Development of asymmetric deacylative allylation

Article abstract of DOI:10.1021/jo400793a

Herein we present the development of asymmetric deacylative allylation of ketone enolates. The reaction directly couples readily available ketone pronucleophiles with allylic alcohols using facile retro-Claisen cleavage to form reactive intermediates in situ. The simplicity and robustness of the reaction conditions is demonstrated by the preparation of >6 g of an allylated tetralone from commercially available materials. Furthermore, use of nonracemic PHOX ligands allows intermolecular formation of quaternary stereocenters directly from allylic alcohols.

Full text of DOI:10.1021/jo400793a

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Note
Development of Asymmetric Deacylative Allylation
Alexander J Grenning, Christie K Van Allen, Tapan Maji, Simon B Lang, and Jon A Tunge
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400793a • Publication Date (Web): 05 Jun 2013
Downloaded from http://pubs.acs.org on June 11, 2013
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Development of Asymmetric Deacylative Allylation
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Alexander J. Grenning, Christie K. Van Allen, Tapan Maji, Simon B. Lang, Jon A. Tunge*
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Department of Chemistry, The University of Kansas 1251 Wescoe Hall Drive, Lawrence, KS
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66045-7582 (USA)
tunge@ku.edu
Table of Contents/Abstract Graphic:
Abstract:
Herein we present the development of asymmetric deacylative allylation of ketone enolates. The
reaction directly couples readily available ketone pronucleophiles with allylic alcohols using
facile retroꢀClaisen cleavage to form reactive intermediates in situ. The simplicity and robustness
of the reaction conditions is demonstrated by the preparation of > 6 grams of an allylated
tetralone from commercially available materials. Furthermore, use of nonꢀracemic PHOX ligands
allows intermolecular formation of quaternary stereocenters directly from allylic alcohols.
The asymmetric allylation of ketone enolates to form αꢀquaternary ketones has recently
garnered significant attention from the synthetic community.1ꢀ12 The synthetic flexibility of the
product ketones has led to the use of these methods in complex molecule synthesis.10,13ꢀ17 The
most commonly utilized method for preparing αꢀquaternary αꢀallylated ketones is Pdꢀcatalyzed
asymmetric allylic alkylation (AAA). First, Trost reported the AAA of nonstabilized ketone
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enolates (pKa > 24) involving the allylation of tetralones with allylic acetates in the presence of
LDA with or without Me3SnCl.3ꢀ5 More recently, asymmetric decarboxylative allylation (DcA)
methods were reported, which allowed similar allylation in the absence of base and other
additives (Scheme 1).6ꢀ17 Although DcA is an attractive advancement, the required substrates A
and B necessitate coupling of the allyl electrophile with the enolate nucleophiles prior to DcA.
This process is not ideal because it requires one to control O vs. C alkylation using allyl
chloroformate derivatives that are not readily available with a variety of substitution patterns.
Scheme 1: Asymmetric allylic alkylation (AAA) of tetralones
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Recently, we have developed deacylative allylation (DaA) as a robust approach to the
synthesis of allylated chemical building blocks (Scheme 2).18,19 This intermolecular coupling
allows the direct allylation of ketone pronucleophiles (derived from simple active methylene
compounds C) with readily available allylic alcohols,20ꢀ26 and generates little waste product. DaA
takes advantage of the facile retroꢀClaisen reaction of α,αꢀdisubstituted active methylene
compounds to generate enolates and allylic acetates in situ.27ꢀ31 In other words, retroꢀClaisen
cleavage results in the formation of the active nucleophile and simultaneously activates the
electrophile toward palladiumꢀcatalyzed coupling. One example of its utility, we have previously
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demonstrated DaA’s ability to construct 1,6ꢀdienes (cycloisomerization substrates32ꢀ39) in a
single pot via sequential palladiumꢀcatalysis.18ꢀ19,40
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Scheme 2: Deacylative allylation (DaA)
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Herein, we report the use of the DaA concept for the asymmetric allylic alkylation of
nonstabilized ketone enolates. To demonstrate the scalability of DaA, we report a > 6 gram scale
reaction. In addition, we report the asymmetric synthesis of various 1,6ꢀheptadienes (72ꢀ95% ee)
as well as the synthesis of an intermediate en route to the biologically active natural product (+)ꢀ
hamigeran.14,41 We also outline an approach to either enantiomer of chiral 1,6ꢀheptadienes using
the same chiral catalyst.
Table 1. DaA: Various cleaving groups and catalysts
To begin, it was deemed important to utilize ketone reactants that are readily available from
inexpensive starting materials. With this in mind, we synthesized precursors using Claisen
condensations of αꢀtetralone with ethyl formate (1a), acetic anhydride (1b), and propanoic
anhydride (1c) (Table 1).42,43 It is important to point out that the simple, highꢀyielding Claisen
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condensations yield active methylene compounds that undergo mild acetoacetic esterꢀtype
alkylation. With 1aꢀc in hand, we screened conditions for DaA. The formyl derivative (1a)
provided a good yield of allylated product 2a, but significant quantities of protonation product
were also produced. The amount of protonation could be attenuated by use of bidentate rac-
BINAP (entry 2), but could not be avoided entirely. The protonation product could arise from
palladiumꢀcatalyzed reduction by formate ion.44ꢀ46 With this in mind, the diketones 1bꢀc were
subjected to the reaction conditions. Using these ketones, Pd(PPh3)4 was an active catalyst for
DaA and little protonation side reaction took place (Table 1, entries 3ꢀ4).
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With the reaction conditions in hand, we set out to examine the scope of the DaA reaction
(Table 2). Simple allyl and βꢀsubstituted allyl alcohols performed well in the reaction (2aꢀ2c).
An acrylate could likewise be incorporated without competing conjugate additions of alkoxide or
enolate (2c). Unfortunately, low yields were observed with terminally substituted allyl alcohol
coupling partners such as cinnamyl alcohol.
