Photoinduced intramolecular cyclopentanation vs photoprotolytic oxametathesis in polycyclic alkenes outfitted with conformationally constrained aroylmethyl chromophores

Article abstract of DOI:10.1021/jo301909j

Intramolecular photoinduced cyclizations are investigated in photoprecursors assembled in a modular fashion via a Diels-Alder reaction of acetylenic dienophiles with subsequent Michael additions of aromatic ketones to install a chromophore capable of initiating Paternò-Büchi cycloadditions or radical cyclization cascades. The protolytic oxametathesis in these systems allows for rapid access to novel polycyclic scaffolds decorated by formyl groups and carboxylates suitable for subsequent modifications. In conformationally constrained photoprecursors, a radical rearrangement takes place resulting in intramolecular 1,3-diradical cyclopentanation of the double bond.

Full text of DOI:10.1021/jo301909j

Article
pubs.acs.org/joc
Photoinduced Intramolecular Cyclopentanation vs Photoprotolytic
Oxametathesis in Polycyclic Alkenes Outfitted with Conformationally
Constrained Aroylmethyl Chromophores‡
Roman A. Valiulin, Teresa M. Arisco, and Andrei G. Kutateladze*
Department of Chemistry & Biochemistry, University of Denver, Denver, Colorado 80208, United States
S
* Supporting Information
ABSTRACT: Intramolecular photoinduced cyclizations are
investigated in photoprecursors assembled in a modular
fashion via a Diels−Alder reaction of acetylenic dienophiles
with subsequent Michael additions of aromatic ketones to
install a chromophore capable of initiating Paterno−Buchi
̀
̈
cycloadditions or radical cyclization cascades. The protolytic
oxametathesis in these systems allows for rapid access to novel
polycyclic scaffolds decorated by formyl groups and carbox-
ylates suitable for subsequent modifications. In conformation-
ally constrained photoprecursors, a radical rearrangement takes
place resulting in intramolecular 1,3-diradical cyclopentanation
of the double bond.
with the pyrolytic oxametathesis, most functional groups are
expected to tolerate these mild conditions, which enhances the
preparative value of the method.
INTRODUCTION
■
Photoinduced reactions provide expeditious access to prohib-
itively strained polycyclic targets, which are difficult or
impossible to synthesize using ground state chemistry. Often
the photogenerated semiproducts are introduced into secon-
dary transformations to take advantage of the strain installed at
the photochemical step. For example, Rawal’s “general strategy
for increasing molecular complexity”1 utilizes the intra-
In this paper, we examine topological and stereochemical
effects on the outcomes of the intramolecular Paterno−Buchi
̀
̈
reaction and subsequent protolytic cycloreversion in poly-
cycloalkenes tethered to the benzoyl chromophore via a more
flexible tether containing an extra methylene group. We will
show that, unlike the case of aroyl norbornenes or
bicyclo[2.2.2]octenes, i.e. the photoprecursors where benzoyls
are directly attached to the polycyclic scaffold, the overall
reaction course is highly dependent on the stereochemistry of
the starting keto-alkene, allowing for superb reaction control
and at the same time greater diversity of the products. The
impetus behind this research was to evaluate in the context of
diversity-oriented synthesis the prospects of modular design of
photoprecursors for photoprotolytic oxametathesis, and to
probe how subtle variations in the structure of the starting
materials could allow for considerable changes in the reaction’s
regio- and stereochemical outcomes or, alternatively, turn off
molecular Paterno−
̀
Buchi reaction in acyl norbonenes2 to
̈
access extremely strained polycyclic oxetanes, which are
subsequently treated with Cohen’s LDBB3 to trigger a radical
anion fragmentation cascade yielding di- and triquinanes in a
total of two simple steps. We demonstrated that under acidic
conditions, photogenerated polycyclic oxetanes undergo several
spectacular cationic transformations.4 Such oxetanes can also be
reverted pyrolytically,5 or via an electron transfer-induced
reaction,6 to an alternative pair of an alkene and an aldehyde,
Scheme 1, in a manner resembling the metathesis reaction, for
which Jones5 suggested the term “carbonyl-olefin metathesis.”
the Paterno−Buchi channel altogether, switching to a
̀
̈
Scheme 1
completely different photoreactivity.
RESULTS AND DISCUSSION
■
We took inventory of efficient coupling reactions and chose
Diels−Alder additions of reactive dienophiles, dimethyl
acetylene-dicarboxylate (DMAD) and propiolates with cyclic
Such oxametathesis reactions have considerable synthetic
potential. We have recently shown that polycyclic alkenes
outfitted with photoactive benzoyl or heterobenzoyl groups
yield highly strained oxetanes, which undergo protolytic
oxametathetic cycloreversion to offer access to novel polycyclic
scaffolds under very mild conditions, ambient temperature and
catalytic amounts of HCl, as shown in Scheme 2 (top).7 Unlike
Special Issue: Howard Zimmerman Memorial Issue
Received: September 19, 2012
© XXXX American Chemical Society
A
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Scheme 2
Scheme 3
reflects some intrinsic properties of the system. Judging by the
subsequent examples, which involve hydrogen-abstraction
reactions successfully competing with Paterno−Buchi cyclo-
̀
̈
additions, it is most likely that this photochemistry originates
from the triplet state of aroyl pendants. The initial 1,4-diradicals
leading to oxetanes 8a and 10a can be classified as exo-trig and
endo-trig.9 We will refer to the products of exo-trig cyclization
as γ-oxetanes and the endo-trig as δ (with α being the
attachment point of the phenacyl pendant to the bicyclic core).
Oxetanes 8a and 10a form in a nearly 1:1 ratio, indicating
that in these systems there is no intrinsic bias for cyclization
associated with the tether. The γ-oxetane is more strained than
the δ-oxetane: DFT calculations gave 11.2 kcal/mol difference
(Table 1, B3LYP/6-311+G(d,p), Gaussian 09, Revision A.02;
see Supporting Information (SI) for full reference and
computational details). Generally, both γ- and δ-oxetanes
described in this study are not stable on silica gel during
column chromatography. In this particular case only δ-oxetane
could be purified (44% isolated yield) and fully characterized by
NMR and X-ray crystallography. The γ-oxetane 8a was
characterized in a mixture with 10a by 1H NMR and introduced
into subsequent acid-catalyzed cycloreversion without addi-
tional purification.
Both oxetanes undergo cycloreversion, when subjected to
mild acidic conditions, completing the oxametathesis cycle. The
mechanism for formation of the presumed initial products of
oxametathesis, aldehydes 9a and 11a, is shown in Scheme 4.
Expectedly, under slightly acidic reaction conditions
aldehydes 9a and 11a are subject to epimerization via
enolization, which brings their formyl groups into the exo-
position. This is why the preferred experimental procedure for
protolytic oxametathesis involved trapping the aldehydes in a
form of cyclic acetals, 1,3-dioxolanes 12a and 13a, by running
the acid-catalyzed oxetane cycloreversion in the presence of
ethylene glycol to partially prevent such epimerization.
Ultimately, the one-pot procedure was developed in which
dienes,8 with subsequent Michael additions of benzoyl-
containing chromophores to the electrophilic double bond.
This formally allows for three diversity inputs in the synthesis
of photoprecursors. The Diels−Alder step with acetylenes
produces only one type homoconjugated diene, for example,
norbornadiene in the case of cyclopentadiene. However, the
Michael addition step potentially produces several diaster-
eomers of which we isolated and purified the photoactive endo-
phenacyl isomers and utilized them to probe the effects of steric
congestion in the photoprecursors on the outcome of
photoprotolytic oxametathesis.
Moderate endoselectivity of the enolate addition is achieved
with spirocyclopropanonorbornadienes 3, 4 and bicyclo[2.2.2]-
octadienes 5, 6. However, even in the 7-unsubstituted
norbornadienes 1, 2 the addition of substituted enolates (R ≠
H) occurs with modest endo bias. The endoselectivity is
improved with bulkier R groups in the enolate: diphenyletha-
none (R = Ph) exhibits better than 95% of endo-selectivity.
Scheme 2 illustrates that Paterno−Buchi reaction in the endo-
̀
̈
aroyl precursors A, described in ref 7, yields only one type
oxetane B (γ-oxetane), which upon treatment with catalytic
amounts of acid cycloreverts into bicyclo[n.2.1]alkenes C
possessing a formyl group. The modular approach that we
explore in this work gives phenacyl photoprecursors 7 in which
the chromophore is connected to the bicyclic core via a more
the Paterno−Buchi step was carried out in dichloromethane
̀
̈
flexible tether, so that the initial Paterno−
̀
Buchi step can
containing HCl and ethylene glycol, as shown in Scheme 5.
The isolated yields of dioxolanes 12a and 13a are modest,
but this is a straightforward one-pot synthetic photochemical
procedure starting from the readily available 7a.
̈
potentially yield both regioisomeric oxetanes, 8 and 10. The
resulting cycloreversion products in these systems possess
either [3.n.1] (9) or [n.3.0] (11) bicyclic topology.
The first example, shown in Scheme 3, demonstrates the
Addition of the enolate of propiophenone to Michael
acceptor 5 yields several diastereomers. We isolated and
purified the trans-diastereomer 7b (Z = CH2CH2, Y = H, exo-
COOMe), possessing endo-phenacyl and exo-COOMe groups,
regiochemical outcome of the intramolecular Paterno−Buchi
̀
̈
cycloaddition in the simplest case of a bicyclo[2.2.2]octane
system in which the second substituent, methoxycarbonyl
group, is exo-trans to the photoactive phenacyl pendant. In this
case the aroyl group is free to rotate unobstructed, and the
regiochemistry of the [2 + 2] photocycloaddition presumably
which is Paterno−Buchi competent. Under the conditions of
̀
̈
protolytic oxametathesis, this endo-diastereomer showed very
1
high regioselectivity. According to the H NMR of reaction
B
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Table 1. DFT, B3LYP/6-311+G(d,p), Relative Energies of Oxetanes and Triplet 1,4-Diradicals (EDFT‑δ−EDFT‑γ
)
Scheme 4
Scheme 5
to allow for its isolation in 65% yield. Since the length of the
tether is identical in both cases, the regiochemical outcome of
this reaction is likely determined by the conformational bias
introduced by the methyl group, which defines the initial
conformation of the photoactive pendant with respect to the
double bond of the bicyclic core, Scheme 6.
Provided that in the low energy conformation the benzoyl
pendant and the methyl group are “out” (i.e., hydrogen is “in”,
Scheme 6
mixture, irradiation of 7b produced exclusively δ-oxetane 10b
(>95%), which was sufficiently stable on the silica gel column
C
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under the bicyclic core) as shown in Scheme 6, the formation of
oxetane 10b occurs with the least motion of the excited
carbonyl.
generating endo photoprecursors. This is why we focused
mostly on the bicyclic[2.2.1]heptane cores assembled with
DMAD. The Diels−Alder product of DMAD and spirohepta-
diene also improved the endo-selectivity of Michael additions of
enolates of acetophenone, propiophenone, valerophenone, and
3-phenylpropiophenone.
Energetically, in the parent bicyclo[2.2.2]octane system, the
γ-diradical of type DR-8a (Scheme 3) is approximately 7 kcal/
mol more stable than the δ-diradical of type DR-10a. The fact
that oxetanes 8a and 10a are formed in nearly equal amounts
implies that while the γ-diradical may be forming to a greater
extent, it fails to close the oxetane ring after the intersystem
crossing into the singlet manifold because the γ-oxetane is
prohibitively (>11 kcal/mol) more strained than the δ-oxetane.
The relative orientation of singly occupied orbitals in both γ-
and δ-diradicals is similar; there is no reason to believe that the
spin−orbit coupling matrix element is considerably greater for
one of them.10 We suggest that because of the unfavorable
energetics of the reaction channel leading to the γ-oxetane, the
γ-diradicals after intersystem crossing from the triplet to singlet
potential energy surface partition into the Grob fragmentation
channel more frequently than the δ-diradicals (which readily
cyclize to form more stable δ-oxetanes). For 7a these two
trends cancel out leading to nearly equal amounts of 8a and
10a. In contrast, the methyl substitution in the tether of 7b
changes the energetics: the calculated energy difference for
triplet γ- and δ-diradicals is 7.8 kcal/mol for the epimer of 7b,
which produces the diradical with Me out (or exo-). However,
for 7b itself (Me is in or endo- in the diradical) this energy
difference decreases to only 2.8 kcal/mol @ B3LYP/6-
311+G(d,p). Given that the resulting δ-oxetane 10b is still
more than 12 kcal/mol more stable than the γ-oxetane, the
regiospecific outcome in Scheme 6 becomes readily predictable.
As judged by the 1H NMR of the reaction mixture,
acetophenone adduct 7c formed γ-oxetane 8c exclusively,
which in the presence of catalytic acid smoothly transforms into
the product of oxametathesis 9c and subsequently into its acetal
12c (Scheme 8). This is in keeping with the least motion
hypothesis, as the counter clockwise rotation is blocked by the
endo-COOMe.
Scheme 8
Our calculations show that in the parent bicyclo[2.2.1]-
heptane system, the DFT energy difference between γ- and δ-
oxetane, 15.1 kcal/mol, is even greater than in the
bicyclo[2.2.2]octane framework. The endo-COOMe group in
the spirocyclopropano-norbornene-based oxetanes slightly
increases this energy difference to 15.8 kcal/mol. However,
the γ-diradical leading to γ-oxetane is 10.3 kcal/mol more stable
than the δ-diradical, so the δ-channel is no longer competitive.
As we later discovered, further increase in steric congestion
via the introduction of the methyl group in the tether could
It is also possible, but unlikely, that the Paterno−Buchi reaction
̀
̈
in these bicyclic systems occurs via a concerted mechanism, i.e.,
via a singlet four-membered transition state. We failed to
computationally locate singlet transition states on the reaction
hypersurface.
We found that the protolytic transformation of (a relatively
more stable, and therefore purifiable) 10b into 13b requires
elevated temperature of 70 °C. At ambient temperature,
elimination to form 14 occurs (Scheme 7). The structure of
shut down the Paterno−Buchi channel altogether in the
̀
̈
photoprecursors already outfitted with the endo-COOMe brake.
