Quinine-Promoted, Enantioselective Boron-Tethered Diels-Alder Reaction by Anomeric Control of Transition-State Conformation

Article abstract of DOI:10.1021/acs.joc.8b00938

Diels-Alder reactions of tethered vinyl-metal species offer the opportunity to fashion highly functionalized diol intermediates for synthesis. We have developed the first enantioselective boron-tethered Diels-Alder reaction using quinine as a chiral promoter. Quinine recovery, enantioselectivity enhancement, and manipulation of the cyclohexene core are also investigated. DFT modeling calculations confirm the role of quinine as a bidentate ligand enhancing reaction rates. The enantioselectivity of the cycloaddition is proposed to originate from a boron-centered anomeric effect.

Full text of DOI:10.1021/acs.joc.8b00938

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Article
Quinine-Promoted, Enantioselective Boron-Tethered Diels–Alder
Reaction by Anomeric Control of Transition State Conformation.
Katie Scholl, John Dillashaw, Evan Timpy, Yu-hong Lam, Lindsey DeRatt,
Tyler R. Benton, Jacqueline P. Powell, Kendall N. Houk, and Jeremy B Morgan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00938 • Publication Date (Web): 01 May 2018
Downloaded from http://pubs.acs.org on May 2, 2018
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Quinine-Promoted, Enantioselective Boron-Tethered Diels–Alder
Reaction by Anomeric Control of Transition State Conformation.
Katie Scholl,1 John Dillashaw,1 Evan Timpy,1 Yuꢀhong Lam,2 Lindsey DeRatt,1 Tyler R. Benton,1
Jacqueline P. Powell,1 K. N. Houk,*,2 and Jeremy B. Morgan*,1
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1Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Dobo Hall,
Wilmington, North Carolina 28403, United States
2 Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095ꢀ
1569, United States
KEYWORDS: quinine, boron, Diels–Alder, enantioselective, cinchona alkaloids
TOC:
Abstract
Diels–Alder reactions of tethered vinyl–metal species offer the opportunity to fashion
highly functionalized diol intermediates for synthesis. We have developed the first
enantioselective boronꢀtethered Diels–Alder reaction using quinine as a chiral promoter. Quinine
recovery, enantioselectivity enhancement, and manipulation of the cyclohexene core are also
investigated. DFT modeling calculations confirm the role of quinine as a bidentate ligand
enhancing reaction rates. The enantioselectivity of the cycloaddition is proposed to originate
from a boronꢀcentered anomeric effect.
Introduction
We report a unique way to produce formal Diels–Alder (DA) adducts of substituted
dienes and vinyl alcohols, versatile intermediates for synthesis.1 The reaction is highly
stereoselective where regioselectivity and diastereoselectivity are controlled utilizing a boronic
acid tether. The absolute stereochemistry is imparted by use of naturally occurring chiral amino
alcohol ligands. Theory shows that ligand chelation lowers the cycloaddition energy barrier, and
anomeric effects at boron control enantioselectivity.
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The tethering of a diene and vinyl boronate dienophile was initially reported by Batey
and coworkers.2,3 We envisioned that readilyꢀavailable chiral amino alcohols could make this an
enantioselective process. Boronate 1 contains two sites for ligand binding which would produce
intermediate 2 after ligand exchange (Scheme 1). The chiral ligand modifies both electronic and
steric properties of the dienophile and induces stereoselectivity. We discovered that the cyclic
boronate complex 2 provides abundant control of stereoselectivity through the anomeric effect.
Nonꢀracemic diol 3, containing four contiguous stereocenters, is produced upon workꢀup.
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Scheme 1. Boron modification to control the tethered DA reaction.
Results and Discussion
Boronate 4 was chosen for the initial investigation into a ligandꢀpromoted DA reaction.
Following cyclization, the carbon–boron bond was oxidized under basic peroxide conditions to
produce diols 5a and 6. Original published conditions for cyclization of 4 required heating to 190
°C for 3 hours;2a however, at 90 °C only 10 % of the diol was isolated as a single diastereomer
1
by H NMR (entry 1, Table 1). An initial screen of common bidentate ligands pointed toward
amine derivatives as reaction promoters. An amino acid (entry 2) and simple 1,2ꢀamino alcohols
(entries 2–6) produced promising levels of conversion and evidence of enantioselection. A
significant increase in both values was observed with the cinchona alkaloids (entries 7–10).
Efforts to increase the reaction enantioselectivity by structural modification were generally
unproductive. Inversion of the C9 stereocenter4 in quinine (Figure 1) was the most promising
(entry 11), but quinine was chosen for investigation of the substrate scope due to its commercial
availability. The lack of conversion and enantioselectivity for the 9ꢀOTMSꢀquinine5 (entry 12)
suggests bidentate chelation of the promoter to boron is essential for the reaction.
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Table 1. Survey of amine promoters for rate enhancement in the boronꢀtethered DA reaction.a
5
6
7
8
OH
OH
OH
OH
H3C
1. 1 equiv promoter
1,4ꢀdioxane
90 °C, 48 h
O
O
B
+
2. H2O2, NaOH
H2O, 25 °C, 3 h
Ph
Ph
9
CH3
CH3
Ph
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4
5a
6
CH3
5a:6b
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
15:1
>20:1
>20:1
>20:1
>20:1
entry
1
2
3
4
5
6
7
8
promoter
none
Lꢀproline
Lꢀprolinol
(+)ꢀaminoꢀ2ꢀindanol
(+)ꢀnorephedrine
(+)ꢀpseudoephedrine 24
quinine
quinidine
cinchonine
cinchonidine
9ꢀepiꢀquinine
9ꢀOTMSꢀquinine
yield (%)b
ee (%)c
0
10
57
14
28
16
8
15
9
12
17
75
ꢀ65
ꢀ61
60
80
0
74
66
53
56
37
8
9
10
11
12
a Reactions were performed with 0.2 mmol of boronate tether 4 and 0.2 mmol of promoter in dioxane (0.2 M) at 90 °C
for 48 h prior to oxidative workꢀup. bDetermined by H NMR with 1,3,5ꢀtrimethoxybenzene as internal standard.
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cDetermined by HPLC.
Figure 1. Structure of quinine and its derivatives.
Optimized conditions for the quinineꢀpromoted boronꢀtethered DA reaction were applied
to substrates containing structural variation on the dienophile portion. Tethered substrates were
prepared by subjecting boronic acids (7) to anhydrous conditions in the presence of dienol 8.
The requisite tether was heated in the presence of quinine, followed by a basic peroxide
workup. 1,3ꢀDiols (5) were isolated in good yield for aryl substituted dienophiles (entries 1–7,
Table 2). Pure transꢀboronic acids (entries 1–7) led to the isolation of 1,3ꢀdiol 5 as a single
diastereomer by 1H NMR. The moderate levels of enantioselectivity remained unchanged as the
electronic nature of the aromatic substituent was varied. Alkyl substituents were also
investigated as the trans (entry 8) or cis (entry 9) boronate tether. These substrates required
elevated reaction temperatures of 120 °C to achieve yields of 1,3ꢀdiol, which were much lower
than aryl substrates. The moderate enantioselectivity for alkyl substituents (entries 8–9) was in
line with vinyl aryl substituents.
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Table 2. Boronic acid substrate scope.a
H C
OH
1.
3
6
7
8
9
OH
OH
R1
R2
8
TBME, MgSO4
25 °C, 24 h
R1
(HO)2B
2. quinine, 1,4ꢀdioxane
90 °C, 48 h
3. H2O2, NaOH, H2O
R2
CH3
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5
25 °C, 3 h
ee (%)c
entry
yield (%)b
R1
R2
1
Z = H
= CH3
H
5a, 76
5b, 77
5c, 50
5d, 74
5e, 71
60
65
64
61
69
2
3
4
5
H
H
H
H
= Ph
= F
Z
= Cl
6
= OCH3
= CF3
5f, 52
5g, 76
5h, 13
66
65
50
H
H
H
7
8d
CH2Ph
H
9d
CH3
5i, 27
64
aReactions were performed by first generating a boronate tether with 1 equiv of 7, 2 equiv of 8, and 5 equiv MgSO4 in
TBME (0.5 M). A stock solution of boronate tether (0.3 mmol) in dioxane (0.2 M) was reacted with quinine (0.3 mmol)
at 90 °C for 48 h prior to oxidative workꢀup. Isolated yield for an average of 2 or more runs. Determined by HPLC.
dReactions were performed at 120 °C in chlorobenzene.
b
c
The diene structure was varied to explore limitations in the enantioselective boronꢀ
tethered DA (Table 3). Dienols (10) were tethered to boronic acid 9, and used without
purification. 1,3ꢀDiols (11) were again isolated as single diastereomers from geometrically pure
dienols in similar yields and enantioselectivities as observed in Table 2. Manipulation of the
dienol at C5 was well tolerated, where arenes and ethers could be employed in moderate yield
(entries 1–3, Table 3). Addition of substituents at C4 was uneventful (entry 4), and the
introduction of a vinyl bromide was possible (entry 5). A gemꢀdimethyl dienol participated with
reduced yield (entry 6) even though no tether was observed by H NMR prior to quinineꢀ
promoted cyclization. The reaction enantioselectivity was unchanged throughout the series of
dienol substrates.
