Transition-metal-free reactions of boronic acids: 1,3-stereochemical induction in the substrate-controlled conjugate addition

Article abstract of DOI:10.1021/jo402262m

The substrate-controlled 1,3-stereoselective conjugate addition of boronic acids and potassium trifluoroborates under metal-free conditions has been developed. This reaction affords bicyclic acetals, which have been used as key intermediates in the stereodivergent synthesis of polysubstituted tetrahydropyrans.

Full text of DOI:10.1021/jo402262m

Note
pubs.acs.org/joc
Transition-Metal-Free Reactions of Boronic Acids: 1,3-Stereochemical
Induction in the Substrate-Controlled Conjugate Addition
Silvia Roscales, Víctor Ortega, and Aurelio G. Csaky*
́
̈
Instituto Pluridisciplinar, Universidad Complutense, Campus de Excelencia Internacional Moncloa, 28040 Madrid, Spain
S
* Supporting Information
ABSTRACT: The substrate-controlled 1,3-stereoselective
conjugate addition of boronic acids and potassium trifluor-
oborates under metal-free conditions has been developed. This
reaction affords bicyclic acetals, which have been used as key
intermediates in the stereodivergent synthesis of polysub-
stituted tetrahydropyrans.
he formation of C−C bonds is a fundamental reaction in
In the search for new reactions of boronic acids in the
absence of metal catalysis, we have recently reported the 1,2-
stereochemical induction in the tandem conjugate addition −
acetal ring-opening of boronic acids to compounds 1 acids
under trifluoroacetic anhydride (TFAA) activation (Scheme
1).6a In the present paper we have addressed the issue of 1,3-
T
the construction of the carbon backbone of organic
molecules. The conjugate addition of carbon-centered
nucleophiles to electron-deficient alkenes constitutes one of
the most relevant synthetic methods toward this end.1 Control
of the stereoselectivity is crucial in the development of these
procedures. This has been achieved by using a variety of chiral
ligands attached to transition metal catalysts and by organo-
catalytic procedures. Also, the use of covalently bound chiral
inducers and the exploitation of 1,2-stereochemical induction
are common strategies in the realm of conjugate additions to
enantiopure acceptor substrates. Contrarily, 1,3-stereochemical
induction using chiral-pool derived compounds as starting
materials has been much less developed, despite its conceptual
simplicity and practical usefulness in the preparation of
important molecules such as drugs and natural products. This
is particularly important with regard to conformationally
flexible acyclic substrates, where stereocontrol is more
challenging. Most of the reported examples2,3 have been
restricted to cuprates, simple organozinc reagents or carbon-
stabilized nucleophiles, and suffer from modest stereo-
selectivities. In fact, catalyst control has been required in
many of these cases to override poor substrate control and help
to improve the stereoselectivity. The finding of other carbon-
centered nucleophiles and reaction conditions that could enable
1,3-stereochemical induction fully under substrate control
would be a highly attractive addendum to the synthetic arsenal.
Boronic acids4 and potassium trifluororoborates5 are
attractive reagents for the synthesis of complex molecules due
to their low toxicity, thermal stability, and wide compatibility
with functional groups that are readily attacked by other
organometallics. One of the handicaps of these reagents is their
low nucleophilicity. This requires the inclusion of some type of
extra activation in the synthetic procedures. Most frequently,
transition metal catalysis has been used for this purpose.
Comparatively, reactions in which boronic acids act as
nucleophiles in conjugate addition reactions under metal-free
conditions remain scarce.6,7 This is a new rapidly expanding
field of organoboron chemistry that has not been yet fully
explored.