Michael addition of propiophenone enolate to bis-carboxylate
2 produced a single endo-diastereomer 7d. The DFT structure
of its most stable conformer shows that introduction of the
methyl group in the α-position locks the phenyl group in the
anti-conformation to this methyl (its X-ray structure is in
keeping with this computational prediction). As shown, even
upon clockwise rotation, the phenyl group is predicted to
encounter a steric clash with the endo-COOMe before the
excited carbonyl reaches the double bond. This suppresses the
Scheme 7
Paterno−Buchi channel almost completely, as we detect less
̀
̈
than 5% of the γ-oxetane in this series. The major product 15
(75%, Scheme 9) is a result of an unprecedented cascade
photoreaction. The stereochemistry of this transformation is
proved unambiguously, as the structures of both the photo-
precursor 7d and the product 15 are determined by X-ray
analysis.
this elimination product, alkene 14, was characterized with X-
ray crystallography. Remarkably, all these diverse modes of
reactivity are realized with very high degree of selectivity.
Michael additions to dicarboxylates 2 and 4 produced
diastereomeric trans-dicarboxylates, which provided an oppor-
tunity to probe the photochemistry in the systems where the
vicinal endo-carboxylate group severely constrains the con-
formational mobility of the aroyl chromophore. Generally low
yielding Michael additions to bicyclo[2.2.2]octane 6 possessing
two methoxycarbonyl groups rendered it not practical for
The tricycle[3.3.0.03,7]octane (bisnoradamantane11 or stel-
lane in Gleiter’s12 terminology) core of 15 is often accessed via
̀
intramolecular Paterno−Buchi reactions in endo-acyl norbor-
̈
nenes as extensively studied by Sauers.13 In contrast, the
reaction shown in Scheme 9 produces the stellane core as a
result of a radical cyclization in which two C−C bonds are
formed. Two plausible mechanistic rationales are shown in
D
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Scheme 9
Scheme 11
pentanols, a useful addition to the toolbox of photoassisted
synthetic chemistry.
Scheme 12
Scheme 10. Both mechanisms involve the initial β-hydrogen
abstraction (from the Me-group) by the excited benzoyl. This
1,3-diradical can recombine to form the cyclopropane ring as in
the Yang cyclization.14 This is followed by secondary
photoinduced cyclopropane ring-opening to form a more
stable 1,3-diradical, which subsequently adds to the double
bond (top mechanism). An alternative mechanism involves a
1,2-radical shift of the bicyclic core facilitated by the enol
formation, followed by the keto−enol equilibrium, second
excitation with H-abstraction, and an interrupted Yang
cyclization (bottom).
In both cases the secondary 1,3-diradical undergoes cyclo-
addition to the readily accessible double bond, which
constitutes radical cyclopentanation of alkenes. The minor
product 16 (15%) is considerably more strained, possessing a
cyclobutane moiety conceivably resulting from a formal [2 + 2]
cycloaddition of the enol form of the photoprecursor.
The spirocyclopropanonorbornadiene series with propiophe-
none gave the same result: the major photoproduct is derived
from cyclopentanation of the double bond in 7e with the
secondary 1,3-diradical, Scheme 11. As in the case above, both
the structure of the photoprecursor 7e and the product 17 is
determined by X-ray crystallographic analysis.
The general topology of this novel photorearrangement/
cyclopentanation of double bonds is shown in Scheme 12, which
constitutes a one-pot photoinduced synthesis of fused cyclo-
In these transformations we did not observe the products of
cyclopentanation by the initially photogenerated 1,3-diradical.
Presumably it is too short-lived (it has one primary radical
center) to successfully cyclopentanate the double bond.
Although, from the point of relative stability of the products,
the 1,3-cycloaddition of the primary 1,3-diradical ostensibly
produces less strained polycyclic structure. In order to probe
whether such alternative reactivity is possible, we simply
stabilized the second radical center by employing β-phenyl-
propiophenone at the Michael addition step. We were able to
separate chromatographically both diastereomers of the endo-
photoprecursors (7f and 7f′), which are expected to produce
much more stable doubly benzylic initial 1,3-diradical. The
structure of one of these photoprecursors, 7f, was unambigu-
ously determined by X-ray crystallography, and the structure of
7f′ was inferred from that. However, even with this additional
stabilization, the initial 1,3-diradical failed to endo-cyclo-
pentanate the norbornene double bond. This is somewhat in
keeping with the fact that we did not find any literature reports
on 1,3- or 1,4- Yang cyclizations (or Norrish Type II
fragmentations) interrupted by diradical cycloadditions to a
suitably positioned double bond.
Scheme 10
E
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Diastereomeric photoprecursors 7f and 7f′ exhibited very
different reactivity. As it is shown in Scheme 13, diastereomer
7f forms the major photoproduct 19, which is similar to the
formation of 15 described in Scheme 10, and the minor
cyclobutane 20.
Scheme 15
Scheme 13
two diastereomers of the rearranged cyclopentanation products
25, 26 plus the minor product of a formal [2 + 2] cycloaddition
27 (Scheme 16). We did not detect any radical addition
products similar to 21 and 24 above. It is unlikely that we
misassigned any of these, as the benzoyl’s carbonyl group is
easily detectable by 13C NMR. The plausible explanation for
these results is that just like the primary radical derived from 7d
in Scheme 10, the ethyl-stabilized secondary radical does not
live long enough for attacking the double bond. Instead, the
rearrangement and subsequent endo-cyclopentanation to form
25, 26 occurs. The cyclopentanation is not stereospecific in this
case as both epimers at the ethyl bearing center are observed.
The major product 25 was not entirely separable from the
minor [2 + 2] product 27 and was characterized in a mixture by
1H NMR by analogy with 19 and 22.
In contrast, irradiation of diastereomer 7f′ was not a clean
reaction. We isolated the product of benzyl radical addition 21
in poor yield of 20%. As shown in Scheme 14, our mechanistic
rationale for its formation involves the initial hydrogen
abstraction by the excited carbonyl to give a stable 1,3-
diradical, which lives long enough for its benzylic terminus to
attack the double bond. However, instead of recombination to
form the cyclopentyl ring, the ketyl radical simply delivers
hydrogen to terminate the second radical center, restoring the
benzoyl group.
̀
Photoprecursors 7d−7h are not Paterno−Buchi competent,
̈
and therefore they utilize a different reaction pathway available
for them, which is initiated by intramolecular hydrogen
Scheme 14
abstraction. To probe how severe the Paterno−Buchi channel
̀
̈
is impeded in these sterically congested systems, we attempted
to prepare the Michael adducts of dimethyl norbornadiene-2,3-
dicarboxylate with cyclic aromatic ketones, indanone, 3-methyl
indanone, and 3-phenylindanone, in which the carbonyl is held
out and therefore not capable of β-hydrogen abstraction.
Regrettably, we were able to isolate and purify only the exo, i.e.,
photoinactive, Michael products 7l−7p (see Experimental
Section).
We also synthesized the 1:1 Diels−Alder adduct 2815
(obtained with small amounts of 2:1 adducts16 29 and 30) of
furan with DMAD. However, under the conditions of the
subsequent Michael addition step 7-oxanorbornadiene 28
fragmented yielding pyranone 31 instead of the desired endo-
phenacyl bicyclic photoprecursor (two plausible mechanisms
are shown in Scheme 17).
As diastereomer 7f can only form a 1,3-diradical in which the
ketyl, not benzylic, radical center can reach the double bond,
one draws a conclusion that the ketyl radical is not capable of
initiating radical addition to the double bond or such reaction is
too slow and cannot compete with the rearrangement leading
to the secondary 1,3-diradical and, eventually, to the product of
cyclopentanation 19.
SUMMARY
■
In summary, rapid modular assembly of bicyclic scaffolds
outfitted with conformationally flexible aroylmethyl chromo-
phores provides access to Paterno−Buchi competent photo-
̀
̈
The diastereomeric spirocyclopropanes 7g and 7g′ behave in
a similar manner (Scheme 15) with 7g yielding the rearranged
cyclopentanation product 22 as the major product and its
homobenzylic epimer 7g′ producing polycycle 24, presumably
via the same mechanism shown in Scheme 14.
Valerophenone-based photoprecursor 7h also offers stabiliza-
tion of the second radical center, although in this case we
isolated only one endo-diastereomer. Irradiation of 7h yielded
precursors capable of protolytic oxametathesis transformation
leading to novel polycyclic systems decorated with functional
groups useful for subsequent transformations. At the same time,
conformationally constrained photoprecursors can be readily
obtained in a similar fashion. Irradiation of these starting
materials initiates hydrogen abstraction and is accompanied by
a cascade radical rearrangement/1,3-diradical endo-cycloaddi-
tion to the double bond, which amounts to intramolecular
F
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Scheme 16
Scheme 17
1
3.0 mL of 1,3-cyclopentadiene (35.6 mmol): 0.98 g (58%). H NMR
(500 MHz, CDCl3) δ = 7.65 (d, J = 3.2 Hz, 1H), 6.91 (dd, J = 5.1, 3.1
Hz, 1H), 6.73 (dd, J = 5.1, 3.1 Hz, 1H), 3.90 (m, 1H), 3.73 (s, 3H),
3.72 (m, 1H), 2.15 (ddd, J = 6.5, 1.6, 1.6 Hz, 1H), 2.12 (d, J = 6.5 Hz,
1H).
diradical cyclopentanation. This expeditious growth of
complexity in just a few synthetically simple steps attests to
the versatility of these new transformations and offers
additional useful tool for the synthetic chemistry tool chest.
Dimethyl bicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (2).8b
(Procedure B) from 0.7 mL of dimethyl acetylenedicarboxylate (5.69
mmol) and 0.5 mL of 1,3-cyclopentadiene (5.95 mmol): 1.13 g (95%).
(Procedure C) from 6.0 g of acetylenedicarboxylic acid monop-
otassium salt (39.4 mmol) and 0.7 mL of 1,3-cyclopentadiene (83.2
mmol): 7.95 g (97%). 1H NMR (500 MHz, CDCl3) δ = 6.92 (dd, J =
1.9, 1.9 Hz, 2H), 3.94 (m, 2H), 3.79 (s, 6H), 2.28 (ddd, J = 6.8, 1.6,
1.6 Hz, 1H), 2.10 (ddd, J = 6.8, 1.5, 1.5 Hz, 1H). 13C NMR (500
MHz, CDCl3) δ = 165.5, 152.5, 142.4, 73.0, 53.5, 52.1.
EXPERIMENTAL SECTION
■
General Procedure for Preparation of the Diels−Alder
Adducts (1−6, 28). (A): A solution of dimethyl acetylenedicarbox-
ylate in 10 mL of furan (used as a solvent and reagent) was stirred at
room temperature for 24 h (longer reaction time causes the formation
of 1a and 1b). After the reaction was completed, the solvent was
removed on a high vacuum pump. The crude reaction mixture was
purified on a flash silica gel column using a mixture of hexane and
EtOAc as an eluent.
(B): A solution of dimethyl acetylenedicarboxylate (1.0 equiv) in 10
mL of DCM and freshly distilled 1,3-cyclopentadiene (1.0−2.0 equiv)
was stirred at room temperature for 24 h. After the reaction was
completed, the solvent was removed on a high vacuum pump. The
resulting product was used without further purification unless noted
otherwise.
Methyl spiro[bicyclo[2.2.1]hepta-2,5-diene-2-carboxylate-7,1′-
cyclopropane] (3).8c (Procedure D) from 1.5 mL of propiolic acid
methyl ester (16.9 mmol) and 1.25 mL of spiro[4.2]hepta-4,6-diene
1
(12.5 mmol): 0.78 g (35%). H NMR (500 MHz, CDCl3) δ = 7.71
(dd, J = 3.3, 1.1 Hz, 1H), 6.98 (ddd, J = 5.3, 3.2, 0.7 Hz, 1H), 6.81
(ddd, J = 5.3, 3.2, 0.8 Hz, 1H), 3.76 (s, 3H), 3.40 (m, 1H), 3.20 (m,
1H), 0.59−0.52 (m, 4H).
Dimethyl spiro[bicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate-
7,1′-cyclopropane] (4).8d (Procedure B) from 0.6 mL of dimethyl
acetylenedicarboxylate (4.88 mmol) and 0.5 mL of spiro[4.2]hepta-
4,6-diene (4.99 mmol) at −15 °C → 20 °C, gradient (hexane/EtOAc
gradient 30:1 → 20:1): 0.77 g (68%). 1H NMR (500 MHz, CDCl3) δ
= 6.96 (dd, J = 2.0, 2.0 Hz, 2H), 3.79 (s, 6H), 3.43 (dd, J = 2.0, 2.0 Hz,
2H), 0.68−0.64 (m, 2H), 0.59−0.55 (m, 2H). 13C NMR (500 MHz,
CDCl3) δ = 165.4, 152.0, 141.8, 69.3, 58.5, 52.0, 9.4, 9.3.
(C): Acetylenedicarboxylic acid monopotassium salt (1.0 equiv)
and HCl (4.0 M solution in dioxane, 1.0 equiv) were stirred in MeOH
for 10 min. After that, freshly distilled 1,3-cyclopentadiene (2.0 equiv)
was added, and the resulting mixture was stirred at room temperature
for 48−72 h. When the reaction was completed, MeOH was removed,
and the crude residue was dissolved in DCM and washed with
Na2CO3 (sat.), water and brine. The organic layer was dried over
anhydrous Na2SO4. The organic solvent was dried and evaporated to
get pure product.
Methyl bicyclo[2.2.2]octa-2,5-diene-2-carboxylate (5).8e (Proce-
dure D) from 3.0 mL of propiolic acid methyl ester (33.6 mmol) and
(D): A solution of propiolic acid methyl ester (1.0 equiv) and 1,3-
cyclohexadiene (or freshly distilled 1,3-cyclopentadiene) (1.0−5.0
equiv) in 10 mL of 1,2-dichlorobenzene or toluene was heated in a
pressure vessel at 70−75 °C overnight. After the reaction was cooled
to room temperature, the solvent was removed on a high vacuum
pump. The crude reaction mixture was purified on a silica gel column
using a mixture of hexane and EtOAc as an eluent.
1
7.5 mL of 1,3-cyclohexadiene (78.7 mmol): 5.17 g (88%). H NMR
(500 MHz, CDCl3) δ = 7.29 (dd, J = 6.4, 1.9 Hz, 1H), 6.38 (ddd, J =
7.4, 6.1, 1.5 Hz, 1H), 6.27 (ddd, J = 7.3, 5.9, 1.5 Hz, 1H), 4.20 (m,
1H), 3.76 (m, 1H), 3.73 (s, 3H), 1.38−1.29 (m, 4H).
