A general organocatalyzed Michael-Michael cascade reaction generates functionalized cyclohexenes

Article abstract of DOI:10.1021/jo201140a

Although β-dicarbonyl compounds are regularly employed as Michael donors, intermediates arising from the Michael addition of unsaturated β-ketoesters to α,β-unsaturated aldehydes are susceptible to multiple subsequent reaction pathways. We designed cyclic

Full text of DOI:10.1021/jo201140a

ARTICLE
pubs.acs.org/joc
A General Organocatalyzed MichaelꢀMichael Cascade Reaction
Generates Functionalized Cyclohexenes
Patrick G. McGarraugh, Joshua H. Jones, and Stacey E. Brenner-Moyer*
Department of Chemistry, Brooklyn College and the City University of New York, 2900 Bedford Avenue, Brooklyn, New York 11210,
United States
S Supporting Information
b
ABSTRACT: Although β-dicarbonyl compounds are regularly
employed as Michael donors, intermediates arising from the
Michael addition of unsaturated β-ketoesters to R,β-unsatu-
rated aldehydes are susceptible to multiple subsequent reaction
pathways. We designed cyclic unsaturated β-ketoester sub-
strates that enabled the development of the first diphenyl
prolinol silyl ether catalyzed MichaelꢀMichael cascade reaction
initiated by a β-dicarbonyl Michael donor to form cyclohexene
products. The reaction conditions we developed for this
MichaelꢀMichael cascade reaction were also amenable to a
variety of linear unsaturated β-ketoester substrates, including some of the same linear unsaturated β-ketoester substrates that were
previously ineffective in MichaelꢀMichael cascade reactions. These studies thus revealed that a change in simple reaction
conditions, such as solvent and additives, enables the same substrate to undergo different cascade reactions, thereby accessing
different molecular scaffolds. These studies also culminated in the development of a general organocatalyzed MichaelꢀMichael
cascade reaction that generates highly functionalized cyclohexenes with up to four stereocenters, in up to 97% yield, 32:1 dr, and
99% ee, in a single step from a variety of unsaturated β-ketoesters.
’ INTRODUCTION
We recently reported a MichaelꢀMichael cascade reaction,
catalyzed by 1a, that formed highly functionalized, fused carbo-
cycles (10).24 This was the first example of the formation of
cyclohexene products via a 1a-catalyzed MichaelꢀMichael cas-
cade reaction initiated by a β-dicarbonyl Michael donor. These
findings prompted further questions, primarily: are these reac-
tion conditions limited to cyclic unsaturated β-dicarbonyl com-
pounds of type 9? We set out to answer this question and report
the full substrate scope of this transformation herein.
Organocatalytic cascade reactions are an efficient, green
chemical method for rapidly building molecular complexity from
simple starting materials.1 Particularly useful for this purpose are
diphenyl prolinol silyl ether catalysts (i.e., 1a, Scheme 1). These
catalysts have been used to generate carbocyclic products via
cascade reactions in which multiple CꢀC single bonds are
formed by a combination of iminium and/or enamine catalyzed
reactions.2ꢀ12 Although the use of β-dicarbonyl compounds as
Michael donors in organocatalytic conjugate additions is wide-
spread,13ꢀ20 they had previously initiated only one 1a-catalyzed
MichaelꢀMichael cascade reaction (Reaction 1).21
’ RESULTS AND DISCUSSION
Michael reactions initiated by related β-dicarbonyl compounds
resulted in other cascade reactions. Unsaturated β-dicarbonyl
compounds without substitution at the 2-position (5) under-
went a MichaelꢀMoritaꢀBaylisꢀHillman cascade reaction
instead (Reaction 2).22 These unhindered substrates facilitate
conjugate addition of the amine catalyst to the 2-position
(vida infra) and contain a removable proton at the 1-position,
both prerequisites for the MoritaꢀBaylisꢀHillman reaction.
Alternatively, β-dicarbonyl compounds with aryl substituents
at the 2-position (7) underwent a Michael-acetalization cas-
cade reaction in the presence of catalytic p-NO2C6H4CO2H in
CH2Cl2 (Reaction 3).23 These substrates are thermodynami-
cally predisposed to undergo the acetalization pathway, which
generates products (8) in which the extended conjugation is
preserved.
A. Reactions with Cyclic Unsaturated β-Dicarbonyl Sub-
strates. Cyclic unsaturated β-dicarbonyl compounds, 9, were
designed to preclude the MoritaꢀBaylisꢀHillman pathway
(through substitution at the 1-position) and to disfavor the
acetalization pathway (by being void of aryl substituents at the
2-position). When studies began, substrate 9a generated only
13% of the MichaelꢀMichael product after 10 days (entry 1,
Table 1). Use of benzoic acid, an additive known to accelerate the
turnover of catalyst 1a, nearly doubled the yield of the Michaelꢀ
Michael product (entry 2). In 1,2-dichloroethane (DCE) and
other solvents (toluene, Et2O, THF, MeCN), the initial Michael
addition went to completion overnight, whereas the subsequent
Received: June 2, 2011
Published: June 29, 2011
r
2011 American Chemical Society
6309
dx.doi.org/10.1021/jo201140a J. Org. Chem. 2011, 76, 6309–6319
|

The Journal of Organic Chemistry
ARTICLE
Scheme 1. Cascade Reactions Catalyzed by 1a
Table 1. Summary of Key Optimizationsa
entry
additive
solvent
DCE
time (h)
conversionb (%)
ratiob (10a:10b)
drb (10:11)
% eec (10a)
% eec (10b)
1
240
168
168
2
13
25
61
12
17
85
87
1:1.1
1.5:1
1:1.1
1:29
1:5
4:1
5:1
nd
99
99
nd
99
99
99
nd
99
99
nd
99
99
99
2
PhCO2H
PhCO2H
PhCO2H
PhCO2H
DCE
3
EtOH
4:1
4
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
8:1
5
41
10:1
9:1
6
7d
17
1:1.1
17
1:1.1
10:1
a Reaction conditions: 3a (1 equiv), 9a (1 equiv), 1a (20 mol %), additive (20 mol %), solvent (0.3 M), rt. b Determined by 1H NMR. c Determined by
chiral phase HPLC. d 10 mol % 1a used.
Michael addition required prolonged reaction times. Additionally,
in all solvents, the ratio of 10a:10b was approximately 1:1. Ethanol
as solvent further doubled the yield of the MichaelꢀMichael
product, presumably by activating the second Michael addition
through hydrogen bonding interactions with the ketoester
moiety (entry 3). Use of a stronger hydrogen bonding solvent,
trifluoroethanol, ultimately proved optimal after considera-
tion of the results for this solvent in the context of the catalytic
cycle (Scheme 2).
Although trifluoroethanol as solvent led to a rapid Michaelꢀ
Michael cascade reaction (entry 4 vs entry 1), longer reac-
tion times led only to a nominal improvement in conversion
6310
dx.doi.org/10.1021/jo201140a |J. Org. Chem. 2011, 76, 6309–6319

The Journal of Organic Chemistry
ARTICLE
Scheme 2. Catalytic Cycle
(entry 5 vs entry 4). This was partly because the initial Michael
addition had still not gone to completion, which was indicative of
either a preference for the “catalyst release 1” pathway (12 f 3a)
over the productive Michael addition pathway (12 f 14) or of a
reversible Michael addition (14 f 3a). Resubjecting single
Michael adduct 14 to reaction conditions resulted in rapid
conversion to 10 only. This revealed that the formation of 14
was effectively irreversible and confirmed that the “catalyst
release 1” pathway was predominating under these conditions.
It also revealed that the second Michael addition (pathway A)
was rapid in trifluoroethanol. This was substantiated by the
formation of cascade product in this solvent after just 2 h
(entry 4). The plateau in conversion can be explained by the
predominance of the “catalyst release 2” pathway over the
productive pathway (pathway A) using benzoic acid in trifluor-
oethanol. Additionally, under these conditions, 3a is present in
sufficient quantities (as explained above) to compete with
intermediate 14 for the catalyst, thereby inhibiting 14 from re-
entering the catalytic cycle and proceeding to product.
intermediate (16) and not via an enol intermediate, since catalyst
1a was required for epimerization, which did not occur in the
presence of benzoic acid alone. The dramatically reduced rate of
epimerization in these conditions versus in other solvents can be
explained by the predominance of “catalyst release 3” over
formation of enamine 16 either from 15 prior to catalyst release
or from 10b (via 15) after its ejection from the catalytic cycle.
