context unsuccess-
ful Diels-Alder cycloadditions toward the central trisubsti-
tuted cyclohexene core using Lewis acid promoted
(“LUMO” lowering) conditions have been documented,31a
whereas in the absence of any promoter rather harsh condi-
tions (benzene, sealed tube, 220 °C, 24 h) are required to give
regioisomeric mixtures of the respective cycloadducts.31b We
decided to test our Brønsted acid promoted Diels-Alder
methodology in this endeavor and pursued the first asym-
metric synthesis of nicolaioidesin C,32 a natural product
isolated by Kinghorn and co-workers in racemic form from
the roots of Renealmia nicolaioides.30c
Application to the Synthesis of Natural and Bioactive
Products. Given the outstanding position the Diels-Alder
reaction holds as a tool for creating carbocycles of varying
degree of skeletal complexity, the present methodology may
prove to be useful in the synthesis of relatively complex target
molecules, where a difficult Diels-Alder reaction is key for
success. An illustrative example has recently been described
by Philips and Pfeiffer within the context of an elegant total
synthesis of (þ)-cyanthiwigin U (Scheme 6). After unfruitful
results using other alternate protocols to construct the
required building-block 60, the authors found that the reac-
tion between camphor-based R0-hydroxy enone 59 and 1,4-
dimethyl cyclohexadiene with the assistance of TfOH was the
only best suited protocol.29
We were delighted to observe that the reaction of enone
12d with myrcene 61 (12d:61 ratio 1:5) in the presence of
10 mol % TfOH at -78 °C in CH2Cl2 proceeded smoothly
to afford the corresponding cycloadduct 62 as a single
Our efforts in this direction focused on the “condensed”
chalcone structure A, Figure 4, which represents an interest-
ing target present in several bioactive constituents, such as
the panduratins, nicolaioidesins, crinatusins, and fissistins
(30) (a) Tuntiwachwuttikul, P.; Pancharoen, O.; Reutrakul, V.; Byrne,
L. T. Aust. J. Chem. 1984, 37, 449–453. (b) Alias, Y.; Awang, K.; Hadi, A. H.
A. J. Nat. Prod. 1995, 58, 1160–1166. (f) Shibata, K.; Tatsukawa, A.;
Umeoka, K.-i.; Lee, H. S.; Ochi, M. Tetrahedron 2000, 56, 8821–8824.
(c) Gu, J.-Q.; Park, E. J.; Vigo, J. S.; Graham, J. G.; Fong, H. H. S.; Pezzuto,
J. M.; Kinghorn, A. D. J. Nat. Prod. 2002, 65, 1616–1620. (d) Cheenpracha,
S.; Karalai, C.; Ponglimanont, C.; Subhadhirasakul, S.; Tewtrakul, S.
Bioorg. Med. Chem. 2006, 14, 1710–1714. (e) Win, N. N.; Awale, S.; Esumi,
H.; Tezuka, Y.; Kadota, S. J. Nat. Prod. 2007, 70, 1582–1587.
(31) (a) Cong, H.; Ledbetter, D.; Rowe, G. T.; Caradonna, J. P.; Porco, J.
A. Jr. J. Am. Chem. Soc. 2008, 130, 9214–9215. (b) Jung, E. M.; Lee, Y. R.
Bull. Korean Chem. Soc. 2008, 29, 1199–1204.
(32) For racemic syntheses of nicolaioidesin C based on an electron-
transfer-initiated Diels-Alder cycloaddition and thermal Diels-Alder reac-
tion, respectively, of 20-hydroxychalcones, see refs 31a and 31b.
(27) For advances in metal-catalyzed enantioselective Diels-Alder reac-
tions involving monodentate ketone dienophiles (single-point binding
activation), see refs 5c-f (cationic oxazaborolidine catalysts); ref 5h
(monomeric Schiff base-CrIII catalysts). For asymmetric organocatalytic
methods mainly involving enals, see refs 6 and 7.
(28) (a) For detailed information on the experimental procedures employed
and conditions variation, see Supporting Information. For substrate dependence in
Diels-Alder reactions via iminium activation, see: (b) Kinsman, A. C.; Kerr,
M. A. J. Am. Chem. Soc. 2003, 125, 14120–14125.
(29) For detailed information, see: (a) Pfeiffer, M. W. B.; Phillips, A. J.
J. Am. Chem. Soc. 2005, 127, 5334–5335. For a recent case of R0-hydroxy
dienones as diene components of asymmetric Diels-Alder cycloadditions in
the context of biomimetic natural products synthesis, see: (b) Dong, S.;
Hamel, E.; Bai, R.; Covell, D. G.; Beutler, J. A.; Porco, J. A., Jr. Angew.
Chem., Int. Ed. 2009, 48, 1494 –1497.
(33) Absolute configuration of several extracted prenylchalcones, includ-
ing (þ) and (-)-panduratin A, has recently been determined by CD:
Yoshikawa, M.; Morikawa, T.; Funakoshi, K.; Ochi, M.; Pongpiriyadacha,
Y.; Matsuda, H. Heterocycles 2008, 75, 1639–1650. Note that these
determinations are in conflict with the structures of (-)-panduratin A
depicted in refs 30e and 31a.
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SCHEME 7. Total Synthesis of (-)-Nicolaioidesin C Relying on Our Brønsted Acid Catalyzed Diels-Alder Reaction As a Key Step
diastereomer in 85% yield, Scheme 7. It is important to note
that, in agreement with difficulties previously encountered
by other authors in similar transformations, the Lewis acid
promoted Diels-Alder reaction between enone 43 and myr-
cene did not work at all, extensive polymerization of myrcene
being the major detectable product instead. We believe that
the remarkable performance of the Brønsted acid promoted
reaction is primarily due to the efficient activation of the
hydroxy enone even at quite low temperatures (-78 °C).34
With 62 at hand, next the two-step transformation of 62 into
65, consisting of the nucleophilic addition of the correspond-
ing aryl-lithium reagent to 62 and oxidative cleavage of the
expected diol adduct, was attempted unsuccessfully. As a
matter of fact, the addition step under several reaction
conditions failed, a result that may be due to the high steric
demand of both the ketone 62 and the 2,4,6-trisubstituted
aryl-lithium reagent. Finally, the synthesis continued
through reduction of the carbonyl group in 62 with LiAlH4
and oxidative cleavage of the resulting diol with Pb(AcO)4,35
which provided aldehyde 63 in 84% overall yield. Again,
attempts to access this aldehyde adduct directly from cinna-
maldehyde and myrcene via iminium ion activation were
completely unfruitful and mainly unchanged starting mate-
rials were observed.28
Once the trisubstituted cyclohexene is built with the
appropriate configuration, addition reaction of the lithium
anion of di-MOM-protected methoxyresorcinol to the car-
baldehyde afforded epimeric alcohol 64 in 82% yield. Oxida-
tion of 64 with periodinane in dichloromethane and
subsequent deprotection of the MOM group gave the (-)-
enantiomer of nicolaioidesin C (65) in 81% yield (two steps).