Dimethyl bicyclo[2.2.2]octa-2,5-diene-2,3-dicarboxylate (6).8f
(Procedure B) from 0.5 mL of dimethyl acetylenedicarboxylate
(4.07 mmol) and 0.6 mL of 1,3-cyclohexadiene (6.30 mmol) for 120 h
Methyl bicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (1).8a (Pro-
cedure B) from 1.0 mL of propiolic acid methyl ester (11.2 mmol) and
1
(hexane/EtOAc gradient 50:1 → 10:1): 0.20 g (22%). H NMR (500
G
dx.doi.org/10.1021/jo301909j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
MHz, CDCl3) δ = 6.38 (dd, J = 4.4, 3.2 Hz, 2H), 4.04 (m, 2H), 3.77
(s, 6H), 1.51−1.45 (m, 2H), 1.44−1.39 (m, 2H). 13C NMR (500
MHz, CDCl3) δ = 166.5, 142.3, 133.6, 52.1, 38.9, 24.5.
Dimethyl spiro[exo-5-phenacylbicyclo[2.2.1]hept-2-ene-endo-5-
endo-6-dicarboxylate-7,1′-cyclopropane] (7c-exo). 0.15 g (20%)
1
colorless crystals, mp 89−92 °C. H NMR (500 MHz, CDCl3) δ =
7.92 (d, J = 7.2 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz,
2H), 6.43 (m, 2H), 3.98 (d, J = 15.5 Hz, 1H), 3.62 (s, 3H), 3.58 (d, J =
15.5 Hz, 1H), 3.43 (s, 3H), 3.17 (d, J = 3.2 Hz, 1H), 2.70 (m, 1H),
2.45 (m, 1H), 0.81−0.77 (m, 1H), 0.76−0.71 (m, 1H), 0.43 (m, 2H).
13C NMR (500 MHz, CDCl3) δ = 197.7, 173.0, 172.9, 137.3, 136.4,
135.9, 133.2, 128.7, 128.1, 59.6, 56.2, 54.8, 52.0, 51.6, 51.6, 46.0, 43.0,
Preparation of the Michael Adducts. General Procedure.
(A): Diisopropylamine (1.4 equiv) was dissolved in THF at −10 °C,
and then n-BuLi (1.6 M solution in hexanes 1.2 equiv) was added, and
the resulting mixture was stirred for 20 min at −10 °C (in some cases
−78 °C) to 0 °C gradient. After that, carbonyl compound was added
(1.0 equiv), and the mixture was stirred at room temperature for
additional 30−40 min. After the anion was generated, the Diels−Alder
adduct (1−7) was added (1.0 equiv) at 20 °C, and the resulting
mixture was stirred overnight. After the reaction was completed, DCM
was added, and the resulting mixture was quenched with NH4Cl and
washed with water and brine. The organic layer was dried over
anhydrous Na2SO4 and removed under a vacuum. The crude mixture
was purified on a silica gel column using a mixture of hexane and
EtOAc as an eluent.
(B): Fresh LDA (1.8 M solution, 1.3 equiv) was added under
nitrogen atmosphere to the solution of a carbonyl compound (1.0
equiv) in THF at −5 to 0 °C. After the anion was generated (in 20−30
min), the Diels−Alder adduct (1−6) was added (1.0 equiv) at room
temperature, and the resulting mixture was stirred for 10−20 h. After
the reaction was completed DCM was added, and the resulting
mixture was quenched with NH4Cl and washed with water and brine.
The organic layer was dried over anhydrous Na2SO4 and removed
under a vacuum. The crude mixture was purified on a silica gel column
using a mixture of hexane and EtOAc as an eluent.
+
10.8, 3.6. HRMS (ESI/TOF) calcd for C21H22NaO5 (MNa+)
377.1359, found 377.1368. See SI for X-ray data.
Dimethyl (1RS,4SR,5RS,6SR)-endo-5-((1′RS)-1′-benzoylethyl)-
bicyclo[2.2.1]hept-2-ene-exo-5-endo-6-dicarboxylate (7d). (Proce-
dure A) from 0.23 mL of diisopropylamine (1.64 mmol), 1.0 mL of n-
BuLi (1.60 mmol), 0.15 mL of propiophenone (1.13 mmol) and 0.23
g of 2 (1.10 mmol) (hexane/EtOAc gradient 30:1 → 20:1): 0.125 g
(34%), colorless crystals, mp 97−101 °C. 1H NMR (500 MHz,
CDCl3) δ = 7.90 (d, J = 7.2 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.47 (t, J
= 7.6 Hz, 2H), 6.33 (dd, J = 5.6, 2.9 Hz, 1H), 5.81 (dd, J = 5.6, 3.2 Hz,
1H), 3.95 (q, J = 7.2 Hz, 1H), 3.84 (s, 3H), 3.72 (s, 3H), 3.35 (d, J =
3.3 Hz, 1H) overlaps with 3.34 (m, 1H), 3.02 (m, 1H), 1.52 (ddd, J =
9.2, 1.8, 1.8 Hz, 1H), 1.46 (d, J = 9.2 Hz, 1H), 1.08 (d, J = 7.1 Hz,
1
3H). H NMR (500 MHz, C6D6) δ = 7.98 (m, 2H), 7.07 (m, 1H),
7.00 (m, 2H), 6.35 (dd, J = 5.6, 3.0 Hz, 1H), 5.86 (dd, J = 5.6, 3.2 Hz,
1H), 4.24 (q, J = 7.1 Hz, 1H), 3.59 (s, 3H), 3.57 (m, 1H), 3.46 (d, J =
3.3 Hz, 1H), 3.33 (s, 3H), 2.69 (m, 1H), 1.41−1.33 (m, 2H) overlaps
with 1.34 (d, J = 7.1 Hz, 3H). 13C NMR (500 MHz, CDCl3) δ = 202.7,
175.6, 174.0, 137.6, 136.4, 134.2, 133.1, 128.8, 128.4, 62.0, 52.1, 51.8,
51.3, 50.2, 49.5, 47.1, 43.6, 16.3. HRMS (ESI/TOF) calcd for
Methyl endo-5-phenacylbicyclo[2.2.2]oct-2-ene-exo-6-carboxy-
late (7a). (Procedure B) from 10.7 mL of LDA (19.18 mmol), 1.75
mL of acetophenone (15.06 mmol) and 2.25 g of 5 (13.70 mmol)
(hexane/EtOAc gradient 50:1 → 10:1): 1.40 g (37%). 1H NMR (500
MHz, CDCl3) δ = 7.95 (d, J = 8.1 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H),
7.47 (t, J = 7.8 Hz, 2H), 6.40 (ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 6.25 (t, J
= 7.1 Hz, 1H), 3.74 (s, 3H), 2.91 (dd, J = 16.3, 7.6 Hz, 1H), 2.86−2.80
(m, 2H), 2.77 (dddd, J = 12.7, 5.4, 1.8, 1.8 Hz, 1H), 2.54 (m, 1H),
2.07 (dt, J = 5.4, 2.3 Hz, 1H), 1.73−1.62 (m, 2H), 1.34−1.27 (m, 1H),
1.17−1.10 (m, 1H). 13C NMR (500 MHz, CDCl3) δ = 198.4, 175.0,
137.0, 134.3, 133.0, 132.9, 128.5, 128.1, 51.8, 50.1, 46.0, 36.8, 34.3,
+
C20H23O5 (MH+) 343.1540, found 343.1546. See SI for X-ray data.
Dimethyl exo-5-(1′-benzoylethyl)bicyclo[2.2.1]hept-2-ene-endo-
5-endo-6-dicarboxylate (7d-exo). 0.092 g (25%). 1H NMR (500
MHz, CDCl3) δ = 7.91 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H),
7.1249 (t, J = 7.7 Hz, 2H), 6.34 (dd, J = 5.5, 3.0 Hz, 1H), 6.16 (dd, J =
5.5, 3.2 Hz, 1H), 3.90 (q, J = 7.0 Hz, 1H), 3.68 (s, 3H), 3.60 (s, 3H),
3.05 (d, J = 3.1 Hz, 1H), 3.00 (m, 1H), 2.76 (m, 1H), 1.72 (d, J = 9.1
Hz, 1H), 1.49 (t, J = 7.0 Hz, 3H) overlaps with 1.48 (ddd, J = 9.1, 1.7,
1.7 Hz, 1H). 13C NMR (500 MHz, CDCl3) δ = 201.8, 173.6, 171.7,
138.0, 136.6, 136.3, 133.3, 128.8, 128.1, 64.3, 54.5, 51.7, 51.4, 49.8,
48.9, 46.4, 46.0, 15.4. HRMS (ESI/TOF) calcd for C20H23O5+ (MH+)
343.1540, found 343.1555.
+
33.0, 25.2, 20.1. HRMS (ESI/TOF) calcd for C18H20NaO3 (MNa+)
307.1310, found 307.1292.
Methyl endo-5-(1-methylphenacyl)bicyclo[2.2.2]oct-2-ene-exo-6-
carboxylate (7b). (Procedure A) from 0.53 mL of diisopropylamine
(3.78 mmol), 2.0 mL of n-BuLi (3.24 mmol), 0.40 mL of
propiophenone (3.01 mmol) and 0.49 g of 5 (3.01 mmol) (hexane/
Dimethyl (1RS,4RS,5RS,6SR)-spiro[(1″RS)-endo-5-(1″-
benzoylethyl)bicyclo[2.2.1]hept-2-ene-exo-5-endo-6-dicarboxylate-
7,1′-cyclopropane] (7e). (Procedure A) from 0.19 mL of diisopropyl-
amine (1.36 mmol), 0.96 mL of n-BuLi (1.54 mmol), 0.14 mL of
propiophenone (1.05 mmol) and 0.24 g of 4 (1.02 mmol) (hexane/
1
EtOAc gradient 30:1 → 10:1): 0.24 g (29%). H NMR (500 MHz,
CDCl3) δ = 7.92 (d, J = 7.6 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J
= 7.8 Hz, 2H), 6.34 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.24 (t, J = 7.3 Hz,
1H), 3.73 (s, 3H), 3.26 (dt, J = 15.3, 7.1 Hz, 1H), 2.75−2.71 (m, 1H),
2.71−2.67 (m, 1H), 2.61 (ddd, J = 8.3, 5.7, 1.7 Hz, 1H), 2.01−1.99
(m, 1H), 1.67−1.61 (m, 2H), 1.35−1.27 (m, 1H), 1.17 (d J = 7.0 Hz,
3H), 1.14−1.06 (m, 1H). 13C NMR (500 MHz, CDCl3) δ = 204.0,
175.1, 137.0, 133.75, 133.0, 132.8, 128.6, 128.3, 51.7, 49.4, 46.1, 43.2,
1
EtOAc gradient 30:1 → 10:1): 0.23 g (61%). H NMR (500 MHz,
CDCl3) δ = 7.88 (d, J = 7.2 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.47 (t, J
= 7.6 Hz, 2H), 6.41 (ddd, J = 5.8, 2.9, 0.8 Hz, 1H), 5.84 (ddd, J = 5.8,
3.2, 0.8 Hz, 1H), 4.02 (q, J = 7.2 Hz, 1H), 3.82 (s, 3H), 3.77 (d, J = 3.4
Hz, 1H), 3.74 (s, 3H), 2.98 (m, 1H), 2.39 (m, 1H), 1.03 (d, J = 7.2
Hz, 3H), 0.50 (m, 1H), 0.44−0.38 (m, 3H). 13C NMR (500 MHz,
CDCl3) δ = 202.5, 174.5, 173.9, 137.4, 137.0, 134.4, 132.9, 128.7,
128.3, 63.8, 54.0, 52.6, 52.2, 51.8, 51.8, 45.1, 42.7, 15.9, 9.3, 5.4. HRMS
+
33.4, 31.3, 25.3, 20.5, 15.8. HRMS (ESI/TOF) calcd for C19H23NaO3
(MH+) 299.1642, found 299.1649.
+
(ESI/TOF) calcd for C22H25O5 (MH+) 369.1697, found 369.1693.
Dimethyl spiro[endo-5-phenacylbicyclo[2.2.1]hept-2-ene-exo-5-
endo-6-dicarboxylate-7,1′-cyclopropane] (7c). (Procedure B) from
1.4 mL of LDA (2.52 mmol), 0.25 mL of acetophenone (2.14 mmol)
and 0.50 g of 4 (2.13 mmol) (hexane/EtOAc gradient 40:1 → 10:1):
Dimethyl (1RS,4SR,5RS,6SR)-endo-5-((1′RS)-1′-benzoyl-2′-
phenylethyl)bicyclo[2.2.1]hept-2-ene-exo-5-endo-6-dicarboxylate
(7f). (Procedure B) from 0.80 mL of LDA (1.44 mmol), 0.20 g of 3-
phenylpropiophenone (β-phenylpropiophenone) (0.95 mmol) and
0.20 g of 2 (0.96 mmol) (hexane/EtOAc gradient 30:1 → 20:1): 47.7
1
0.23 g (30%) colorless crystals, mp 81−83 °C. H NMR (500 MHz,
1
CDCl3) δ = 7.89 (d, J = 7.1 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.42 (t, J
= 7.7 Hz, 2H), 6.47 (ddd, J = 5.8, 3.1, 0.9 Hz, 1H), 6.44 (ddd, J = 5.8,
2.8, 0.9 Hz, 1H), 4.38 (d, J = 3.5 Hz, 1H), 3.70 (s, 3H), 3.63 (d, J =
17.8 Hz, 1H), 3.50 (d, J = 17.8 Hz, 1H), 3.44 (s, 3H), 2.65 (m, 1H),
2.58 (m, 1H), 0.65 (ddd, J = 9.4, 5.8, 5.8 Hz, 1H), 0.49 (ddd, J = 9.6,
5.7, 5.7 Hz, 1H), 0.44−0.35 (m, 2H). 13C NMR (500 MHz, CDCl3) δ
= 198.6, 175.4, 173.6, 138.6, 136.7, 135.1, 132.9, 128.5, 127.9, 57.4,
57.4, 53.2, 52.3, 51.5, 48.6, 44.3, 43.3, 10.2, 4.3. HRMS (ESI/TOF)
mg (12%). H NMR (500 MHz, CDCl3) δ = 7.37 (m, 3H), 7.22 (m,
2H), 7.09 (m, 4H), 7.01 (m, 1H), 6.25 (dd, J = 5.7, 2.9 Hz, 1H), 5.46
(dd, J = 5.7, 3.2 Hz, 1H), 4.06 (dd, J = 12.0, 2.3 Hz, 1H), 3.91 (s, 3H),
3.81 (s, 3H), 3.45 (d, J = 3.3 Hz, 1H), 3.04 (m, 2H), 2.93 (dd, J =
13.5, 12.0 Hz, 1H), 2.74 (dd, J = 13.5, 2.3 Hz, 1H), 1.47 (ddd, J = 9.1,
1.8, 1.8 Hz, 1H), 1.35 (d, J = 9.1 Hz, 1H). 1H NMR (500 MHz, C6D6)
δ = 7.58 (m, 2H), 7.40 (m, 2H), 6.98 (m, 2H), 6.90−6.80 (m, 4H),
6.30 (dd, J = 5.6, 3.0 Hz, 1H), 5.64 (dd, J = 5.6, 3.1 Hz, 1H), 4.43 (dd,
J = 11.9, 2.3 Hz, 1H), 3.67 (s, 3H), 3.57 (d, J = 3.1 Hz, 1H), 3.48 (dd,
J = 13.5, 11.9 Hz, 1H), 3.39 (s, 3H), 3.25 (m, 1H), 3.12 (dd, J = 13.5,
+
calcd for C21H23O5 (MH+) 355.1540, found 355.1561. See SI for X-
ray data.