Thus, whereas in all other solvents an exceedingly sluggish
second Michael addition was the primary culprit in the low yields,
in trifluoroethanol, multiple predominant “catalyst release” (i.e.,
turnover) pathways were detrimental to this transformation.
Running this reaction in the absence of benzoic acid, an additive
known to accelerate the turnover of catalyst 1a, resulted in nearly
complete conversion to cascade products overnight and restored
the 1:1 ratio of 10a:10b (entry 6). Reducing the catalyst loading
to 10 mol % provided the optimal reaction conditions (entry 7),
although the catalyst loading could be reduced to 1 mol % before
the conversion and diastereoselectivity were impacted.
The reaction was run with a variety of substrates, the results of
which are summarized in Table 2. In all cases, the ratio of a:b
was approximately 1:1. Also, R,β-unsaturated aldehydes with an
o-nitro-phenyl or an alkyl R group were unreactive.
B. Reactions with Linear Alkyl-Substituted Unsaturated
β-Dicarbonyl Substrates. We next sought to determine whether
Finally, while the conversion to 10a and 10b did not change
dramatically over the course of 39 h in trifluoroethanol, the ratio
of 10a to 10b did (entries 4 and 5). This suggested that 10b
formed first and was slowly epimerizing to and equilibrating with
10a. This epimerization is believed to occur via an enamine
6311
dx.doi.org/10.1021/jo201140a |J. Org. Chem. 2011, 76, 6309–6319

The Journal of Organic Chemistry
ARTICLE
Table 2. Cyclic Unsaturated β-Dicarbonyl Substratesa
a Reaction conditions: 3 (1 equiv), 9 (1 equiv), 1a (10 mol %), CF3CH2OH (0.3 M), rt. Yield = isolated yield. dr determined by 1H NMR. ee determined
by chiral phase HPLC. dr = ratio of MAJOR:MINOR.
linear alkyl-substituted unsaturated β-dicarbonyl substrates of
type 25a (Table 3) would furnish MichaelꢀMichael adducts
under these conditions. Compound 25a lacks an aromatic sub-
stituent at the 2-position and therefore, for reasons explained
earlier, may not be prone to a Michael-acetalization reaction
pathway. It does, however, contain a proton at the 1-position and
may be susceptible to the MichaelꢀMoritaꢀBaylisꢀHillman
reaction pathway. Pleasingly, using the optimal reaction condi-
tions for β-ketoesters of type 9, β-ketoester 25a generated the
desired MichaelꢀMichael cascade product in high conversion
and good diastereoselectivity (entry 1). There was also non-
insignificant conversion (13%) to the corresponding Michaelꢀ
MoritaꢀBaylisꢀHillman product. However, the ee of both
epimers of the major MichaelꢀMichael adduct (26a and 26b)
was excellent, and notably, the ee of the minor diastereomer (27)
was also high. Additionally, epimers 26a and 26b were present in
a 1:8 ratio, which is in contrast to what was observed with
products arising from cyclic unsaturated β-dicarbonyl substrates.
In light of the high selectivity of MichaelꢀMichael reactions
using 25a, efforts were directed toward minimizing the formation
of the MichaelꢀMoritaꢀBaylisꢀHillman byproduct.
However, if 28 undergoes a catalyst turnover, both the catalyst
and aldehyde 30 will be liberated. Subsequent intermolecular
conjugate addition of the catalyst to 30 would initiate the
MoritaꢀBaylisꢀHillman reaction, leading to byproducts of
type 6a. Thus, conditions that would impact intermolecular
reactions between catalyst and substrate, as well as catalyst
turnover, were varied.
Dilute reaction concentration, lower catalyst loading, and
electronically or sterically less nucleophilic catalysts were exam-
ined in an effort to hamper the intermolecular conjugate addition
of the catalyst to 30 (entries 2ꢀ7). Additionally, additives that
affect catalyst turnover were also examined (entries 8 and 9). In
all cases, either the amount of 6a formed did not decrease, or it
decreased at the expense of decreased conversion to or ee of the
desired product. The original conditions (i.e., those reported for
cyclic unsaturated β-ketoesters; entry 1) were therefore chosen
as optimal for linear alkyl-substituted unsaturated β-ketoesters.
Using these conditions, several linear alkyl-substituted unsa-
turated β-ketoesters were examined (Table 4). In all cases, the
MichaelꢀMichael adduct was obtained in high conversion and
dr, and the β-epimer of the major diastereomer was formed in
greater proportion and in excellent ee (entries 1ꢀ4). Notably,
this cascade reaction is amenable to β-ketoesters with sterically
demanding R substituents, such as i-Pr, which gave the best
results (entry 4). β-Ketoesters of type 25 where R = H (i.e., 5,
Scheme 1) were not compatible with these conditions.
Consideration of the competing reaction pathways for the
direct product of the initial Michael addition (28, Scheme 3)
identified variables for optimization. If 28 undergoes an intra-
molecular Michael addition, intermediate 29 will be generated and
will ultimately furnish the desired MichaelꢀMichael product, 26a.
6312
dx.doi.org/10.1021/jo201140a |J. Org. Chem. 2011, 76, 6309–6319

The Journal of Organic Chemistry
ARTICLE
Table 3. Optimizations To Minimize Byproduct Formationa
entry
catalyst
additive
concn (M)
conversionb,c (%)
drb (26:27)
% eed (26a)
% eed,e (26b)
1
2
3
4
5
6
7
8
9
1a
1a
1ah
1b
1c
1d
1e
1a
1a
0.30
0.15
0.30
0.30
0.30
0.30
0.30
0.30
0.30
87 (13)
79 (21)g
84 (16)
trace
4:1f
4:1
4:1
nd
93
nd
nd
nd
90
84
85
nd
nd
94 (82)
nd
nd
nd
89 (11)
89 (8)
91 (7)
77 (9)
78 (22)
5:1
5:1
7:1
4:1
4:1
91
84
88
4 Å MS
PhCO2Hi
nd
nd
a Reaction conditions: 25a (1 equiv), 3a (1 equiv), catalyst (10 mol %), CF3CH2OH, rt, 2 days. b Determined by 1H NMR. c Number in parentheses is
conversion to products of type 6. d Determined by chiral phase HPLC. e Number in parentheses is ee of 27. f Ratio of 26a:26b = 1:8. g Reaction time = 1
day. h 5 mol % 1a used. i 10 mol % PhCO2H used.
Scheme 3. Competing Pathways for the Single Michael Adduct
C. Reactions with Linear Aryl-Substituted Unsaturated β-
Dicarbonyl Substrates. To our delight, β-ketoesters of type 7,
the exact same substrates that form Michael-acetalization pro-
ducts, generated the MichaelꢀMichael cascade product in high
conversion and selectivity using our reaction conditions (Table 5)!
These β-ketoesters furnished the desired product with R,
β-unsaturated aldehydes with electron-deficient, -neutral, and -rich
aromatic R groups (entries 1ꢀ3). Additionally, an R,β-unsatu-
rated aldehyde with an ortho-substituted phenyl R group was
tolerated, without detriment to the yield or selectivity of this
reaction (entry 4). This is in contrast to what was observed with
cyclic unsaturated β-dicarbonyl compounds; as mentioned pre-
viously, no reaction occurred with an R,β-unsaturated aldehyde
with an o-nitro phenyl R group. R,β-Unsaturated aldehydes with
heteroaromatic and nonaromatic R groups also furnished the
desired products in high yield and dr and in excellent ee (entries 5
and 6). Even R,β-unsaturated aldehydes with aliphatic R groups
were amenable to this reaction (entry 7), whereas no reaction
occurred when used in conjunction with cyclic unsaturated
β-dicarbonyl compounds. This may be because linear compounds
of type 7 have a proton at the 1-position, proximal to the nucleo-
philic β-ketoester moiety, whereas cyclic compounds of type 9 have
alkyl substitution at the 1-position. Compounds of type 7, being less
hindered, may be more reactive nucleophiles, and thus capable of
reacting with less reactive R,β-unsaturated aldehydes, such as those
with ortho-substituted phenyl and alkyl R groups.
6313
dx.doi.org/10.1021/jo201140a |J. Org. Chem. 2011, 76, 6309–6319

The Journal of Organic Chemistry
ARTICLE
Table 4. Linear Alkyl-Substituted Unsaturated β-Dicarbonyl Substratesa
a Reaction conditions: 3a (1 equiv), 25 (1 equiv), 1a (10 mol %), CF3CH2OH (0.3 M), rt. Conversion, dr, and ratio of a:b determined by 1H NMR. ee
determined by chiral phase HPLC. dr = ratio of MAJOR:MINOR.