Scheme 1. Metal-Free Conjugate Addition of Boronic Acids
to Enones with a Pending Acetal Moiety
stereochemical induction using compounds 2 as starting
materials. Boronic acids and potassium trifluoroborates have
not been previously used in the context of substrate-controlled
1,3-stereochemical induction, despite their proven utility as
carbon nucleophiles in stereoselective metal-catalyzed con-
jugate addition reactions.8,9
We have chosen for our study the δ-oxygen-substituted α,β-
unsaturated carbonyl compounds 2, which are easily prepared
optically pure from the chiral pool. To the best of our
knowledge, no conjugate additions of carbon-centered
nucleophiles to these type of compounds have been previously
reported.10 On the basis of recent studies on conjugate addition
reactions of alkenylboronic acids catalyzed by acylating
Received: October 10, 2013
Published: November 19, 2013
© 2013 American Chemical Society
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Note
reagents,7a we first examined the reaction of ketone 2a with
(E)-styrylboronic acid (5a) (eq 1).
entry 8) were also good reagents for this type of trans-
formation. However, no reaction was found for potassium
phenyltrifluoroborate (Table 1, entry 9).
In addition, we examined the reaction of other substrates 2.
We found no reaction between the boronic acid 5a and
methylketone 2b or aldehyde 2c (Table 1, entries 10 and 11).
However, we found that both transformations were possible
when using instead the corresponding potassium trifluorobo-
rate 5j (Table 1, entries 12 and 13).
A reaction mechanism that accounts for the formation of
compounds 4 and the observed stereochemistry is proposed in
Scheme 2. Reaction of TFAA with a boronic acid may give a
After optimization of reaction conditions, we found that this
process was efficiently promoted by using TFAA (3.0 equiv) in
CH2Cl2 under mild reaction conditions (4 h at rt). The 6,8-
dioxa[3.2.1]bicycle 4a was isolated exclusively as a single
diastereomer,11 with an exo relative disposition of the pending
styryl chain.
Scheme 2. Proposed Mechanism
It is worth mentioning that this type of bicyclic acetals are
key structures in certain natural products frameworks.12 Also,
they have attracted recent interest as agrochemicals13 and as
squalane synthase inhibitors,14 apart from being interesting
synthetic intermediates for the preparation of natural
products.15
In order to investigate the scope of this transformation, we
examined the reaction of 2a with different boronic acids. The
results are gathered in Table 1. We observed that this reaction
a
Table 1. Synthesis of 6,8-Dioxa[3.2.1]bicycles 4a
4
b
entry
1
2
5
R1
R2−[B]
(yield %)
mono- or a diacylboronate16 intermediate, where the Lewis
acidity of the boron atom is enhanced with respect to that of
the starting boronic acid. Similarly, potassium trifluoroborates
are known to produce organodifluoroboranes under the
influence of Lewis acids.17 Therefore, we suggest the transient
formation of an electron-deficient trivalent boron species
(RBX2) by the reaction of the starting boronic acid or
potassium trifluoroborate with TFAA.18 The enhanced Lewis
acidity of the boron acid in these species enables coordination
with the lone pair of the δ-oxygen of the acetal group,6a,19
facilitated by the lone pair on the ε-oxygen. The intramolecular
delivery (syn-addition) of the R2 group from the boronate
intermediate thus generated would finally afford the inter-
mediate compounds 6 (not isolated), which rendered in situ
the 6,8-dioxa[3.2.1]bicycles 4 by intramolecular transacetaliza-
tion.
2a
5b
Ph
(E)-pMe-C6H4CHCH-
4b (64)
B(OH)2
2
3
4
2a
2a
2a
5c
5d
5e
Ph
Ph
Ph
(E)-pFC6H4CHCH-
4c (61)
4d (66)
4e (67)
B(OH)2
(E)-pClC6H4CHCH-
B(OH)2
(E)-pCF3C6H4CHCH-
B(OH)2
5
6
2a
2a
5f
Ph
Ph
(E)-Biphenyl-CHCH-B(OH)2
4f (59)
5g
(E)-pMeO-C6H4CHCH-
−
B(OH)2
7
2a
2a
2a
2b
2c
2b
2c
5h
5i
Ph
Ph
Ph
Ph-B(OH)2
−
−
8
Ph-B(OH)2
9
5j
(E)-PhCHCH-BF3K
4a (70)
10
11
12
13
5a
5a
5j
Me (E)-PhCHCH-B(OH)2
−
−
H
(E)-PhCHCH-B(OH)2
Me (E)-PhCHCH-BF3K
4g (71)
6,8-Dioxa[3.2.1]bicycles constitute useful materials for the
5j
H
(E)-PhCHCH-BF3K
4h (52)
stereodivergent synthesis of optically pure tetrahydropyrans,20
a
a
Reaction conditions: 2 (0.13 mmol), 5 (0.26 mmol), TFAA (0.39
mmol, 3 equiv), CH2Cl2 (0.8 mL), 4 h, rt. Isolated yield of 4 after
column chromatography.