H
dx.doi.org/10.1021/jo301909j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2.3 Hz, 1H), 2.70 (m, 1H), 1.31 (ddd, J = 9.1, 1.8, 1.8 Hz, 1H), 1.24
(d, J = 9.1 Hz, 1H). 13C NMR (500 MHz, CDCl3) δ = 203.8, 175.3,
173.9, 139.3, 138.8, 137.3, 134.4, 132.4, 129.2, 128.3, 128.2, 128.1,
126.8, 63.1, 52.3, 52.0, 51.7, 50.9, 50.0, 49.7, 47.1, 37.6. See SI for X-
ray data.
Dimethyl (1RS,4SR,5RS,6SR)-endo-5-((1′SR)-1′-benzoyl-2′-
phenylethyl)bicyclo[2.2.1]hept-2-ene-exo-5-endo-6-dicarboxylate
(7f′). 119 mg (30%). 1H NMR (500 MHz, CDCl3) δ = 7.33 (m, 2H),
7.25 (m, 1H), 7.06 (m, 2H), 7.00−6.93 (m, 5H), 6.69 (dd, J = 5.6, 3.0
Hz, 1H), 6.46 (dd, J = 5.6, 2.9 Hz, 1H), 4.19 (d, J = 3.4 Hz, 1H), 3.98
(s, 3H), 3.68 (dd, J = 11.1, 3.6 Hz, 1H), 3.52 (m, 1H), 3.39 (dd, J =
13.6, 3.6 Hz, 1H), 3.21 (dd, J = 13.6, 11.1 Hz, 1H), 3.06 (m, 1H), 2.60
(s, 3H), 1.49 (ddd, J = 9.1, 1.8, 1.8 Hz, 1H), 1.43 (d, J = 9.1 Hz, 1H).
1H NMR (500 MHz, C6D6) δ = 7.54 (m, 2H), 6.94 (m, 2H), 6.85−
6.75 (m, 6H) overlaps with 6.74 (dd, J = 5.6, 3.0 Hz, 1H), 6.31 (dd, J
= 5.6, 2.9 Hz, 1H), 4.42 (d, J = 3.4 Hz, 1H), 3.95 (dd, J = 11.0, 3.9 Hz,
1H), 3.76 (s, 3H), 3.48 (dd, J = 13.6, 11.0 Hz, 1H) overlaps with 3.46
(m, 1H), 3.37 (dd, J = 13.6, 3.9 Hz, 1H), 2.81 (m, 1H), 2.46 (s, 3H),
1.40 (d, J = 8.9 Hz, 1H), 1.32 (ddd, J = 8.9, 1.8, 1.8 Hz, 1H). 13C
NMR (500 MHz, CDCl3) δ = 201.7, 176.0, 173.6, 140.4, 139.0, 136.8,
132.4, 132.0, 129.3, 128.6, 128.1, 127.6, 126.3, 62.7, 52.7, 52.7, 52.3,
50.8, 50.2, 46.9, 46.5, 39.1. See SI for X-ray data.
Dimethyl exo-5-(1′-benzoyl-2′-phenylethyl)bicyclo[2.2.1]hept-2-
ene-endo-5-exo-6-dicarboxylate (7f-exo). 71.5 mg (18%). 1H
NMR (500 MHz, CDCl3) δ = 7.51 (m, 2H), 7.34 (m, 1H), 7.18
(m, 2H), 7.11−7.02 (m, 5H), 6.32 (dd, J = 5.6, 3.0 Hz, 1H), 6.06 (dd,
J = 5.6, 3.0 Hz, 1H), 4.22 (dd, J = 9.2, 4.3 Hz, 1H), 3.80 (s, 3H), 3.65
(dd, J = 14.3, 4.3 Hz, 1H), 3.47 (m, 1H), 3.37 (d, J = 2.0 Hz, 1H), 3.05
(dd, J = 14.3, 9.2 Hz, 1H), 2.97 (m, 1H), 2.74 (s, 3H), 2.36 (d, J = 9.3
Hz, 1H), 1.58 (dddd, J = 9.3, 1.8, 1.8, 1.8 Hz, 1H) overlaps with HOD.
1H NMR (500 MHz, C6D6) δ = 7.68 (m, 2H), 7.01 (m, 2H), 6.91−
Dimethyl (1RS,4RS,5RS,6SR)-spiro[(1″RS)-endo-5-(1″-
benzoylbutyl)bicyclo[2.2.1]hept-2-ene-exo-5-endo-6-dicarboxylate-
7,1′-cyclopropane] (7h). (Procedure B) from 0.57 mL of LDA (1.03
mmol), 0.14 mL of valerophenone (0.85 mmol) and 0.20 g of 4 (0.85
1
mmol) (hexane/EtOAc gradient 50:1 → 10:1): 118 mg (35%). H
NMR (500 MHz, CDCl3) δ = 7.88 (d, J = 7.1 Hz, 2H), 7.58 (t, J = 7.4
Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 6.34 (ddd, J = 5.9, 3.0, 0.7 Hz, 1H),
5.65 (ddd, J = 5.7, 3.2, 0.9 Hz, 1H), 3.89 (dd, J = 11.2, 2.0 Hz, 1H),
3.81 (s, 3H), 3.77 (d, J = 3.4 Hz, 1H), 3.72 (s, 3H), 2.62 (m, 1H), 2.35
(m, 1H), 1.64−1.58 (m, 1H) overlaps with HOD, 1.37−1.30 (m, 1H),
1.11 (m, 1H), 1.01 (m, 1H), 0.78 (t, J = 7.3 Hz, 3H), 0.43−0.31 (m,
1
4H). H NMR (500 MHz, C6D6) δ = 8.03 (m, 2H), 7.09 (m, 1H),
7.03 (m, 2H), 6.43 (ddd, J = 5.9, 3.0, 0.8 Hz, 1H), 5.89 (dd, J = 5.8,
3.2, 0.8 Hz, 1H), 4.25 (dd, J = 11.0, 1.8 Hz, 1H), 4.03 (d, J = 3.6 Hz,
1H), 3.60 (s, 3H), 3.38 (s, 3H), 2.82 (m, 1H), 2.13 (dddd, J = 13.8,
11.0, 11.0, 4.7 Hz, 1H), 2.03 (m, 1H), 1.69 (dddd, J = 13.8, 12.0, 5.1,
1.7 Hz, 1H), 1.39−1.29 (m, 1H), 1.22−1.13 (m, 1H), 0.79 (t, J = 7.3
Hz, 3H), 0.48−0.39 (m, 4H).
Photoinactive Exo Compounds 7i−7q. Dimethyl exo-5-
phenacylbicyclo[2.2.1]hept-2-ene-bis-endo-5,6-dicarboxylate (7i).
(Procedure A) from 0.13 mL of diisopropylamine (0.93 mmol),
0.50 mL of n-BuLi (0.80 mmol), 0.08 mL of acetophenone (0.68
mmol) and 0.14 g of 2 (0.67 mmol) (hexane/EtOAc gradient 30:1 →
1
10:1): 57 mg (26%) colorless crystals, mp 142.5−144 °C. H NMR
(500 MHz, CDCl3) δ = 7.92 (d, J = 7.1 Hz, 2H), 7.56 (t, J = 7.4 Hz,
1H), 7.45 (t, J = 7.7 Hz, 2H), 6.35 (dd, J = 5.7, 3.1 Hz, 1H), 6.02 (dd,
J = 5.6, 2.9 Hz, 1H), 3.98 (d, J = 18.1 Hz, 1H), 3.75 (d, J = 18.1 Hz,
1H), 3.62 (s, 3H), 3.43 (s, 3H) overlaps with 3.43 (m, 1H), 3.00 (m,
1H), 2.94 (m, 1H), 2.26 (d, J = 9.2 Hz, 1H), 1.56 (ddd, J = 9.2, 1.7, 1.7
Hz, 1H) overlaps with HOD. 1H NMR (500 MHz, C6D6) δ = 7.86 (d,
J = 7.1 Hz, 2H), 7.09 (t, J = 7.3 Hz, 1H), 7.02 (t, J = 7.5 Hz, 2H), 6.09
(dd, J = 5.6, 3.1 Hz, 1H), 5.94 (dd, J = 5.6, 2.9 Hz, 1H), 4.08 (d, J =
18.0 Hz, 1H), 3.81 (d, J = 1.8 Hz, 1H), 3.68 (d, J = 18.0 Hz, 1H), 3.32
(s, 3H), 3.17 (s, 3H), 2.82 (m, 1H) overlaps with 2.80 (m, 1H), 2.36
(d, J = 9.0 Hz, 1H), 1.44 (dddd, J = 9.0, 1.7, 1.7, 1.7 Hz, 1H). 13C
NMR (500 MHz, CDCl3) δ = 198.5, 175.5, 174.7, 138.7, 136.4, 134.8,
133.2, 128.6, 128.0, 53.9, 52.8, 52.3, 51.8, 48.6, 47.0, 46.4, 45.8. HRMS
6.82 (m, 6H), 6.05 (m, 2H), 4.51 (dd, J = Hz, 1H), 3.68−3.62 (m,
2H), 3.59 (s, 3H), 3.45 (m, 1H), 3.31 (dd, J = 14.0, 9.6 Hz, 1H), 2.83
(m, 1H), 2.61 (s, 3H), 2.56 (d, J = 9.2 Hz, 1H), 1.51 (dddd, J = 9.2,
1.8, 1.8, 1.8 Hz, 1H). 13C NMR (500 MHz, CDCl3) δ = 201.3, 175.2,
174.7, 139.7, 139.5, 136.4, 136.0, 132.7, 129.2, 128.9, 128.4, 127.8,
126.3, 59.9, 52.1, 51.9, 51.1, 49.0, 48.9, 47.8, 45.9, 38.0. HRMS (ESI/
+
(ESI/TOF) calcd for C19H20NaO5 (MNa+) 351.1203, found
+
TOF) calcd for C26H27O5 (MH+) 419.1853, found 419.1849. See SI
351.1196.
for X-ray data.
Dimethyl exo-5-phenacylbicyclo[2.2.1]hept-2-ene-bis-endo-5,6-
Dimethyl (1RS,4RS,5RS,6SR)-spiro[(1″RS)-endo-5-(1″-benzoyl-2″-
phenylethyl)bicyclo[2.2.1]hept-2-ene-exo-5-endo-6-dicarboxylate-
7,1′-cyclopropane] (7g). (Procedure B) from 1.55 mL of LDA (2.79
mmol), 0.45 g of 3-phenylpropiophenone (2.14 mmol) and 0.50 g of 4
(2.13 mmol) (hexane/EtOAc gradient 30:1 → 5:1): 0.17 g (18%). 1H
NMR (500 MHz, CDCl3) δ = 7.38 (m, 3H), 7.25 (m, 2H), 7.10 (m,
4H), 7.02 (m, 1H), 6.33 (dd, J = 5.8, 3.0 Hz, 1H), 5.46 (ddd, J = 5.8,
3.2, 0.9 Hz, 1H), 4.17 (dd, J = 12.0, 2.4 Hz, 1H), 3.89 (s, 3H), 3.81 (s,
3H), 3.80 (d, J = 3.5 Hz, 1H), 2.85 (dd, J = 13.5, 12.0 Hz, 1H), 2.71
(dd, J = 13.5, 2.4 Hz, 1H), 2.60 (m, 1H), 2.40 (m, 1H), 0.49−0.33 (m,
1
dicarboxylate (7i′). 33 mg (15%). H NMR (500 MHz, CDCl3) δ
= 7.87 (d, J = 7.2 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz,
2H), 6.34 (m, 2H), 4.08 (d, J = 3.4 Hz, 1H), 3.70 (s, 3H), 3.55 (s,
2H), 3.45 (s, 3H), 3.17 (m, 1H), 3.10 (m, 1H), 1.79 (d, J = 8.9 Hz,
1H), 1.44 (ddd, J = 8.9, 1.7, 1.7 Hz, 1H). 1H NMR (500 MHz, C6D6)
δ = 7.89 (d, J = 7.0 Hz, 2H), 7.08 (t, J = 7.3 Hz, 1H), 7.02 (t, J = 7.5
Hz, 2H), 6.28 (dd, J = 5.6, 2.9 Hz, 1H), 6.10 (dd, J = 5.7, 3.2 Hz, 1H),
4.41 (d, J = 3.2 Hz, 1H), 3.76 (d, J = 18.0 Hz, 1H), 3.50 (dd, J = 18.0
Hz, 1H), 3.38 (s, 3H), 3.16 (s, 3H), 2.97 (m, 2H), 1.89 (d, J = 8.8 Hz,
1H), 1.28 (ddd, J = 8.8, 1.7, 1.7 Hz, 1H). 13C NMR (500 MHz,
CDCl3) δ = 198.9, 176.1, 173.9, 138.1, 136.5, 134.8, 133.0, 128.5,
127.9, 55.5, 52.9, 52.6, 51.5, 48.4, 47.5, 46.8, 43.9. HRMS (ESI/TOF)
1
4H). H NMR (500 MHz, C6D6) δ = 7.62 (m, 2H), 7.45 (m, 2H),
7.01 (m, 3H), 6.86 (m, 3H), 6.42 (ddd, J = 5.8, 3.0, 0.8 Hz, 1H), 5.76
(dd, J = 5.8, 3.1, 0.9 Hz, 1H), 4.58 (dd, J = 12.0, 2.2 Hz, 1H), 4.02 (d, J
= 3.5 Hz, 1H), 3.66 (s, 3H), 3.44 (dd, J = 13.5, 12.0 Hz, 1H) overlaps
with 3.42 (s, 3H), 3.13 (dd, J = 13.5, 2.2 Hz, 1H), 2.82 (m, 1H), 2.04
(m, 1H), 0.52 (m, 1H), 0.23−0.16 (m, 3H). 13C NMR (500 MHz,
CDCl3) δ = 203.3, 174.1, 173.8, 139.4, 139.2, 137.0, 134.7, 132.3,
129.2, 128.3, 128.2, 127.9, 126.2, 64.5, 53.5, 52.8, 52.0, 51. 9, 51.5,
+
calcd for C19H20NaO5 (MNa+) 351.1203, found 351.1209.