It is worth mentioning that the absolute configuration
and optical rotation sign determined for product 65 are
in good agreement with recent determinations by CD for
related compounds.33 Clearly, this approach offers an attrac-
tive way to construct prenylflavonoid natural products
whose absolute and relative configuration still need to be
established.
Mechanistic Insights into the Brønsted Acid Catalyzed
Diels-Alder Reaction of r0-Hydroxy Enones. The above
results demonstrate that R0-hydroxy enone 1 and its β-sub-
stituted congeners 12 can be conveniently activated upon
addition of substoichiometric quantities of Brønsted acids
and thus effectively participate in D-A reactions that nor-
mally do not perform well with other protocols. In order to get
a better understanding of this activation mechanism, identify
plausible reactive intermediate species, and provide a rationale
for the stereochemical outcome of the reaction, some addi-
tional experimental and theoretical studies were carried out.
Animportantparameter thatwould helptocharacterize the
structure of the formed substrate-catalyst complex is the
actual stoichiometry of such complexes, and relevant infor-
mation in this respect could beobtained from kinetic measure-
ments. Accordingly, the reaction order with regard to enone
and catalyst (TFA) for the aforementioned reaction between
enone 1 and 2,3-dimethylbutadiene was determined as fol-
lows. In a set of experiments using a large excess of the diene,
variations of ln([1]/[1]0), with [1] and [1]0 being the actual and
the initial concentration of enone 1, respectively, were deter-
mined as a function of time for four different catalyst con-
centrations. Plots (see the Supporting Information for details)
showed a linear behavior and thus first-order dependence of
reaction rate with respect to enone 1 in either of the four
conditions tested. Additionally, plotting the four apparent
rate constants (kobs) thus obtained versus catalyst concentra-
tion (Figure 5) fits well to a straight line (R2 = 0.9836), which
indicates a first-order reaction also with respect to the added
Brønsted acid (TFA). The conclusion from these experiments
is that a 1:1 hydroxy enone-Brønsted acid complex is the
most likely active species participating in the rate-limiting step
of these Diels-Alder reactions.
Quantum Calculations. Complementing these experimen-
tal data, some DFT-computing work36 was undertaken to
(34) Under our optimized conditions (10 mol% TfOH, 5 equiv of
myrcene, -78 °C, 20 h) a minute amount of polymer formation was detected.
However, an increase of the reaction temperature up to about -30 °C or the
loading of the promoter TfOH up to about 30 mol% led to extensive
production of the undesired polymer.
(35) The use of the CAN/acetonitrile/water oxidation system was not
practical in this particular case due to the poor solubility of the substrate diol
in the polar media.
(36) DFT has been shown to reliably predict the results of Diels-Alder
cycloaddition reactions; see: (a) Goldstein, E.; Beno, B.; Houk, K. N. J. Am.
Chem. Soc. 1996, 118, 6036. (b) Wiest, O.; Montiel, D. C.; Houk, K. N. J.
Phys. Chem. A 1997, 101, 8378. (c) Garcıa, J. I.; Martınez-Merino, V.;
Mayoral, J. A.; Salvatella, L. J. Am. Chem. Soc. 1998, 120, 2415. (d) Birney,
D. M. J. Am. Chem. Soc. 2000, 122, 10917.
1468 J. Org. Chem. Vol. 75, No. 5, 2010

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Additional stabilization as well as geometry constraints
may be due to interactions between the hydroxy group in 1
and the external acid.
From the calculated energies, the first, expected observa-
tion is that the external acid reduces the energy of the
transition states by formation of H-bonds between the acid
and 1. Furthermore, these interactions are stronger in the
transition states than in the starting enone/acid complexes,
and therefore reaction acceleration is predicted to occur.
Thus, the uncatalyzed reaction shows a free Gibbs activation
energy of 30.1 kcal/mol (TSA1), which is reduced in the
presence of TFA to 26.1 kcal/mol (TSB1). The more acidic
triflic acid exerts a more pronounced barrier reduction (23.9
kcal/mol, TSC1), which accounts for the 6 kcal/mol lower
barrier compared with that of the uncatalyzed reaction, that
is, more than 104-fold enhancement of reaction speed, in fair
agreement with the catalytic effect experimentally observed
with 10 mol % triflic acid.
FIGURE 5. Observed rate constants (20 °C) as a function of
catalyst loading.
On the other hand, the calculated TS geometries allow for
a rational explanation of the facial selectivity observed
experimentally in the laboratory. In particular, the methyl
group at C1 of the camphor-structure strongly shields the re
face of enone making the si-face approaching of cyclopenta-
diene more feasible. For example, in the uncatalyzed reac-
tion, the large energy difference between the re (TSA1) and si
(TSA3) approaches (ΔΔG‡ = þ4.4 kcal/mol) is in good
agreement with the ratio of diastereomers experimentally
observed (>98:2). This facial selectivity is essentially not
affected by incorporating one molecule of TFA or TfOH,
and for these latter cases transition states involving the less
favorable re face attack (structures not shown in Figure 6) lie
about 3 kcal/mol higher in energy.