Aside from αꢀmethyl substitution such as that in 2a, allylic systems could be easily
incorporated via TsujiꢀTrost allylation prior to DaA (2bꢀ2k). The use of TsujiꢀTrost allylation
prior to DaA highlights an important advantage of DaA as compared to decarboxylative
allylation: The ketone substrates for DaA are compatible with a variety of metalꢀcatalyzed
couplings (including TsujiꢀTrost) that are incompatible with the allyl ester/carbonate structures
required for DcA. Due to the robust nature of the TsujiꢀTrost allylation, a diverse pool of
bisallylated αꢀtetralones could be prepared. Related 1,6ꢀheptadienes undergo a wide variety of
cycloisomerization and cycloaddition reactions.32ꢀ39 With regard to the R1 substituent introduced
via TsujiꢀTrost allylation, terminal (2g) and βꢀaryl (2d) substitution on the allyl motif were
allowed. Importantly, the synthetically useful cyclopropylallyl (2h) moiety could be
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incorporated, allowing for the rapid synthesis of a unique precursor for [5+2] cycloaddition.39
Other important allylic acetates could also be incorporated via TsujiꢀTrost allylation. For
example, crotyl (2f), cinnamyl (2g), prenyl (2i), geranyl (2k), and myrtenyl (2j) carbon skeletons
could be incorporated on to the tetralone scaffold.
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Table 2. Racemic DaA
R2
O
OH
Ac
O
2.5 mol% Pd(PPh3)4
NaH, THF, rt, 12h
R1
R1
2a-p
R2
t
CO2 Bu
O
O
O
b
2b
2a
2c
68%
90%
81%
O
O
O
R
Ph
2e
2d
80%
O
R =
62%
Me
Ph
2g
77%
2f
84%b,c
2h
80%b
O
O
b
b
2k
, 88%
2i
, 66%
2j
, 95%, 2:1 dr
O
O
O
7
( )n
R
6
OMe
2n
2o
2a
2p
n = 1, 88%
n = 2, 90%
n = 3, 93%
d
75%
2l
2m
R = 7-F, 70%
b
R = 6-OMe, 55%
O
6.2 grams, 86%
0.5 mol% Pd
Ph
2qe,f
a
standard conditions: (0.2-0.3 mmol scale) 1:1 acetyltetralone : allyl
b
alcohol, 2 equiv. NaH, 2.5 mol% Pd(PPh3)4, 12 h, 0.075M
.
gram
≥0.5
c
scale: 1 mol% Pd(PPh3)4, 40οC 5-12h, 0.5 M starting material was 4:1
d
mixture of E/Z crotyl isomers and is reflected in the product standard
conditions for 48h e 23.5 mmol scale,1:1 acetyl tetralone : allyl alcohol, 1.5
o
f
−
equiv. NaH, THF, 0 C rt 0.5 M, 16-18h average of 2 runs by 2 different
experimenters
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Regarding the tetralone core, electron withdrawing (e.g., fluoro, 2l) and donating (2m,n)
groups were compatible. Aside from tetralone cores, both indanone (2o) and benzosubarone (2p)
were compatible substrates.
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Since the starting materials for DaA are commercially available and/or easily prepared, many
of the products in Table 2 were prepared on the > 0.5 gram scale (Table 2, footnote b). To better
test the scalability of the DaA reaction, we further developed the protocol for multiꢀgram
synthesis (Table 2, 2q). We prepared > 6 grams of 2q using allyl alcohol as a coupling partner
and were able to reduce the loadings of Pd (0.5 mol%) and base (1.5 equiv.).
Table 3. Development of asymmetric DaA
Next we turned our attention to the development of an asymmetric reaction to synthesize
enantioenriched 2a (Table 3). We were pleased to see that useful ee’s (79ꢀ85 % ee) could be
achieved using the formyl, acetyl, and propanoyl cleaving groups (1aꢀc) by utilizing the
commercially available tBuPHOX ligand L1 (entries 1ꢀ3).
While the acetyl group provided the highest ee (entry 2), the enantioselectivity of the
coupling was not strongly dependent on the cleaving group. Importantly, excess alkoxide had a
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detrimental effect on the ee (entry 4) and thus the acetyl tetralone must be used in slight excess
(1.05 equiv) compared to alkoxide. One potential explanation for this observation is that excess
alkoxide competes with the enolate for coordination to palladium. Such a process would
interfere with the innerꢀsphere mechanism for allylation as proposed by Stoltz.47 Lastly,
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t
commercially available BuPHOX derivative L2 was a significantly poorer ligand (58ꢀ62 % ee,
entries 5ꢀ6) in this transformation.
Table 4. Synthesis of enantioenriched 1,6-dienes via DaA
To demonstrate the scope of this asymmetric variant, we prepared an assortment of
enantioenriched 1,6ꢀheptadienes (Table 4). The 1,6ꢀheptadienes were prepared by 2ꢀstep Tsujiꢀ
Trost/asymmetric DaA. One advantage of sequential allylation is that either enantiomer of the
product can be prepared by simply interconverting the two allylic coupling partners (e.g. 2b and
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ent-2b, Table 4). It is noteworthy that the yield and ee of ent-2b was superior using the
fluorinated tertꢀbutyl PHOX ligand L3. This type of ligand has been shown by Stoltz to be
particularly useful for sluggish allylation reactions.48,49 In our hands we noticed a similar reaction
efficiency increase. As before, important naturally occurring allylic carbon chains such as prenyl
(2i) and geranyl (2k) groups could also be incorporated.
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Scheme 3. Synthesis of CliveꢀStoltz intermediate 2n en route to (+)ꢀhamigeran
In addition to the heptadiene synthesis, DaA was also utilized to synthesize a key intermediate
used for the synthesis of (+)ꢀhamigeran. The synthesis of the CliveꢀStoltz intermediate 2n
(Scheme 2) proceeded via acetylation and methylation of the known tetralone 4. The
asymmetric deacylative allylation reaction went without incident providing the required
intermediate 2n in high yield (93%) and ee (86%). DaA provides intermediate 2n in similar yield
and ee to that achieved by Stoltz using the same ligand under similar conditions.50 It is important
to point out that Stoltz and coworkers, using a different ligand, can achieve increased ee (91ꢀ
94%).50 That said, the DaA route has several advantages. First, the prior methods for preparing
2n, introduce the αꢀmethyl group by a cryogenic LDA/HMPA mediated methylation.14,41 Our
DaA method allows alkylation under simple K2CO3 mediated alkylation conditions. Secondly,
the decarboxylative coupling method also requires the 2ꢀstep allyl enol carbonate formation
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(with allyl chloroformate) followed by asymmetric DcA. The DaA method reported herein
allows the intermolecular introduction of the allyl group directly from allyl alcohol with the
potential for analoging.