Methyl spiro[exo-6-phenacylbicyclo[2.2.1]hept-2-ene-endo-5-
carboxylate-7,1′-cyclopropane] (7j). 21.9 mg (13%). 1H NMR
(500 MHz, CDCl3) δ = 8.00 (d, J = 7.1 Hz, 2H), 7.59 (t, J = 7.4
Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 6.43 (ddd, J = 5.9, 3.2, 0.7 Hz, 1H),
6.15 (ddd, J = 5.8, 2.7, 0.7 Hz, 1H), 3.66 (s, 3H), 3.42 (dd, J = 16.2,
6.4 Hz, 1H), 3.30 (dd, J = 16.2, 8.7 Hz, 1H), 2.86 (dd, J = 4.8, 3.6 Hz,
1H), 2.56 (m, 1H), 2.47 (ddd, J = 8.7, 6.4, 5.0 Hz, 1H), 2.21 (m, 1H),
0.72 (ddd, J = 9.6, 5.3, 5.3 Hz, 1H), 0.65 (ddd, J = 9.4, 5.5, 5.5 Hz,
1H), 0.44 (ddd, J = 9.5, 5.2, 5.2 Hz, 1H), 0.38 (ddd, J = 9.5, 5.4, 5.4
Hz, 1H). 1H NMR (500 MHz, C6D6) δ = 7.94 (m, 2H), 7.13 (m, 1H),
7.08 (m, 2H), 6.28 (ddd, J = 5.8, 3.2, 0.7 Hz, 1H), 6.19 (ddd, J = 5.8,
2.8, 0.7 Hz, 1H), 3.37 (s, 3H), 3.17−3.12 (m, 1H), 2.99−2.93 (m,
1H), 2.73−2.69 (m, 2H), 2.38 (m, 1H), 2.06 (m, 1H), 0.41−0.36 (m,
1H), 0.28−0.16 (m, 3H). 13C NMR (500 MHz, CDCl3) δ = 199.49,
174.41, 138.51, 136.85, 133.51, 133.03, 128.61, 128.14, 51.58, 51.48,
51.26, 51.14, 43.16, 42.64, 41.68, 9.27, 3.34. HRMS (ESI/TOF) calcd
+
51.1, 45.6, 36.9, 9.5, 5.4. HRMS (ESI/TOF) calcd for C28H28NaO5
(MNa+) 467.1829, found 467.1812. See SI for X-ray data.
Dimethyl (1RS,4RS,5RS,6SR)-spiro[endo-5-((1″SR)-1″-benzoyl-2″-
phenylethyl)bicyclo[2.2.1]hept-2-ene-exo-5-endo-6-dicarboxylate-
7,1′-cyclopropane] (7g′). 0.22 g (23%). 1H NMR (500 MHz, CDCl3)
δ = 7.35 (m, 2H), 7.25 (m, 1H), 7.08 (m, 2H), 6.99−6.93 (m, 5H),
6.78 (dd, J = 5.8, 3.0 Hz, 1H), 6.58 (ddd, J = 5.8, 3.0, 0.9 Hz, 1H), 4.33
(d, J = 3.5 Hz, 1H), 3.96 (s, 3H), 3.75 (dd, J = 11.2, 3.7 Hz, 1H), 3.33
(dd, J = 13.5, 3.7 Hz, 1H), 3.20 (dd, J = 13.5, 11.2 Hz, 1H), 3.07 (m,
1H), 2.59 (s, 3H), 2.46 (m, 1H), 0.53−0.41 (m, 4H). 13C NMR (500
MHz, CDCl3) δ = 201.7, 175.4, 173.6, 140.6, 139.0, 137.2, 132.6,
132.4, 129.6, 128.8, 128.3, 127.8, 126.5, 64.3, 57.0, 52.6 overlaps with
52.6, 52.5, 51.3, 51.0, 43.0, 39.5, 9.6, 4.9. See SI for X-ray data.
+
for C19H21O3 (MH+) 297.1485, found 297.1492.
I
dx.doi.org/10.1021/jo301909j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Methyl exo-6-(1′-benzoylethyl)bicyclo[2.2.1]hept-2-ene-endo-5-
carboxylate (7k). (Procedure A) from 0.33 mL of diisopropylamine
(2.35 mmol), 1.70 mL of n-BuLi (2.72 mmol), 0.24 mL of
propiophenone (1.80 mmol) and 0.27 g of 5 (1.80 mmol) (hexane/
EtOAc gradient 30:1→10:1): 0.27 g (53%). 1H NMR (500 MHz,
CDCl3) δ = 7.97 (d, J = 7.1 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.49 (t, J
= 7.6 Hz, 2H), 6.27 (dd, J = 5.6, 3.2 Hz, 1H), 6.00 (dd, J = 5.6, 2.8 Hz,
1H), 3.65 (s, 3H), 3.39 (dddd, J = 10.8, 7.0, 7.0, 7.0 Hz, 1H), 3.19 (m,
1H), 2.66 (dd, J = 4.6, 3.7 Hz, 1H), 2.46 (m, 1H), 2.33 (ddd, J = 10.8,
4.8, 1.6 Hz, 1H), 1.54 (d, J = 8.7 Hz, 1H), 1.44 (dddd, J = 8.7, 1.7, 1.7,
1.7 Hz, 1H), 1.27 (d, J = 7.0 Hz, 3H). 1H NMR (500 MHz, C6D6) δ =
7.89 (d, J = 7.0 Hz, 2H), 7.15 (m, 1H), 7.09 (t, J = 7.3 Hz, 2H), 6.12
(dd, J = 5.6, 3.2 Hz, 1H), 6.03 (dd, J = 5.6, 2.8 Hz, 1H), 3.34 (s, 3H),
3.10 (m, 1H), 3.04 (dddd, J = 10.9, 7.0, 7.0, 7.0 Hz, 1H), 2.68 (ddd, J
= 10.9, 4.7, 1.6 Hz, 1H), 2.44 (m, 2H), 1.25 (dddd, J = 8.7, 1.7, 1.7, 1.7
Hz, 1H), 1.20 (d, J = 7.0 Hz, 3H) overlaps with 1.20 (m, 1H). 13C
NMR (500 MHz, CDCl3) δ = 204.1, 174.6, 138.8, 137.1, 133.5, 133.1,
128.8, 128.2, 51.7, 49.1, 46.6, 46.5, 46.5, 46.1, 45.7, 17.7. HRMS (ESI/
6.53 (dd, J = 5.5, 3.2 Hz, 1H), 6.10 (dd, J = 5.5, 3.0 Hz, 1H), 4.21 (d, J
= 3.4 Hz, 1H), 3.63 (s, 3H), 3.30 (dddd, J = 7.0, 7.0, 7.0, 3.0 Hz, 1H),
3.23 (m, 1H), 3.16 (m, 1H), 3.04 (s, 3H), 2.41 (d, J = 3.0 Hz, 1H),
1.79 (d, J = 9.3 Hz, 1H), 1.57 (ddd, J = 9.3, 1.7, 1.7 Hz, 1H) overlaps
with HOD, 1.41 (d, J = 7.0 Hz, 3H). 13C NMR (500 MHz, CDCl3) δ
= 205.2, 173.3, 172.7, 157.0, 137.1, 136.8, 134.6, 134.2, 127.5, 125.1,
123.5, 63.8, 61.0, 51.8, 51.5, 50.8, 50.3, 47.8, 46.4, 38.4, 23.1. HRMS
+
(ESI/TOF) calcd for C21H23O5 (MH+) 355.1540, found 355.1548.
Dimethyl exo-5-(3′-methyl-1′-indanon-2′-yl)bicyclo[2.2.1]hept-
2-ene-endo-5,exo-6-dicarboxylate (7n′). 51 g (20%). 1H NMR
(500 MHz, CDCl3) δ = 7.69 (d, J = 7.6 Hz, 1H), 7.53 (m, 1H), 7.39−
7.33 (m, 2H), 6.22 (m, 1H), 6.01 (m, 1H), 3.82 (m, 4H), 3.20 (m,
1H) overlaps with 3.14 (m, 1H), 2.95 (m, 1H), 2.88 (m, 1H), 2.74 (m,
3H), 2.59 (m, 1H), 1.64 (dddd, J = 9.4, 1.8, 1.8, 1.8 Hz, 1H), 1.15 (m,
3H). 13C NMR (500 MHz, CDCl3) δ = 174.9, 173.2, 158.2, 138.9,
137.6, 136.0, 134.5, 127.6, 125.7, 125.6, 123.2, 63.9, 58.1, 52.1, 51.0,
49.1, 48.7, 46.3, 45.4, 38.7, 24.5. HRMS (ESI/TOF) calcd for
+
C21H23O5 (MH+) 355.1540, found 355.1542.
+
TOF) calcd for C18H21O3 (MH+) 285.1485, found 285.1492.
Dimethyl (1SR,4RS,5RS,6RS)-exo-5-((2′SR, 3′SR)-3′-phenyl-1′-in-
danon-2′-yl)bicyclo[2.2.1]hept-2-ene-endo-bis-5,6-dicarboxylate
(7o). (Procedure A) from 0.10 mL of diisopropylamine (0.71 mmol),
0.50 mL of t-BuLi (1.7 M, 0.85 mmol), 0.10 mL of 3-phenyl-1-
indanone (0.48 mmol) and 0.10 g of 2 (0.48 mmol) at −78 °C → 20
°C gradient (hexane/EtOAc gradient 30:1 → 4:1): 96 mg (48%),
colorless crystals, mp 168.5−170.0 °C. 1H NMR (500 MHz, CDCl3) δ
= 7.80 (d, J = 7.7 Hz, 1H), 7.50 (ddd, J = 7.5, 7.5, 1.3 Hz, 1H), 7.38 (t,
J = 7.5 Hz, 1H), 7.32−7.28 (m, 2H), 7.23 (m, 1H), 7.11 (m, 3H), 6.48
(dd, J = 5.5, 3.1 Hz, 1H), 6.08 (dd, J = 5.5, 3.1 Hz, 1H), 4.41 (d, J =
3.8 Hz, 1H), 4.18 (d, J = 3.4 Hz, 1H), 3.66 (s, 3H), 3.16 (m, 1H), 3.14
(s, 3H), 3.09 (m, 1H), 2.98 (d, J = 3.8 Hz, 1H), 1.48 (d, J = 9.4 Hz,
1H), 1.31 (ddd, J = 9.4, 1.8, 1.8 Hz, 1H). 1H NMR (500 MHz, C6D6)
δ = 7.86 (d, J = 7.6 Hz, 1H), 7.01−6.95 (m, 4H), 6.91 (t, J = 7.4 Hz,
1H), 6.84 (m, 2H), 6.80 (d, J = 7.6 Hz, 1H), 6.70 (dd, J = 5.5, 3.1 Hz,
1H), 6.14 (dd, J = 5.5, 3.0 Hz, 1H), 4.55 (d, J = 3.9 Hz, 1H), 4.37 (d, J
= 3.4 Hz, 1H), 3.40 (s, 3H), 3.27 (m, 1H), 3.01 (s, 3H), 2.94 (d, J =
3.9 Hz, 1H), 2.87 (m, 1H), 1.16 (d, J = 9.3 Hz, 1H), 1.06 (ddd, J = 9.3,
1.7, 1.7 Hz, 1H). 13C NMR (500 MHz, CDCl3) δ = 205.0, 173.3,
172.8, 155.6, 143.8, 137.1, 136.7, 135.0, 134.2, 129.1, 127.9, 127.8,
127.1, 126.4, 123.3, 63.9, 62.2, 51.9, 51.8, 51.0, 50.4, 50.2, 47.6, 46.5.
Dimethyl exo-5-(1′-indanon-2′-yl)bicyclo[2.2.1]hept-2-ene-bis-
endo-5,6-dicarboxylate (7l). (Procedure A) from 0.26 mL of
diisopropylamine (1.86 mmol), 1.35 mL of n-BuLi (2.16 mmol),
0.20 mL of 1-indanone (1.51 mmol) and 0.30 g of 2 (1.44 mmol)
1
(hexane/EtOAc gradient 30:1 → 5:1): 0.14 g (28%). H NMR (500
MHz, CDCl3) δ = 7.76 (d, J = 7.7 Hz, 1H), 7.57 (ddd, J = 7.5, 7.5, 1.1
Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 6.50 (dd, J
= 5.5, 3.0 Hz, 1H), 6.06 (dd, J = 5.5, 3.2 Hz, 1H), 4.22 (m, 1H), 3.70
(s, 3H), 3.51 (dd, J = 17.7, 4.1 Hz, 1H), 3.43 (dd, J = 17.7, 7.9 Hz,
1H), 3.16 (s, 3H), 3.13 (m, 1H), 3.00 (d, J = 3.1 Hz, 1H), 2.91 (dd, J
= 7.9, 4.1 Hz, 1H), 1.79 (d, J = 9.4 Hz, 1H), 1.63 (ddd, J = 9.4, 1.7, 1.7
1
Hz, 1H). H NMR (500 MHz, C6D6) δ = 7.83 (d, J = 7.6 Hz, 1H),
7.09 (ddd, J = 7.4, 7.4, 1.2 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.94 (t, J
= 7.4 Hz, 1H), 6.62 (dd, J = 5.5, 3.0 Hz, 1H), 6.10 (d, J = 5.5, 3.1 Hz,
1H), 4.53 (m, 1H), 3.57 (dd, J = 17.5, 4.1 Hz, 1H), 3.46 (s, 3H), 2.99
(dd, J = 17.5, 8.1 Hz, 1H), 2.87 (m, 1H), 2.81 (s, 3H), 2.59 (d, J = 3.1
Hz, 1H), 2.44 (dd, J = 8.1, 4.1 Hz, 1H), 1.45 (ddd, J = 9.2, 1.8, 1.8 Hz,
1H), 1.39 (d, J = 9.2 Hz, 1H). 13C NMR (500 MHz, CDCl3) δ =
204.7, 173.4, 172.1, 152.4, 138.2, 137.3, 134.5, 134.3, 127.4, 126.4,
123.7, 63.3, 55.9, 54.3, 51.8, 51.3, 48.5, 46.2, 46.2, 31.7. HRMS (ESI/
+
HRMS (ESI/TOF) calcd for C26H25O5 (MH+) 417.1697, found
+
TOF) calcd for C20H21O5 (MH+) 341.1384, found 341.1390.