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Table 3. Substrate scope with respect to dienols.a
R3
OH
OH
1. dienol (10)
TBME, MgSO4
25 °C, 24 h
7
8
9
R3
Ph
(HO)2B
2. quinine, 1,4ꢀdioxane
R1
Ph
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90 °C, 48 h
3. H2O2, NaOH, H2O
25 °C, 3 h
R2
11
entry
dienol
product
OH
yield (%)b
ee (%)c
OH
Ph
OH
1
2
3
11a, 59
58
10a
OH
OH
Ph
OH
11b, 61
11c, 60
53
59
Ph
10b
10c
Ph
OH
OH
Ph
OH
BnO
OBn
OH
OH
CH3
59
56
4
5
11d, 72
11e, 54
H3C
OH
H3C
Ph
10d
CH3
OH
Br
OH
Ph
Ph
OH
OH
Br
10e
Ph
H3C
H3C
OH
OH
Ph
6d
11f, 45
61
H3C
H3C CH3
10f
CH3
aReactions were performed by first generating a boronate tether with 1 equiv of 9, 2 equiv of 10, and 5 equiv MgSO4
in TBME (0.5 M). A stock solution of boronate tether (0.3 mmol) in dioxane (0.2 M) was reacted with quinine (0.3
mmol) at 90 °C for 48 h prior to oxidative workꢀup. Isolated yield for an average of 2 or more runs. Determined by
HPLC. dBoronate tether was not preformed.
b
c
Moderate enantioselectivities and a requirement for stoichiometric amounts of quinine
are two major aspects of the enantioselective boronꢀtether DA reaction that diminish its practical
use in synthesis. A largeꢀscale reaction was performed with boronate tether 4 to address these
concerns (Scheme 2). Standard conditions were employed, but the reaction was heated to 80
°C for 96 hours in an effort to improve enantioselectivity. Diol 5a was isolated in 65% yield with
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71% ee. A majority of the quinine promoter could be recovered unchanged from the organic
extraction solution by an aqueous acid wash. Recrystallization of 5a in cyclohexane provided an
increase in enantiomeric excess with 72% recovery and 94% ee. The reꢀisolation of quinine and
increased enantioselectivity greatly improve the method’s synthetic potential.
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Scheme 2. Reaction scaleꢀup with quinine recovery and enantioenrichment of 5a.
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Highly enantioenriched diol 5a contains four contiguous stereocenters and represents a
molecule with significant synthetic utility. The absolute stereochemistry of 5a was obtained from
single crystal Xꢀray analysis following enantioenrichment (Scheme 3). Functionalization of 5a
began with protection of the 1,3ꢀdiol as the acetonide (12) in 98% yield. We anticipated that
acetonide formation would lock the cyclohexene conformation where the allylic methyl group is
in the axial position. Dihydroxylation occurred on the opposite face relative to the methyl group
to produce diol 13 as a single diastereomer in 81% yield. Ring cleavage of 13 can be
accomplished to generate the acyclic diol 14 in excellent yield after aldehyde reduction without
epimerization. Diol 14 represents additional synthetic potential as an acyclic synthon containing
four contiguous stereocenters.
Scheme 3. Crystal structure and functionalization of diol 5a.
OH
OH
Ph
O
O
H3CO OCH3
O
HO
HO
O
1% OsO4
NMO, H2O
tꢀBuOH, 25 °C
10% TsOH
25 °C, 18 h
Ph
Ph
CH3
CH3
CH3
12
98% yield
13
81% yield
>20:1 dr
5a
1. NaIO4
THF/H2O
0ꢀ25 °C
2. NaBH4
0ꢀ25 °C
O
HO
HO
O
Ph
CH3
14
89% yield
crystal structure of 5a
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We explored the mechanism and origins of stereoselectivity by density functional theory
(DFT) computations.6 The geometry optimizations and frequency computations were performed
at the B3LYP7/6ꢀ31G(d) level of theory, and singleꢀpoint energies were obtained on the
optimized geometries using the more accurate M06ꢀ2X functional8 and the def2ꢀTZVPP basis
set.9 The vinyl group of quinine was truncated to a methyl group (Q') for simplicity. Molecule 4',
in which a methyl group replaces one of the dienyl chains of 4, was also used in the
computations for simplicity. The ligand exchange between 4' and Q', leading to the bidentate
complex 15 and methanol, is exergonic (∆Grxn = –1.5 kcal/mol; Scheme 4). The boron atom in
complex 15 has an S configuration (Figure 1). The corresponding Rꢀconfigured bidentate
complex (16) is 4.8 kcal/mol less stable than 15 and thus its formation by the ligand exchange
process is thermodynamically uphill.
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Scheme 4. Ligand exchange between 4’ and Q’ to form 15 and methanol.
The preference for the S configuration at the boron atom of the reactant can be
explained by the structure of the fiveꢀmembered ring formed upon chelation by the amino
alcohol moiety of quinine (Figure 2). In 15, the ring adopts an envelope conformation with boron
at the flap position, while in 16 the ring is slightly more twisted. In both 15 and 16, the chelating
ring is rigidified by fusion with the quinuclidine cage along its N–C bond and by the presence of
the quinoline ring, which occupies a pseudoequatorial position. The oxygen substituent is
positioned axial on the flap in 15 and pseudoequatorial in 16. This axial preference is as
expected for an anomeric effect, minimizing OꢀO lone pair repulsions and maximizing nO → σBO*
hyperconjugation.10 To investigate the impact of the orientation of the oxygen substituent on
energy, geometry optimizations of models 17-ax and 17-eq, with the ring dihedrals constrained
at the values found in 15 and 16, respectively, were performed (Figure 3). Both 17-ax and 17-eq
display an envelope conformation. 17-ax is more stable than 17-eq by 2.4 kcal/mol. Thus, the
oxygen substituent prefers an axial position, as in pyranoses, forming the favored conformation
resulting from the exoꢀanomeric effect. In 15, or the model 17-ax, the COBOC unit is
gauche+,gauche+, while in 16, or the model 17-eq, it is anti,anti, and the former is strongly
preferred in dimethoxymethane or related anomeric systems due to hyperconjugative
stabilization.
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Figure 2. Computed structures and energies (in kcal/mol) of bidentate complexes 15 and 16.
Figure 3. Structures and energies (in kcal/mol) of axial and equatorial conformers 17-ax and
17-eq.
The free energy of activation of the intramolecular DA reaction of 4' was calculated as
30.5 kcal/mol. Reaction from the bidentate complexes was predicted to be more facile, (∆G‡ =
26.8 kcal/mol), while the monodentate pathway (not shown) has a higher activation free energy
(∆G‡ = 34.1 kcal/mol) than the reaction of 4'. Thus, only the bidentate transition structures are
discussed in detail here. Figure 4 shows the lowest energy transition structures for the formation
of the four possible DA stereoisomers. View (A) reveals the forming fused 6/5 rings and the
conformation of the tether in detail, while view (B) emphasizes the quinine moiety and the
chelated ring. The tether’s B–O bond occupies a pseudoaxial position with respect to the
chelated rings in all of the transition structures. The major stereoisomer arises from the endo1
TS. This TS is lower in energy than the exo1ꢀTS by 2.2 kcal/mol, in good agreement with the
exclusive endo diastereoselectivity observed experimentally. The endo1ꢀTS is also favored to
the endo2ꢀTS by 0.6 kcal/mol. This is consistent with the sense of enantiocontrol experimentally
observed, although the level of enantioselectivity was underestimated.
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Figure 4. DA transition structure geometries and energies (in kcal/mol). (A) Newman projections
along the shorter of the forming C–C bonds. (B) View emphasizing the quinine moieties and the
chelated rings.
The endo1 and exo1 transition structures expose the same face of the dienophile for
cycloaddition. The configuration of boron in both transition structures is S, as formed by the
anomeric effect. As shown in the overlay in Figure 5, these two transition structures have
practically the same geometries with respect to the dienophile, the chelated ring, and the
quinine moieties. The endo1ꢀTS is less strained because of the trans 6/5 ring junction formed by
the partial C–C bond. The intrinsic stereoselectivity in the intramolecular DA reaction of nonaꢀ
1,3,8ꢀtriene is only slightly (69:31 at 250 °C) in favor of trans fusion (endo),11 but here the exo1ꢀ
TS experiences significant 1,3ꢀdiaxial repulsion between the cyclic B–O bond and the diene C–
H bond.
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Figure 5. Overlay of endo1 (yellow) and exo1 (magenta) transition structures.
The endo1 and endo2 transition structures, which lead to opposite enantiomers, feature
the boron atom in opposite absolute configurations. The boron atom in the endo1ꢀTS has the S
configuration, while the higher energy endo2ꢀTS display the less favorable R configuration.
Thus, the preference for a boronꢀS configuration observed in the reactant, due to the anomeric
effect, is preserved at the transition state and critical for enantioinduction.
Conclusions
In summary, an enantioselective boronateꢀtethered intramolecular Diels–Alder reaction
has been developed. The mechanism and origins of enantioselection by the quinine promoter
were delineated by DFT calculations. The highly functionalized diol products are produced in
good yield with moderate enantioselectivity that can be enhanced by crystallization. The
endo/exo stereoselectivity is determined by the anomeric effect and the stereochemistry of the
6/5 ring junction formed upon cycloaddition. Quinine controls the sense of asymmetric induction
through binding the boron atom in a fiveꢀmembered ring, such that the quinoline ring is
pseudoequatorial and the B–O bond in the tether occupies the anomerically favorable axial
position (Figure 6). Future experiments will be directed toward improvement of
enantioselectivities based on the proposed transition state model and development of a
catalytic, enantioselective process.