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To conclude, we have developed a new method for allylic alkylation of αꢀtetralones via
deacylative allylation. The reaction directly couples readily available ketone pronucleophiles
with allylic alcohols using facile retroꢀClaisen cleavage to form reactive intermediates in situ.
The simplicity and robustness of the reaction conditions is demonstrated by the preparation of >
6 grams of an allylated tetralone in one pot from commercially available materials. Furthermore,
use of nonꢀracemic PHOX ligands allows intermolecular formation of quaternary stereocenters
directly from allylic alcohols. To demonstrate the utility of this new reaction, enantioenriched
1,6ꢀheptadienes as well as a key intermediate in the synthesis of (+)ꢀhamigeran were prepared.
Experimental Section:
General Experimental Methods
All reactions were run under an argon atmosphere using a Schlenkꢀargon line, unless noted.
Pd(PPh3)4 and Pd2dba3 was purchased from Strem, stored in a glove box and used as is. PHOX
ligands were purchased from Aldrich or prepared by the known literature procedures.48,49 THF
was distilled over Na using benzophenone as an indicator. Allyl alcohol and βꢀmethylallyl
alcohol were purchased from Aldrich, stored over 3Å MS in a sealed vial equipped with a rubber
septum for removal by syringe. Acetyltetralones were prepared by their literature procedure.42ꢀ43
All other substrates were prepared according to the procedures outlined below in the
experimental section. 2ꢀacetyltetralone 1 is commercially available from Aldrich. It can also be
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prepared by the Claisen condensation (see procedure below). 4 was prepared by the literature
procedures.14,41
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Chiral separation was performed on an HPLC instrument using an ODꢀH chiracel column.
Stereochemical configuration is based on Stoltz’s assignment as retention times, chiral column
(chiracel ODꢀH), and catalyst ((S)ꢀtBuPHOX) were the same with same products (e.g. 2a, 2n).7,14
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General procedure (small scale) for racemic deacylative allylation: Synthesis of 2a
A flameꢀdried 10mL Schlenk flask equipped with a stir bar was brought into a glove box and
charged with NaH (2 equiv. 0.50, 12mg) and Pd(PPh3)4 (2.5 mol%, 0.0063 mmol, 7.2 mg). The
flask was capped, removed from the glove box and attached to a argon line. 4 mL of dry THF
was added to the flask and allyl alcohol (0.25 mmol, 15 mg) and tetralone 1b (0.255 mmol, 51
mg) were added in that order. Both syringes used to transfer reagents were washed with the
reaction mixture solvent and reinjected. The vessel was capped, wrapped in parafilm and the
system was completely sealed over argon and allowed to react for 5h.
After the allotted reaction time as determined by TLC (5h), the reaction mixture was diluted
with 15% EtOAc in hexanes and filtered through a SiO2 plug with excess (50ꢀ75 mL) of the 15%
EtOAc in hexanes solvent mixture. The solvent was evaporated and subjected to silica gel
chromatography (3% EtOAc in Hexanes) to yield the pure product 2a.
General procedure for asymmetric deacylative allylation: synthesis of enantioenriched 2a
Two flameꢀdried 10mL Schlenk flasks equipped with stir bars were flame dried and brought
into a glove box. The catalyst (Pd2dba3, 1.25 mol % 0.0063 mmol, 5.7 mg and tertꢀbutylPHOX
ligand, 3 mol%, 0.015 mmol, 6 mg) was loaded into one flask and NaH (2 equiv., 1 mmol, 25
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mg) was loaded into the other. Both were capped, removed from the glove box and attached to a
Schlenk argon line. 2mL of dry THF was added to the catalyst flask, which was then stirred for
10 min at 40 °C. In the meantime, 3 mL of dry THF was added to the flask containing NaH. To
the NaH containing flask was added allyl alcohol (via syringe, 0.50 mmol, 29mg) and tetralone
derivative 1a (via syringe, 0.51 mmol, 95mg) in that order. Both syringes used to transfer
reagents were washed with the reaction mixture solvent and reinjected. Directly after the final
reagent addition, the preformed catalyst was then transferred via syringe and injected as a shot
(no need to wash this syringe). The vessel was capped, wrapped in parafilm and the system was
completely closed and allowed to react for 5h.
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After the allotted reaction time as determined by TLC (12h), the reaction mixture was diluted
with 15% EtOAc in hexanes and filtered through a SiO2 Plug with excess (50ꢀ75mL) of the 15%
EtOAc in hexanes solvent mixture. The solvent was evaporated and subjected to silica gel
chromatography (3% EtOAc in Hexanes) to yield the pure product 2a.
General procedure (large scale) for deacylative allyation: Synthesis of 2q
A flameꢀdried 200 mL Schlenk flask was equipped with an eggꢀshaped stir bar and brought
into a glove box where it was charged with NaH (95% purity, 1.5 equiv., 35.3 mmol, 890 mg)
and Pd(PPh3)4 (0.5 mol%, 0.118 mmol, 136 mg). The flask was capped, removed from the glove
box, and attached to an argon line. 25 mL of THF was added and the heterogeneous mixture was
chilled to 0 °C in an ice bath. Allyl alcohol (23.5 mmol, 1.364 g) was then added neat dropwise
over 5 minutes. The flask was allowed to warm to roomꢀtemperature, and upon ceased H2 (g)
effervescence, was reꢀchilled to 0 °C in an ice bath. Substrate ketone (23.5 mmol, 7.14 g) was
dissolved in 15 mL of THF and added dropwise over ~5 min. The transfer vessel and syringe
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were rinsed with 2 x 5 mL portions of dry THF to ensure complete transfer of the ketone to the
reaction vessel. The reaction vessel was then sealed, equipped with an empty balloon (a small
amount of pressure builds up over time), removed from the ice bath, and allowed to react at room
temperature for 16 − 18 h.
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After the allotted reaction time, the reaction mixture was diluted with 100 mL of a 1:4
mixture of ethyl acetate and hexanes and filtered through a pad of silica gel using vacuum
filtration. The reaction vessel was washed with 4 x 100 mL portions of the ethyl acetate and
hexanes mixture. The filtrate was collected and rotary evaporation yielded the crude product.
The crude product was purified by silica gel column chromatography (~ column size 3 cm
diameter x 20 cm height, mobile phase ~2 L of 2.0 % EtOAc in hexanes) yielding the desired
product as a viscous yellow oil (6.18 g, 87% yield) as well as ~0.8 g of an 85% pure fraction.