β-Ketoesters of type 7 with electron-rich, electron-deficient, or
ortho-substituted phenyl Ar groups all produced the desired
MichaelꢀMichael products in high yield and excellent ee, and
in moderate to high dr (entries 8ꢀ10). Finally, β-ketoesters of
type 7 with a heteroaromatic Ar group also gave the desired
product in excellent ee, albeit in reduced yield and dr (entry 11).
As with linear alkyl-substituted unsaturated β-ketoesters, linear
aryl-substituted unsaturated β-ketoesters formed the β-epimer of
the major diastereomer in greater proportion in all but three cases
(entries 5, 8, and 10). The absolute stereochemistry of 42 was
established by X-ray crystallography.25 Additionally, as with 10a and
10b, we established that 26a and 26b were epimers by resubjecting
pure 26a to 1a in CF3CH2OH, whichproducedamixtureof26a and
26b. All other stereochemical assignments were made by analogy.
For all β-ketoesters of type 7, no MichaelꢀMoritaꢀBaylisꢀ
Hillman product and no Michael-acetalization product was
observed. The direct product of the initial Michael addition of
β-ketoester 7 to enal 3, activated by catalyst 1a through iminium
ion formation, is 45 (Scheme 4). In a nonpolar aprotic solvent
such as CH2Cl2, the ketoꢀenol equilibrium of the β-ketoester
moiety may favor the enol form, as in 46, due to stabilization by
extended conjugation and by an intramolecular hydrogen bond.
Moreover, in the presence of catalytic acid, the enamine moiety
in 45 can be protonated to from an iminium species, as in 46.
Alternatively, the catalytic acid can facilitate catalyst turnover,
liberating the corresponding free aldehyde. Intermediate 46 (or
its corresponding free aldehyde) undergoes an intramolecular
acetalization to form dihydropyrans (8) in moderate to good
yields and in good to excellent enantioselectivities.23 On the
other hand, a polar protic solvent such as CF3CH2OH disrupts
the intramolecular hydrogen bond in 46, biasing the ketoꢀenol
equilibrium of the β-ketoester moiety toward the keto form.
Moreover, CF3CH2OH presumably activates the Michael accep-
tor moiety toward the intramolecular conjugate addition through
hydrogen bonding. Intermediate 45 undergoes a subsequent
Michael addition to form cyclohexenes (34ꢀ44) in moderate to
excellent yields and in excellent enantioselectivities.
This is illustrative of a powerful concept: the same substrates,
using the same organocatalyst and identical catalyst loadings, can
produce completely different molecular scaffolds in high yields
and selectivities by simply changing the solvent and additives
used. Since, as mentioned, β-dicarbonyl compounds are widely
employed as Michael donors in organocatalytic conjugate addi-
tion reactions, it is anticipated that this idea can be exploited in
many other organocatalytic cascade reactions.
’ CONCLUSION
In conclusion, despite the fact that unsaturated β-dicarbonyl
compounds are susceptible to multiple reaction pathways, we
have developed general conditions for a 1a-catalyzed Michaelꢀ
Michael cascade reaction that are compatible with cyclic un-
saturated β-dicarbonyl compounds as well as linear unsaturated
β-dicarbonyl compounds with both alkyl and aryl substituents.
This cascade reaction generates highly functionalized cyclohex-
ene rings with up to four chiral centers in up to 97% yield, 32:1 dr,
and 99% ee in a single step from achiral starting materials. More-
over, this cascade reaction demonstrates that the same starting
materials and catalyst enable efficient access to diverse molecular
scaffolds through modification of simple reaction conditions, a
principle that should be applicable to many other organocascade
reactions.
’ EXPERIMENTAL SECTION
1
General Information. H and 13C NMR spectra were collected
using a 400 MHz spectrometer. The NMR data herein uses the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, dd = doublet of doublets, ddd = doublet of doublets of
doublets, td = triplet of doublets, dt = doublet of triplets, qd = quartet of
doublets. Enantiomeric excesses were determined using chiral phase
HPLC with Chiralpak AD-H (0.46 ꢁ 25 cm) and Chiralpak AS-H
(0.46 ꢁ 25 cm) columns. Optical rotations were determined using a
polarimeter. IR spectra were collected using a FT-IR. High-resolution mass
spectra were collected using a MS spectrometer. Flash chromatography
6314
dx.doi.org/10.1021/jo201140a |J. Org. Chem. 2011, 76, 6309–6319

The Journal of Organic Chemistry
ARTICLE
Table 5. Linear Aryl-Substituted Unsaturated β-Dicarbonyl Substratesa
a Reaction conditions: 3 (1 equiv), 7 (1 equiv), 1a (10 mol %), CF3CH2OH (0.3 M), rt. Yield = isolated yield. Conversion, dr, and ratio of a:b
determined by 1H NMR. ee determined by chiral phase HPLC. dr = ratio of MAJOR:MINOR.
was carried out with F60, 40ꢀ63 μm 60 Å silica gel and with EMD silica
60 F254 glass TLC plates. Solvents were dried and kept air-free in a
solvent purification unit or stored under an argon atmosphere. Solvents
were evaporated using a standard rotovapor and a high vacuum. All
reactions were carried out in oven-dried glassware and conducted under
an argon atmosphere.
and 3d via 1H NMR was in agreement with that in the literature.
β-Ketoesters of type 25 and type 7 (except 7a, 7b, and 7c whose
preparation and characterization are described below) were prepared
according to a known literature procedure.29 Characterization of
β-ketoesters of type 25 and type 7 via 1H NMR was in agreement with
that in the literature.
Characterization and Supporting Information for 10aꢀb,
11, and 17ꢀ24. Full chracterization of 10aꢀb, 11, and 17ꢀ24 as well
as copies of 1H NMR spectra, 13C NMR spectra, HPLC chromatograms,
and X-ray crystal data for compound 10a are contained in the Support-
ing Information for ref 24.
Preparation of Catalysts (1aꢀe), Enals (3cꢀ3d), and
β-Ketoesters (7 and 25). Catalysts 1aꢀe26 were prepared from
the corresponding diarylprolinols27 using known procedures. Character-
ization of 1aꢀe via 1H NMR was in agreement with that in the literature.