Figure 6. Origins of asymmetric induction by quinine in the endo boronateꢀtethered DA reaction.
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General: 1H NMR spectra were recorded on a 300 MHz, 400 MHz, or 600 MHz
spectrometer. Chemical shifts are reported in ppm from tetramethylsilane with the solvent
resonance as the internal standard (CDCl3: 7.27 ppm). Data are reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet),
coupling constants (Hz) and integration. 13C NMR spectra were recorded on the same
spectrometers (75, 100, or 151 MHz) with complete proton decoupling. Chemical shifts are
reported in ppm from tetramethylsilane with the solvent as the internal standard (CDCl3: 77.0
ppm). High resolution mass spectrometry data was acquired with a MicrOTOFꢀQ instrument
with electron spray ionization (ESI, positive mode). Infrared (IR) spectra were obtained using an
FTꢀIR spectrometer.
Liquid chromatography was performed using forced flow (flash chromatography) on
silica gel (SiO2, 32 to 63ꢀm). Thin layer chromatography (TLC) was performed on 0.25 mm
silica gel 60 plates with visualization by a UV lamp (254 nm) or basic potassium permanganate
in water followed by heating. Analytical high performance liquid chromatography (HPLC) was
performed on an instrument equipped with an autosampler and a UV detector. A Daicel
CHIRALPAK column 0.46 cm x 25 cm) using a mixed solvent (hexane/isopropanol) at a flow
rate of 1 mL/minute for data pertaining to enantiomeric excess calculations.
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All reactions were conducted in ovenꢀ or flameꢀdried glassware under an inert
atmosphere of argon. All solvents were purchased as anhydrous solvents and used under an
inert atmosphere. Quinine and trans, transꢀ2,4ꢀhexadienꢀ1ꢀol was purchased from Alfa Aesar.
(2E,4E)ꢀoctaꢀ2,4ꢀdienꢀ1ꢀol was purchased from Ark Pharm. Boronic acids, boronic acid pinacol
esters, and DLꢀproline were purchased from Sigma Aldrich and used as received.
Dienol Synthesis. (2E,4E)ꢀ5ꢀphenylpentaꢀ2,4ꢀdienꢀ1ꢀol (10b),12 (2E,4E)ꢀ4ꢀmethylhexaꢀ
2,4ꢀdienꢀ1ꢀol (10d),13 and (3E,5E)ꢀ2ꢀmethylheptaꢀ3,5ꢀdienꢀ2ꢀol (10f)14 were synthesized by
known procedures.
(2E,4E)-6-(Benzyloxy)hexa-2,4-dien-1-ol (10c): transꢀ4ꢀ(Benzyloxy)butꢀ2ꢀenal15 (0.969
g, 5.5 mmol, 1 eq) and dichloromethane (11 mL) were added to a flameꢀdried round bottom
flask containing a magnetic stir bar. (Ethoxycarbonylmethylene)triphenylphosphorane (2.090 g,
6.0 mmol, 1.1 equiv) was added at room temperature and the reaction turned pale yellow. The
reaction was stirred under argon at room temperature for 24 h. The crude mixture was
concentrated to a brown oil, which was taken to the next step without further purification.
Toluene (11 mL) and a magnetic stir bar were added to the crude diene ester. The flask was
purged with argon and cooled to 0 °C. A 1.0 M solution in toluene of DIBALꢀH (11 mL, 11 mmol,
2 equiv) was added dropwise fast, and the reaction was warmed to room temperature and
stirred for 3 h. Saturated Rochelle’s salt (9 mL) and ethyl acetate (10 mL) were added. The
solution was stirred 30 min until two visible layers formed. The mixture was transferred to a
separatory funnel and diluted with H2O (10 mL) and ethyl acetate (10 mL). The layers were
separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined
organic layers were washed with saturated brine (35 mL) and dried with MgSO4. All solids were
filtered off through a vacuum fritted filter, and the solution was concentrated to a brown residue.
Purification by flash chromatography afforded 488.0 mg (44%, 8:1 (2E,4E):(2E:4Z)) of the title
1
compound as a viscous oil. H NMR (CDCl3, 600 MHz) δ 7.38ꢀ7.32 (4H, m), 7.32ꢀ7.28 (1H, m),
6.33ꢀ6.24 (2H, m), 5.89ꢀ5.78 (2H, m), 4.53 (2H, s), 4.19 (2H, d, J = 5.2 Hz), 4.09 (2H, d, J = 5.6
Hz), 1.72 (1H, br s). 13C NMR (CDCl3, 150 MHz): δ 137.7, 132.4, 129.8, 129.2, 128.0, 127.4,
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127.3, 71.7, 69.9, 62.4. IR (KBr plate): 3381.1, 3029, 2854, 1453, 1361, 1085 cmꢀ1. HRMS:
Calculated for C13H16O2Na+: 227.1048 (M+Na+), found 227.1048 (M+Na+).
(2E,4Z)-4-bromo-5-phenylpenta-2,4-dien-1-ol (10e): αꢀBromocinnamaldehyde (2.110
g, 10 mmol, 1 equiv) and dichloromethane (20 mL) were added to a flameꢀdried round bottom
flask containing a magnetic stir bar. (Ethoxycarbonylmethylene)triphenylphosphorane (3.83 g,
11 mmol, 1.1 equiv) was added to the solution in one portion. The reaction was stirred at room
temperature for 24 h and concentrated to afford ethyl (2E,4Z)ꢀ4ꢀbromoꢀ5ꢀphenylpentaꢀ2,4ꢀ
dienoate (2.6513 g, 94%) as a crude residue. NMR data collected matched previously reported
spectra.16 Crude (2E,4Z)ꢀ4ꢀbromoꢀ5ꢀphenylpentaꢀ2,4ꢀdienoate (2.6513 g, 9.4 mmol, 1 equiv)
was dissolved in toluene (12 mL) and a magnetic stir bar was added. A 1.0 M solution of
DIBALꢀH in toluene (18.8 mL, 18.8 mmol, 2 equiv) was added at 0 °C under argon. The
reaction was warmed to room temperature and stirred for 4 hours. Saturated Rochelle’s salt (18
mL) and ethyl acetate (20 mL) were added. The solution was stirred 30 min until two visible
layers formed. The mixture was transferred to a separatory funnel and diluted with H2O (20 mL)
and ethyl acetate (20 mL). The layers were separated, and the aqueous layer was extracted
with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated brine
(35 mL) and dried with MgSO4. The mixture was filtered and concentrated by rotary
evaporation. The crude residue was purified by flash chromatography to afford 1.8430 g (82%)
of the title compound as a viscous oil. 1H NMR (CDCl3, 400 MHz) δ 7.71ꢀ7.67 (2H, m), 7.42ꢀ
7.29 (3H, m), 6.99 (1H, br s), 6.52ꢀ6.47 (1H, m), 6.41ꢀ6.34 (1H, m), 4.39 (2H, br s), 1.50 (1H, br
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s). C NMR (CDCl3, 150 MHz): δ 135.6, 134.1, 131.9, 131.1, 129.5, 128.3, 128.2, 122.6, 62.7.
IR (KBr plate): 3328, 2919, 1445 cmꢀ1. HRMS: Calculated for C11H11BrONa+: 260.9885
(M+Na+), found 260.9884 (M+Na+).
Procedure for Amine Promoter Screening: trans, transꢀ2,4ꢀHexadienꢀ1ꢀol (785.1 mg,
8 mmol, 2 equiv), transꢀ2ꢀphenylvinylboronic acid (591.9 mg, 4 mmol, 1 equiv), and MgSO4 (20
mmol, 5 equiv) were suspended in methyl tertꢀbutyl ether (8 mL) in an ovenꢀdried 20 mL vial
containing a Teflonꢀcoated magnetic stir bar. The reaction was stirred under argon at room
temperature for 24 h. The suspension was filtered over Celite and concentrated in vacuo,
yielding the boronate tether (4) which was dissolved in dry 1,4ꢀdioxane (0.2 M final
concentration) and used without further purification.
An ovenꢀdried 4 mL vial containing a Teflonꢀcoated magnetic stir bar was charged with a
0.2 M stock solution of boronate tether 4 (0.5 mL, 0.1 mmol) in 1,4ꢀdioxane. A promoter (0.1
mmol) was added, and the vial was sealed under argon with a screw cap containing a Teflon
insert. The reaction was stirred at 90 °C for 48 h. The reaction was cooled to room temperature
and diluted with THF (0.5 mL). 10% NaOH (0.5 mL) was added, followed by dropwise addition
of 30% H2O2 (0.3 mL) (CAUTION: EXOTHERMIC). The mixture was stirred at room
temperature for 2 h. After this time, the reaction was quenched with 1 mL of 10% sodium
thiosulfate. The layers were separated, and the aqueous layer was extracted two times with 5
mL ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and
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concentrated. The ratio of 5a:6 was determined by HꢀNMR. The yield of 5a was determined
after purification by silica gel chromatography (1:1 hexanes/ethyl acetate).