General procedure for methylation of diketones:
A 25mL Schlenk flask equipped with a stir bar was charged with anhydrous K2CO3 and
attached to an argon line. The substrate (2.5 mmol) was added followed by 5 mL of anhydrous
DMSO. 500 ꢁL of MeI was then added over 0.5 min. The vessel was capped and stirred for 30
min.
After the allotted reaction time, the reaction mixture was diluted with 15mL of EtOAc
and transferred to a seperatory funnel. The vessel was washed with an extra 15mL EtOAc to
ensure complete transfer of its contents. The organic layer was washed with 2 x 50mL portions
of 1N HCl. The organic layer was dried, evaporated, and subjected to column chromatography
to yield the pure methylated ketone.
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General procedure 1 for Tsuji-Trost allylation:
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In a glove box, a flameꢀdried Schlenk flask equipped with a stir bar was charged with 1
equiv. NaH and 1 mol% Pd(PPh3)4. The vessel was capped and removed from the glove box and
attached to an argon line. THF (0.2M) was added followed by 2ꢀacetyltetralone (1 equiv.) was
added to the flask. After the rapid effervescence, allyl acetate derivative (1.2 equiv.) was added
and the reaction was heated at 40 °C until reaction was complete (as monitored by TLC or GCꢀ
MS). Following complete coupling, the reaction mixture was transferred to a seperatory funnel,
diluted with EtOAc and extracted with 0.5 M HCl (2 x 10 mL) and brine (1 x 20 mL). The
organic layer was dried over MgSO4, volatile organics were removed by rotary evaporation and
the residue was subjected to column chromatography yielding the pure allylated 2ꢀacetyltetralone
derivative.
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General procedure 2 for Tsuji-Trost allylation:
In a glove box, a flameꢀdried Schlenk flask equipped with a stir bar was charged with 1
mol% Pd(PPh3)4. The vessel was capped and removed from the glove box and attached to an
argon line. K2CO3 (5 equiv.), DMSO (0.2M) and 2ꢀacetyltetralone (1 equiv.) were added
sequentially. While stirring, the allyl acetate derivative (2.5ꢀ3 equiv.) was added and the vessel
was capped and stirred at 40 °C until reaction completion (as monitored by TLC or GCꢀMS).
Following complete coupling, the reaction mixture was transferred to a seperatory funnel, diluted
with EtOAc and extracted with 0.5 M HCl (2 x 10 mL) and brine (1 x 20 mL). The organic layer
was dried over MgSO4, volatile organics were removed by rotary evaporation and the residue
was subjected to column chromatography yielding the pure allylated 2ꢀacetyltetralone derivative.
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Baylis-Hillman synthesis of tert-butyl 2-(hydroxymethyl)acrylate:
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A 250 mL roundꢀbottom flask equipped with a stir bar was charged with DABCO (50
mmol, 5.6 g). 30 mL of H2O was then added followed by paraformaldehyde (100 mmol, 3.03 g).
MeCN was then added with heating at 80 °C until the reaction mixture is homogeneous (~30
mL). Tertꢀbutyl acrylate (50 mmol, 6.4 g, 7.3 mL) was then added as a single shot. The resulting
reaction mixture was heated for 2.5 h.
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After the allotted reaction time, the reaction mixture was diluted with 100 mL of DCM
and transferred to a seperatory funnel. An additional 100 mL DCM is used to wash the reaction
vessel to ensure complete transfer. The DCM layer was then washed with 100 mL of 1N HCl
followed by brine (50 mL). The volatiles were removed by rotary evaporation and the crude oil
was subjected to column chromatography (20% EtOAc in hexanes) to yield the desired product.
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2a:6 Isolated as a yellow oil (0.25 mmol scale, 0.045 g, 90%). H NMR (500 MHz, CDCl3): δ
7.97 (dd, J = 7.9, 1.1 Hz, 1H), 7.39 (td, J = 7.5, 1.4 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.15 (d, J =
7.6 Hz, 1H), 5.72 (m, 1H), 5.02 (s, 1H), 5.00 (dm, J = 8.65 Hz, 1H), 2.91 (dd, J = 12.1, 5.1 Hz,
2H), 2.40 (dd, J = 13.8, 7.3 Hz, 1H), 2.21 (ddt, J = 13.8, 7.5, 1.1 Hz, 1H), 2.01 (m, 1H), 1.84
(ddd, J = 13.7, 7.1, 5.5 Hz, 1H), 1.12 (s, 3H).
13C NMR (126 MHz, CDCl3): δ 202.1, 143.3, 133.9, 133.1, 131.6, 128.7, 128.0, 126.6, 118.2,
44.6, 41.1, 33.3, 25.3, 21.9. HPLC: Chiracel ODꢀH column, mobile phase = Hexanes : 2ꢀ
propanol 99.7 : 0.3, flow rate = 0.4 ꢁL/min
2b: Isolated as a yellow oil (0.3 mmol scale, 0.049 g, 68%). 1H NMR (500 MHz, CDCl3): δ 7.98