(E)-3-(p-Tolyl)acrylaldehyde (3c) and(E)-3-(2-fluorophenyl)acrylaldehyde
(3d) were prepared using a known procedure.28 Characterization of 3c
(E)-3-(4-Bromophenyl)acrylaldehyde, 3b. Enal 3b was pre-
pared by adapting a known procedure.30 A solution of 4-bromobenzal-
dehyde (2.41 g, 13.0 mmol) and triphenylphosphoranylidene acetal-
dehyde (4.75 g, 15.6 mmol) in toluene (103 mL) was heated at 80 °C for
16 h. To the reaction mixture was added triphenylphosphoranylidene
acetaldehyde (250 mg, 0.06 mmol) again, and the reaction mixture was
further refluxed for 19 h. After the reaction mixture was concentrated in
vacuo, the crude residue was chromatographed on silica gel eluting with
Et2O/petroleum ether (7.5:92.5) to give 3b (1.82 g, 66%) as a yellow
solid. The 1H and 13C NMR spectra for 3b were in agreement with that
in the literature (see Supporting Information for spectra).31
6315
dx.doi.org/10.1021/jo201140a |J. Org. Chem. 2011, 76, 6309–6319

The Journal of Organic Chemistry
ARTICLE
Scheme 4. Solvent and Additives Determine Product Structure
(E)-Ethyl 5-(2-Fluorophenyl)-3-oxopent-4-enoate, 7b. To a
round-bottom flask were added THF (22 mL) and diisopropylamine
(844 μL 6.6 mmol), and the mixture was cooled to ꢀ78 °C. n-BuLi
(2.5 M in hexanes, 6.6 mmol) was added slowly, and the mixture was
stirred for 15 min. Ethyl acetate (586 μL, 6.0 mmol) was then added
dropwise, and the solution was stirred for 50 min. (E)-3-(2-Fluorophenyl)-
acrylaldehyde (3d) (6.0 mmol) was added dropwise and stirred for
10 min. The reaction was quenched by the addition of sat’d. aq. NH4Cl
(1.7 mL), followed by immediate transfer to a separatory funnel
containing diethyl ether (25 mL). The mixture was extracted with
diethyl ether (25 mL), washed with brine (2 ꢁ 25 mL) and water (2 ꢁ
25 mL), and dried over MgSO4. Removal of solvent yielded the
corresponding hydroxyester in >99% yield. No further purification
was needed before the oxidation with Jones’ Reagent. Jones’ Reagent
was prepared by the addition of concentrated H2SO4 (1.8 mL) to CrO3
(2.0 g) followed by careful dilution with water to give a total volume of
15 mL. Then, Jones’ Reagent (9.0 mL, 9.0 mmol) was added dropwise to
a stirred solution of the β-hydroxyester (6.0 mmol) in acetone (24 mL)
at 0 °C. After complete addition of the oxidizing agent, the reaction was
stirred for 10 min, when the absence of starting material was determined
by thin-layer chromatography. Methanol (1.5 mL) was added slowly to
quench excess Jones’ Reagent. The reaction mixture was poured into a
separatory funnel and extracted with diethyl ether (30 mL). The organic
extracts were washed with water (3 ꢁ 20 mL) and then brine (2 ꢁ
20 mL). The organic layer was dried (MgSO4) and filtered, and the
solvent was removed under reduced pressure. Purification of the crude
product mixture was achieved by flash chromatography on silica gel
eluting with Et2O/petroleum ether (2.5:97.5), which gave 7b as a white
crystalline solid (338 mg, 24% yield): white solid, mp 57ꢀ58 °C; IR
(thin film, KBr) 2983, 1741, 1649, 1596, 1486, 1458, 1422, 1235, 1148,
1094, 1039, 969, 799, 755 cmꢀ1; 1H NMR (400 MHz, CDCl3) (1:2 ratio
of keto: enol) δ 11.96 (d, J = 1.3 Hz, 1H, enol), 7.81ꢀ6.81 (m,
10H), 6.55 (dd, J = 16.1, 1.5 Hz, 2H), 5.18 (s, 1H, enol),
4.23 (qd, J = 7.1, 4.6 Hz, 4H), 3.71 (s, 2H, keto), 1.36ꢀ1.24
(m, 6H); 13C NMR (101 MHz, CDCl3) δ 192.1, 172.8, 168.9, 167.3,
162.9, 162.4, 159.9, 137.0, 136.9, 132.4, 132.3, 130.7, 130.6, 129.5,
129.4, 129.2, 129.1, 128.7, 128.6, 127.4, 127.4, 124.6, 124.6, 124.5, 124.4, 124.4,
124.3, 123.5, 123.4, 116.4, 116.2, 116.2, 116.0, 92.5, 61.5, 60.3, 47.6, 14.3,
14.1 ppm; HRMS (ESI) calcd for C13H13F O3 [M]+ 236.0849, found
236.0860.
(E)-Ethyl 5-(Furan-2-yl)-3-oxopent-4-enoate, 7c23. β-Ketoester
7c was prepared by a modification of the same procedure used for 7b. To a
round-bottom flask were added THF (22 mL) and diisopropylamine
(844 μL 6.6 mmol). The reaction was cooled to ꢀ78 °C. n-BuLi (2.5 M
in hexanes, 6.6 mmol) was added slowly and stirred for 15 min. Ethyl acetate
(586 μL, 6.0 mmol) was then added dropwise, and the solution was stirred
for 50 min. (E)-3-(Furan-2-yl)acrylaldehyde (732.7 mg, 6.0 mmol) was
added dropwise and stirred for 10 min. The reaction was quenched by the
addition of sat’d. aq. NH4Cl (1.7 mL), followed by immediate transfer to a
separatory funnel containing diethyl ether (25 mL). The mixture was
extracted with diethyl ether (25 mL), washed with brine (2 ꢁ 25 mL) and
water (2 ꢁ 25 mL), and then dried over MgSO4. Removal of solvent yielded
the hydroxyester. No further purification was needed before the oxidation
with DMP. However, purification could be achieved on silica gel with
15ꢀ25% Et2O in petroleum ether. To a solution of the corresponding
hydroxyester (420.5 mg, 2.0 mmol) in CH2Cl2 (55.5 mL) and MeCN
(77.1 mL) at rt was added NaHCO3 (330.6 mg, 3.9 mmol). The mixture
was cooled to 0 °C, and DessꢀMartin periodinane (848.3 mg, 2.0 mmol)
was added. The reaction mixture was stirred at 0 °C for 1 h. TLC (10%
EtOAc in petroleum ether) indicated ∼10% starting material remaining, so
the reaction mixture was warmed to room temperature and stirred for an
additional 30 min. TLC at this point indicated all starting material had been
consumed. The reaction was quenched with a 1:1 solution (110 mL) of
saturated NaHCO3 and saturated Na2S2O3 and was stirred vigorously until
the organic layer was no longer cloudy. The quenched reaction mixture was
then poured into a separatory funnel. The aqueous layer was extracted with
CH2Cl2 (2 ꢁ 40 mL). The organic layers were combined, dried over
Na2SO4, filtered, and concentrated. Purification by column chromatography
6316
dx.doi.org/10.1021/jo201140a |J. Org. Chem. 2011, 76, 6309–6319

The Journal of Organic Chemistry
ARTICLE
(silica gel, 5% Et2O/petroleum ether) provided 7c as a yellow solid (220.7
mg, 53% yield). The 1H and 13C NMR spectra for 7c were in agreement
with that in the literature (see Supporting Information for spectra).23
(E)-Ethyl 5-(4-Methoxyphenyl)-3-oxopent-4-enoate, 7d32.
β-Ketoester 7d was prepared according to the same procedure used for
the synthesis of 7c and was collected in 55% yield (273.1 mg). The 1H
NMR spectra for 7d was in agreement with that in the literature (see
Supporting Information for spectra).32
1H NMR (400 MHz, CDCl3) δ 12.56 (s, 1H), 9.81 (d, J = 0.6 Hz, 1H),
8.10ꢀ8.19 (m, 2H), 7.32ꢀ7.40 (m, 2H), 4.40 (d, J = 3.8 Hz, 1H), 4.01
(qd, J = 7.1, 2.9 Hz, 2H), 2.62 (dd, J = 18.5, 5.6 Hz, 1H), 2.53 (t, J = 3.4
Hz, 1H), 2.33 (dd, J = 18.1, 10.0 Hz, 1H), 2.22 (dd, J = 6.8, 3.4 Hz, 1H),
1.13 (d, J = 6.9 Hz, 3H), 0.95 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 201.2, 172.9, 171.4, 152.3, 146.7, 128.6, 123.6, 97.2, 60.7, 57.9,
38.5, 34.9, 24.9, 17.4, 13.8 ppm; the enantiomeric excess was determined
by HPLC with an AD-H column (n-hexane/i-PrOH = 99:1), 0.2 mL/min;
major enantiomer tR = 38.4 min, minor enantiomer tR = 43.8 min. HRMS
(ESI) calcd for C17H19NO6 [M ꢀ H]ꢀ 332.1139, found 332.1121.
(1S,5S,6S)-Ethyl 5-Ethyl-6-formyl-3-hydroxy-40-nitro-1,4,
5,6-tetrahydro-[1,10-biphenyl]-2-carboxylate, 32. Clear oil.
General Procedure for Synthesis of Carbocycles (26, 31ꢀ44).
To an oven-dried flask were added catalyst 1a (13.0 mg, 0.04 mmol),
CF3CH2OH (1.33 mL), β-ketoester 7a (79.3 mg, 0.4 mmol), and enal
3a (70.8 mg, 0.4 mmol). The reaction was allowed to stir for the
indicated time at room temperature. The reaction mixture was concen-
trated and filtered through a plug of silica, followed by concentration
again. The percent conversion of the crude reaction mixture was
determined using an internal standard (allyl alcohol). The diastereo-
meric ratio was determined through comparison of the relative integra-
tions of the aldehyde peaks in this 1H NMR spectrum. The diastereo-
meric mixture was then purified via column chromatography (silica gel,
95:5, petroleum ether/Et2O, unless noted otherwise), and an isolated
yield of the diastereomeric mixture was determined. Pure major
diastereomer 26a was obtained by one further chromatography (silica
gel, 9:1, petroleum ether/Et2O). Pure minor diastereomer 26b was
obtained after two additional chromatographies (silica gel, 9:1, petro-
leum ether/Et2O). Carbocycles 31ꢀ44 were prepared and purified
using the same procedure. In certain cases (34, 35, 36), the major epimer
of the major diastereomer was inseparable from the minor epimer of the
major diastereomer and the epimers were characterized as a mixture.