More in-depth examination of the geometries and bond
distances in the most salient TSs for the TfOH- and TFA-
assisted Diels-Alder reactions is worthy of comment. Con-
sidering first the TFA-assisted reaction, for the endo/re
approach two lowest-energy transition states (TSB1 and
TSB2) were located after extensive structural search. In
TSB1, the ketone-carbonyl is doubly H-bonded to the in-
tramolecular hydroxy group, on the one hand (r = 1.9 A),
and the OH group of TFA, on the other hand (r = 1.6 A). In
TSB2 comparatively less stabilization (ΔΔG‡ = þ1.4 kcal/
mol) is observed, and it corresponds to a cyclic arrangement
of the H-bonding complex between the hydroxy-ketone and
the carboxylic acid. A similar trend is observed for the two
main transition states identified in the exo approach (TSB3
vs. TSB4). Slight differences are observed with respect to the
calculated transition states for the TfOH-assisted reactions.
In general, the higher acidity and conformational ambiguity
of TfOH, which bears two SdO groups that become diaster-
eotopic within the complex, induce a larger number of
possible transition states. The lowest in energy (activation
barrier 23.9 kcal/mol) is TSC1 wherein the ketone is fully
protonated by the strong acid. In contrast to the TFA-
assisted reaction, in the TfOH-assisted reaction TS structure
showing the ketone carbonyl doubly H-bonded (TSC2) is the
second most stable (activation barrier 24.9 kcal/mol) with
get more information about the structure and energetic
profiles of the activated complexes and the transition states
involved in the Diels-Alder reaction of R0-hydroxy enone
137 with cyclopentadiene promoted by Brønsted acids. We
compared the reactions in the absence of an external acid and
in the presence of one molecule of TFA or TfOH. All
structures were optimized using the functional B3LYP38 and
the 6-311þG** basis set as implemented in Gaussian 03.39,40
The activation energies (ΔG‡*) reported in this work refer to
the energy difference computed for the transition states and
the corresponding H-bonded initial complexes.
Given the presence of various sites with H-bond donor/
acceptor character in both the hydroxy-ketone substrate and
the added acid, several complexes involving both compo-
nents and each with a distinct H-bond network can be
conceived. At the outset, about a dozen of the most plausible
combinations were evaluated,41 from which a selection of the
lowest in energy was made for further refinement (Figure 6).
Of the various H-bonds identified, the intramolecular
OH OdC interaction in 1 and the intermolecular H-bond
3 3 3
between the ketone carbonyl group of 1 and external acid
are of special importance regarding enone activation.
(37) In the discussion that follows, the reactivity concerning the enone
moiety is considered only in its s-cis conformation. TS involving the s-trans-
enone lie much higher in energy (>3 kcal/mol) in all cases and will not be
discussed here.
(38) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789. (b)
Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (c) Kohn, W.; Becke, A. D.;
Parr, R. G. J. Phys. Chem. 1996, 100, 12974–12980.
(39) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A. Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A.
D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komar-
omi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision E.01;
Gaussian, Inc.: Wallingford CT, 2004.
H
O distances of 1.4 and 2.0 A for the inter- and intra-
3 3 3
molecular H-bonds, respectively. Similar comments apply to
the exo structures TSC3 and TSC4
.
(40) For details on computational methods, see Supporting Information.
(41) For the full collection of H-bonded structures considered for first
evaluation, see Supporting Information.
Interestingly, the endo/exo selectivity increases as the pKa
of the acid decreases. Thus the endo/exo ratio ranges from
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FIGURE 6. Computational data for the Diels-Alder reaction of enone 1 with cyclopentadiene: (TSA) uncatalyzed reaction; (TSB)
trifluoroacetic acid assisted reaction; (TSC) triflic acid assisted reaction. Activation free energies in kcal/mol.
4.4:1 for the uncatalyzed reaction to 5.5:1 for the TFA-
assisted reaction and to 45:1 for the TfOH-assisted reaction,
a correlation that has also been observed experimentally
(Table 3). In this regard, three of the four endo transition
states for the catalyzed reaction (TSC1, TSC2, TSB1) present
an additional H-bond interaction between the SdO or CdO
lone pairs of the Brønsted acid and a hydrogen atom at the
sp2 hybridized carbon of the diene. This secondary H-bond
interaction,42 which to the best of our knowledge has been
previously unnoticed for Diels-Alder reactions, although
weak, may contribute in creating an efficient H-bond net-
work during the TS with consequences in both the reactivity
and endo/exo selectivity of the reaction.43,44
features: (1) Both chiral and achiral versions of R0-hydroxy
enones are readily available from (1R)-(þ)-camphor and
acetone, respectively, two commodity chemicals available
in bulk. (2) Catalytic activation (LUMO lowering) of R0-
hydroxy enones against [4 þ 2] cycloadditions with dienes
can be achieved by either Lewis acids, particularly Cu(OTf)2,
or Brønsted acids, particularly triflic acid. (3) The resulting
catalytically formed 1,4-metal or 1,4-proton coordination
complexes are tight enough to allow for an efficient chirality
transfer in either of the two feasible alternatives: substrate-
controlled Diels-Alder reactions (chiral R0-hydroxy enones
derived from camphor) or catalyst-controlled Diels-Alder
reactions (simple achiral R0-hydroxy enones in combination
with Evans chiral bisoxazoline-Cu catalysts). (4) The afore-
mentioned transient complexes exhibit remarkable reactivity
and stereoselectivity even against poorly reactive diene/
dienophile counterparts, which perform badly with most
previous Diels-Alder protocols. (5) Removal of the auxili-
ary from the Diels-Alder adducts to afford the correspond-
ing carboxylic acids, ketones, and aldehydes, proceeds
smoothly, with camphor or acetone as the only organic side
product that can be easily recovered and recycled. As illu-
strated, these methods based on R0-hydroxy enones are
extremely attractive for the asymmetric synthesis of complex
molecules such as natural products. We hope this robust
Brønsted acid catalyzed Diels-Alder technology will con-
tinue to provide a convenient platform for the access of
building blocks that remain elusive or difficult targets for
Conclusions
R0-Hydroxy enones are efficient and versatile dienophiles
for asymmetric catalytic Diels-Alder reactions and consti-
tute competitive bidentate templates based on the following
(42) For relevant information on the CH O hydrogen bond, see: (a)
3 3 3
Desiraju, G. R. Chem. Comm. 2005, 2995–3001. For the importance of dual
activation of substrate acceptors and donors in asymmetric synthesis, see:
(b) Ma, J.-A.; Cahard, D. Angew. Chem. 2004, 116, 4666–4683. (c) Angew.