(dd, J = 7.9, 1.1 Hz, 1H), 7.39 (td, J = 7.5, 1.4 Hz, 1H), 7.24 (t, J = 7.51 Hz, 1H), 7.15 (d, J = 7.6
Hz, 1H), 5.72 (m, 1H), 5.03 (dm, J = 4.61 Hz, 1H), 5.00 (dm, J = 14.02 Hz, 1H), 2.92 (m, 2H),
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2.67 (d, J = 13.6 Hz, 1H), 2.44 (dt, J = 13.9, 7.03, 1.03 Hz 1H), 2.16 (m, 2H), 1.98 (ddd, J = 13.9,
8.6, 5.3 Hz, 1H), 1.90 (ddd, J = 14.0, 6.4, 5.3 Hz, 1H), 1.53 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 200.0, 142.1, 141.4, 132.9, 132.1, 131.0, 127.6, 127.1, 125.7, 117.5, 114.0, 46.7, 41.7,
39.1, 29.2, 24.1, 23.4. HRMS data: Calc. for C17H20O (M + H) = 241.1592. Found 241.1581;
HPLC: Chiracel ODꢀH column, mobile phase = hexanes : 2ꢀpropanol 99.6 : 0.8, flow rate = 0.4
ꢁL/min
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2c: Isolated as a yellow oil (2.0 mmol scale, 0.550 g, 81%) H NMR (500 MHz, CDCl3): δ 7.96
(dd, J = 7.9, 1.2 Hz, 1H), 7.38 (td, J = 7.51, 1.4 Hz, 1H), 7.23 (t, J = 7. 73 Hz, 1H), 7.14 (d, J =
7.6 Hz, 1H), 6.09 (d, J = 1.8 Hz, 1H), 5.45 (s, 1H), 4.74 (s, 1H), 4.61 (s, 1H), 3.02 (ddd, J = 17.0,
9.3, 4.8 Hz, 1H), 2.88 (dt, J = 17.05, 5.76 Hz, 1H), 2.74 (d, J = 13.8 Hz, 1H), 2.71 (d, J = 13.8
Hz, 1H), 2.61 (d, J = 13.4 Hz, 1H), 2.08 (m, 1H), 2.02 (d, J = 13.7 Hz, 1H), 1.78 (ddd, J = 14.0,
6.4, 4.9 Hz, 1H), 1.52 (s, 3H), 1.35 (s, 9H). 13C NMR (126 MHz, CDCl3): δ 200.2, 166.9, 143.1,
142.4, 138.3, 133.1, 132.4, 128.6, 128.1, 126.6, 115.4, 80.6, 48.7, 43.9, 36.4, 30.2, 27.9, 25.3,
24.5. HRMS data: Calc. C22H28O3 (M + Na = 363.1936), found 363.1914
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2d: Isolated as a yellow oil (0.27 mmol scale, 0.051 g, 62%). H NMR (500 MHz, CDCl3): δ
7.80 (dd, J = 7.9, 1.1 Hz, 1H), 7.35 (td, J = 7.5, 1.4 Hz, 1H), 7.19 (m, 8H), 7.09 (d, J = 7.6 Hz,
1H), 5.63 (m, 1H), 5.20 (d, J = 1.7 Hz, 1H), 5.03 (s, 1H), 4.96 (dm, J = 10.21 1H), 4.90 (dm, J =
17.0, 1.3 Hz, 1H), 2.95 (d, J = 13.9 Hz, 1H), 2.81 (m, 2H), 2.75 (d, J = 13.9 Hz, 1H), 2.43 (dd, J
= 14.0, 6.7 Hz, 1H), 2.06 (dd, J = 14.0, 7.9 Hz, 1H), 1.83 (m, 2H). 13C NMR (126 MHz, CDCl3):
δ 200.7, 145.5, 142.9, 134.1, 133.0, 132.1, 128.5, 128.2, 128.0, 127.3, 126.6, 126.5, 118.4, 118.1,
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48.9, 39.8, 39.5, 30.4, 25.1. HRMS data: Calc. For C22H22O ( M + H = 303.174, M + Na =
325.1568), found 303.1710, 325.1540
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2e: Isolated as a yellow oil (0.3 mmol scale, 0.061 g, 80%). 1H NMR (500 MHz, CDCl3): δ 7.98
(dd, J = 7.9, 1.2 Hz, 1H), 7.38 (td, J = 7.5, 1.4 Hz, 1H), 7.23 (t, J = 7.34 Hz, 1H), 7.14 (d, J = 7.6
Hz, 1H), 5.70 (m, 1H), 5.04 (m, 1H), 5.00 (s, 1H), 4.97 (m, 1H), 2.91 (t, J = 6.4 Hz, 2H), 2.46
(ddt, J = 14.14, 6.45, 1.45 Hz, 1H), 2.32 (dd, J = 14.6, 7.0 Hz, 1H), 2.19 (ddd, J = 14.0, 9.2, 8.2
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Hz, 2H), 1.96 (t, J = 6.41 Hz, 2H), 1.63 (s, 3H), 1.50 (s, 3H). C NMR (126 MHz, CDCl3): δ
201.3, 143.2, 134.4, 134.3, 133.0, 132.0, 128.7, 128.0, 126.6, 119.2, 118.0, 48.5, 39.3, 33.1, 30.5,
26.1, 25.2, 18.0. HRMS data: Calc. for C18H22O (M + H = 255.1749), Found 255.1732; Chiral
Resolution: Chiracel ODꢀH column, mobile phase = hexanes : 2ꢀpropanol 99.7 : 0.3, flow rate =
0.4 ꢁL/min
2f: Isolated as a yellow oil (2.06 mmol scale, 0.441 g, 84%). 1H NMR (500 MHz, CDCl3): δ 7.98
(d, J = 8.14 Hz, 1H), 7.38 (td, J = 7.5, 1.4 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 7.7 Hz,
1H), 5.41 (m, 1H), 5.33 (m, 1H), 4.73 (s, 1H), 4.60 (s, 1H), 2.91 (m, 2H), 2.66 (d, J = 13.7 Hz,
1H), 2.35 (dd, J = 14.22, 6.81 Hz, 1H), 2.10 (m, 2H), 1.92 (m, 2H), 1.59 (dd, J = 6.2, 1.2 Hz,
2H), 1.52 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 201.3, 143.2, 142.7, 133.1, 133.0, 132.1,
129.1, 128.6, 128.1, 126.7, 126.6, 126.1, 114.9, 114.9, 47.9, 42.7, 38.8, 30.0, 25.2, 24.5, 18.1.
HRMS data: Calc. for C18H22O (M + H = 255.1748 and M + Na = 277.1568) found 255.1713
and 277.1593.
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2g: Isolated as a yellow oil (0.20 mmol scale, 0.049g, 77%) 1H NMR (500 MHz, CDCl3): δ 8.00
(dd, J = 7.9, 1.2 Hz, 1H), 7.40 (td, J = 7.5, 1.4 Hz, 1H), 7.26 (m, 3H), 7.21 (t, J = 7.43 Hz, 2H),
7.13 (m, 2H), 6.36 (d, J = 15.7 Hz, 1H), 6.12 (m, 1H), 4.76 (s, 1H), 4.63 (s, 1H), 2.95 (dd, J =
12.3, 6.0 Hz, 2H), 2.69 (d, J = 13.6 Hz, 1H), 2.63 (ddd, J = 14.0, 7.2, 1.3 Hz, 1H), 2.31 (ddd, J =
14.0, 7.8, 1.1 Hz, 1H), 2.20 (d, J = 13.7 Hz, 1H), 1.99 (m, 2H), 1.56 (s, 3H). 13C NMR (126
MHz, CDCl3): δ 201.1, 143.1, 142.3, 137.4, 133.5, 133.2, 132.0, 128.7, 128.5, 128.1, 127.2,
126.7, 126.1, 125.8, 115.2, 48.3, 43.0, 39.4, 30.5, 25.3, 24.5.