Diol Esterification for HPLC Analysis: The cyclized diol (0.03 mmol), pꢀnitrobenzoyl
chloride (0.075 mmol), triethylamine (0.09 mmol) and dichloromethane (0.3 mL) were added to
an ovenꢀdried 4 mL vial containing a Teflonꢀcoated magnetic stir bar. The solution was stirred
under argon at room temperature for 12 h, concentrated to a crude residue, and purified by flash
chromatography. 1HꢀNMR confirmed the sole formation of the least hindered, monoꢀester
product. Addition of 10 mol % of N,Nꢀdimethylaminopyridine (DMAP) will facilitate the
benzoylation of both alcohols to generate the diꢀether product. The pure isolate was then
redissolved and analyzed by chiral HPLC for determination of enantiomeric excess.
General Procedure for the Diels−Alder Cyclization Sequence: Boronate tethers were
generated as 0.2 M solutions based on the boronic acid as described in Procedure A. All
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tethers were checked for formation by 1HꢀNMR in CDCl3 and used without further purification. A
0.2 M solution of the crude boronate diene tether in dry 1,4ꢀdioxane or chlorobenzene (1.5 mL,
0.3 mmol) and quinine (93.7 mg, 0.3 mmol) were added to an ovenꢀdried 4 mL vial containing a
Teflonꢀcoated magnetic stir bar. The vial was sealed under argon with a screw cap containing a
Teflon insert. The reaction was stirred under argon at 90 °C for 48ꢀ72 h before cooling to room
temperature. The mixture was diluted with THF (1.5 mL) and 10% NaOH (1.5 mL) was added.
30% H2O2 (0.9 mL) was added dropwise (CAUTION: EXOTHERMIC), and the mixture was
stirred under open air at room temperature for 2 h. After this time, the reaction was quenched
by addition of 10% sodium thiosulfate (3 mL). The organic layer was separated, and the
aqueous layer was extracted two times with 10 mL of ethyl acetate. The organic layers were
combined and dried with anhydrous MgSO4 and concentrated to a crude residue. Purification
by flash chromatography afforded the cyclized diol where yield was based on the amount of
boronic acid initially added. Racemic product for enantiomer separation was produced by the
same general method with DLꢀProline (34.5 mg, 0.3 mmol) as promoter.
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(1R,2R,3S,6S)-3-(Hydroxymethyl)-6-methyl-1,2,3,6-tetrahydro-[1,1'-biphenyl]-2-ol
(5a):2a A 0.2 M 1,4ꢀdioxane solution of the crude boronate diene tether, which corresponds to
58.9 mg (0.6 mmol) of trans, transꢀ2,4ꢀhexadienꢀ1ꢀol and 44.4 mg (0.3 mmol) of transꢀ2ꢀ
phenylvinylboronic acid (44.3 mg, 0.3 mmol), was reacted via the general procedure.
Purification by silica gel chromatography (1:1 hexanes/ethyl acetate) afforded a white solid (39.0
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mg, 60% yield, 60% ee). H NMR (400Hz, CDCl3) δ 7.39ꢀ7.35 (2H, m), 7.29ꢀ7.23 (3H, m), 5.85
(1H, ddd, J = 9.9, 4.9, 2.7 Hz), 5.38ꢀ5.35 (1H, m), 4.29 (1H, dd, J = 11.5, 8.3 Hz), 3.87 (1H, dd,
J = 10.5, 4.1 Hz), 3.75 (1H, dd, J = 10.5, 8.2 Hz), 3.17 (1H, dd, J = 11.5, 5.7 Hz), 2.76 (1H, br
s), 2.57ꢀ2.51 (1H, m), 2.50ꢀ2.45 (1H, m), 2.36 (1H, br s), 0.74 (3H, d, J = 7.2 Hz). 13C NMR (100
MHz, CDCl3): δ 139.6, 135.1, 129.0, 128.7, 126.7, 123.5, 69.2, 67.0, 51.3, 47.0, 37.0, 16.9. IR
+
(KBr plate): 3371, 1663, 1448, 1035 cmꢀ1. HRMS: Calculated for C14H18NaO2 : 241.1199
(M+Na+), found 241.1199 (M+Na+).
(1R,2R,3S,6S)-3-(Hydroxymethyl)-4',6-dimethyl-1,2,3,6-tetrahydro-[1,1'-biphenyl]-2-
ol (5b): A 0.2 M 1,4ꢀdioxane solution of the crude boronate diene tether, which corresponds to
58.9 mg (0.3 mmol) of trans, transꢀ2,4ꢀhexadienꢀ1ꢀol and 48.6 mg (0.6 mmol) of transꢀ2ꢀ(4ꢀ
methylphenyl)vinylboronic acid, was reacted via the general procedure. Purification by silica gel
chromatography (1:1 hexanes/ethyl acetate) afforded a white solid (52.4 mg, 75% yield, 65%
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ee). H NMR (CDCl3, 400Hz) δ 7.19ꢀ7.12 (4H, m), 7.13 (2H, d, J = 8.1 Hz), 5.84 (1H, ddd, J =
9.9, 5.0, 2.7 Hz), 5.35 (1H, ddd, J= 9.9, 2.2, 1.3 Hz), 4.27ꢀ4.22 (1H, m), 3.86ꢀ3.82 (1H, m), 3.73
(1H, dd, J = 10.5, 8.1 Hz), 3.13 (1H, dd, J = 11.5, 5.6 Hz), 2.92 (1H, br s), 2.55ꢀ2.49 (1H, m),
2.47ꢀ2.40 (2H, m), 2.35 (3H, s), 0.74 (3H, d, J = 7.3 Hz). Spectral data matched that previously
published.2a
(1R,2R,3S,6S)-3-(Hydroxymethyl)-6-methyl-1,2,3,6-tetrahydro-[1,1':4',1''-terphenyl]-
2-ol (5c): A 0.2 M 1,4ꢀdioxane solution of the crude boronate diene tether, which corresponds
to 58.9 mg (0.6 mmol) of trans, transꢀ2,4ꢀhexadienꢀ1ꢀol and 67.2 mg (0.3 mmol) of transꢀ2ꢀ(4ꢀ
biphenyl)vinylboronic acid, was reacted via the general procedure. Purification by silica gel
chromatography (1:1 hexanes/ethyl acetate) afforded a white solid (43.6 mg, 49% yield, 64%
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ee). H NMR (CDCl3, 400Hz) δ 7.63ꢀ7.60 (4H, m), 7.47ꢀ7.43 (2H, m), 7.38ꢀ7.35 (1H, m), 7.34ꢀ
7.31 (2H, m), 5.87 (1H, ddd, J = 9.9, 4.9, 2.7 Hz), 5.39ꢀ5.36 (1H, m), 4.33 (1H, dd, J = 11.5, 8.2
Hz), 3.90 (1H, dd, J = 10.5, 4.1 Hz), 3.77 (1H, dd, J = 10.5, 8.2 Hz), 3.22 (1H, dd, J= 11.5, 5.6
Hz), 2.60ꢀ2.47 (3H, m), 1.28 (1H, br s), 0.79 (3H, d, J = 7.2 Hz). 13C NMR (CDCl3, 100 MHz): δ
140.8, 139.6, 138.8, 135.1, 129.5, 128.8, 127.3, 127.2, 127.0, 123.5, 69.2, 67.0, 51.0, 47.1,
+
37.0, 17.0. IR (KBr Plate): 3381, 2958, 1486, 1075 cmꢀ1. HRMS: Calculated for C20H22NaO2 :
317.1509 (M+Na+), found 317.1512 (M+Na+).
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(1R,2R,3S,6S)-4'-Fluoro-3-(hydroxymethyl)-6-methyl-1,2,3,6-tetrahydro-[1,1'-
biphenyl]-2-ol (5d): A 0.2 M 1,4ꢀdioxane solution of the crude boronate diene tether, which
corresponds to 58.9 mg (0.6 mmol) of trans, transꢀ2,4ꢀhexadienꢀ1ꢀol and 49.8 mg (0.3 mmol) of
transꢀ2ꢀ(4ꢀfluorophenyl)vinylboronic acid, was reacted via the general procedure. Purification by
silica gel chromatography (2:1 hexanes/ethyl acetate) afforded a white solid (53.2 mg, 75%
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yield, 61% ee). H NMR (CDCl3, 400Hz) δ 7.22ꢀ7.17 (2H, m), 7.08ꢀ7.02 (2H, m), 5.83 (1H, ddd,
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J = 9.9, 4.9, 2.7 Hz), 5.33 (1H, dt, J = 9.9, 1.5 Hz), 4.21 (1H, dd, J = 11.5, 8.2 Hz), 3.85 (1H, dd,
J = 10.5, 4.1 Hz), 3.70 (1H, dd, J = 10.5, 8.4 Hz), 3.15 (1H, dd, J = 11.5, 5.6 Hz), 2.86 (1H, br
s), 2.66 (1H, br s), 2.54ꢀ2.39 (2H, m), 0.71 (3H, d, J = 7.3 Hz). C NMR (CDCl3, 100 MHz): δ
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161.6 (d, J= 243.1 Hz), 135.5 (d, J= 3.3 Hz), 134.9, 130.4 (d, J= 7.7 Hz), 123.4, 115.3 (d, J=
21.1 Hz), 69.2, 66.9, 50.3, 47.1, 37.0, 16.7. IR (KBr Plate): 3257, 2877, 1886, 1267 cmꢀ1.
HRMS: Calculated for C14H17NaFO2 : 259.1107 (M+Na+), found 259.1105 (M+Na+).