b
ubiquitous skeleton among pharmaceuticals and natural
products. Considerable efforts have been made in recent
times toward the stereoselective preparation of di- and
trisubstituted tetrahydropyrans.21 In this paper, we have used
compounds 4 as key intermediates for the stereodivergent
synthesis of trisubstituted tetrahydropyrans.
could be extended to other styrylboronic acids 5 substituted in
the benzene ring with electron-withdrawing substituents (Table
1, entries 1−5). On the other hand, the reaction did not
support the presence of a p-MeO group (Table 1, entry 6).
Phenylboronic acid (Table 1, entry 7) did not react under these
reaction conditions. Potassium vinyltrifluoroborates (Table 1,
Thus, reaction of compounds 4a−e (R1 = Ph) and 4g (R1 =
Me) with Et3SiH/BF3 afforded the corresponding 2,4-trans-4,6-
trans-2,4,6-trisubstituted tetrahydropyrans 7a−f (Table 2,
entries 1−6). Similar treatment of 4h (R1 = H) permitted
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Note
solvents were evaporated to afford (S)-2-(2,2-dimethyl-1,3-dioxolan-4-
yl)acetaldehyde (398 mg, 2.76 mmol, 81%) as a colorless oil.22 To a
stirred solution of this aldehyde (220 mg, 1.53 mmol) in 5 mL of THF
was added the corresponding phosphonium ylide (1.68 mmol). The
solution was stirred at reflux for 10 h and concentrated in vacuo. The
crude product was chromatographed on silica gel (Hexane:AcOEt
7:3).
Table 2. Stereodivergent Synthesis of Tetrahydropyrans
(S,E)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-1-phenylbut-2-en-1-one
2a. Following the general procedure, the reaction performed with
(benzoylmethylene)-triphenylphosphorane (639 mg) afforded 280 mg
(74%) of the title compound as a yellow solid: 1H NMR (CDCl3, 300
MHz) δ 1.30 (s, 3H), 1.37 (s, 3H), 2.43−2.63 (m, 2H), 3.57 (dd, J =
8.2 Hz, J = 6.7 Hz, 1H), 4.02 (dd, J = 8.2 Hz, J = 6.0 Hz, 1H), 4.22 (q,
J = 6.3 Hz, 1H), 6.78−7.01 (m, 2H), 6.85−7.01 (m, 3H), 7.83−7.88
(m, 2H); 13C NMR (CDCl3, 75 MHz) δ 25.7, 27.0, 37.2, 69.0, 74.4,
109.5, 128.4, 128.7 (4C), 132.9, 144.2, 190.6. Anal. Calc. for
C15H18O3: C, 73.15; H, 7.37. Found: C, 73.20; H, 7.40.