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HRMS data: Calc. C23H24O (M + H = 317.1905), found 317.1911
2h: Isolated as a yellow oil (2.0 mmol scale, 0.449 g, 80%). 1H NMR (500 MHz, CDCl3): δ 7.98
(dd, J = 7.9, 1.1 Hz, 1H), 7.38 (td, J = 7.5, 1.4 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.6
Hz, 1H), 5.39 (dt, J = 14.9, 7.4 Hz, 1H), 4.94 (dd, J = 15.1, 8.6 Hz, 1H), 4.72 (dd, J = 2.1, 1.5 Hz,
1H), 4.61 (s, 1H), 2.90 (m, 2H), 2.66 (d, J = 13.6 Hz, 1H), 2.35 (ddd, J = 14.0, 7.1, 1.1 Hz, 1H),
2.12 (d, J = 13.7 Hz, 1H), 2.07 (ddd, J = 14.1, 7.6, 0.9 Hz, 1H), 1.92 (m, 2H), 1.54 (s, 3H), 1.28
(m, 1H), 0.58 (m, 2H), 0.24 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 201.3, 143.2, 142.6, 138.2,
133.0, 132.1, 128.6, 128.1, 126.6, 122.5, 114.9, 48.0, 42.7, 38.7, 30.0, 25.2, 24.5, 13.7, 6.6, 6.5.
HRMS data: Calc. for C20H24O (M + H = 281.1905), Found 281.1918
2i: Isolated as a yellow oil (2.95 mmol scale, 0.523 g, 66%). 1H NMR (500 MHz, CDCl3): δ 7.99
(dd, J = 7.9, 1.1 Hz, 1H), 7.38 (td, J = 7.5, 1.4 Hz, 1H), 7.23 (t, J = 7.32 Hz, 1H), 7.14 (d, J = 7.7
Hz, 1H), 5.07 (m, 1H), 4.72 (s, 1H), 4.60 (s, 1H), 2.90 (m, 2H), 2.69 (d, J = 13.6 Hz, 1H), 2.30
(dd, J = 14.7, 6.9 Hz, 1H), 2.15 (m, 1H), 2.11 (d, J = 13.7 Hz, 1H), 1.93 (m, 2H), 1.64 (s, 3H),
1.53 (s, 3H), 1.51 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 201.5, 143.2, 142.7, 134.7, 133.0,
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132.1, 128.6, 128.1, 126.6, 119.2, 114.8, 48.4, 42.7, 33.96, 29.9, 26.1, 25.3, 24.5, 18.1. HRMS
data: Calc. for C19H24O ( M + Na = 291.1724), found 291.1693; Chiral Resolution: Chiracel ODꢀ
H column, mobile phase = Hexanes : 2ꢀpropanol 99.7 : 0.3, flow rate = 0.4 ꢁL/min 17.95 min.
and 18.45 min.
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2j: Isolated as a yellow oil (1.9 mmol scale, 0.604 g, 95%). H NMR (500 MHz, CDCl3): δ 7.97
(m, 1H), 7.38 (t, J = 7.6 Hz 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 5.22 (s, 1H),
4.70 (m, 1H), 4.59 (d, J = 6.8 Hz, 1H), 2.98 (m, 1H), 2.87 (m, 1H), 2.73 (d, J = 13.6 Hz, 1H),
2.37 (d, 1H), 2.03 (m, 9H), 1.51 (s, 2H), 1.18 (s, 2H), 0.77 (s, 2H). 13C NMR (126 MHz, CDCl3):
δ 201.3, 144.0, 143.2, 143.1, 143.0, 133.0, 132.9, 132.4, 128.6, 128.5, 128.1, 128.1, 126.6, 126.6,
122.6, 122.5, 114.9, 114.8, 48.9, 48.0, 47.4, 43.7, 43.6, 43.3, 43.0, 40.4, 40.2, 37.9, 31.8, 31.8,
31.7, 31.7, 29.8, 29.4, 26.4, 26.4, 25.6, 25.5, 24.6, 24.6, 21.3, 21.3. HRMS data: Calc. for
C24H30O (M + H = 335.2374 and M + Na = 357.2194), found 335.2338 and 357.2197.
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2k: Isolated as a yellow oil (0.3 mmol scale, 0.085 g, 88%). H NMR (500 MHz, CDCl3): δ 7.98
(dd, J = 7.9, 1.1 Hz, 1H), 7.38 (td, J = 7.5, 1.4 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.6
Hz, 1H), 5.70 (m, 1H), 5.06 (t, J = 7.35 1H), 4.99 (s, 1H), 4.97 (m, 2H), 2.90 (t, J = 6.3 Hz, 2H),
2.45 (dd, J = 13.9, 7.0 Hz, 1H), 2.33 (dd, J = 14.6, 7.0 Hz, 1H), 2.19 (m, 2H), 1.96 (m, 6H), 1.54
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(s, 3H), 1.52 (s, 6H). C NMR (126 MHz, CDCl3): δ 201.3, 143.3, 137.9, 134.3, 133.0, 132.0,
131.4, 128.6, 128.0, 126.6, 124.3, 119.3, 118.0, 48.6, 40.0, 39.3, 33.0, 30.4, 26.5, 25.7, 25.3,
17.7, 16.3. HRMS Data: C23H31O (M + H = 323.2375) found, 323.2364. Chiral Resolution:
Chiracel ODꢀH column, mobile phase = Hexanes : 2ꢀpropanol 99.7 : 0.3, flow rate = 0.4 ꢁL/min
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2l: Isolated as a yellow oil (0.3 mmol scale, 0.054 g, 70%). H NMR (500 MHz, CDCl3): δ 7.64
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(dd, J = 9.3, 2.7 Hz, 1H), 7.11 (m, 2H), 5.70 (ddt, J = 17.3, 10.2, 7.3 Hz, 1H), 5.01 (m, 2H), 4.75
(s, 1H), 4.61 (s, 1H), 2.87 (m, 2H), 2.65 (d, J = 13.7 Hz, 1H), 2.42 (dd, J = 14.0, 7.1 Hz, 1H),
2.15 (m, 2H), 1.93 (m, 2H), 1.52 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 200.0, 161.7 (d, 249.9
Hz), 142.2, 138.8 (d, J = 2.97 Hz), 133.6, 130.5 (d, J = 7.03 Hz 120.55 (d, J = 22.21 Hz), 118.7,
115.3, 113.9 (d, J = 22.0 Hz), 47.5, 42.7, 40.0, 30.3, 24.5, 24.4. HRMS data: C17H19FO (M + Na
= 281.1318) found, 281.1322. Chiral Resolution: Chiracel ODꢀH column, mobile phase =
Hexanes : 2ꢀpropanol 99.9 : 0.1, flow rate = 0.4 ꢁL/min
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2m: Isolated as a yellow oil (0.3 mmol scale, 0.045 g, 55%). H NMR (500 MHz, CDCl3): δ
7.96 (d, J = 8.8 Hz, 1H), 6.76 (dd, J = 8.8, 2.5 Hz, 1H), 6.59 (d, J = 2.5 Hz, 1H), 5.72 (m, 1H),
5.02 (dm, J = 3.29 Hz 1H), 4.99 (dm, J = 11.31 Hz 1H), 4.73 (s, 1H), 4.61 (s, 1H), 3.78 (s, 3H),
2.88 (m, 2H), 2.67 (d, J = 13.6 Hz, 1H), 2.42 (dd, J = 14.0, 7.0 Hz, 1H), 2.15 (m, 1H), 2.11 (d, J
= 13.7 Hz, 1H), 1.95 (ddd, J = 14.0, 8.9, 5.2 Hz, 1H), 1.88 (ddd, J = 14.0, 8.9, 5.2 Hz 1H), 1.53
(s, 3H). 13C NMR (126 MHz, CDCl3): δ 199.8, 163.4, 145.6, 142.6, 134.1, 130.6, 125.7, 118.3,
114.9, 113.3, 112.3, 55.4, 47.4, 42.9, 40.4, 30.2, 25.6, 24.4.