+
(1R,2R,3S,6S)-4'-Chloro-3-(hydroxymethyl)-6-methyl-1,2,3,6-tetrahydro-[1,1'-
biphenyl]-2-ol (5e): A 0.2 M 1,4ꢀdioxane solution of the crude boronate diene tether, which
corresponds to 58.9 mg (0.6 mmol) of trans, transꢀ2,4ꢀhexadienꢀ1ꢀol and 54.7 mg (0.3 mmol) of
transꢀ2ꢀ(4ꢀchlorophenyl)vinylboronic acid, was reacted via the general procedure. Purification
by silica gel chromatography (1:1 hexanes/ethyl acetate) afforded a white solid (54.6 mg, 72%
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yield, 69% ee). H NMR (CDCl3, 400Hz) δ 7.36ꢀ7.32 (2H, m), 7.20.7.17 (2H, m), 5.84 (1H, ddd,
J = 9.9, 4.9, 2.7 Hz), 5.34 (1H, dt, J = 9.9, 1.5 Hz), 4.24 (1H, dd, J = 11.5, 8.2 Hz), 3.89 (1H, m),
3.73 (1H, dd, J = 10.4, 8.4 Hz), 3.15 (1H, dd, J = 11.5, 5.7 Hz), 2.65ꢀ2.39 (4H, m), 0.72 (3H, d, J
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= 7.3 Hz). C NMR (CDCl3, 100 MHz): δ 138.4, 134.9, 132.4, 130.3, 128.7, 123.4, 69.1, 67.0,
50.6, 47.1, 36.9, 16.8. IR (KBr Plate): 3365, 2875, 1492, 1089 cmꢀ1. HRMS: Calculated for
+
C14H17NaClO2 : 275.0811 (M+Na+), found 275.0809 (M+Na+).
(1R,2R,3S,6S)-3-(Hydroxymethyl)-4'-methoxy-6-methyl-1,2,3,6-tetrahydro-[1,1'-
biphenyl]-2-ol (5f): A 0.2 M 1,4ꢀdioxane solution of the crude boronate diene tether, which
corresponds to 58.9 mg (0.6 mmol) of trans, transꢀ2,4ꢀhexadienꢀ1ꢀol and 53.4 mg (0.3 mmol) of
transꢀ2ꢀ(4ꢀMethoxyphenyl)vinylboronic acid, was reacted via the general procedure. Purification
by silica gel chromatography (1:1 hexanes/ethyl acetate) afforded a white solid (40.8 mg, 55%
yield, 66% ee). 1H NMR (CDCl3, 400MHz) δ 7.20ꢀ7.14 (2H, m), 6.95ꢀ6.89 (2H, m), 5.85 (1H,
ddd, J = 9.9, 4.9, 2.7 Hz), 5.36 (1H, d, J = 10.0 Hz), 4.23 (1H, dd, J = 11.5, 8.3 Hz), 3.91ꢀ3.84
(1H, m), 3.82 (3H, s), 3.80ꢀ3.71 (1H, m), 3.12 (1H, dd, J = 11.5, 5.6 Hz), 2.65 (1H, br s), 2.58ꢀ
2.50 (1H, m), 2.49ꢀ2.38 (1H, m), 2.20 (1H, br s), 0.75 (3H, d, J = 7.2 Hz). Spectral data
matched that previously published.2a
(1R,2R,3S,6S)-3-(Hydroxymethyl)-6-methyl-4'-(trifluoromethyl)-1,2,3,6-tetrahydro-
[1,1'-biphenyl]-2-ol (5g): A 0.2 M 1,4ꢀdioxane solution of the crude boronate diene tether,
which corresponds to 58.9 mg (0.6 mmol) of trans, transꢀ2,4ꢀhexadienꢀ1ꢀol and 64.8 mg (0.3
mmol) of transꢀ2ꢀ[4ꢀ(Trifluoromethyl)phenyl]vinylboronic acid, was reacted via the general
procedure. Purification by silica gel chromatography (3:1 hexanes/ethyl acetate) afforded the
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title compound (57.8 mg, 67% yield, 58% ee). H NMR (CDCl3, 400MHz) δ 7.60 (2H, d, J = 8.0
Hz), 7.35 (2H, d, J = 8.0 Hz), 5.93ꢀ5.78 (1H, m), 5.30 (1H, d, J = 9.9 Hz), 4.28 (1H, dd, J = 11.5,
8.1 Hz), 3.85 (1H, dd, J = 10.4, 4.1 Hz), 3.70ꢀ3.63 (1H, m), 3.21 (1H, dd, J = 11.5, 5.6 Hz), 2.94
(2H, br s), 2.54ꢀ2.40 (2H, m), 0.69 (3H, d, J = 7.2 Hz). 13C NMR (CDCl3, 100 MHz): δ 144.5,
134.8, 129.3, 128.8 (q, J = 32.4 Hz), 125.3 (q, J = 3.7 Hz), 124.23 (q, J = 271.9 Hz), 123.3,
69.0, 67.0, 50.8, 47.1, 36.9, 16.7. IR (KBr plate): 3272, 2922, 1327, 1158 cmꢀ1. HRMS:
Calculated for C15H17F3O2Na+: 309.1073 (M+Na+), found 309.1078 (M+Na+).
(1R,2S,5S,6S)-6-benzyl-2-(hydroxymethyl)-5-methylcyclohex-3-en-1-ol (5h): A 0.2
M chlorobenzene solution of the crude boronate diene tether, which corresponds to 58.9 mg
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(0.6 mmol) of trans, transꢀ2,4ꢀhexadienꢀ1ꢀol and 48.6 mg (0.3 mmol) of transꢀ3ꢀphenylꢀ1ꢀ
propenꢀ1ꢀylboronic acid, was reacted via the general procedure, except heating to 120 °C.
Purification by silica gel chromatography (1:1 hexanes/ethyl acetate) afforded a white solid (9.2
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mg, 13% yield, 50% ee). H NMR (CDCl3, 400Hz) δ 7.33ꢀ7.24 (4H, m), 7.23ꢀ7.17 (1H, m), 5.72
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(1H, ddd, J = 9.9, 5.3, 2.7 Hz), 5.22 (1H, ddd, J = 9.8, 2.3, 1.1 Hz), 3.90 (1H, dd, J = 10.3, 4.0
Hz), 3.80 (1H, dd, J = 11.0, 8.2 Hz), 3.67 (1H, dd, J = 10.3, 8.9 Hz), 3.33 (1H, dd, J = 14.1, 4.5
Hz), 2.80 (1H, br s), 2.49ꢀ2.40 (2H, m), 2.30 (1H, br s), 2.27ꢀ2.18 (1H, m), 2.18ꢀ2.08 (1H, m),
1.62 (1H, br s), 0.91 (3H, d, J = 7.1 Hz). 13C NMR (CDCl3, 100 MHz): δ 140.7, 135.7, 128.9,
128.4, 125.8, 122.9, 72.4, 67.5, 47.8, 44.7, 33.5, 31.8, 15.4. IR (KBr Plate): 3348, 2875, 1495,
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+
1092 cmꢀ1. HRMS: Calculated for C15H20NaO2 : 255.1359 (M+Na+), found 255.1356 (M+Na+).
(1R,2S,5S,6R)-2-(hydroxymethyl)-5,6-dimethylcyclohex-3-en-1-ol (5i): A 0.2 M
chlorobenzene solution of the crude boronate diene tether, which corresponds to 58.9 mg (0.6
mmol) of trans, transꢀ2,4ꢀhexadienꢀ1ꢀol and 25.8 mg (0.6 mmol) of cisꢀ1ꢀpropenꢀ1ꢀylboronic
acid, was reacted via the general procedure, except heating to 120 °C. Purification by silica gel
chromatography (1:1 hexanes/ethyl acetate) afforded a white solid (12.6 mg, 27% yield, 64%
1
ee). H NMR (CDCl3, 400Hz) δ 5.65 (1H, ddd, J = 10.0, 4.0, 2.4 Hz), 5.30 (1H, ddd, J = 10.0,
2.9, 1.7 Hz), 3.89 (1H, dd, J = 6.7, 3.3 Hz), 3.81 (1H, dd, J = 10.5, 4.3 Hz), 3.60 (1H, dd, J =
10.5, 8.7 Hz), 2.42ꢀ2.20 (3H, m), 2.14ꢀ2.03 (1H, m), 1.72ꢀ1.62 (1H, m), 1.06 (3H, d, J = 7.2 Hz),
1.01 (3H, d, J = 7.0 Hz). 13C NMR (CDCl3, 100 MHz): δ 134.2, 122.6, 71.9, 66.6, 43.0, 38.4,
36.2, 20.6, 14.1. IR (KBr Plate): 3352, 2875, 1455, 1124 cmꢀ1. HRMS: Calculated for
+
C9H16NaO2 : 179.1048 (M+Na+), found 179.1043 (M+Na+).