Racemic samples of the MichaelꢀMichael products 26 and 31ꢀ44 were
prepared in a similar manner using racemic catalyst 1a.
(1S,5S,6S)-Ethyl 5-Butyl-6-formyl-3-hydroxy-40-nitro-1,4,
5,6-tetrahydro-[1,10-biphenyl]-2-carboxylate, 26b. Clear oil.
[R]26D = +80.4 (c 0.60, CHCl3, 93% ee); IR (thin film, KBr) 2957, 2928,
2858, 1721, 1653, 1519, 1347, 1277, 1230, 1094, 1044, 854 cmꢀ1; 1H
NMR (400 MHz, CDCl3) δ 12.56 (s, 1H), 9.83 (s, 1H), 8.17 (d, J = 8.7
Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 4.40 (d, J = 2.7 Hz, 1H), 4.02 (qd, J =
7.1, 1.7 Hz, 2H), 2.50ꢀ2.68 (m, 2H), 2.32 (dd, J = 18.8, 10.8 Hz, 1H),
1.95 (dd, J = 16.3, 6.2 Hz, 1H), 1.42ꢀ1.54 (m, 2H), 1.21ꢀ1.22 (m, 4H),
0.96 (t, J = 7.1 Hz, 3H), 0.83 (dd, J = 9.1, 4.6 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 201.5, 173.2, 171.4, 152.1, 146.7, 128.6, 123.7, 97.2,
60.7, 56.6, 38.9, 33.0, 31.9, 30.1, 29.4, 22.5, 13.9, 13.8 ppm; the
enantiomeric excess was determined by HPLC with an AD-H column
(n-hexane/i-PrOH = 99:1), 0.1 mL/min; major enantiomer tR = 22.9
min, minor enantiomer tR = 20.3 min; HRMS (ESI) calcd for
C20H25NO6 [M]+ 375.1682, found 375.1687.
[R]23 = +62.9 (c 1.67, CHCl3, 95% ee); IR (thin film, KBr) 2965,
D
2933, 2877, 1721, 1652, 1519, 1348, 1275, 1222, 853, 756, 737,
701 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 12.57 (s, 1H), 9.83 (s, 1H),
8.17 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 4.41 (d, J = 2.7 Hz, 1H),
4.02 (qd, J = 7.1, 1.7 Hz, 2H), 2.53ꢀ2.70 (m, 2H), 2.31 (dd, J = 18.8, 10.9
Hz, 1H), 1.79ꢀ1.95 (m, 1H), 1.54 (ddd, J = 29.7, 14.3, 6.9 Hz, 2H), 0.97
(t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 201.5, 173.2, 171.4, 152.1, 146.7, 128.6, 123.7, 97.2, 60.7, 56.5, 38.9, 32.6,
31.8, 25.2, 13.8, 11.8 ppm; the enantiomeric excess was determined by
HPLC with an AD-H column (n-hexane/i-PrOH = 97:3), 0.5 mL/min;
major enantiomer tR = 25.8 min, minor enantiomer tR = 32.7 min. HRMS
(ESI) calcd for C18H21NO6 [M]+ 347.1369, found 347.1360.
(1S,5R,6S)-Ethyl 6-Formyl-3-hydroxy-5-isopropyl-40-nitro-1,
4,5,6-tetrahydro-[1,10-biphenyl]-2-carboxylate, 33. Clear oil.
[R]24 = +71.7 (c 1.71, CHCl3, >99% ee); IR (thin film, KBr) 2962,
D
2927, 2872, 1720, 1655, 1519, 1348, 1301, 1281,1264, 1223, 1096, 1033,
854, 832 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 12.55 (s, 1H), 9.85 (s,
1H), 8.18 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 4.42 (s, 1H), 4.04
(qd, J = 7.1, 0.8 Hz, 2H), 2.76 (s, 1H), 2.66 (dd, J = 19.1, 6.1 Hz, 1H),
2.31 (dd, J = 19.0, 12.1 Hz, 1H), 1.78ꢀ1.94 (m, 1H), 1.35ꢀ1.48 (m,
1H), 0.99 (t, J = 7.1 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.78 (d, J = 6.6 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 201.7, 173.7, 171.3, 151.6, 146.8,
128.4, 123.7, 96.6, 60.8, 54.0, 39.4, 36.9, 31.7, 31.6, 29.7, 21.1, 20.6, 13.9
ppm; the enantiomeric excess was determined by HPLC with an AS-H
column (n-hexane/i-PrOH = 99:1), 0.3 mL/min; major enantiomer tR =
31.6 min, minor enantiomer tR = 50.4 min. HRMS (ESI) calcd for
C19H22NO6 [M ꢀ H]ꢀ 360.1447, found 360.1448.
(10S,20S,30S)-Ethyl 20-Formyl-50-hydroxy-400-nitro-10,20,30,
60-tetrahydro-[1,10:30,100-terphenyl]-40-carboxylate, 34. White
amorphous solid. [R]23 = +247.5 (c 0.93, CHCl3, 99% ee (34), >99%
D
ee (epi-34)); IR (thin film, KBr) 2983, 1722, 1653, 1618, 1596, 1518, 1403,
1347, 1259, 1217, 1065, 853, 829, 753, 700 cmꢀ1 1H NMR (400 MHz,
CDCl3) (10:1 mixture of 18 to its C4 epimer) δ 12.69 (s, 1H, 34), 12.55
(s, 1H, epi-34), 9.68 (s, 1H, 34), 8.88 (d, J = 3.8 Hz, 1H, epi-34),
8.28ꢀ8.17 (m, 4H, 34 + epi-34), 7.50ꢀ7.04 (m, 14H, 34 + epi-34), 4.66ꢀ
4.49 (m, 2H, 34 +epi-34), 4.12ꢀ4.07 (m, 4H, 34 +epi-34), 3.55ꢀ3.26 (m,
2H, 34 +epi-34), 3.06ꢀ3.19 (m, 1H, epi-34), 3.05ꢀ2.75 (m, 4H, 34 +epi-
34), 2.66 (dd, J = 19.0, 11.4 Hz, 1H, epi-34), 1.06ꢀ0.93 (m, 6H, 34 + epi-
34); 13C NMR (101 MHz, CDCl3) (10:1 mixture of 18 to its C4 epimer) δ
203.4 (epi-18), 200.8, 172.5, 172.2 (epi-18), 172.1 (epi-18), 171.4, 152.1,
146.9, 140.5 (epi-18), 139.2, 130.2 (epi-18), 129.3 (epi-18), 128.9, 128.6,
127.7 (epi-18), 127.6 (epi-18), 127.4, 127.3, 123.9, 123.6 (epi-18), 97.1,
60.8, 58.5, 54.3 (epi-18), 41.4 (epi-18), 38.8, 37.5 (epi-18), 35.3 (epi-18),
34.3, 31.0, 30.9 (epi-18), 13.8 ppm; the enantiomeric excess was deter-
mined by HPLC with an AS-H column (n-hexane/i-PrOH = 95:5),
1.0 mL/min; major diastereomer: major enantiomer tR = 27.9 min, minor
enantiomer tR = 35.9 min; minor diastereomer: major enantiomer tR = 48.7
min, minor enantiomer tR = 56.1 min. HRMS (ESI) calcd for C22H21NO6
[M ꢀ H]ꢀ 394.1291, found 394.1271. Purification on silica gel was best
achieved using 60/40 CH2Cl2/petroleum ether.
(1S,5S,6R)-Ethyl 5-Butyl-6-formyl-3-hydroxy-40-nitro-1,4,
5,6-tetrahydro-[1,10-biphenyl]-2-carboxylate, 26a. Clear oil.
[R]23D = +26.2 (c 0.59, CHCl3, 94% ee); IR (thin film, KBr) 2957, 2930,
2860, 1722, 1655, 1621, 1520, 1347, 1278, 1221, 1156, 1109, 854,
705 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 12.47 (s, 1H), 9.12 (d, J =
4.4 Hz, 1H), 8.18 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 4.33 (d, J =
5.6 Hz, 1H), 4.02 (dd, J = 12.5, 7.1 Hz, 2H), 2.82 (dd, J = 18.6, 5.7 Hz,
1H), 2.50ꢀ2.55 (m, 1H), 2.15ꢀ2.35 (m, 2H), 1.14ꢀ1.40 (m, 6H), 1.00
(t, J = 7.1 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 204.3, 172.5, 170.9, 148.0, 147.1, 129.9, 123.5, 99.0, 60.7, 54.9,
41.2, 33.9, 33.7, 28.2, 27.9, 22.7, 13.9, 13.8 ppm; the enantiomeric excess
was determined by HPLC with an AS-H column (n-hexane/i-PrOH =
90:10), 0.5 mL/min; major enantiomer tR = 20.2 min, minor enantiomer
tR = 37.8 min. HRMS (ESI) calcd for C20H25NO6 [M]+ 375.1682, found
375.1690.