HRMS data: C18H22O2 (M + Na = 293.1517), found 293.1545. Chiral Resolution: Chiracel ODꢀ
H column, mobile phase = Hexanes : 2ꢀpropanol 99.7 : 0.3, flow rate = 1 ꢁL/min
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2n:14,41 Isolated as a yellow oil (0.25 mmol scale, 0.046 g, 75%). H NMR (500 MHz, CDCl3): δ
7.40 (s, 1H), 6.76 (s, 1H), 5.71 (ddt, J = 16.6, 10.5, 7.4 Hz, 1H), 5.01 (m, 1H), 4.98 (dm, J = 9.53
Hz, 1H), 3.78 (s, 3H), 2.76 (m, 2H), 2.35 (dd, J = 13.8, 7.3 Hz, 1H), 2.30 (s, 3H), 2.18 (dd, J =
13.8, 7.5 Hz, 1H), 1.95 (ddd, J = 13.6, 7.1, 5.4 Hz, 1H), 1.80 (m, 1H), 1.09 (s, 3H). 13C NMR
(126 MHz, CDCl3): δ 202.6, 156.6, 136.8, 134.1, 132.1, 129.4, 119.6, 118.1, 115.0, 55.6, 44.3,
40.9, 32.8, 21.8, 21.5, 18.9. Chiral Resolution: Chiracel ODꢀH column, mobile phase = Hexanes
: 2ꢀpropanol 99.7 : 0.3, flow rate = 0.4 ꢁL/min.
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2o:6 Isolated as a yellow oil (0.45 mmol scale, 0.074 g, 88%). H NMR (500 MHz, CDCl3): δ
7.55 (d, J = 7.7 Hz, 1H), 7.39 (td, J = 7.5, 1.1 Hz, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.17 (t, J = 7.5
Hz, 1H), 5.45 (m, 1H), 4.87 (d, J = 17.0 Hz, 1H), 4.81 (d, J = 10.1 Hz, 1H), 2.97 (d, J = 17.2
Hz, 1H), 2.64 (d, J = 17.2 Hz, 1H), 2.19 (ddt, J = 13.6, 6.7, 1.2 Hz, 1H), 2.10 (dd, J = 13.7, 8.0
13
Hz, 1H), 1.02 (s, 3H). C NMR (126 MHz, CDCl3): δ 210.8, 152.6, 135.9, 134.9, 133.9, 127.4,
126.6, 124.3, 118.4, 48.8, 42.5, 39.4, 23.8.
2p:6 Isolated as a yellow oil (2.5 mmol scale, 0.496 g, 93%). 1H NMR (500 MHz, CDCl3): δ 7.37
(m, 1H), 7.27 (dd, J = 4.9, 0.9 Hz, 2H), 7.13 (d, J = 7.5 Hz, 1H), 5.75 (ddt, J = 16.3, 10.7, 7.5 Hz,
1H), 5.07 (m, 1H), 5.04 (dm, J = 8.97 Hz, 1H), 2.80 (m, 2H), 2.34 (ddd, J = 7.1, 3.2, 2.1 Hz, 2H),
1.93 (m, 2H), 1.78 (m, 1H), 1.62 (m, 2H), 1.20 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 214.4,
141.6, 137.2, 133.7, 130.7, 128.4, 127.1, 126.5, 118.3, 49.1, 43.9, 34.5, 32.9, 22.8, 22.3.
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2q: Isolated as a yellow oil (23.5 mmol scale, 6.2 g, 86%). H NMR (500 MHz, CDCl3): δ 8.00
(dd, J = 7.9, 1.1 Hz, 1H), 7.39 (td, J = 7.5, 1.4 Hz, 1H), 7.23 (m, 5H), 7.12 (m, 2H), 6.35 (d, J =
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15.8 Hz, 1H), 6.12 (m, 1H), 5.73 (m, 1H), 5.03 (dd, J = 3.2, 2.0 Hz, 1H), 5.00 (ddd, J = 4.5, 2.0,
1.2 Hz, 1H), 2.93 (m, 2H), 2.62 (ddd, J = 14.0, 7.2, 1.3 Hz, 1H), 2.47 (dd, J = 14.0, 7.1 Hz, 1H),
2.34 (ddd, J = 14.0, 7.8, 1.1 Hz, 1H), 2.25 (dd, J = 14.0, 7.5 Hz, 1H), 2.01 (m, 2H). 13C NMR
(126 MHz, CDCl3): δ 200.9, 143.2, 137.4, 133.8, 133.3, 133.2, 131.8, 128.7, 128.5, 128.1, 127.2,
126.7, 126.1, 125.8, 118.4, 48.3, 39.3, 38.5, 30.7, 25.2.