(1R,2R,3S,6S)-3-(hydroxymethyl)-6-propyl-1,2,3,6-tetrahydro-[1,1'-biphenyl]-2-ol
(11a): A 0.2 M 1,4ꢀdioxane solution of the crude boronate diene tether, which corresponds to
75.7 mg (0.6 mmol) of (2E,4E)ꢀoctaꢀ2,4ꢀdienꢀ1ꢀol (10a) and 44.4 mg (0.3 mmol) of transꢀ2ꢀ
phenylvinylboronic acid, was reacted via the general procedure. Purification by silica gel
chromatography (2:1 hexanes/ethyl acetate) afforded a white solid (44.9 mg, 61% yield, 58%
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ee). H NMR (CDCl3, 400Hz) δ 7.40ꢀ7.34 (2H, m), 7.30ꢀ7.20 (3H, m), 5.97 (1H, ddd, J = 10.0,
5.9, 2.7 Hz), 5.42 (1H, ddd, J = 10.0, 2.3, 1.2 Hz), 4.30 (1H, dd, J = 11.6, 8.1 Hz), 3.87 (1H, dd,
J = 10.5, 4.2 Hz), 3.74 (1H, dd, J = 10.5, 8.1 Hz), 3.18 (1H, dd, J = 11.5, 5.6 Hz), 2.75 (1H, br
s), 2.57ꢀ2.49 (1H, m), 2.37ꢀ2.29 (1H, m), 1.39ꢀ1.21 (1H, m), 1.17ꢀ0.91 (3H, m), 0.74 (3H, t, J =
7.2 Hz). 13C NMR (CDCl3, 100 MHz): δ 139.5, 133.3, 129.2, 128.6, 126.6, 124.2, 69.5, 66.9,
51.6, 47.2, 41.6, 33.8, 20.6, 14.1. IR (KBr Plate): 3445, 2957, 1602, 1496 cmꢀ1. HRMS:
+
Calculated for C16H22NaO2 : 269.1516 (M+Na+), found 269.1512 (M+Na+).
(1'S,2'R,3'R,4'S)-4'-(hydroxymethyl)-1',2',3',4'-tetrahydro-[1,1':2',1''-terphenyl]-3'-ol
(11b): A 0.2 M 1,4ꢀdioxane solution of the crude boronate diene tether, which corresponds to
96.1 mg (0.6 mmol) of (2E,4E)ꢀ5ꢀphenylpentaꢀ2,4ꢀdienꢀ1ꢀol (10b) and 44.4 mg (0.3 mmol) of
transꢀ2ꢀphenylvinylboronic acid, was reacted via the general procedure. Purification by silica
gel chromatography (2:1 hexanes/ethyl acetate) afforded a white solid (55.2 mg, 66% yield,
1
56% ee). H NMR (CDCl3, 400MHz) δ 7.18ꢀ7.07 (6H, m), 6.73ꢀ6.66 (4H, m), 5.92 (1H, ddd, J =
9.9, 4.9, 2.8 Hz), 5.77ꢀ5.73 (1H, m), 4.31 (1H, ddd, J = 10.9, 8.3, 1.9 Hz), 4.06ꢀ3.99 (1H, m),
3.97ꢀ3.89 (1H, m), 3.73ꢀ3.68 (1H, m), 3.40 (1H, dd, J = 11.6, 6.0 Hz), 2.71ꢀ2.64 (1H, m), 2.66
(1H, m), 2.03 (1H, d, J = 2.2 Hz). 13C NMR (CDCl3, 100 MHz): δ 138.9, 138.6, 130.6, 130.2,
129.1, 128.1, 127.4, 126.7, 126.6, 69.2, 66.8, 52.6, 49.3, 46.8. IR (KBr plate): 3418, 2923,
1652, 1453 cmꢀ1. HRMS: Calculated for C19H20O2Na+: 303.1361 (M+Na+), found 303.1376
(M+Na+).
(1R,2R,3S,6S)-6-((benzyloxy)methyl)-3-(hydroxymethyl)-1,2,3,6-tetrahydro-[1,1'-
biphenyl]-2-ol (11c): A 0.2 M 1,4ꢀdioxane solution of the crude boronate diene tether, which
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corresponds to 58.9 mg (0.6 mmol) of 10c and 44.4 mg (0.3 mmol) of transꢀ2ꢀ
phenylvinylboronic acid, was reacted via the general procedure. Purification by silica gel
chromatography (1:1 hexanes/ethyl acetate) afforded the title compound as a white solid (59.2
mg, 61% yield, 59% ee). 1H NMR (CDCl3, 400 Hz) δ 7.38ꢀ7.26 (10H, m), 5.92 (1H, ddd, J =
10.0, 4.8, 2.7 Hz), 5.59 (1H, dt, J = 10.0, 1.9, 1.9 Hz), 4.58 (1H, dd, J = 11.5, 8.1 Hz), 4.37 (1H,
s), 3.88 (1H, dd, J = 11.6, 4.0 Hz), 3.75 (1H, dd, J = 10.4, 7.7 Hz), 3.25ꢀ3.16 (3H, m), 2.86 (1H,
br s), 2.61ꢀ2.57 (1H, m), 2.55ꢀ2.50 (1H, m), 2.38 (1H, br s). 13C NMR (CDCl3, 100 MHz): δ
139.2, 138.1, 130.6, 128.8, 128.7, 128.2, 127.5, 127.4, 126.8, 126.5, 73.0, 70.2, 69.8, 66.5,
50.7, 46.5, 42.8. IR (KBr plate): 3386, 3027, 2871, 1495, 1361 cmꢀ1. HRMS: Calculated for
C21H24O3Na+: 347.1618 (M+Na+), found 347.1612 (M+Na+).
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(1R,2R,3S,6R)-3-(hydroxymethyl)-5,6-dimethyl-1,2,3,6-tetrahydro-[1,1'-biphenyl]-2-
ol (11d): A 0.2 M 1,4ꢀdioxane solution of the crude boronate diene tether, which corresponds to
67.3 mg (0.6 mmol) of (2E,4E)ꢀ4ꢀmethylhexaꢀ2,4ꢀdienꢀ1ꢀol (10d) and 44.4 mg (0.3 mmol) of
transꢀ2ꢀphenylvinylboronic acid, was reacted via the general procedure. Purification by silica
gel chromatography (1:1 hexanes/ethyl acetate) afforded a white solid (50.6 mg, 73% yield,
1
59% ee). H NMR (CDCl3, 400Hz) δ 7.40ꢀ7.33 (2H, m), 7.29ꢀ7.23 (3H, m), 5.09 (1H, br s), 4.30
(1H, dd, J = 10.4, 8.4 Hz), 3.87ꢀ3.79 (1H, m), 3.69 (1H, dd, J = 10.4, 8.1 Hz), 3.16 (1H, dd, J=
11.6, 5.3 Hz), 2.75 (1H, br s), 2.53ꢀ2.44 (1H, m), 2.40 (1H, br s), 2.22 (1H, p, J = 7.7, 7.3 Hz),
1.76ꢀ1.73 (3H, m), 0.79 (3H, d, J = 7.2 Hz). 13C NMR (CDCl3, 100 MHz): δ 141.5, 139.9, 129.1,
128.6, 126.6, 119.1, 68.8, 67.1, 51.9, 47.1, 41.3, 22.0, 15.0. IR (KBr Plate): 3254, 2882, 1602,
+
1251 cmꢀ1. HRMS: Calculated for C15H20NaO2 : 255.1358 (M+Na+), found 255.1356 (M+Na+).
(1'S,2'R,3'R,4'S)-6'-bromo-4'-(hydroxymethyl)-1',2',3',4'-tetrahydro-[1,1':2',1''-
terphenyl]-3'-ol (11e): A 0.2 M 1,4ꢀdioxane solution of the crude boronate diene tether, which
corresponds to 143.5 mg (0.6 mmol) of 10e and 44.4 mg (0.3 mmol) of transꢀ2ꢀ
phenylvinylboronic acid, was reacted via the general procedure. Purification by silica gel
chromatography (1:1 hexanes/ethyl acetate) afforded a yellow solid (56.4 mg, 52% yield, 58%
ee). 1H NMR (CDCl3, 300 MHz) δ 7.25ꢀ7.08 (6H, m), 6.84ꢀ6.54 (4H, m), 6.19 (1H, d, J = 2.5
Hz), 4.40ꢀ4.28 (1H, m), 4.08ꢀ3.92 (2H, m), 3.88 (1H, d, J = 6.0 Hz), 3.56 (1H, dd, J = 11.6, 5.8
Hz), 2.76ꢀ2.65 (1H, m), 2.46ꢀ2.33 (1H, m) 1.92 (1H, br s). 13C NMR (CDCl3, 100 MHz): δ 137.4,
136.6, 129.8, 129.10, 128.4, 127.8, 127.3, 124.6, 67.3, 65.7, 57.7, 53.9, 48.7; IR (KBr plate):
3348, 3027, 1452, 1048.2 cmꢀ1. HRMS: Calculated for C19H19BrO2Na+: 381.0160 (M+Na+),
found 381.0153 (M+Na+).