417.1679.
Dimethyl exo-5-(1′-indanon-2′-yl)bicyclo[2.2.1]hept-2-ene-bis-
1
endo-5,6-dicarboxylate (7l′). Trace amount. H NMR (500 MHz,
Dimethyl (1RS,4SR,5SR,6RS)-exo-5-((2′SR, 3′SR)-3′-phenyl-1′-in-
danon-2′-yl)bicyclo[2.2.1]hept-2-ene-endo-5-exo-6-dicarboxylate
CDCl3) δ = 7.77 (d, J = 7.7 Hz, 1H), 7.55 (ddd, J = 7.5, 7.5, 1.2 Hz,
1H), 7.41 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 6.54 (dd, J =
5.5, 3.1 Hz, 1H), 6.09 (dd, J = 5.5, 3.1 Hz, 1H), 4.27 (d, J = 3.4 Hz,
1H), 3.64 (s, 3H), 3.33 (dd, J = 17.5, 8.2 Hz, 1H), 3.17 (m, 1H), 3.12
(s, 3H), 3.09 (m, 1H), 2.96 (dd, J = 17.5, 4.1 Hz, 1H), 2.85 (dd, J =
8.2, 4.1 Hz, 1H), 1.77 (d, J = 9.3 Hz, 1H), 1.55 (ddd, J = 9.3, 1.7, 17
Hz, 1H). 13C NMR (500 MHz, CDCl3) δ = 205.1, 173.3, 172.7, 151.5,
137.7, 137.3, 134.4, 133.7, 127.5, 126.2, 123.8, 63.2, 52.7, 51.8, 51.6,
1
(7o′). 56 mg (28%), colorless crystals, mp 151.0−154.5 °C. H NMR
(500 MHz, CDCl3) δ = 7.73 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.4 Hz,
1H), 7.32 (t, J = 7.4 Hz, 1H), 7.23 (m, 3H), 7.15 (m, 1H), 7.06 (m,
2H), 6.24 (dd, J = 5.5, 3.1 Hz, 1H), 6.00 (m, 1H), 4.32 (m, 1H), 3.95
(m, 1H), 3.57 (m, 1H), 3.22 (m, 1H), 3.03 (m, 4H), 2.92 (m, 1H),
2.84 (m, 2H), 2.56 (m, 1H), 1.61 (m, 1H). HRMS (ESI/TOF) calcd
+
for C26H25O5 (MH+) 417.1697, found 417.1684.
+
Methyl (1RS,4SR,5RS,6SR)-exo-6-((2′RS)-1′-indanon-2′-yl)bicyclo-
[2.2.1]hept-2-ene-endo-5-carboxylate (7p). (Procedure A) from 0.40
mL of diisopropylamine (2.85 mmol), 2.0 mL of n-BuLi (3.2 mmol),
0.18 mL of 1-indanone (1.36 mmol) and 0.20 g of 5 (1.33 mmol)
(hexane/EtOAc gradient 30:1 → 2:1): 52.5 mg (14%), colorless
crystals, mp 99.5−102.0 °C. 1H NMR (500 MHz, CDCl3) δ = 7.77 (d,
J = 7.6 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.62 (m, 1H), 7.42 (t, J = 7.3
Hz, 1H), 6.24 (dd, J = 5.6, 3.3 Hz, 1H), 6.02 (d, J = 5.7, 2.8 Hz, 1H),
3.61 (s, 3H), 3.40 (ddd, J = 9.9, 7.5, 2.8 Hz, 1H), 3.23 (m, 1H), 3.09
(m, 1H), 2.88 (dd, J = 10.0, 7.5 Hz, 1H), 2.71 (dd, J = 4.6, 3.6 Hz,
1H), 2.67 (dd, J = 18.6, 2.9 Hz, 1H), 2.03 (ddd, J = 9.5, 4.7, 1.6 Hz,
1H), 1.67 (d, J = 8.9 Hz, 1H), 1.55 (dddd, J = 8.9, 1.7, 1.7, 1.7 Hz,
1H). 13C NMR (500 MHz, CDCl3) δ = 205.5, 174.5, 157.1, 138.3,
137.4, 134.4, 134.3, 127.9, 127.1, 123.9, 51.8, 50.0, 49.3, 46.2, 46.0,
45.8, 43.3, 43.0. HRMS (ESI/TOF) calcd for C18H22NO3 (MNH4 )
300.1594, found 300.1583.
Dimethyl exo-5-(1′-benzoyl-1′-phenylmethyl)bicyclo[2.2.1]hept-
2-ene-endo-5-exo-6-dicarboxylate (7q). (Procedure B) from 1.04
mL of LDA (1.87 mmol), 0.28 g of 2-phenylacetophenone
(deoxybenzoin) (1.43 mmol) and 0.30 g of 2 (1.44 mmol)
51.0, 50.9, 47.8, 46.7, 31.3. HRMS (ESI/TOF) calcd for C20H21O5
(MH+) 341.1384, found 341.1390.
Dimethyl (1RS,4SR,5SR,6RS)-exo-5-((2′SR)-1′-indanon-2′-yl)-
bicyclo[2.2.1]hept-2-ene-endo-5-exo-6-dicarboxylate (7m). 58.8
1
mg (12%). H NMR (500 MHz, CDCl3) δ = 7.74 (d, J = 7.8 Hz,
1H), 7.53 (ddd, J = 7.5, 7.5, 1.1 Hz, 1H), 7.35 (m, 2H), 6.27 (dd, J =
5.6, 3.1 Hz, 1H), 6.02 (dd, J = 5.6, 3.1 Hz, 1H), 4.22 (m, 1H), 3.77 (m,
3H), 3.25−3.19 (m, 2H), 3.07−2.97 (m, 5H), 2.84 (dd, J = 17.5, 2.7
Hz, 1H), 2.53 (d, J = 9.5 Hz, 1H), 1.67 (dddd, J = 9.5, 1.7, 1.7, 1.7 Hz,
1H). 13C NMR (500 MHz, CDCl3) δ = 175.1, 173.3, 151.8, 139.1,
137.4, 136.8, 134.4, 127.5, 126.4, 123.5, 52.0, 51.7, 51.3, 49.1, 49.0,
+
48.2, 45.7, 45.0. HRMS (ESI/TOF) calcd for C20H21O5 (MH+)
341.1384, found 341.1386.
Dimethyl (1SR,4RS,5RS,6RS)-exo-5-((2′SR, 3′RS)-3′-methyl-1′-in-
danon-2′-yl)bicyclo[2.2.1]hept-2-ene-bis-endo-5,6-dicarboxylate
(7n). (Procedure B) from 0.60 mL of LDA (1.08 mmol), 0.10 mL of 3-
methyl-1-indanone (0.74 mmol) and 0.15 g of 2 (0.72 mmol)
+
+
1
(hexane/EtOAc gradient 30:1 → 20:1): 66.3 mg (26%). H NMR
(500 MHz, CDCl3) δ = 7.73 (d, J = 7.7 Hz, 1H), 7.57 (ddd, J = 7.5,
7.5, 1.3 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H),
J
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1
(hexane/EtOAc gradient 30:1 → 5:1): 0.13 g (23%). H NMR (500
MHz, CDCl3) δ = 7.84 (m, 2H), 7.43 (m, 1H), 7.34−7.27 (m, 7H)
overlaps with CDCl3, 6.32 (dd, J = 5.6, 3.1 Hz, 1H), 5.88 (dd, J = 5.6,
3.0 Hz, 1H), 5.16 (s, 1H), 3.73 (s, 3H), 3.54 (d, J = 2.0 Hz, 1H), 3.09
(s, 3H), 2.95 (m, 1H), 2.76 (m, 1H), 2.48 (d, J = 9.2 Hz, 1H), 1.64
(dddd, J = 9.2, 1.8, 1.8, 1.8 Hz, 1H). 13C NMR (500 MHz, CDCl3) δ =
196.5, 175.7, 174.4, 139.8, 135.9, 135.7, 135.1, 133.0, 130.9, 128.9,
128.5, 128.3, 127.9, 59.2, 57.7, 51.6, 51.6, 50.3, 49.4, 47.5, 46.3. HRMS
7.38 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.27 (t, J = 7.2 Hz,
1H), 4.66 (dd, J = 7.9, 5.1 Hz, 1H), 3.78 (s, 3H), 3.42 (d, J = 4.7 Hz,
1H), 3.07 (ddd, J = 7.8, 4.9, 1.3 Hz, 1H), 2.85 (t, J = 5.1 Hz, 1H), 2.50
(q, J = 9.4, 4.7 Hz, 1H), 2.27−2.18 (m, 2H), 1.91−1.82 (m, 1H),
1.67−1.60 (m, 1H), 1.54−1.47 (m, 1H), 1.13−1.05 (m, 1H), 0.92, (d,
J = 6.9 Hz, 3H). 13C NMR (500 MHz, CDCl3) δ = 176.9, 143.9, 128.0,
126.6, 126.0, 124.0, 96.1, 51.7, 48.1, 47.8, 42.8, 37.6, 35.1, 32.5, 14.7,
+
17.1, 6.4. HRMS (ESI/TOF) calcd for C19H22NaO3 (MNa+)
+
(ESI/TOF) calcd for C25H25O5 (MH+) 405.1697, found 405.1687.
321.1467, found 321.1450.
Methyl endo-3-(1,3-dioxalan-2-yl)-8-phenylbicyclo[4.3.0]non-7-
ene-exo-2-carboxylate (13a). A solution of 0.18 g of 7a (0.63
mmol), 0.22 mL of HCl solution (4 M in dioxane, 0.89 mmol) and
0.08 g ethylene glycol (1.26 mmol) was prepared in dichloromethane
(130 mL) in a Pyrex reaction vessel. This solution was irradiated for 29
h. The crude reaction mixture was purified on a silica gel column using
a mixture of hexane and EtOAc as an eluent. The reaction mixture was
then concentrated in vacuo to a volume of 20 mL and washed with
saturated sodium bicarbonate solution (2 × 15 mL), and the aqueous
layer was extracted with dichoromethane (2 × 20 mL). The combined
organic layers were dried over anhydrous sodium sulfate, and the
solvent was removed in vacuo to give a crude yellow oil. The crude
mixture was purified on a silica gel column using hexane and ethyl
acetate as the eluent (hexane/EtOAc gradient 30:1 → 5:1), 63 mg
Dimethyl exo-5-(1′-benzoyl-1′-phenylmethyl)bicyclo[2.2.1]hept-
2-ene-bis-endo-5,6-dicarboxylate (7q′). (Procedure B, same reaction
as for 7q) 81.5 mg (14%). 1H NMR (500 MHz, CDCl3) δ = 7.78 (m,
2H), 7.38 (m, 1H), 7.33−7.21 (m, 7H) overlaps with CDCl3, 6.57 (m,
2H), 4.86 (s, 1H), 4.42 (d, J = 3.6 Hz, 1H), 3.79 (s, 3H), 3.13 (m,
1H), 3.05 (s, 3H), 2.94 (m, 1H), 1.41 (m, 2H). 13C NMR (500 MHz,
CDCl3) δ = 197.5, 175.5, 174.0, 139.4, 135.8, 135.7, 134.2, 132.6,
131.3, 128.8, 128.3, 128.0, 127.6, 62.9, 58.5, 52.2, 52.1, 51.3, 49.7, 47.3,
47.1. HRMS (ESI/TOF) calcd for C25H25O5+ (MH+) 405.1697, found
405.1690.
Irradiation Experiments. General Procedure. Approximately
1−5 mM solution of the endo-Michael adduct in benzene was
irradiated in Pyrex or borosilicate glass reaction vessels in a Rayonet
reactor equipped with RPR-3500 UV lamps (broadband 300−400 nm
UV source with peak emission at 350 nm) for 1−24 h. The crude
reaction mixture was purified on a silica gel column using a mixture of
hexane and EtOAc as an eluent.
1
(30%). H NMR (500 MHz, CDCl3) δ = 7.44 (d, J = 7.9 Hz, 2H),
7.34 (t, J = 7.4 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 6.01 (t, J = 2.2 Hz,
1H), 4.71 (d, J = 3.9 Hz, 1H), 3.94−3.77 (m, 4H), 3.72 (s, 1H), 3.11
(s, 1H), 2.80 (dddd, J = 15.4, 6.2, 3.7, 2.6 Hz, 1H), 2.59 (dt, J = 12.8,
6.5 Hz, 1H), 2.53 (d, J = 15.4 Hz, 1H), 2.32 (t, J = 11.2 Hz, 1H),
2.05−2.96 (m, 2H), 1.77−1.67 (m, 2H), 1.35−1.24 (m, 2H). 13C
NMR (500 MHz, CDCl3) δ = 176.9, 142.0, 136.6, 129.6, 128.3, 127.1,
125.5, 106.1, 65.0, 64.9, 51.5, 45.2, 45.0, 41.2, 41.1, 38.9, 26.1, 22.0.
Dimethyl (1RS,5SR,6RS,8SR)-spiro[6-formyl-3-phenylbicyclo-
[3.2.1]oct-2-ene-5,8-dicarboxylate-7,1′-cyclopropane] (9c). From
140 mg of 7c (0.40 mmol) for 20 h (hexane/EtOAc gradient 30:1
→ 5:1): 74 mg (53%). 1H NMR (500 MHz, CDCl3) δ = 9.49 (d, J =
4.9 Hz, 1H), 7.40 (m, 2H), 7.33 (m, 2H), 7.28 (m, 1H) overlaps with
CDCl3, 6.41 (d, J = 6.6 Hz, 1H), 3.86 (d, J = 4.0 Hz, 1H), 3.82 (s,
3H), 3.64 (s, 3H), 3.36 (d, J = 18.8 Hz, 1H), 2.87 (d, J = 18.8 Hz, 1H),
2.72 (d, J = 4.9 Hz, 1H), 2.48 (dd, J = 6.6, 4.0 Hz, 1H), 0.82 (m, 2H),
0.71−0.66 (m, 1H), 0.49−0.44 (m, 1H). 13C NMR (500 MHz,
CDCl3) δ = 201.9, 174.1, 170.2, 139.0, 134.5, 128.5, 127.8, 126.7,
125.1, 62.3, 54.0, 52.7, 52.4, 51.9, 46.4, 31.2, 30.7, 14.5, 5.9. HRMS
+
HRMS (ESI/TOF) calcd for C20H24LiO4 (MLi+) 335.1835, found
335.1829.