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HRMS data: Calc. for C22H23O: (M + H = 303.1749), Found 303.1729
Acknowledgment
Funding for this research was provided by the National Institute of General Medical Sciences
(NIGMS 1R01M079644) and the National Science Foundation (CHEꢀ1058855), and the Kansas
Bioscience Authority Rising Star program.
Supporting Information Available
1
Additional experimental procedures, H NMR and 13C NMR reprints available for all
compounds herein. This material is available free of charge via the Internet at
http://pubs.acs.org/.
References
1. Review of DcA: Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011,
111, 1846.
2. Review of DcA: Mohr, J. T.; Stoltz, B. M. Chem. Asian J. 2007, 2, 1476.
3. Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759.
4. You, S.ꢀL.; Hou, X.ꢀL.; Dai, L.ꢀX.; Zhu, X.ꢀZ. Org. Lett. 2000, 3, 149.
5. Trost, B. M.; Schroeder, G. M. Chem. Eur. J. 2005, 11, 174.
6. Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846.
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5
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7. Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044.
8. Burger, E. C.; Barron, B. R.; Tunge, J. A. Synlett 2006, 2824.
7
8
9
9. Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343.
10. Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K. B.
R.; Seto, M.; Ma, S.; Novák, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J.
A.; White, D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M.
Chem. Eur. J. 2011, 17, 14199.
10
11
12
13
14
15
16
17
18
19
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21
22
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25
26
27
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
11. Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat.
Chem. 2012, 4, 130.
12. Trudeau, S. P.; Morken, J. P. Tetrahedron 2006, 62, 11470.
13. Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem. Int. Ed. 2006, 45, 3109.
14. Mukherjee, H.; McDougal, N. T. ; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2011, 13, 825.
15. Enquist Jr, J. A.; Stoltz, B. M.; Nature 2008, 453, 1228.
16. White, D. E.; Stewart, I. C.; Grubbs, R. H.; Stoltz, B. M.; J. Am. Chem. Soc. 2007, 130, 810.
17. McFadden, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738.
18. Grenning, A. J.; Tunge, J. A. Angew. Chem. Int. Ed. 2011, 50, 1688.
19. Grenning, A. J.; Tunge, J. A. J. Am. Chem. Soc. 2011, 133, 14785.
20. Allylic alcohols have found use in diverse transitionꢀmetal catalyzed reactions. Generally
speaking, their substitution requires the use of acidic activators to compensate for the poor
leaving group abilities of hydroxide. See refs. 21ꢀ26.
21. Selander, N.; Paasch, J. R.; Szabó, K. J. J. Am. Chem. Soc. 2011, 133, 409.
22. Raducan, M.; Alam, R.; Szabó, K. J. Angew. Chem. Int. Ed. 2012, 51, 13050.
23. M. Lafrance, M. Roggen, E.M. Carreira, Angew. Chem. Int. Ed. 2012, 51, 3470.
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24. J.Y. Hamilton, D. Sarlah, E.M. Carreira, J. Am. Chem. Soc. 2013, 135, 994.
25. Usui, I.; Schmidt, S.; Breit, B. Org. Lett. 2009, 11, 1453.
7
8
9
26. Kimura, M.; Horino, Y.; Mukai, R.; Tanaka, S.; Tamaru, Y. J. Am. Chem. Soc. 2001, 123,
10401–10402.
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27. RetroꢀClaisen condensation is a powerful, but under utilized approach to generating
nucleophiles in situ. See references 18ꢀ19, and 28ꢀ31.
28. Ballini, R.; Petrini, M.; Polimanti, O. J. Org. Chem. 1996, 61, 5652.
29. Giorgi, G.; Arroyo, F. J.; LópezꢀAlvarado, P.; Menéndez, J. C. Synlett 2010, 2465.
30. Giorgi, G.; Arroyo, F. J.; LópezꢀAlvarado, P.; Menéndez, J. C.; Tetrahedron 2011, 67, 5582.
31. Han, C.; Kim, E. H.; Colby, D. A.; J. Am. Chem. Soc. 2011, 133, 5802.
32. Lemiére, G.; Cacciuttolo, B.; Belhassen, E.; Duñach, E.; Org. Lett. 2012, 14, 2750.
33. Grau, F.; Heumann, A.; Duñach, E. Angew. Chem. Int. Ed. 2006, 45, 7285.
34. Inagaki, F.; Kitagaki, S.; Mukai, C. Synlett 2011, 594.
35. Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.; Simonneau, A. Chem. Rev. 2011, 111,
1954.
36. Soriano, E.; MarcoꢀContelles, J. Acc. Chem. Res. 2009, 42, 1026.
37. Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 6075.
38. Widenhoefer, R. A. Chem. Eur. J. 2008, 14, 5382.
39. Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J. A.; J. Am. Chem. Soc. 1998, 120,
1940.
40. Trost, et al. have recently disclosed a route to similar 1,6ꢀdienes via sequential Pd(0)/Pd(II)
catalysis: Trost, B. M.; Thaisrivongs, D. A.; Hansmann, M. M.; Angew. Chem., Int. Ed.,
2012, 51, 11522.
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41. Clive, D. L. J.; Wang, J. Angew. Chem. Int. Ed. 2003, 42, 3406.
42. Johnson, W. S.; Shelberg, W. E.; J. Am. Chem. Soc. 1945, 67, 1745.
43. Minuti, L.; Taticchi, A.; Marrocchi, A.; Synth. Commun. 1998, 28, 2181.
44. Tsuji, J.; Mandai, T.; Synthesis 1996, 1996, 1.
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45. Chau, A.; Paquin, J.ꢀF.; Lautens, M. J. Org. Chem. 2006, 71, 1924.
46. Cheng, H.ꢀY.; Sun, C.ꢀS.; Hou, D.ꢀR. J. Org. Chem. 2007, 72, 2674.
47. Keith, J. A.; Behenna, D. C.; Sherden, N.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Nielsen, R.
J.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc., 2012, 134, 19050.
48. McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Tetrahedron Lett.
2010, 51, 5550.
49. Tani, K.; Behenna, D. C.; McFadden, R. M.; Stoltz, B. M. Org. Lett. 2007, 9, 2529.
50. A fluorinated PHOX catalyst ligand increases the ee of the DcA reaction (91ꢀ94% ee). See
ref. 14.
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