Chem., Int. Ed. 2004, 43, 4566-4583.
(43) The possibility of such H-bonding network between the acid catalyst
and both the diene and the dienophile being also established in other systems,
especially those involving enones, should not be discarded. See Supporting
Information.
(44) One referee suggested that the observed selectivity trend could be
rationalized on the basis of sterics alone, considering the triflate, the one that
imparts the best selectivity, is the largest counterion.
1470 J. Org. Chem. Vol. 75, No. 5, 2010

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Banuelos et al.
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other methodologies. Finally, a rationale of both substrate
activation and efficient chirality transfer can be drawn for
these Brønsted acid promoted Diels-Alder reactions in
which multiple H-bonding is crucial. The way specific H-
bonds contribute to keep in close contact both diene and
dienophile reactants as well as the Brønsted acid promoter in
our models may also serve to help better understand the role
played by such weak interactions in a more general context
within catalysis.
[R]25D -29.0 (c 1.0, CH2Cl2); IR (neat, cm-1) 3534 (OH), 1693
(CO); 1H NMR (CDCl3) δ 6.40 (t, 1H, J = 6.9 Hz), 5.86 (t, 1H,
J = 7.0 Hz), 2.96 (m, 1H), 2.75 (dd, 1H, J1 = 1.83 Hz, J2 = 5.5
Hz), 2.65 (m, 1H) 2.32 (s, 1H), 2.07-0.81 (m, 23H), 1.09 (s, 3H),
1.04 (s, 3H), 0.81 (s, 3H); 13C NMR (CDCl3) δ 214.3, 137.3,
129.6, 86.0, 53.2, 52.7, 49.8, 44.8, 42.4, 42.0, 40.9, 32.9, 32.6,
31.3, 30.5, 29.8, 27.0, 26.5, 26.3, 25.9, 20.7, 20.4, 19.0, 10.9.
Anal. Calcd for C25H38O2 (370.57) C, 81.03; H, 10.34. Found:
C, 81.06; H, 10.32.
(1R)-2-endo-[(1S,6R)-6-Cyclohexyl-4-methylcyclohex-3-en-1-
ylcarbonyl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (23). The ti-
tle compound was prepared according to General Procedure C
from enone 12b (0.145 g, 0.5 mmol) and isoprene (0.25 mL, 2.5
Experimental Section
mmol) in 55 h: 0.103 g (57%); white solid; mp 90-92 °C; [R]25
General Procedure A: Uncatalyzed Diels-Alder Reactions of
1. To a solution of the R0-hydroxy enone 1 (0.208 g, 1 mmol) in
CH2Cl2 (4 mL) was added dropwise the corresponding diene (5
mmol), and the mixture was stirred at room temperature until
TLC analysis indicated that the reaction was complete. The
solvent was removed under reduced pressure, and the crude
product was purified by flash silica gel column chromatography
using ethyl acetate/hexane 1:60 as eluant.
General Procedure B: Cu(OTf)2-Catalyzed Diels-Alder Re-
actions of 1. To a solution of the R0-hydroxy enone 1 (0.208 g, 1
mmol) in CH2Cl2 (4 mL) cooled to 0 °C under nitrogen atmo-
sphere, the corresponding diene (5 mmol) and Cu(OTf)2 (36 mg,
0.1 mmol) were added, and the mixture was stirred at the same
temperature until TLC analysis indicated that the reaction was
complete. Then CH2Cl2 (10 mL) and water (10 mL) were added,
the layers were separated, and the aqueous layer was extracted
with CH2Cl2 (2 ꢀ 10 mL). The combined organics were dried
over MgSO4, and the solvent was removed under reduced
pressure. Purification of the crude product was effected by flash
silica gel column chromatography using ethyl acetate/hexane
1:60 as eluant.
General Procedure C: Brønsted Acid Catalyzed Diels-Alder
Reactions. To a solution of triflic acid in CH2Cl2 (0.125 M, 0.4
mL, 0.05 mmol for enones 1, 12a, and 12g; 0.125 M, 2 mL, 0.25
mmol, for enones 12b and 12c; 0.125 M, 1.2 mL, 0.15 mmol, for
enones 12d, 12e, and 12f) cooled to -78 °C under a nitrogen
atmosphere were added the corresponding R0-hydroxy enone 1
or 12 (0.5 mmol) and diene (2.5 mmol). The mixture was stirred
at -78 °C for the specified time (from 1 to 72 h) and then was
quenched with a saturated aqueous solution of NaHCO3 (5
mL). The resulting mixture was allowed to warm to room
temperature, after which the layers were separated, and the
aqueous layer was extracted with CH2Cl2 (2 ꢀ 10 mL). The
combined organics were dried over MgSO4, and the solvent was
removed under reduced pressure. Purification of the crude
product was effected by flash silica gel column chromatography
using ethyl acetate/hexane 1:60 as the eluant.
D
þ51.0 (c 0.5, CH2Cl2); IR (neat, cm-1) 3529 (OH), 1690 (CO);
1H NMR (CDCl3) δ 5.29 (m, 1H), 3.19 (m, 1H), 2.29 (d, 1H, J =
12.8 Hz), 2.21 (s, 1H), 2.16-0.94 (m, 22H), 1.65 (s, 3H), 1.11 (s,
3H), 0.97 (s, 3H), 0.82 (s, 3H); 13C NMR (CDCl3) δ 218.0, 133.6,
118.3, 88.2, 52.5, 50.7, 44.9, 43.9, 41.7, 39.9, 32.6, 30.2, 29.9,
29.7, 28.1, 27.1, 26.8, 26.7, 26.6, 23.5, 20.9, 20.5, 10.9. Anal.
Calcd for C24H38O2 (358.62) C, 80.37; H, 10.70. Found: C,
80.41; H, 10.77.
(1R)-2-endo-[(1S,6R)-6-Cyclohexyl-3,4-dimethylcyclohex-3-
en-1-ylcarbonyl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (24).