Methyl 6-(1,3-dioxalan-2-yl)-3-phenylbicyclo[3.3.1]non-2-ene-
syn-9-carboxylate (12a). From the reaction mixture above, isolated
as 6-epimeric mixture, 38 mg (18%). HRMS (ESI/TOF) calcd for
+
C20H24NaO4 (MNa+) 351.1572, found 351.1558.
+
(ESI/TOF) calcd for C21H22NaO5 (MNa+) 377.1359, found
Methyl endo-3-(1,3-dioxalan-2-yl)-endo-10-methyl-8-
phenylbicyclo[4.3.0]non-7-ene-exo-2-carboxylate (13b). A solution
of 0.21 g of 10b (0.70 mmol), 0.25 mL of HCl solution (4 M in
dioxane, 0.99 mmol) and 0.09 g ethylene glycol (1.40 mmol) was
prepared in chloroform (10 mL) and then heated to 70 °C while
stirring for 4 h. The reaction mixture was then concentrated in vacuo
to remove chloroform, diluted with dichoromethane (10 mL), and
washed with saturated sodium bicarbonate solution (2 × 15 mL), and
the aqueous layer extracted with dichoromethane (2 × 10 mL). The
combined organic layers were dried over anhydrous sodium sulfate,
and the solvent removed in vacuo to give a crude yellow oil. The crude
mixture was purified on a silica gel column using hexane and ethyl
acetate as the eluent (hexane/EtOAc gradient 30:1 → 5:1), 0.17 g
(71%). 1H NMR (500 MHz, CDCl3) δ = 7.35−7.31 (m, 4H), 7.25 (t,
J = 7.2 Hz, 1H), 5.87 (t, J = 2.1 Hz, 1H), 4.79 (d, J = 3.7 Hz, 1H),
4.01−3.85 (m, 3H), 3.71 (s, 3H), 3.31 (tt, J = 7.7, 1.7 Hz, 1H), 2.95−
2.82 (m, 2H), 2.68 (t, J = 11.5 Hz, 1H), 2.08−2.00 (m, 2H), 1.78−
1.71 (m, 2H), 1.56−1.48 (m, 2H), 1.08 (d, J = 7.4 Hz, 3H).
377.1354.
Dimethyl (1RS,5SR,6RS,8SR)-spiro[6-(1,3-dioxolan-2-yl)-3-
phenylbicyclo[3.2.1]oct-2-ene-5,8-dicarboxylate-7,1′-cyclopropane]
(12c). From 70 mg of 9c (0.20 mmol), one drop of HCl (4.0 M
solution in 1,4-dioxane) in 5 mL of THF/ethylene glycol mixture
1
(1:1) (hexane/EtOAc gradient 30:1 → 5:1): 77 mg (98%). H NMR
(500 MHz, CDCl3) δ = 7.45 (m, 2H), 7.32 (m, 2H), 7.25 (m, 1H),
6.33 (d, J = 6.7 Hz, 1H), 4.76 (d, J = 8.5 Hz, 1H), 3.81 (s, 3H), 3.80
(d, J = 4.2 Hz, 1H), 3.76−3.70 (m, 4H), 3.60 (s, 3H), 3.32 (d, J = 18.8
Hz, 1H), 3.01 (d, J = 18.8 Hz, 1H), 2.64 (d, J = 8.5 Hz, 1H), 2.31 (dd,
J = 6.7, 4.2 Hz, 1H), 1.20 (m, 1H), 0.73 (m, 1H), 0.45 (m, 2H). 13C
NMR (500 MHz, CDCl3) δ = 176.0, 170.9, 139.9, 133.8, 128.3, 127.3,
126.9, 125.1, 104.8, 64.7, 64.5, 56.3, 53.3, 52.9, 52.4, 51.7, 46.4, 30.0,
+
29.9, 15.5, 6.0. HRMS (ESI/TOF) calcd for C23H27O6 (MH+)
399.1802, found 399.1817.
Methyl (1RS,3SR,4RS,5RS,6SR,9RS, 10SR)-11-oxa-3-
phenyltetracyclo[4.3.1.13,5.04,9]undecane-10-carboxylate (10a).
From 0.18 g of 7a (0.63 mmol) irradiated for 20 h; (hexane/EtOAc
gradient 30:1 → 5:1): 79 mg (44%). 1H NMR (500 MHz, CDCl3) δ =
7.40−7.36 (m, 3H), 2H in aromatic region obscured by CDCl3, 4.67
(dd, J = 8.0, 5.1 Hz, 1H), 3.78 (s, 3H), 3.33 (d, J = 4.5 Hz, 1H), 3.12
(dd, J = 6.4, 5.1 Hz, 1H), 3.05−3.01 (m, 1H), 2.52 (q, J = 9.4, 4.7 Hz,
1H), 2.22−2.18 (m, 1H), 2.16−2.02 (m, 1H), 1.91−1.83 (m, 1H),
1.65−1.58 (m, 1H), 1.56−1.50 (m, 1H), 1.14−1.06 (m, 1H). 13C
NMR (500 MHz, CDCl3) δ = 176.6, 142.4, 128.2, 126.9, 124.0, 96.0,
51.7, 47.4, 44.1, 44.1, 36.2, 32.6, 17.2, 17.0. HRMS (ESI/TOF) calcd
for C18H20NaO3+ (MNa+) 307.1310, found 307.1317. See SI for X-ray
data.
Methyl endo-5-hydroxy-2-methyl-3-phenyltricyclo[4.3.1.04,9]dec-
2-ene-exo-10-carboxylate (14). A solution of 0.11 g of 10b (0.37
mmol) and 0.13 mL of HCl solution (4 M in dioxane, 0.51 mmol) was
prepared in chloroform (10 mL) and stirred at ambient temperature
for 4 h. The reaction mixture was then concentrated in vacuo to
remove chloroform, diluted with dichoromethane (10 mL), and
washed with saturated sodium bicarbonate solution (2 × 15 mL), and
the aqueous layer extracted with dichoromethane (2 × 10 mL). The
combined organic layers were dried over anhydrous sodium sulfate,
and the solvent removed in vacuo to give a crude yellow oil. The crude
mixture was purified on a silica gel column using hexane and ethyl
acetate as the eluent (hexane/EtOAc gradient 30:1 → 5:1), 80 mg
(73%). The structure is characterized by X-ray (see Supporting
Methyl (1SR,2SR,3SR,4RS,5RS,6SR,9RS,10SR)-1-methyl-11-oxa-3-
phenyltetracyclo[4.3.1.13,5.04,9]undecane-10-carboxylate (10b).
From 55 mg of 7b (0.18 mmol) irradiated for 20 h; (hexane/EtOAc
gradient 30:1 → 5:1): 36 mg (65%).1H NMR (500 MHz, CDCl3) δ =
1
Information). H NMR (500 MHz, CDCl3) δ = 7.45 (d, J = 8.4 Hz,
2H), 7.37 (t, J = 7.7 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 4.03 (dt, J = 8.5,
K
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2.2 Hz, 1H), 3.75 (s, 3H), 3.15 (dd, J = 8.7, 4.3 Hz, 1H), 2.88 (d, J =
4.5 Hz, 1H), 2.76−2.74 (m, 1H), 2.54−2.50 (m, 1H), 2.32−2.28 (m,
1H), 2.03 (s, 3H), 1.80−1.59 (m, 4H) . 13C NMR (500 MHz, CDCl3)
δ = 175.9, 145.5, 137.7, 137.3, 128.2, 128.1, 126.5, 69.3, 51.8, 51.4,
48.2, 42.3, 38.3, 38.1, 21.9, 18.1, 14.6. HRMS (ESI/TOF) calcd for
C19H22LiO3+ (MLi+) 305.1728, found 305.1729. See SI for X-ray data.
Dimethyl (1SR,2RS,3RS,5SR,6SR,7RS,9SR,10SR)-3-hydroxy-3-
phenyltetracyclo[3.3.1.17,9.02,6]decane-9,10-dicaboxylate (15).
From 120 mg of 7d (0.35 mmol) for 3 h (hexane/EtOAc gradient
30:1 → 2:1): 90 mg (75%), colorless crystals, mp 101.5−103.5 °C. 1H
NMR (500 MHz, CDCl3) δ = 7.47 (d, J = 7.3 Hz, 2H), 7.34 (t, J = 7.5
Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 3.02 (s,
1H), 2.92 (ddd, J = 2.7, 2.7, 2.7 Hz, 1H), 2.87 (m, 1H), 2.75 (ddd, J =
3.0, 3.0, 3.0 Hz, 1H), 2.56 (m, 1H) overlaps with 2.56 (s, OH), 2.46
(m, 1H), 2.41 (d, J = 14.9 Hz, 1H), 2.24 (dd, J = 14.9, 4.6 Hz, 1H),
Dimethyl (1SR,2RS,3SR,4SR,5RS,6SR,7RS,9RS,10SR)-3-hydroxy-
3,4-diphenyltetracyclo[3.3.1.17,9.02,6]decane-9,10-dicaboxylate (19).
From 0.23 g of 7f (0.55 mmol) for 6 h (hexane/EtOAc gradient 30:1
1
→ 10:1): 0.15 g (65%). H NMR (500 MHz, CDCl3) δ = 7.67 (m,
2H), 7.40 (m, 2H), 7.26 (m, 1H) overlaps with CDCl3, 7.23−7.18 (m,
4H), 7.13 (m, 1H), 3.39 (d, J = 3.3 Hz, 1H), 3.93 (s, OH), 3.90 (ddd, J
= 3.0, 3.0, 1.5 Hz, 1H), 3.81 (s, 3H), 3.33 (s, 3H), 3.01 (m, 2H), 2.98
(s, 1H), 2.80 (ddd, J = 3.1, 3.1, 3.1 Hz, 1H), 2.64 (m, 1H), 1.72 (dd, J
= 10.4, 2.8 Hz, 1H), 1.59 (dd, J = 10.5, 2.8 Hz, 1H). 13C NMR (500
MHz, CDCl3) δ = 174.1, 172.7, 149.5, 137.3, 128.3, 128.2, 127.8,
126.5, 125.9, 124.7, 76.9 overlaps with CDCl3, 70.9, 62.7, 55.2, 53.9,
53.6, 51.9, 51.8, 49.8, 46.1, 42.1, 41.5. HRMS (ESI/TOF) calcd for
+
C26H26NaO5 (MNa+) 441.1672, found 441.1668.
Dimethyl (1SR,3RS,4RS,5SR,6SR,7SR,8SR,9SR)-5-benzyl-6-hy-
droxy-6-phenyltetracyclo[3.2.1.13,8.04,7]nonane-8,9-dicaboxylate
1
1
(20). 58 mg, (25%). H NMR (500 MHz, CDCl3) δ = 7.39 (m, 2H),
1.78 (dd, J = 10.4, 3.0 Hz, 1H), 1.61 (dd, J = 10.4, 2.7 Hz, 1H). H
7.11−7.05 (m, 3H), 6.88−6.83 (m, 3H), 6.67 (m, 2H), 4.31 (s, OH),
3.83 (s, 3H), 3.58 (s, 3H), 3.15 (m, 2H), 3.03 (d, J = 16.2 Hz, 1H),
2.91 (m, 1H), 2.84 (m, 2H), 2.69 (d, J = 16.2 Hz, 1H), 1.83 (dd, J =
10.3, 2.7 Hz, 1H), 1.69 (dd, J = 10.3, 1.6 Hz, 1H). 13C NMR (500
MHz, CDCl3) δ = 175.6, 172.1, 141.8, 138.0, 129.9, 127.7, 127.3,
127.1, 127.0, 124.7, 75.1, 69. 5, 63.6, 59.7, 58.1, 52.5, 51.7, 50.9, 48.34,
41.5, 38.5, 32.6.
NMR (500 MHz, C6D6) δ = 7.34 (m, 2H), 7.19 (m, 2H), 7.10 (m,
1H), 3.46 (s, 3H), 3.34 (s, 3H), 2.91 (m, 2H), 2.65 (m, 1H), 2.55 (d, J
= 14.5 Hz, 1H) overlaps with 2.56 (ddd, J = 3.0, 3.0, 3.0 Hz, 1H)
overlaps with 2.52 (m, 1H), 2.07 (dd, J = 14.5, 4.7 Hz, 1H) overlaps
with 2.05 (m, 1H), 1.42 (dd, J = 10.3, 3.0 Hz, 1H), 1.13 (dd, J = 10.3,
2.7 Hz, 1H). 13C NMR (500 MHz, CDCl3) δ = 173.9, 172.4, 148.9,
128.3, 126.8, 124.6, 78.7, 67.2, 63.8, 54.0, 52.0, 51.9, 51. 8, 51.2, 46.0,
Dimethyl (1RS,2SR,3RS,4SR,5RS,6SR,7RS)-6-benzoyl-5-
phenyltricyclo[2.2.2.13,7]nonane-1,2-dicaboxylate (21). From 400
mg of 7f′ (0.95 mmol) for 72 h (hexane/EtOAc gradient 30:1 → 1:1):
+
42.6, 41.0, 40.1. HRMS (ESI/TOF) calcd for C20H23O5 (MH+)
343.1540, found 343.1544. See SI for X-ray data.
Dimethyl (1SR,3RS,4RS,5SR,6SR,7SR,8SR, 9SR)-6-hydroxy-5-meth-
1
80 mg (20%). H NMR (500 MHz, CDCl3) δ = 7.98 (m, 2H), 7.53
yl-6-phenyltetracyclo [3.2.1.13,8.04,7]nonane-8,9-dicaboxylate (16).
(m, 1H), 7.47 (m, 2H), 7.30 (m, 2H), 7.25 (m, 2H) overlaps with
CDCl3, 7.14 (m, 1H), 5.28 (d, J = 2.8 Hz, 1H), 3.59 (s, 3H), 3.48 (m,
1H), 3.08 (m, 1H), 3.03 (m, 1H), 2.90 (dddd, J = 7.8, 5.1, 3.4, 1.6 Hz,
1H), 2.84 (s, 3H), 2.75 (s, 1H), 1.87−1.80 (m, 2H), 1.74−1.69 (m,
2H). 13C NMR (500 MHz, CDCl3) δ = 205.5, 175.2, 171.0, 142.9,
138.8, 132.0, 128.6, 128.2, 128.0, 127.4, 126.1, 124.7, 57.1, 52.0, 50.9,
50.8, 50.1, 46.7, 45.6, 43.7, 40.2, 39.7, 33.6. HRMS (ESI/TOF) calcd
1
18 mg (15%). H NMR (500 MHz, CDCl3) δ = 7.49 (m, 2H), 7.34
(m, 2H), 7.26 (m, 1H) overlaps with CDCl3, 4.61 (s, OH), 3.86 (s,
3H), 3.59 (s, 3H), 3.10−3.07 (m, 3H), 2.66 (m, 1H), 2.41 (ddd, J =
3.1, 3.1, 3.1 Hz, 1H), 1.78 (dd, J = 10.4, 2.6 Hz, 1H), 1.69 (dd, J =
10.4, 2.7 Hz, 1H) overlaps with 1.68 (d, J = 7.3 Hz, 1H), 0.89 (s, 3H).