(1S,5S,6S)-Ethyl 6-Formyl-3-hydroxy-5-methyl-40-nitro-
1,4,5,6-tetrahydro-[1,10-biphenyl]-2-carboxylate, 31. Clear
oil. [R]25 = +59.8 (c 0.45, CHCl3, 98% ee); IR (thin film, KBr) 2962,
(10S,20S,30S)-Ethyl 20-Formyl-50-hydroxy-10,20,30,60-tetra-
hydro-[1,10:30,100-terphenyl]-40-carboxylate, 35. Clear oil.
D
2925, 1722, 1651, 1519, 1348, 1277, 1225, 1099, 853, 736, 700 cmꢀ1
;
6317
dx.doi.org/10.1021/jo201140a |J. Org. Chem. 2011, 76, 6309–6319

The Journal of Organic Chemistry
ARTICLE
[R]26 = +86.2 (c 2.0, CHCl3, 99% ee); IR (thin film, KBr) 3060,
3.55 (td, J = 11.8, 6.2 Hz, 1H), 2.93 (dt, J = 12.4, 4.5 Hz, 1H), 2.81 (dd, J =
18.9, 6.2 Hz, 1H), 2.52 (dd, J = 18.9, 11.3Hz, 1H), 1.15 (t, J =7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 203.1, 171.9, 171.4, 153.9, 141.9, 141.2,
129.1, 127.7, 127.4, 110.3, 108.5, 97.9, 60.7, 54.4, 37.5, 36.4, 35.1, 14.0
ppm; the enantiomeric excess was determined by HPLC with an AS-H
column (n-hexane/i-PrOH = 97:3), 0.5 mL/min; major enantiomer
tR = 32.7 min, minor enantiomer tR = 36.5 min. HRMS (ESI) calcd for
C20H20O5 [M]+ 340.1311, found 340.1311.
D
3027, 2907, 2829, 2732, 1722, 1652, 1621, 1495, 1452, 1403, 1370,
1351, 1292, 1259, 1216, 1066, 1032, 831, 756, 700 cmꢀ1; 1H NMR
(400 MHz, CDCl3) (5:1 mixture of 35 to its C4 epimer) δ 12.68 (s,
1H, 35), 12.53 (s, 1H, epi-35), 9.72 (s, 1H, 35), 8.84 (d, J = 4.4 Hz,
1H, epi-35), 7.05ꢀ7.44 (m, 20H, 35 + epi-35), 4.39ꢀ4.51 (m, 2H,
35 + epi-35), 3.98ꢀ4.17 (m, 4H, 35 + epi-35), 3.58 (td, J = 11.9, 6.2
Hz, 1H, epi-35), 3.36ꢀ3.48 (m, 1H, 35), 2.73ꢀ3.10 (m, 6H, 35 +
epi-35), 1.01 (t, J = 7.1 Hz, 6H, 35 + epi-35); 13C NMR (101 MHz,
CDCl3) (5:1 ratio of major 35 to its C4 epimer) δ 204.7 (epi-19),
201.9, 171.9, 171.9, 171.4 (epi-19), 144.0, 141.2 (epi-19), 140.2,
139.5 (epi-19), 129.3 (epi-19), 129.1 (epi-19), 128.7, 128.5, 128.4
(epi-19), 127.7 (epi-19), 127.6, 127.4 (epi-19), 127.4, 127.1 (epi-
19), 127.0, 126.6, 99.9 (epi-19), 97.9, 60.5, 59.0, 54.6 (epi-19), 41.7
(epi-19), 38.9, 37.5 (epi-19), 35.2 (epi-19), 34.1, 31.1, 13.8 ppm; the
enantiomeric excess of a mixture of 35 and epi-35 was determined by
HPLC with an AS-H column (n-hexane/i-PrOH = 97:3), 0.5 mL/min;
major diastereomer: major enantiomer tR = 14.8 min, minor en-
antiomer tR = 17.8 min; minor diastereomer: major enantiomer
tR = 59.6 min, minor enantiomer tR = 28.5 min. HRMS (ESI) calcd
for C22H22O4 [M]+ 350.1518, found 350.1505.
(1S,2S,3R)-Diethyl 2-Formyl-5-hydroxy-1,2,3,6-tetrahydro-
[1,10-biphenyl]-3,4-dicarboxylate, 39. Clear oil. [R]23 = +18.5
D
(c 1.1, CHCl3, 91% ee); IR (thin film, KBr) 2982, 2936, 2736, 1724, 1660,
1624, 1406, 1371, 1264, 1218, 1183, 1069, 1032, 830, 758, 737, 699 cmꢀ1
;
1H NMR (400 MHz, CDCl3) δ 12.44 (s, 1H), 9.54 (s, 1H), 7.34 (dt, J =
12.5, 7.8 Hz, 5H), 4.13ꢀ4.36 (m, 4H), 4.01 (d, J = 1.5 Hz, 1H),
3.43ꢀ3.54 (m, 1H), 3.30 (s, 1H), 2.77 (ddd, J = 23.4, 18.3, 8.6 Hz,
2H), 1.30 (dd, J = 12.9, 7.1 Hz, 6H); 13C NMR (101 MHz, CDCl3)
δ 200.2, 173.6, 171.7, 171.5, 139.3, 128.9, 127.4, 95.5, 61.4, 60.8, 53.5,
39.4, 36.4, 30.7, 14.4, 14.1 ppm; the enantiomeric excess was determined
by HPLC with an AS-H column (n-hexane/i-PrOH = 97:3), 0.5 mL/min;
major enantiomer tR = 21.2 min, minor enantiomer tR = 32.3 min; HRMS
(ESI) calcd for C19H22O6 [M ꢀ H]ꢀ 345.1338, found 345.1345.
(1S,2S,3R)-Ethyl 3-Butyl-2-formyl-5-hydroxy-1,2,3,6-tetra-
(10S,20S,30S)-Ethyl 20-Formyl-50-hydroxy-400-methyl-10,20,30,
60-tetrahydro-[1,10:30,100-terphenyl]-40-carboxylate, 36. Clear
hydro-[1,10-biphenyl]-4-carboxylate, 40. Clear oil. [R]23
=
D
oil. [R]23 = +101.3 (c 2.0, CHCl3, 99% ee (36) 95% ee (epi-36)); IR
ꢀ44.5 (c 2.23, CHCl3, 98% ee); IR (thin film, KBr) 2956, 2930, 2871,
D
1722, 1617, 1403, 1261, 1213, 1064, 831, 698 cmꢀ1 1H NMR
;
(thin film, KBr) 2979, 2922, 2730, 1723, 1652, 1619, 1510, 1497, 1454,
1403, 1365, 1259, 1215, 1096, 1065, 821, 759, 699; 1H NMR (400 MHz,
CDCl3) (2.5:1 ratio of 36 to its C4 epimer) δ 12.63 (s, 1H, 36), 12.48
(s, 1H, epi-36), 9.69(d, J= 0.6 Hz, 1H, 36), 8.80(d, J= 4.4 Hz, 1H, epi-36),
6.96ꢀ7.36 (m, 18H, 36 + epi-36), 4.29ꢀ4.42 (m, 2H, 36 + epi-36), 3.97ꢀ
4.13 (m, 4H, 36 + epi-36), 3.27ꢀ3.64 (m, 2H, 36 + epi-36), 2.69ꢀ3.04
(m, 6H, 36 + epi-36), 2.29ꢀ2.38 (m, 6H, 36 + epi-36), 1.02 (td, J = 7.1, 1.1
Hz, 6H, 36 + epi-36);13C NMR (101 MHz, CDCl3) (2.5:1ratioof36 to its
C4 epimer) δ 204.9 (epi-20), 202.1, 172.0, 171.8, 171.5 (epi-20), 171.2
(epi-20), 141.3 (epi-20), 140.9, 140.3, 136.6 (epi-20), 136.4 (epi-20),
136.0, 129.2, 129.1 (epi-20), 129.0 (epi-20), 128.7, 127.7 (epi-20), 127.5,
127.4, 127.0 (epi-20), 100.1 (epi-20), 98.1, 60.5, 59.1, 54.6 (epi-20), 41.2
(epi-20), 38.5, 37.5 (epi-20), 35.2 (epi-20), 34.1, 31.1, 21.0, 13.8 ppm; the
enantiomeric excess of a mixture of 36 and epi-36 was determined by
HPLC with an AS-H column (n-hexane/i-PrOH = 97:3), 0.5 mL/min;
major diastereomer: major enantiomer tR = 14.3 min, minor enantiomer
tR = 17.9 min; minor diastereomer: major enantiomer tR = 47.3 min, minor
enantiomer tR = 27.3 min. HRMS (ESI) calcd for C23H24O4 [M]+
364.1675, found 364.1675.