The title compound was prepared according to General Proce-
dure C from enone 12b (0.145 g, 0.5 mmol) and 2,3-dimethyl-
1,3-butadiene (0.29 mL, 2.5 mmol) in 72 h: 0.112 g (60%); white
solid; mp 60-62 °C; [R]25D þ51 (c 1.0, CH2Cl2); IR (neat, cm-1
)
3547 (OH), 1691 (CO); 1H NMR (CDCl3) δ 3.23 (m, 1H), 2.30
(d, 1H, J = 12.4 Hz), 2.23 (s, 1H), 2.06-0.88 (m, 22H), 1.62 (s,
3H), 1.58 (s, 3H), 1.12 (s, 3H), 0.99 (s, 3H), 0.83 (s, 3H); 13C
NMR (CDCl3) δ 218.0, 125.2, 123.0, 88.1, 52.5, 50.6, 45.2, 44.9,
42.0, 41.7, 39.9, 36.6, 32.7, 31.4., 29.8, 28.0, 27.2, 26.9, 26.8, 26.7,
20.9, 20.5, 19.0, 18.6, 10.9. Anal. Calcd for C25H40O2 (372.65) C,
80.57; H, 10.84. Found: C, 80.52; H, 10.87.
(1R)-2-endo-[(1R,2S,3S,4S)-3-tert-Butylbicyclo[2.2.1]hept-5-
en-2-ylcarbonyl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (25).
The title compound was prepared according to General Proce-
dure C from enone 12c (0.132 g, 0.5 mmol) and cyclopentadiene
(0.20 mL, 2.5 mmol) in 18 h: 0.088 g (53%); solid; mp 110-113
°C. [R]25 þ91.0 (c 1.0, CH2Cl2); IR (neat, cm-1) 3507 (OH),
D
1686 (CO); 1H NMR (CDCl3) δ 6.36 (dd, 1H, J1 = 3.3 Hz, J2 =
5.5 Hz), 5.69 (dd, 1H, J1 = 2.6 Hz, J2 = 5.1 Hz), 3.30 (m, 1H),
3.22 (m, 1H), 2.70 (m, 1H), 2.32 (d, 1H, J = 13.5 Hz), 2.19 (s,
1H), 2.06-0.82 (m, 9H), 1.10 (s, 3H), 1.05 (s, 3H), 0.87 (s, 9H),
0.82 (s, 3H); 13C NMR (CDCl3) δ 214.3, 140.2, 131.8, 86.9, 52.9,
52.5, 50.0, 48.7, 47.9, 47.0, 44.8, 44.5, 42.2, 32.3, 29.8, 29.1, 26.9,
20.8, 20.5, 10.9. Anal. Calcd for C22H34O2 (330.56) C, 79.93; H,
10.39. Found: C, 79.95; H, 10.43.
(1R)-2-endo-[(1S,6S)-3,4-Dimethyl-6-tert-butylcyclohex-3-en-1-
ylcarbonyl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (26). The
title compound was prepared according to General Procedure
C from enone 12c (0.132 g, 0.5 mmol) and 2,3-dimethyl-1,3-
butadiene (0.29 mL, 2.5 mmol) in 72 h: 0.091 g (53%); colorless
oil; [R]25D þ30 (c 1.0, CH2Cl2); IR (neat, cm-1) 3546 (OH), 1691
(1R)-2-endo-[(1R,2S,3S,4S)-3-Cyclohexylbicyclo[2.2.1]hept-
5-en-2-ylcarbonyl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (21).
The title compound was prepared according to General Proce-
dure C from enone 12b (0.145 g, 0.5 mmol) and cyclopentadiene
(0.20 mL, 2.5 mmol) in 18 h: 0.112 g (63%); oil; [R]25 þ48.0
D
1
(c 1.0, CH2Cl2); IR (neat, cm-1) 3484 (OH), 1689 (CO); 1H NMR
(CDCl3) δ 6.28 (dd, 1H, J1 = 3.3 Hz, J2 = 5.5 Hz), 5.69 (dd, 1H,
J1 = 2.2 Hz, J2 = 5.5Hz), 3.21 (m, 2H), 2.80(m, 1H), 2.39 (d, 1H,
J = 9.5 Hz) 2.30 (s, 1H), 2.07-0.81 (m, 20H), 1.08 (s, 3H), 1.01 (s,
3H), 0.81 (s, 3H); 13C NMR (CDCl3) δ 214.7, 138.9, 131.9, 86.4,
52.7, 52.1, 49.8, 48.5, 47.6, 47.1, 44.7, 41.6, 41.3, 32.9, 32.1, 29.8,
26.6, 26.5, 26.4, 20.7, 20.3, 10.6. Anal. Calcd for C24H36O2
(356.60) C, 80.83; H, 10.20. Found: C, 80.80; H, 10.23.
(CO); H NMR (CDCl3) δ 3.25 (m, 1H), 2.47 (s, 1H), 2.19 (d,
1H, J = 13.5 Hz), 2.07-0.90 (m, 11H), 1.57 (s, 3H), 1.50 (s, 3H),
1.05 (s, 3H), 0.88 (s, 3H), 0.81 (s, 9H), 0.77 (s, 3H); 13C NMR
(CDCl3) δ 215.7, 124.7, 120.4, 87.1, 51.8, 49.6, 43.9, 42.4, 41.2,
40.6, 33.2, 32.0, 30.2, 29.2, 27.8, 25.6, 19.8, 19.5, 18.0, 17.7, 9.7.
Anal. Calcd for C23H38O2 (346.61) C, 79.69; H, 11.07. Found: C,
79.74; H, 11.03.
(1R)-2-endo-[(1R,2S,3S,4S)-3-Phenylbicyclo[2.2.2]oct-5-en-
2-ylcarbonyl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (28). The
title compound was prepared according to General Procedure C
from enone 12d (0.14 g, 0.5 mmol) and 1,3-cyclohexadiene
(0.20 mL, 2.5 mmol) in 16 h at -50 °C. Purification was effected
by flash chromatography using a 1:50 ethyl acetate/hexane
(1R)-2-endo-[(1R,2S,3S,4S)-3-Cyclohexylbicyclo[2.2.1]oct-5-
en-2-ylcarbonyl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (22).