(1R,2R,3R,6S)-3-(2-hydroxypropan-2-yl)-6-methyl-1,2,3,6-tetrahydro-[1,1'-biphenyl]-
2-ol (11f): A 0.2 M 1,4ꢀdioxane solution of 75.7 mg (0.6 mmol) of (3E,5E)ꢀ2ꢀmethylheptaꢀ3,5ꢀ
dienꢀ2ꢀol (10f) and 44.4 mg (0.3 mmol) of transꢀ2ꢀphenylvinylboronic acid was reacted via the
general procedure. Purification by silica gel chromatography (3:1 hexanes/ethyl acetate)
afforded a white solid (32.2 mg, 43% yield, 60% ee). 1H NMR (CDCl3, 400 MHz) δ 7.36ꢀ7.30
(2H, m), 7.31ꢀ22 (3H, m), 5.84 (1H, ddd, J = 10.1, 5.2, 2.7 Hz), 5.42 (1H, d, J = 10.1 Hz), 4.52
(1H, dd, J = 11.4, 8.3 Hz), 3.50 (1H, br s), 3.17 (1H, dd, J = 11.4, 5.5 Hz), 3.0 (1H, br s), 2.54ꢀ
2.47 (1H, m), 2.46ꢀ2.36 (1H, m), 1.39 (3H, s), 1.25 (3H, s), 0.75 (3H, d, J = 7.2 Hz). Spectral
data matched that previously published.2a
Large Scale Diels–Alder and Product Recrystallization: trans, transꢀ2,4ꢀHexadienꢀ1ꢀ
ol ( 2.44 g, 15.8 mmol, 2 equiv), transꢀ2ꢀphenylvinylboronic acid (1.17 g, 7.9 mmol, 1 equiv),
and MgSO4 (19 g, 158 mmol, 5 equiv) were suspended in methyl tertꢀbutyl ether (8 mL) in an
ovenꢀdried round bottom flask containing a Teflonꢀcoated magnetic stir bar. The reaction was
stirred under argon at 50 °C for 24 h. The suspension was filtered over Celite and concentrated
in vacuo, yielding the boronate tether which was dissolved in 40 mL of dry 1,4ꢀdioxane (0.2 M
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final concentration). Quinine (2.56 g, 7.9 mmol, 1 equiv) was added and the reaction was stirred
under argon at 90 °C for 48 h, then cooled to room temperature. The mixture was diluted with
THF (40 mL) and 10% NaOH (40 mL) was added. Aqueous 30% H2O2 (13.2 mL) was added
dropwise, and the reaction was stirred under open air for 1 hour. The reaction was quenched
with 25 mL of 10% sodium thiosulfate and extracted with 3 x 50 mL of ethyl acetate. To recover
quinine, the combined organic layer was washed with 1 M HCl (40 mL). The combined organic
layers were then washed with water (3 x 15 mL) and brine (1 x 30 mL). The solution was dried
over anhydrous MgSO4, and concentrated. The crude residue was purified by flash
chromatography to afford 1.125 g (65%, 72% ee) of cyclized diol 5a. Quinine was recovered by
neutralizing the acidic wash with 3 M NaOH (40 mL) and extracting with methyl tertꢀbutyl ether
to provide 2.17 g (85% recovery) of pure quinine.
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A portion of the diol 5a (990.5 mg) was dissolved in 30 mL cyclohexane and heated in
an Erlenmeyer flask. Once dissolved completely, the solution was allowed to cool to room
temperature. The product was filtered using a Buchner funnel yielding enantioenriched crystals
of diol 5a (716.2 mg, 72% recovery, 94% ee).
(4aR,7R,8S,8aS)-2,2,7-trimethyl-8-phenyl-4a,7,8,8a-tetrahydro-4H-
benzo[d][1,3]dioxine (12): Diol 5a (133 mg, 0.61 mmol, 1 equiv) was dissolved in 2,2ꢀ
dimethoxypropane (3 mL) in a round bottom flask containing a Teflonꢀcoated magnetic stir bar,
and and pꢀtoluenesulfonic acid monohydrate (11.4 mg, 0.06 mmol, 0.10 equiv) was added. The
reaction was stirred at room temperature for 4 h, at which point it was transferred to a
separatory funnel, diluted in dichloromethane (20 mL), and washed with saturated NaHCO3 (20
mL). The aqueous layer was extracted with dichloromethane (2 x 10 mL), and the combined
organic layers were washed with brine (20 mL). The reaction mixture was concentrated, and
the crude residue was passed through a short silica column (6:1 hexanes/ethyl acetate) to
1
afford 155 mg (98%) of acetonide 12 as a clear oil. H NMR (CDCl3, 400 Hz) δ 7.18ꢀ7.07 (6H,
m), 6.73ꢀ6.66 (4H, m), 5.92 (1H, ddd, J = 10.0, 2.4 Hz), 5.75 (1H, dt, J = 10.0, 1.6 Hz), 4.30 (1H,
q, J = 11.2, 3.2 Hz), 4.02 (1H, dd, J = 10.4, 6.4 Hz), 3.92 (1H, dd, J = 10.6, 2.4 Hz), 3.70 (1H, t,
J = 5.2 Hz), 3.40 (1H, q, J = 11.6, 5.6 Hz), 2.75 (1H, bs), 2.66 (1H, m), 2.03 (1H, s), 1.65 (1H,
bs). 13C NMR (CDCl3, 100 MHz): δ 138.9, 138.5, 130.6, 130.2, 129.1, 128.1, 127.4, 126.7,
126.5, 69.2, 66.7, 52.5, 49.3, 46.8. IR (KBr plate): 2990, 1455, 1379, 1194 cmꢀ1. HRMS:
Calculated for C17H22O2Na+: 281.1517 (M+Na+), found 281.1515 (M+Na+).
(4aS,5S,6R,7S,8S,8aS)-2,2,7-trimethyl-8-phenylhexahydro-4H-benzo[d][1,3]dioxine-
5,6-diol (13): Alkene 12 (155 mg, 0.6 mmol, 1 equiv) and osmium tetraoxide (1% aqueous
solution, 38 ꢁL, 0.006 mmol, 0.01 equiv), 4ꢀMethylmorpholine Nꢀoxide (NMO solution) (50 wt.
% in H2O, 211 ꢁL, 0.9 mmol, 1.5 equiv) were added to tertꢀbutanol (2.5 mL) and H2O (2.5 mL) in
an ovenꢀdried 20 mL vial containing a Teflonꢀcoated magnetic stir bar. The reaction was stirred
at room temperature for 6 h. The reaction mixture was diluted with 10 mL of H2O and 10 mL of
ethyl acetate. Organics were taken and the aqueous layer was extracted 2 x 20 mL of ethyl
acetate. The combined organic layers were washed with 10 mL of brine and dried over MgSO4.
The mixture was filtered and concentrated via rotary evaporation. The crude residue was
purified by silica gel chromatography (3:1 ethyl acetate/hexanes) to afford 142 mg (81%) of diol
1
13 as a white solid. H NMR (CDCl3, 300 Hz) δ 7.35ꢀ7.25 (2H, m), 7.23ꢀ7.09 (3H, m), 4.23 (1H,
t, J = 10.7 Hz), 4.14 (1H, dd, J = 11.4, 4.5 Hz), 2.69 (1H, br s), 2.43ꢀ2.17 (3H, m), 1.71 (2H, br
s), 1.57 (3H, s), 1.31 (3H, s), 0.68 (3H, d, J = 7.7 Hz). 13C NMR (CDCl3, 75 MHz): δ 140.0,
128.4, 127.9, 125.9, 98.8, 74.7, 67.9, 67.2, 63.3, 43.8, 41.5, 29.9, 19.0, 12.4. IR (KBr plate):
+
3436, 2908, 2880, 1383 cmꢀ1. HRMS: Calculated for C17H24NaO4 : 315.1572 (M+Na+), found
315.1569 (M+Na+).
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(2S,3S)-3-((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)-2-methyl-3-
phenylpropan-1-ol (14): An ovenꢀdried 4 mL vial containing a Teflonꢀcoated magnetic stir bar
was charged with diol 13 (58.5 mg, 0.20 mmol, 1 equiv) in a solution of THF (1.6 mL) and H2O
(0.4 mL). The solution was cooled to 0 °C, and NaIO4 (55.6 mg, 0.26 mmol, 1.3 equiv) was
added. The reaction was warmed to room temperature and stirred for 20 h, until consumption of
starting material and formation of a dialdehyde intermediate was observed by TLC. The
reaction was cooled to 0 °C, and NaBH4 (30.3 mg, 0.80 mmol, 4 equiv) was added. The
reaction was warmed to room temperature and stirred for 30 min. After disappearance of the
dialdehyde, the reaction was cooled to 0 °C, and saturated NH4Cl (3 mL) was added. The
mixture was warmed to room temperature, transferred to a separatory funnel and diluted with
H2O (10 mL) and ethyl acetate (10 mL). The layers were separated, and the aqueous layer was
extracted with ethyl acetate (2 x 10 mL). The organic layers were combined, dried over MgSO4,
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and concentrated.