(400 MHz, CDCl3) δ 12.45 (s, 1H), 9.60 (s, 1H), 7.32 (ddd, J = 17.9,
12.8, 5.6 Hz, 5H), 4.27 (dddd, J = 25.1, 10.8, 7.1, 3.7 Hz, 2H), 3.36ꢀ3.53
(m, 1H), 2.94ꢀ3.08 (m, 2H), 2.89 (d, J = 1.7 Hz, 1H), 2.64 (dd, J = 18.5,
5.8 Hz, 1H), 1.72ꢀ1.84 (m, 1H), 1.29ꢀ1.54 (m, 8H), 0.96 (dd, J = 9.7,
3.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 202.8, 172.2, 170.8, 140.9,
128.8, 127.5, 127.0, 100.6, 60.6, 53.2, 34.6, 34.2, 32.8, 31.0, 30.1, 22.4,
14.2, 14.0 ppm; the enantiomeric excess was determined by HPLC with
an AS-H column (n-hexane/i-PrOH = 99:1), 0.3 mL/min; major enan-
tiomer tR = 26.3 min, minor enantiomer tR = 29.5 min. HRMS (ESI)
calcd for C20H26O4 [M + H]+ 331.1904, found 331.1904.
(1S,2S,3R)-Ethyl 2-Formyl-3-(furan-2-yl)-5-hydroxy-40-
methoxy-1,2,3,6-tetrahydro-[1,10-biphenyl]-4-carboxylate,
41. Clear oil. [R]23D = +106.1 (c 0.47, CHCl3, 97% ee); IR (thin film,
KBr) 2927, 2837, 1723, 1653, 1513, 1306, 1278, 1250, 1214, 1179, 1062,
1
1035, 1012, 831, 737 cmꢀ1; H NMR (400 MHz, CDCl3) δ 12.47
(s, 1H), 9.04 (d, J = 4.2 Hz, 1H), 7.29ꢀ7.37 (m, 1H), 7.08 (d, J = 8.6 Hz,
2H), 6.83 (d, J = 8.6 Hz, 2H), 6.30 (dd, J = 2.9, 1.9 Hz, 1H), 6.07 (d, J =
3.2 Hz, 1H), 4.40 (d, J = 5.0 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.76
(s, 3H), 3.50 (td, J = 11.7, 6.1 Hz, 1H), 2.69ꢀ2.96 (m, 2H), 2.48 (dd, J =
18.9, 11.3 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 203.4, 172.0, 171.4, 158.8, 153.9, 141.8, 133.1, 128.7, 114.5,
110.3, 108.4, 97.9, 60.7, 55.2, 54.6, 37.7, 35.6, 35.2, 14.0 ppm; the
enantiomeric excess was determined by HPLC with an AS-H column
(n-hexane/i-PrOH = 90:10), 0.5 mL/min; major enantiomer tR = 33.7
min, minor enantiomer tR = 54.0 min. HRMS (ESI) calcd for C21H22O6
[M + H]+ 371.1489, found 371.1481.
(10S,20S,30R)-Ethyl 200-Fluoro-20-formyl-50-hydroxy-10,20,30,
60-tetrahydro-[1,10:30,100-terphenyl]-40-carboxylate, 37. Clear
oil. [R]23D = +82.5 (c 2.0, CHCl3, 98% ee); IR (thin film, KBr) 2982,
2929, 2734, 1724, 1620, 1654, 1486, 1454, 1404. 1259, 1216, 1094, 1066,
1
1034, 699 cmꢀ1; H NMR (400 MHz, CDCl3) δ 12.68 (s, 1H), 9.71
(s, 1H), 6.99ꢀ7.39 (m, 9H), 4.80 (s, 1H), 4.09 (tdd, J = 10.8, 7.1, 3.6 Hz,
2H), 3.26ꢀ3.40 (m, 1H), 3.02 (dd, J = 18.3, 12.4 Hz, 2H), 2.79 (dd, J =
18.4, 5.5 Hz, 1H), 1.02 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 201.6, 172.9, 171.9, 161.8, 159.3, 140.3, 129.5, 129.0, 127.7, 127.4,
124.2, 124.2, 115.9, 115.7, 97.2, 60.9, 56.9, 34.9, 32.3, 32.3, 31.2, 14.1
ppm; the enantiomeric excess was determined by HPLC with an AD-H
column (n-hexane/i-PrOH = 97:3), 0.5 mL/min; major enantiomer
tR = 27.1 min, minor enantiomer tR = 18.8 min. HRMS (ESI) calcd for
C22H21FO4 [M]+ 368.1424, found 368.1426.
(1S,2S,3R)-Ethyl 2-Formyl-3-(furan-2-yl)-5-hydroxy-1,2,3,
6-tetrahydro-[1,10-biphenyl]-4-carboxylate, 38. Yellow amor-
phous solid. [R]23D = +123.4 (c 1.7, CHCl3, 98% ee); IR (thin film, KBr)
2926, 2851, 2731, 1724, 1654, 1620, 1498, 1277, 1239, 1218, 1096, 1060,
828, 761, 741, 701 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 12.49 (s, 1H),
9.07 (d, J = 4.0 Hz, 1H), 7.10ꢀ7.40 (m, 6H), 6.31 (d, J = 1.9 Hz, 1H),
6.08 (d, J = 3.0 Hz, 1H), 4.43 (d, J = 4.9 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H),
(10S,20S,30S)-Ethyl 4,400-Dibromo-20-formyl-50-hydroxy-10,
20,30,60-tetrahydro-[1,10:30,100-terphenyl]-40-carboxylate, 42.
Colorless crystals, mp 118ꢀ120 °C; [R]24 = +81.6 (c 0.53, CHCl3,
D
99% ee); IR (thin film, KBr) 2924, 2853, 1723, 1653, 1488, 1406, 1287,
1258, 1215, 1095, 1072, 1009, 821 cmꢀ1; 1H NMR (400 MHz, CDCl3)
δ 12.63 (s, 1H), 9.64 (s, 1H), 7.44 (dd, J = 22.2, 8.5 Hz, 4H), 7.12 (d, J =
8.3 Hz, 2H), 6.99 (d, J = 8.3 Hz, 2H), 4.38 (d, J = 1.7 Hz, 1H), 4.06 (tt, J =
7.1, 3.5 Hz, 2H), 3.22ꢀ3.30 (m, 1H), 2.81ꢀ3.02 (m, 2H), 2.74 (dd,
J = 18.4, 5.4 Hz, 1H), 1.02 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 200.9, 171.9, 171.6, 142.9, 138.9, 131.8, 131.7, 129.3, 129.1,
121.1, 120.6, 97.5, 60.8, 58.7, 38.4, 33.7, 30.9, 13.9 ppm; the enan-
tiomericexcesswasdeterminedbyHPLCwithanAS-Hcolumn(n-hexane/
i-PrOH = 97:3), 0.5 mL/min; major enantiomer tR = 22.0 min,
6318
dx.doi.org/10.1021/jo201140a |J. Org. Chem. 2011, 76, 6309–6319

The Journal of Organic Chemistry
ARTICLE
minor enantiomer tR = 31.0 min. HRMS (ESI) calcd for C22H20Br2O4
[M ꢀ H]ꢀ 504.9650, found 504.9665.
(3) Enders, D.; Jeanty, M.; Bats, J. W. Synlett 2009, 3175–3178.
(4) Enders, D.; Kr€ull, R.; Bettray, W. Synthesis 2010, 567–572.
(5) Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C. Chem.—Eur. J.
2010, 16, 2852–2856.
(6) Enders, D.; Wang, C.; Mukanova, M.; Greb, A. Chem. Commun.
2010, 46, 2447–2449.