The title compound was prepared according to General Proce-
dure C from enone 12b (0.145 g, 0.5 mmol) and 1,3-cyclo-
hexadiene (0.20 mL, 2.5 mmol) in 60 h: 0.124 g (67%); oil;
J. Org. Chem. Vol. 75, No. 5, 2010 1471

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JOCArticle
mixture: 0.169 g (93%); oil; [R]25 þ73.3 (c 1.0, CH2Cl2); IR
layer was extracted with CH2Cl2 (2 ꢀ 15 mL). The combined
organics were dried over MgSO4, and the solvent was removed
under reduced pressure. Purification of the crude product was
effected by flash silica gel column chromatography using hexane
D
(neat, cm-1) 3510 (OH), 1689 (CO); 1H NMR (CDCl3) δ
7.44-7.27 (m, 5H) 6.70 (t, 1H, J = 7.3 Hz), 6.14 (t, 1H, J =
7.0 Hz), 3.59 (d, 1H, J = 6.6 Hz), 3.32 (d, 1H, J = 4.8 Hz), 3.03
(s, 1H), 2.96 (d, 1H, J = 4.8 Hz) 2.57 (d, 1H, J = 3.7 Hz), 2.32 (d,
1H, J = 13.9 Hz), 2.19-0.43 (m, 10H), 1.16 (s, 3H), 0.88 (s, 3H),
0.83 (s, 3H); 13C NMR (CDCl3) δ 215.8, 142.1, 136.4, 129.9,
128.2, 127.9, 126.3, 85.9, 53.4, 49.9, 46.5, 45.0, 40.4, 37.8, 33.1,
29.3, 27.1, 26.5, 20.6, 20.0, 17.9, 9.8. Anal. Calcd for C25H32O2
(364.57) C, 82.36; H, 8.86. Found: C, 82.41; H, 8.83.
as the eluant: 0.36 g (85%); colorless oil; [R]25 þ9 (c 1.0,
D
CH2Cl2); IR (neat, cm-1) 3559 (OH), 1700 (CO), 1453; 1H
NMR (CDCl3) δ 7.32-7.21 (m, 5H), 5.50 (m, 1H), 5.14
(t, 1H, J = 6.6 Hz), 3.54 (m, 1H), 3.05 (dt, 1H, J1 = 11.4 Hz,
J2 = 5.1 Hz), 2.60-0.60 (m, 14H), 1.94 (d, 1H, J = 13.2 Hz),
1.71 (s, 3H), 1.63 (s, 3H), 0.96 (s, 3H), 0.90 (s, 3H), 0.76 (s, 3H),
0.58 (s, 1H); 13C NMR (CDCl3) δ 216.5, 143.7, 136.9, 131.5,
128.4, 128.3, 126.9, 124.0, 118.9, 87.8, 51.9, 51.0, 48.0, 44.8, 44.2,
41.8, 37.3, 34.6, 30.4, 30.2, 26.4, 26.0, 25.7, 20.9, 20.6, 17.8, 11.2.
Anal. Calcd for C29H40O2 (420.63) C, 82.80; H, 9.60. Found: C,
82.85; H, 9.63.
Diels-Alder Reaction with Enol Phosphate 33. Synthesis of
(1R)-2-endo-[(1R)-4-Diethylphosphoryloxycyclohex-3-en-1-
ylcarbonyl]-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (34). To a
solution of 1 (0.104 g, 0.5 mmol) in CH2Cl2 (2 mL) cooled to 0 °C
under a nitrogen atmosphere were added dienyl phosphate 33
(0.515 g, 2.5 mmol) and copper triflate (0.054 g, 0.15 mmol). The
mixture was stirred at 0 °C for 72 h and then was quenched with
water (5 mL). The resulting mixture was allowed to warm to
room temperature, after which the layers were separated, and
the aqueous layer was extracted with CH2Cl2 (2 ꢀ 10 mL). The
combined organics were dried over MgSO4, and the solvent was
removed under reduced pressure. Purification of the crude
product 34 was effected by flash silica gel column chromatog-
raphy using a 1:4 ethyl acetate/hexane mixture as the eluant:
0.185 g (89%); yellow oil; [R]25D -11 (c 1.0, CH2Cl2); IR (neat,
cm-1) 3377 (OH), 1701 (CO), 1255, 1135 (phosphate); 1H NMR
(CDCl3) δ 5.42 (m, 1H), 4.08 (m, 4H), 3.04 (m, 1H), 2.27 (s, 1H),
2.18 (m, 1H), 2.11-1.10 (m, 12H), 1.29 (m, 6H), 1.06 (s, 3H),
0.91 (s, 3H), 0.78 (s, 3H); 13C NMR (CDCl3) δ 216.2, 146.8 (d),
108.9 (d), 88,1, 64.1 (d), 52.2, 50.4, 44.9, 41.6, 41.0, 30.3, 27.2,
26.7 (d), 26.3, 20.7, 20.4, 16.1, 16.0, 10.8. Anal. Calcd for
C21H35O6P (414.47) C, 60.85; H, 8.51. Found: C, 60.79; H, 8.47.
Oxidative Removal of the Auxiliary from Adducts. Synthesis
of (1R,2S,3S,4S)-3-Phenylbicyclo[2.2.2]oct-5-ene-2-carbalde-
hyde (58). To a stirred solution of the adduct 28 (0,366 g,
1 mmol) in dry THF (5 mL) at 0 °C under nitrogen atmosphere
was added dropwise LiAlH4 (1 M in THF, 3 mL, 3 mmol). After
stirring at 0 °C for 1 h, the reaction mixture was quenched with
1 N HCl (2 mL) and was diluted with Et2O. The organic extract
was washed with water (2 ꢀ 10 mL), dried over MgSO4, and
concentrated in vacuo. The crude product obtained was suffi-
ciently pure to use in the next step without further purification.