The crude residue was purified by flash chromatography (1:1
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hexanes/acetone) to afford 52.3 mg (89%) of diol 14 as a white solid. H NMR (CDCl3, 400 Hz)
δ 7.37 (2H, d, J = 7.5 Hz), 7.30ꢀ7.20 (3H, m), 4.20 (1H, dd, J = 10.2, 3.1 Hz), 3.80 (1H, t, J =
10.9 Hz), 3.71 (1H, dd, J = 11.6, 5.2 Hz), 3.58ꢀ3.50 (2H, m), 3.33 (1H, dd, J = 10.8, 4.2 Hz),
3.15 (1H, dd, J = 10.8, 5.0 Hz), 2.66 (1H, dd, J = 9.6, 3.1 Hz), 2.23ꢀ2.16 (1H, m), 1.50 (4H, s),
13
1.45 (3H, s), 1.10 (3H, d, J = 6.7 Hz). C NMR (CDCl3, 100 MHz) 140.2, 130.2, 128.2, 126.7,
98.4, 70.3, 66.5, 62.2, 61.0, 49.9. 38.5, 37.7. 29.2, 19.2, 15.8. δ IR (KBr plate): 3386, 2989,
+
2935, 2878, 1453, 1380 cmꢀ1. HRMS: Calculated for C17H26NaO4 : 317.1729 (M+Na+), found
317.1737 (M+Na+).
ASSOCIATED CONTENT
Supporting Information. This material is available free of charge via the Internet at
http://pubs.acs.org.”
•
•
•
•
Experimental data, including HPLC traces and Xꢀray crystallography data
Copies of NMR spectra
Computational details
Cartesian coordinates and thermodynamic parameters (in hartrees) of all stationary
points
Corresponding Author
* morganj@uncw.edu; houk@chem.ucla.edu
Present Addresses
Modeling and Informatics, Merck & Co., Inc., P. O. Box 2000, Rahway, NJ 07065. (Y.ꢀh. L.)
Author Contributions
All authors have given approval to the final version of the manuscript.
Acknowledgements
The authors thank Dr. John Bacsa and the Emory XꢀRay Crystallography Facility for the Xꢀray
structural analysis. We also acknowledge the use of the Rigaku SYNERGY diffractometer,
supported by the National Science Foundation under grant CHEꢀ1626172. JBM is grateful to the
University of North Carolina Wilmington for financial support. HRMS data was collected from a
Bruker MicrOTOFꢀQ II instrument purchased with funds from the National Science Foundation
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(CHEꢀ1039784) and University of North Carolina Wilmington. The 600 MHz NMR data was
obtained using a Bruker instrument purchased with funds from the National Science Foundation
(CHEꢀ0821552). This work used computational and storage services associated with the
Hoffman2 Shared Cluster provided by UCLA Institute for Digital Research and Education’s
Research Technology Group, and the Extreme Science and Engineering Discovery
Environment (XSEDE), which is supported by National Science Foundation grant number ACIꢀ
1053575.
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References
1 (a) Takao, K.; Munakata, R.; Tadano, K. Recent Advances in Natural Product Synthesis by Using Intramolecular
Diels−Alder Reacꢀons. Chem. Rev. 2005, 105, 4779–4807. (b) Juhl, M.; Tanner, D. Recent Applications of Intramolecular
Diels–Alder Reactions to Natural Product Synthesis. Chem. Soc. Rev. 2009, 38, 2983–2992.
2
(a) Batey, R. A.; Thadani, A. N.; Lough, A. J. Alkenylboronate Tethered Intramolecular Diels–Alder Reactions. J. Am. Chem. Soc.
1999, 121, 450–451. For a tethered DA reaction of boron-substituted dienes, see: (b) Batey, R. A.; Thadani, A. N.; Lough, A. J.
Diels–Alder Reactions of Dienylboron Compounds with Unactivated Dienophiles: an Application of Boron Tethering for
Substituted Cyclohexenol Synthesis. Chem. Commun. 1999, 475–476.
3 For Diels–Alder reactions that incorporate alternative vinyl–metal dienophiles, see: (a) Stork, G.; Chan, T. Y.; Breault, G. A. The
Temporary Silicon Connection in the Control of the Regiochemistry of 4+2 Cycloadditions. J. Am. Chem. Soc. 1992, 114, 7578–
7579. (b) Sieburth, S. M.; Fensterbank, L. An Intramolecular Diels–Alder Reaction of Vinylsilanes. J. Org. Chem. 1992, 57, 5279–
5281. (c) Stork, G.; Chan, T. Y. Temporary Magnesium and Aluminum Connections in 4+2 Cycloadditions. J. Am. Chem. Soc.
1995, 117, 6595–6596. (d) Trost, B. M.; Ball, Z. T. Alkyne Hydrosilylation Catalyzed by a Cationic Ruthenium Complex:
Efficient and General Trans Addition. J. Am. Chem. Soc. 2005, 127, 17644–17655. (e) Shvartsbart, A.; Smith, A. B. Total
Synthesis of (–)-Calyciphylline N. J. Am. Chem. Soc. 2014, 136, 870–873.
4
Franz, M. H.; Roper, S.; Wartchow, R.; Hoffmann, H. M. R. The First and Second Cinchona Rearrangement. Two Fundamental
Transformations of Alkaloid Chemistry. J. Org. Chem. 2004, 69, 2983–2991.
5
Belmessieri, D.; de la Houpliere, A.; Calder, E. D. D.; Taylor, J. E.; Smith, A. D. Stereodivergent Organocatalytic Intramolecular
Michael Addition/Lactonization for the Asymmetric Synthesis of Substituted Dihydrobenzofurans and Tetrahydrofurans. Chem.
Eur. J. 2014, 20, 9762–9769.
6
All of the quantum chemical computations were performed on Gaussian 09. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato,
M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2013.
7
(a) Vosko, S. H.; Wilk, L.; Nusair, M. Accurate Spin-Dependent Electron Liquid Correlation Energies for Local Spin Density
Calculations: A Critical Analysis. Can. J. Phys. 1980, 58, 1200–1211. (b) Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-
Salvetti Correlation-Energy Formula into a Functional of the Electron Density. Phys. Rev. B 1988, 37, 785–789. (c) Becke, A. D.
Density-Functional Thermochemistry. III. The Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648–5652. (d) Stephens, P. J.;
Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using
Density Functional Force Fields. J. Phys. Chem. 1994, 98, 11623–11627.
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Zhao, Y.; Truhlar, D. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics,
5
Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-
6
Class Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120, 215–241.
7
8
9
(a) Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for H
to Rn: Design and Assessment of Accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297–3305. (b) Simón, L.; Goodman, J. M. How
Reliable are DFT Transition Structures? Comparison of GGA, Hybrid-meta-GGA and meta-GGA Functionals. Org. Biomol. Chem.
2011, 9, 689–700.
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This boron-centered anomeric effect was first invoked by Shiner to explain the axial orientation of the B–Cl bond in an
internally coordinated alkylchloroborane featuring a six-membered ring, see: (a) Shiner, C. S.; Garner, C. M.; Haltiwanger, R. C.
Synthesis and Crystal Structure of an Optically Active, Internally Coordinated Alkylchloroborane. The Boron-Centered Anomeric
Effect. J. Am. Chem. Soc. 1985, 107, 7167–7172. The effect has also been invoked in stereocontrolling transition states in boron-
mediated asymmetric allylations, see: (b) Chen, J. L.-Y.; Scott, H. K.; Hesse, M. J.; Willis, C. L.; Aggarwal, V. K. Highly Diastereo-
and Enantioselective Allylboration of Aldehydes using α-Substituted Allyl/Crotyl Pinacol Boronic Esters via in Situ Generated
Borinic Esters. J. Am. Chem. Soc. 2013, 135, 5316–5319. (c) Chen, J. L.-Y.; Aggarwal, V. K. Highly Diastereoselective and
Enantiospecific Allylation of Ketones and Imines Using Borinic Esters: Contiguous Quaternary Stereogenic Centers. Angew.
Chem. Int. Ed. 2014, 53, 10992–10996.
11
Diedrich, M. K.; Klärner, F.-G.; Beno, B. R.; Houk, K. N; Senderowitz, H.; Still, W. C. Experimental Determination of the
Activation Parameters and Stereoselectivities of the Intramolecular Diels–Alder Reactions of 1,3,8-Nonatriene, 1,3,9-
Decatriene, and 1,3,10-Undecatriene and Transition State Modeling with the Monte Carlo-Jumping Between Wells/Molecular
Dynamics Method. J. Am. Chem. Soc. 1997, 119, 10255–10259.
12 Cao, X.-P. Stereoselective Synthesis of Substituted All-Trans 1,3,5,7-Octatetraenes by a Modified Ramberg–Bäcklund
Reaction. Tetrahedron 2002, 58, 1301–1307.
13 Deboef, B.; Counts, W. R.; Gilbertson, S. R. Rhodium-Catalyzed Synthesis of Eight-Membered Rings. J. Org. Chem. 2007, 72,
799– 804.
14 Shull, B. K.; Sakai, T.; Koreeda, M.; Arbor, A.; August, R. V. Eu(fod)3-Catalyzed Rearrangement of Allylic Methoxyacetates. J.
Am. Chem. Soc. 1996, 118, 11690–11691.
15 Clarke, P. A.; Rolla, G. A.; Cridland, A. P.; Gill, A. A. An Improved Synthesis of (2E,4Z)-6-(Benzyloxy)-4-bromohexa-2,4-dien-1-
ol. Tetrahedron 2007, 63, 9124–9128.
16 Dockendorff, C.; Sahli, S.; Olsen, M.; Milhau, L.; Lautens, M. Synthesis of Dihydronaphthalenes via Aryne Diels−Alder
Reactions:ꢁ Scope and Diastereoselectivity. J. Am. Chem. Soc. 2005, 127, 15028–15029.
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