Dimethyl (1RS,2RS,3RS,5SR,6RS,7RS,9SR,10SR)-spiro[3-hydroxy-
3-phenyltetracyclo[3.3.1.17,9.02,6] decane-9,10-dicaboxylate-8,1′-cy-
clopropane] (17). From 65 mg of 7e (0.18 mmol) for 12 h (hexane/
+
for C26H26NaO5 (MNa+) 441.1672, found 441.1659.
1
Dimethyl (1RS,2RS,3SR,4SR,5RS,6SR,7RS,9SR,10SR)-spiro[3-hy-
droxy-3,4-diphenyltetracyclo[3.3.1.17,9.02,6]decane-9,10-dicaboxy-
late-8,1′-cyclopropane] (22). From 48 mg of 7g (0.11 mmol) for 5 h
(hexane/EtOAc gradient 30:1 → 1:1): 17 mg (35%), colorless crystals,
mp 173.5−176.5 °C. 1H NMR (500 MHz, CDCl3) δ = 7.68 (m, 2H),
7.41 (m, 2H), 7.27 (m, 1H) overlaps with CDCl3, 7.21 (m, 4H), 7.13
(m, 1H), 3.97 (m, 2H), 3.86 (s, OH), 3.80 (s, 3H), 3.55 (s, 1H), 3.34
(s, 3H), 3.10 (m, 1H), 3.05 (m, 1H), 2.45 (ddd, J = 2.8, 2.8, 1.0 Hz,
1H), 2.21 (dd, J = 3.3, 3.3 Hz, 1H), 0.79−0.72 (m, 2H), 0.58−0.49
(m, 2H). 13C NMR (500 MHz, CDCl3) δ = 174.1, 172.8, 149.6, 137.3,
128.3, 128.2, 127.8, 126.5, 125.9, 124.8, 69.5, 61.6, 54.8, 54.6, 53.6,
52.2, 51.9, 51.9, 50.7, 47.9, 38.5, 9.8, 9.7. HRMS (ESI/TOF) calcd for
EtOAc gradient 30:1 → 1:1): 50 mg (77%). H NMR (500 MHz,
CDCl3) δ = 7.49 (m, 2H), 7.36 (m, 2H), 7.25 (m, 1H), 3.82 (s, 3H),
3.68 (s, 3H), 3.58 (m, 1H), 2.95 (m, 1H), 2.88 (m, 1H), 2.62 (m, 1H),
2.52 (s, OH), 2.40 (d, J = 14.8 Hz, 1H), 2.36 (ddd, J = 2.7, 2.7, 1.0 Hz,
1H), 2.25 (dd, J = 14.8, 4.7 Hz, 1H), 2.17 (dd, J = 3.3, 3.3 Hz, 1H),
0.87−0.82 (m, 1H), 0.80−0.76 (m, 1H), 0.55−0.48 (m, 2H). 1H
NMR (500 MHz, C6D6) δ = 7.43 (m, 2H), 7.20 (m, 2H), 7.11 (m,
1H), 3.63 (m, 1H), 3.48 (s, 3H), 3.38 (s, 3H), 2.77 (m, 1H), 2.73 (m,
1H) overlaps with 2.71 (m, 1H), 2.58 (d, J = 14.7 Hz, 1H), 2.39 (m,
1H), 2.19 (br. s, OH), 2.13 (dd, J = 14.7, 4.7 Hz, 1H), 2.03 (dd, J =
3.2. 3.2 Hz, 1H), 0.62 (ddd, J = 9.7, 5.0, 5.0 Hz, 1H), 0.39 (ddd, J =
1
9.7, 5.0, 5.0 Hz, 1H), 0.18 (m, 1H), 0.12 (m, 1H). H NMR (500
+
C28H28NaO5 (MNa+) 467.1829, found 467.1813. See SI for X-ray
MHz, CD3OD) δ = 7.45 (m, 2H), 7.32 (m, 2H), 7.20 (m, 1H), 3.78
(s, 3H), 3.66 (s, 3H), 3.55 (m, 1H), 2.88 (m, 1H), 2.82 (m, 1H), 2.43
(m, 1H), 2.37 (d, J = 14.6 Hz, 1H), 2.34 (ddd, J = 2.7, 2.7, 1.0 Hz,
1H), 2.15 (m, 1H) overlaps with 2.13 (dd, J = 14.6, 4.9 Hz, 1H),
0.88−0.79 (m, 2H), 0.57−0.48 (m, 2H). 13C NMR (500 MHz,
CDCl3) δ = 173.9, 172.6, 149.0, 128.3, 126.7, 124.6, 78.3, 65.7, 62.7,
55.3, 52.2, 52.0, 52.0, 51.8, 51.1, 46.5, 40.8, 38.9, 9.8 (two overlapping
peaks). 13C NMR (500 MHz, CD3OD) δ = 176.3, 174.6, 143.5, 129.0,
129.0, 128.4, 77.8, 64. 6, 64.5, 61.8, 58.1, 57.6, 52.6, 52.1, 51.8, 46.2,
data.
Dimethyl (1RS,2SR,3RS,4SR,5SR,6SR,7RS)-spiro[6-benzoyl-5-
phenyltricyclo[2.2.2.13,7]nonane-1,2-dicaboxylate-9,1′-cyclopropyl]
(24). From 0.22 mg of 7g′ (0.49 mmol) for 24−48 h (hexane/EtOAc
gradient 20:1 → 1:1): 7 mg (30%). 1H NMR (500 MHz, CDCl3) δ =
7.98 (m, 2H), 7.53 (m, 1H), 7.47 (m, 2H), 7.31 (m, 2H), 7.25 (m,
2H), 7.14 (m, 1H), 5.29 (d, J = 2.7 Hz, 1H), 3.60 (s, 3H), 3.52 (m,
1H), 3.46 (s, 1H), 3.02 (m, 1), 2.83 (s, 3H), 2.40 (m, 2H), 2.20 (ddd,
J = 11.5, 7.8, 1.5 Hz, 1H), 1.81 (d, J = 11.5 Hz, 1H), 1.05−1.00 (m,
1H), 0.93−0.88 (m, 1H), 0.68−0.60 (m, 2H). 13C NMR (500 MHz,
CDCl3) δ = 205.5, 175.1, 171.1, 142.8, 138.7, 132.0, 128.6, 128.2,
128.0, 127.4, 126.1, 56.2, 52.0, 51.2 (two overlapping peaks), 50.8
(two overlapping peaks), 46.5 (two overlapping peaks), 40.4, 38.8,
34.4, 10.3, 9.7.
+
39.3, 13. 7, 8.4, 8.3. HRMS (ESI/TOF) calcd for C22H24NaO5
(MNa+) 391.1516, found 391.1527.
Dimethyl (1RS,3RS,4RS,5SR,6SR,7RS,8SR,9SR)-spiro[6-hydroxy-5-
methyl-6-phenyltetracyclo [3.2.1.13,8.04,7]nonane-8,9-dicaboxylate-
2,1′-cyclopropyl] (18). 13 mg (20%). 1H NMR (500 MHz, CDCl3) δ
= 7.53 (m, 2H), 7.35 (m, 2H), 7.27 (m, 1H) overlaps with CDCl3,
4.62 (s, OH), 3.87 (s, 3H), 3.68 (m, 1H), 3.59 (s, 3H), 3.33 (dd, J =
3.1, 1.9 Hz, 1H), 2.51 (ddd, J = 2.3, 2.3, 2.3 Hz, 1H), 2.48 (m, 1H),
2.07 (dd, J = 3.1, 3.1 Hz, 1H), 0.98−0.94 (m, 1H), 0.92 (s, 3H), 0.82−
0.75 (m, 2H), 0.69−0.64 (m, 1H), 0.59−0.54 (m, 1H). 13C NMR
(500 MHz, CDCl3) δ = 175.8, 172.6, 141.9, 128.0, 127.8, 127.2, 77.0
overlaps with CDCl3, 63.7, 62.5, 60.7, 57.3, 56.7, 52.5, 51.5, 50.0, 44.2,
Dimethyl (1RS,2RS,3RS,4SR,5RS,6SR,7RS,9SR,10SR)-spiro[4-ethyl-
3-hydroxy-3-phenyltetracyclo[3.3.1.17,9.02,6]decane-9,10-dicaboxy-
late-8,1′-cyclopropane] (26). From 118 mg of 7h (0.30 mmol) for 20
1
h (hexane/EtOAc gradient 30:1 → 10:1): 41 mg (35%). H NMR
(500 MHz, CDCl3) δ = 7.46 (d, J = 7.9 Hz, 2H), 7.33 (t, J = 7.7 Hz,
2H), 7.23 (t, J = 7.3 Hz, 1H), 3.82 (s, 3H), 3.69 (s, 3H), 3.60 (s, 1H),
3.14 (m, 1H), 2.97 (m, 1H), 2.62 (s, OH), 2.46 (m, 1H), 2.38 (m,
1H), 2.28 (dd, J = 11.1, 4.4 Hz, 1H), 2.24 (dd, J = 3.3, 3.3 Hz, 1H),
0.88−0.76 (m, 3H), 0.66 (t, J = 7.1 Hz, 3H), 0.61−0.53 (m, 2H),
+
38.2, 12.1, 7.8, 7.6. HRMS (ESI/TOF) calcd for C22H24NaO5
(MNa+) 391.1516, found 391.1526.
L
dx.doi.org/10.1021/jo301909j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
0.51−0.46 (m, 1H). 13C NMR (500 MHz, CDCl3) δ = 174.0, 172.6,
145.4, 127.7, 126.7, 126.1, 81.8, 66.6, 62.9, 55.9, 54.5, 52.2, 52.0, 51.8
(two overlapping peaks), 51.2, 46.7, 38.7, 25.2, 13.0, 9.8 (two
CDCl3) δ = 164.0, 161.8, 161.3, 144.3, 131.3, 131.0, 129.1, 125.8,
115.7, 99.3, 53.3.
+
overlapping peaks). HRMS (ESI/TOF) calcd for C24H28NaO5
ASSOCIATED CONTENT
* Supporting Information
■
(MNa+) 419.1829, found 419.1818. See SI for X-ray data.
Compounds 25 and 27 were only partially purified, as we were able
to obtain only enriched fractions described with 1H NMR;
additionally, isomers 26 and 27 were characterized by X-ray
crystallography.
S
Additional experimental data, NMR spectra, X-ray data (CIF
file), computational details. This material is available free of
charge via the Internet at http://pubs.acs.org.
Dimethyl (1RS,2RS,3RS,4RS,5RS,6SR,7RS,9SR,10SR)-spiro[4-ethyl-
3-hydroxy-3-phenyltetracyclo [3.3.1.17,9.02,6]decane-9,10-dicaboxy-
AUTHOR INFORMATION
Corresponding Author
*E-mail: akutatel@du.edu.
Notes
1
■
late-8,1′-cyclopropane] (25). H NMR (500 MHz, CDCl3) δ = 7.49
(m, 2H), 7.34 (m, 2H), 7.23 (m, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 3.48
(m, 1H), 3.01 (ddd, J = 3.1, 3.1, 1.4 Hz, 1H), 2.98 (ddd, J = 2.7, 1.3,
1.3 Hz, 1H), 2.92 (m, 1H), 2.55 (br. s, OH), 2.47 (ddd, J = 2.9, 2.9,
1.0 Hz, 1H), 2.14 (ddd, J = 9.6, 6.3, 3.4 Hz, 1H) overlaps with 2.12
(dd, J = 3.3, 3.3 Hz, 1H), 1.55−1.42 (m, 1H), 1.00−0.85 (m, 2H),
0.81 (t, J = 7.4 Hz, 3H) overlaps with 0.81−0.73 (m, 2H), 0.58−0.46
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Support of this research by the NIH (GM093930) and NSF
(CHE-1057800) is gratefully acknowledged.
+
(m, 1H). HRMS (ESI/TOF) calcd for C24H28NaO5 (MNa+)
■
419.1829, found 419.1815.
Dimethyl (1RS,3RS,4RS,5SR,6SR,7RS,8SR,9SR)-spiro[6-hydroxy-6-
phenyl-5-propyltetracyclo[3.2.1.13,8.04,7]nonane-8,9-dicaboxylate-
1
2,1′-cyclopropyl] (27). H NMR (500 MHz, CDCl3) δ = 7.58 (m,
DEDICATION
‡Dedicated to Howard E. Zimmerman
■
2H), 7.34 (m, 2H), 7.27 (m, 1H) overlaps with CDCl3, 4.85 (s, OH),
3.87 (s, 3H), 3.67 (m, 1H), 3.58 (s, 3H), 3.30 (dd, J = 3.2, 1.8 Hz,
1H), 2.63 (m, 1H), 2.49 (ddd, J = 2.3, 2.3, 2.3 Hz, 1H), 2.03 (dd, J =
3.7, 2.6 Hz, 1H), 1.55−1.42 (m, 2H), 1.07 (ddd, J = 15.7, 13.2, 4.2 Hz,
1H), 1.00−0.85 (m, 1H), 0.81−0.73 (m, 1H), 0.67−0.63 (m, 1H),
0.58−0.46 (m, 2H) overlaps with 0.53 (t, J = 7.2 Hz, 3H). See SI for
X-ray data.
REFERENCES
■
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1
endo:exo ratio of 3:1, 0.12 g (11%). Syn isomer (29): H NMR (500
MHz, CDCl3) δ = 6.63 (s, 4H), 5.09 (s, 4H), 3.65 (s, 6H). Anti isomer
1
(30): H NMR (500 MHz, CDCl3) δ = 6.69 (s, 2H), 6.52 (s, 2H),
5.20 (s, 2H), 4.55 (s, 2H), 3.75 (s, 6H). 13C NMR of the mixture (500
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Methyl 6-phenylpyran-2-one-4-carboxylate (31).18 Diisopropyl-
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Hz, 1H), 6.93 (d, J = 1.4 Hz, 1H), 4.00 (s, 3H). 13C NMR (500 MHz,
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