To a solution of the crude oil in acetonitrile (12 mL) at 0 °C was
added dropwise a solution of ceric ammonium nitrate (CAN)
(1.64 g, 3 mmol) in water (6 mL) and the mixture was stirred at
0 °C for 15 min. Then, water (3 mL) was added, and the mixture
was extracted with CH2Cl2 (2 ꢀ 20 mL). The combined organic
extracts were dried over MgSO4, filtered, and the solvent was
evaporated. Purification of the crude product was effected by
flash silica gel column chromatography using a 1:30 ethyl
acetate/hexane mixture as the eluant: 0.166 g (78%); white solid;
mp 66-68 °C; [R]25D þ82 (c 1.0, CH2Cl2); IR (neat, cm-1) 1722
(CO); 1H NMR (CDCl3) δ 9.51 (s, 1H), 7.40-7.20 (m, 5H), 6.54
(t, 1H, J = 8.1 Hz), 6.21 (t, 1H, J = 6.6 Hz), 3.23 (d, 1H, J = 6.2
Hz), 3.11 (m, 1H), 2.85 (d, 1H, J = 6.2 Hz), 2.64 (m, 1H),
1.76-1.04 (m, 4H); 13C NMR (CDCl3) δ 202.5, 141.9, 137.0,
130.9, 128.4, 127.9, 126.3, 55.9, 43.2, 36.6, 31.3, 25.6, 18.8. Anal.
Calcd for C15H16O (212.31) C, 84.85; H, 7.61. Found: C, 84.81;
H, 7.66.
Synthesis of Aldehyde 63. To a stirred solution of the aduct 62
(0,42 g, 1 mmol) in dry THF (5 mL) at 0 °C under nitrogen
atmosphere was added dropwise LiAlH4 (1 M in THF, 3 mL, 3
mmol). After stirring at 0 °C for 1 h, the reaction mixture was
quenched with 1 N HCl (2 mL), diluted with Et2O, and filtered
through Celite. The organic extract was washed with water (2 ꢀ
10 mL), dried over MgSO4 and concentrated in vacuo. The
crude product obtained was sufficiently pure to use in the next
step without further purification. Pb(AcO)4 (0.88 g, 2 mmol)
was added in portions to a solution of the crude oil in benzene (4
mL) at 5 °C. After stirring for 50 min, an aqueous saturated
solution of NaHCO3 (4 mL) was slowly added. The resulting
mixture was filtered through a Celite pad eluting with CH2Cl2
(10 mL). The mixture was extracted with CH2Cl2 (2 ꢀ 10 mL),
and dried with MgSO4. The solvent was evaporated and the
resulting crude product was purified by column chromatogra-
phy (eluent EtOAc/Hex 1:50) providing the corresponding
aldehyde as a colorless oil: 0.23 g, (84%); [R]25 þ22 (c 1.0,
D
CH2Cl2); IR (neat, cm-1) 1726 (CO), 1453; 1H NMR (CDCl3) δ
9.49 (d, 1H, J = 2.9 Hz), 7.38-7.23 (m, 5H), 5.52 (m, 1H), 5.11
(t, 1H, J = 6.6 Hz), 3.13 (m, 1H), 2.77 (m, 1H), 2.50-2.06 (m,
8H), 1.71 (s, 3H), 1.62 (s, 3H); 13C NMR (CDCl3) δ 204.2, 143.5,
137.6, 131.6, 128.7, 127.3, 126.6, 124.0, 118.2, 51.3, 41.2, 37.3,
36.0, 26.3, 25.7, 24.9, 17.7. Anal. Calcd for C19H24O (268.43) C,
85.01; H, 9.03. Found: C, 85.07; H, 9.06.
2-Bromo-5-methoxy-1,3-bis(methoxymethoxy)benzene. A so-
lution of 2-bromo-5-methoxyresorcinol45 (0.22 g, 1 mmol) in
dry DMF (2.4 mL) was added slowly to a stirred suspension of
NaH (0.18 g, 7 mmol) in dry DMF (2.4 mL) at 0 °C. After
stirring 20 min at 0 °C, chloromethyl methyl ether (0.31 mL, 4
mmol) was added dropwise. The mixture was stirred at room
temperature for 2 h, diluted with Et2O, and washed with H2O (3
ꢀ 15 mL), a saturated solution of NaHCO3 (15 mL), and brine
(15 mL). The organic phase was dried over MgSO4, concen-
trated in vacuo, and chromatographed on silica (EtOAc/hexane,
1:15) to give the desired compound (0.26 g, 86%) as a white
solid: mp 39-41 °C; IR (neat, cm-1) 1586; 1H NMR (CDCl3) δ
6.45 (s, 2H), 5.21 (s, 4H), 3.75 (s, 3H), 3.50 (s, 6H); 13C NMR
(CDCl3) δ 159.9, 155.0, 96.1, 94.9, 94.5, 56.2, 55.3. Anal. Calcd
for C11H15BrO5 (307.14) C, 43.02; H, 4.92. Found: C, 43.05; H,
4.93.
Nucleophilic Alkylation of Aldehyde 63. Synthesis of Carbinol
64. n-BuLi (2.5 M in hexanes, 0.38 mL, 0.95 mmol) was added to
a solution of 2-bromo-5-methoxy-1,3-bis(methoxymethoxy)-
benzene (0.30 g, 1 mmol) in THF (20 mL) cooled to -78 °C
under a nitrogen atmosphere. After stirring for 30 min at the
same temperature, aldehyde 63 (0.30 g, 1.1 mmol) in THF
(2 mL) was added dropwise. The resulting mixture was allowed
to stir for 2 h at room temperature and then was quenched with a
saturated aqueous solution of NH4Cl (10 mL). The aqueous
layer was extracted with CH2Cl2 (2 ꢀ 15 mL), the combined
Synthesis of (-)-Nicolaioidesin C. TfOH-Catalyzed Diels-
Alder Reaction with Myrcene. Synthesis of 62. To a solution of
R0-hydroxy ketone 12d (0,28 g, 1 mmol) in CH2Cl2 (4 mL) cooled
to -78 °C under a nitrogen atmosphere were added dropwise
myrcene (0.85 mL, 5 mmol) and triflic acid (0.01 mL, 0.1 mmol).
The mixture was stirred at -78 °C for 20 h and then was quen-
ched with a saturated aqueous solution of NaHCO3 (10 mL).
The resulting mixture was allowed to warm to room tempera-
ture, after which the layers were separated, and the aqueous
(45) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090–3100.