(1S,2S,3R)-Ethyl 20-Fluoro-2-formyl-3-(furan-2-yl)-5-hydroxy-
1,2,3,6-tetrahydro-[1,10-biphenyl]-4-carboxylate, 43. Clear
oil. [R]26 = +120.3 (c 0.71, CHCl3, 93% ee); IR (thin film, KBr)
D
2983, 2930, 2826, 2731, 1725, 1654, 1622, 1491, 1406, 1307, 1232, 1217,
1
1097, 1061, 1038, 758 cmꢀ1; H NMR (400 MHz, CDCl3) δ 12.48
(7) Jiang, K.; Jia, Z.-J.; Yin, X.; Wu, L.; Chen, Y.-C. Org. Lett. 2010,
12, 2766–2769.
(s, 1H), 9.14 (d, J = 3.6 Hz, 1H), 7.33 (dd, J = 1.8, 0.8 Hz, 1H), 6.95ꢀ
7.25 (m, 4H), 6.30 (dd, J = 3.2, 1.9 Hz, 1H), 6.09 (d, J = 3.2 Hz, 1H), 4.46
(d, J = 5.0 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.84 (td, J = 11.8, 6.3 Hz,
1H), 2.95ꢀ3.13 (m, 1H), 2.81 (dd, J = 18.8, 6.3 Hz, 1H), 2.59 (dd, J =
18.8, 11.3 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 202.5, 171.7, 171.4, 162.0, 159.6, 153.7, 141.9, 129.1, 129.1,
129.0, 128.9, 128.1, 127.9, 124.8, 124.7, 116.1, 115.9, 110.4, 108.5, 97.9,
60.7, 53.6, 53.5, 35.4, 34.8, 30.3, 14.0 ppm; the enantiomeric excess was
determined by HPLC with an AS-H column (n-hexane/i-PrOH = 97:3),
0.5 mL/min; major enantiomer tR = 31.3 min, minor enantiomer tR =
18.5 min. HRMS (ESI) calcd for C20H19FO5 [M]+ 358.1217, found
358.1218.
(8) Terrasson, V.; van der Lee, A.; de Figueiredo, R. M.; Campagne,
J. M. Chem.—Eur. J. 2010, 16, 7875–7880.
(9) Ma, A.; Ma, D. Org. Lett. 2010, 12, 3634–3637.
(10) Companyꢀo, X.; Zea, A.; Alba, A.-N. R.; Mazzanti, A.; Moyano,
A.; Rios, R. Chem. Commun. 2010, 46, 6953–6955.
(11) Hong, B.-C.; Dange, N. S.; Hsu, C.-S.; Liao, J.-H. Org. Lett.
2010, 12, 4812–4815.
(12) Cassani, C.; Tian, X.; Escudero-Adan, E. C.; Melchiorre, P.
Chem. Commun. 2011, 47, 233–235.
(13) Wu, F.; Hong, R.; Khan, J.; Liu, X.; Deng, L. Angew. Chem., Int.
Ed. 2006, 45, 4301–4305.
(14) Brandau, S.; Landa, A.; Franzꢀen, J.; Marigo, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 4305–4309.
(4S,5S,6R)-Ethyl 5-formyl-4,6-di(furan-2-yl)-2-hydroxycy-
clohex-1-enecarboxylate, 44. Yellow oil. [R]26D = +65.3 (c 0.58,
CHCl3, 95% ee); IR (thin film, KBr) 2925, 2853, 1723, 1654, 1407,
(15) Carlone, A.; Marigo, M.; North, C.; Landa, A.; Jørgensen, K. A.
Chem. Commun. 2006, 4928–4930.
1
1276, 1217, 1094, 1067, 1012, 812, 736 cmꢀ1; H NMR (400 MHz,
(16) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc.
2007, 129, 10886–10894.
(17) Ibrahem, I.; Zhao, G.-L.; Rios, R.; Vesely, J.; Sundꢀen, H.;
Dziedzic, P.; Cꢀordova, A. Chem.—Eur. J. 2008, 14, 7867–7879.
(18) Hayashi, Y.; Toyoshima, M.; Gotoh, H.; Ishikawa, H. Org. Lett.
2009, 11, 45–48.
(19) Companyꢀo, X.; Hejnovꢀa, M.; Kamlar, M.; Vesely, J.; Moyano,
A.; Rios, R. Tetrahedron Lett. 2009, 50, 5021–5024.
(20) Zhao, G.-L; Ullah, F.; Deiana, L.; Lin, S.; Zhang, Q.; Sun, J.;
Ibrahem, I.; Dziedzic, P.; Cꢀordova, A. Chem.—Eur. J. 2010,
16, 1585–1591.
CDCl3) δ 12.57 (s, 1H), 9.69 (s, 1H), 7.32ꢀ7.38 (m, 2H), 6.31 (ddd, J =
19.6, 3.2, 1.8 Hz, 2H), 6.10ꢀ6.16 (m, 1H), 6.00 (dt, J = 3.2, 0.8 Hz, 1H),
4.49 (s, 1H), 4.02ꢀ4.25 (m, 2H), 3.39ꢀ3.56 (m, 1H), 3.22ꢀ3.35 (m,
1H), 2.61ꢀ2.84 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 201.2, 171.7, 171.0, 156.1, 154.1, 141.8, 141.7, 110.4, 110.2,
107.0, 106.1, 96.9, 60.7, 52.3, 32.6, 30.1, 30.0, 14.0 ppm; the enantio-
meric excess was determined by HPLC with an AS-H column (n-
hexane/i-PrOH = 95:5), 1.0 mL/min; major enantiomer tR = 17.9 min,
minor enantiomer tR = 25.2 min. HRMS (ESI) calcd for C18H18O6 [M +
Na]+ 353.1000, found 353.0992.
(21) Zu, L.; Li, H.; Xie, H.; Wang, J.; Jiang, W.; Tang, Y.; Wang, W.
Angew. Chem., Int. Ed. 2007, 46, 3732–3734.
(22) Cabrera, S.; Alemꢀan, J.; Bolze, P.; Bertelsen, S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2008, 47, 121–125.
(23) Zhu, M.-K.; Wei, Q.; Gong, L.-Z. Adv. Synth. Catal. 2008,
’ ASSOCIATED CONTENT
Supporting Information. Copies of 1H, 13C and HPLC
S
b
350, 1281–1285.
spectra for compounds 26a, 26b, 31ꢀ44 and of an X-ray crystal
structure of 42 in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
(24) McGarraugh, P. G.; Brenner, S. E. Org. Lett. 2009, 11, 5654–5657.
(25) See Supporting Information.
(26) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794–797.
’ AUTHOR INFORMATION
(27) Mathre, D.; Jones, T.; Xavier, L.; Blacklock, T.; Reamer, R. A.;
Mohan, J. J.; Jones, E. T. T.; Hoogsteen, K.; Baum, M. W.; Grabowski, E.
J. Org. Chem. 1991, 56, 751–762.
Corresponding Author
*E-mail: SBrenner@brooklyn.cuny.edu.
(28) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Org. Lett. 2003,
5, 777–780.
(29) Zibuck, R.; Streiber, J. M. J. Org. Chem. 1989, 54, 4717–4719.
(30) Hirayama, F.; Koshio, H.; Katayama, N.; Kurihara, H.; Taniuchi,
Y.; Sato, K.; Hisamichi, N.; Sakai-Moritani, Y.; Kawasaki, T.; Matsumoto,
Y.; Yanagisawa, I. Bioorg. Med. Chem. 2002, 10, 1509–1523.
(31) Clerici, A.; Pastori, N.; Porta, O. Tetrahedron Lett. 2004,
45, 1825–1827.
’ ACKNOWLEDGMENT
This work was supported by a grant from the National
Institutes of Health (1SC3GM095404). The authors gratefully
acknowledge Prof. Keith Woerpel (New York University) for use
of his high resolution mass spectrometer, Dr. Chin H. Lin
(New York University), Dr. Hui Xiao (Albert Einstein College
of Medicine) and Mr. Ted Voss (Yale University) for their
assistance with high-resolution mass spectrometry, and
Dr. Christopher Incarvito (Yale University) for his assistance
with X-ray crystallography.
(32) English, J.; Lapides, L. J. J. Am. Chem. Soc. 1943, 65, 2466–2467.
’ REFERENCES
(1) For a recent review, see: Grondal, C.; Jeanty, M.; Enders, D. Nat.
Chem. 2010, 2, 167–178.
(2) For examples more recent than those cited in ref 24, see refs
3ꢀ12.
6319
dx.doi.org/10.1021/jo201140a |J. Org. Chem. 2011, 76, 6309–6319