1472 J. Org. Chem. Vol. 75, No. 5, 2010

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Banuelos et al.
JOCArticle
organics were dried over MgSO4, and the solvent was removed
under reduced pressure. The product was purified by flash silica
gel column chromatography using a 1:10 mixture of EtOAc/
hexane as the eluant: 0.41 g (82%); IR (neat, cm-1) 3568 (OH),
127.8, 125.7, 124.1, 119.1, 115.2, 94.6, 94.5, 56.1, 55.4, 52.7, 42.1,
37.3, 37.2, 28.4, 26.4, 25.7, 17.8. To a stirred solution of the
above ketone (0.49 g, 1 mmol) in a mixture of CH2Cl2 (11 mL)/
MeOH (11 mL) was added p-toluenesulfonic acid monohydrate
(0.096 g, 0.5 mmol). The reaction was refluxed at 40 °C for 3.5 h.
Then, water (15 mL) was added, and the mixture was extracted
with EtOAc (2 ꢀ 20 mL). The combined organic extracts were
washed with brine (15 mL), dried over MgSO4, and filtered, and
the solvent was evaporated. Purification of the crude product
was effected by flash silica gel column chromatography using a
10:1 mixture hexane/EtOAc as the eluant: 0.35 g (86%); yellow
1609, 1592; 1H NMR (CDCl3)
δ (major diastereomer)
7.33-7.18 (m, 5H), 6.41 (s, 2H), 5.49 (m, 1H), 5.15 (m, 1H),
5.15 (s, 4H), 4.91 (m, 1H), 4.05 (m, 1H), 3.78 (s, 3H), 3.46 (s,
6 H), 2.94 (m, 1H), 2.38-1.61 (m, 8H), 1.70 (s, 3H), 1.62 (s, 3H);
13C NMR (CDCl3) (major diastereomer) δ 159.6, 156.1, 146.0,
136.8, 131.3, 128.0, 127.4, 125.8, 124.2, 120.1, 112.5, 94.7, 94.6,
68.8, 56.3, 55.4, 44.9, 42.3, 37.5, 36.4, 26.5, 25.8, 24.0, 17.8. Anal.
Calcd for C30H40O6 (496.63) C, 72.55; H, 8.12. Found: C, 72.57;
H, 8.11.
solid; mp 104-108 °C; [R]25 -49.1 (c 1.0, MeOH); IR (neat,
D
cm-1) 3291 (OH), 1626 (CO), 1583; 1H NMR (CDCl3) δ
7.28-7.08 (m, 5H), 5.89 (s, 2H), 5.54 (d, 1H, J = 4.4 Hz),
5.14 (t, 1H, J = 6.6 Hz), 4.54 (m, 1H), 3.73 (s, 3H), 3.36 (m, 1H),
2.66-2.00 (m, 8H), 1.71 (s, 3H), 1.62 (s, 3H); 13C NMR (CDCl3)
δ 208.9, 165.4, 163.1, 145.4, 137.4, 131.5, 128.3, 127.2, 125.9,
124.1, 119.2, 105.4, 94.3, 55.4, 50.0, 42.8, 38.3, 37.3, 30.7, 26.4,
25.7, 17.8. Anal. Calcd for C26H31O4 (406.56) C, 76.80; H, 7.45.
Found: C, 76.66; H, 7.71. MS (ESI, m/z) 405.0 (M - Hþ).
Oxidation of 64 and Final Deprotection. To a solution of
alcohol 64 (0.50 g, 1 mmol) in dry CH2Cl2 (6 mL) was added
Dess-Martin periodinane (0.85 g, 2 mmol) in two equal batches
in a 5 min interval at room temperature. Water (20 μL, 1.10
mmol) was dissolved in 20 mL of CH2Cl2 by drawing the solvent
mixture into, and expelling it from, a disposable pipet several
times. Thus prepared wet CH2Cl2 was added slowly via drop-
ping funnel to a vigorously stirring solution of alcohol 64 and
Dess-Martin periodinane in CH2Cl2. The clear solution grew
cloudy toward the end of wet CH2Cl2 addition, which required
30 min. After 90 min the reaction was quenched by adding a
Na2S2O3 doped saturated NaHCO3 solution (15 mL) and
stirring until both layers appeared clear. The layers were sepa-
rated, and the aqueous layer was extracted with CH2Cl2 (2 ꢀ 15
mL). The organic layers were combined, washed with saturated
NaCl (35 mL), dried with MgSO4, and filtered, and the solvent
was removed in vacuo. Purification of the crude product was
effected by flash silica gel column chromatography using a 10:1
mixture hexane/EtOAc as the eluant: 0.46 g (94%); colorless oil;
[R]25D -32.0 (c 1.0, CH2Cl2); IR (neat, cm-1) 1700 (CO), 1605;
1H NMR (CDCl3) δ 7.30-7.11 (m, 5H), 6.30 (s, 2H,), 5.47 (m,
1H), 5.11 (m, 1H), 4.95 (d, 2H, J = 2.6 Hz), 4.93 (d, 2H, J = 2.6
Hz), 4.90 (m, 1H), 3.75 (s, 3H), 3.48 (m, 1H), 3.38 (s, 6 H), 3.33
(m, 1H), 2.36-1.87 (m, 8H), 1.68 (s, 3H), 1.59 (s, 3H); 13C NMR
(CDCl3) δ 204.9, 161.9, 155.9, 145.4, 137.1, 131.4, 128.1, 128.0,
Acknowledgment. This work was financially supported by
the University of the Basque Country (UPV/EHU) and
ꢀ
Ministerio de Educacion y Ciencia (Grant CTQ2007-
68095-C02). Thanks are due to SGI/IZO-SGIker (UPV/
EHU) for the generous allocation of computational re-
sources. P.B. and A.H. thank Gobierno de Navarra for a
fellowship.
Supporting Information Available: Preparation of starting
enones; experimental procedures and characterization data of
all remaining new compounds, including NMR spectra; details
of the kinetic measurements; Cartesian coordinates of all com-
puted stationary points and relative and absolute activation
energies for all reactions. This material is available free of charge
via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 5, 2010 1473