a
entry
R1
R2
reaction conditions
7, 8 (yield %)
1
2
Ph
Ph
Ph
Ph
Ph
Me
H
Ph
A
A
A
A
A
A
A
B
B
B
7a (81)
7b (77)
7c (71)
7d (77)
7e (71)
7f (66)
7g (77)
8a (63)
8b (65)
7g (63)
pMe-C6H4
pF-C6H4
pCl-C6H4
pCF3−C6H4
Ph
3
4
5
6
7
Ph
(S,E)-5-(2,2-dimethyl-1,3-dioxolan-4-yl)pent-3-en-2-one 2b. Fol-
lowing the general procedure, the reaction performed with 1-
triphenylphosphoranylidene-2-propanone (280 mg) afforded 124 mg
8
Ph
Me
H
Ph
9
Ph
1
(84%) of the title compound as a pale yellow oil: H NMR (CDCl3,
10
Ph
300 MHz) δ 1.32 (s, 3H), 1.39 (s, 3H), 2.23 (s, 3H), 2.42−2.51 (m,
2H), 3.56 (dd, J = 8.2 Hz, J = 6.6 Hz, 1H), 4.04 (dd, J = 8.2 Hz, J = 6.1
Hz, 1H), 4.21 (q, J = 6.1 Hz, 1H), 6.11 (dt, J = 16.1 Hz, J = 1.4 Hz,
1H), 6.75 (dt, J = 16.1 Hz, J = 7.0 Hz, 1H); 13C NMR (CDCl3, 75
MHz) δ 25.6, 26.9, 27.0, 36.8, 68.8, 74.3, 109.5, 133.6, 143.0, 198.4.
Anal. Calc. for C10H16O3: C, 65.19; H, 8.75. Found: C, 65.22; H, 8.70.
(S,E)-4-(2,2-Dimethyl-1,3-dioxolan-4-yl)-but-2-enal 2c. Following
the general procedure, the reaction performed with
(triphenylphosphoranylidene)acetaldehyde (636 mg) afforded 258
mg (80%) of the title compound as a pale yellow oil: 1H NMR
(CDCl3, 300 MHz) δ 1.29 (s, 3H), 1.36 (s, 3H), 2.53 (td, J = 6.2 Hz, J
= 1.5 Hz, 2H), 3.54 (dd, J = 8.2 Hz, J = 6.2 Hz, 1H), 4.04 (dd, J = 8.2
Hz, J = 6.2 Hz, 1H), 4.21 (q, J = 6.2 Hz, 1H), 6.13 (ddt, J = 15.6 Hz, J
= 7.8 Hz, J = 1.5 Hz, 1H), 6.79 (dt, J = 15.6 Hz, J = 7.0 Hz, 1H), 9.46
(d, J = 7.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 25.5, 26.9, 37.0,
68.8, 74.0, 109.6, 135.0, 153.1, 193.7. Anal. Calc. for C9H14O3: C,
63.51; H, 8.29. Found: C, 63.55; H, 8.32.
General Procedure for the Preparation of 6,8-Dioxa[3.2.1]-
bicycles 4. To a stirred solution of boronic acid 5 (2.0 equiv) and the
corresponding starting material 2 (1.0 equiv) in anhydrous CH2Cl2 (6
mL/mmol) was added trifluoroacetic anhydride (3.0 equiv). After
stirring 4 h at rt, a saturated solution of Na2CO3 was added. The layers
were separated, and the aqueous one was extracted with Et2O. The
combined organic layers were dried over MgSO4 and concentrated in
vacuo. The crude product was chromatographed on silica gel
(Hexane:AcOEt 8:2) to afford the title compounds.
a
Reaction conditions A: 4 (0.06 mmol), BF3·OEt (0.16 mmol), Et3SiH
(0.32 mmol), CH2Cl2 (1.8 mL), overnight, −40 °C → r.t. Reaction
conditions B: 4 (0.062 mmol), DIBALH (1.5 M toluene, 0.49 mmol),
CH2Cl2 (2 mL), overnight, 0 °C → r.t.
the synthesis of the 2,4-trans-disubstituted compound 7g
(Table 2, entry 7). On the other hand, reaction of 4a or 4g
with DIBAL in CH2Cl2 gave rise to the 2,4-cis-4,6-trans isomers
8a,b (Table 2, entries 8, 9). The disubstituted compound 7h
was again obtained from 4h (Table 1, entry 10), although
under these reaction conditions (DIBALH), the yield was lower
than when Et3SiH/BF3 was used as reducer (Table 2, entry 7).
In conclusion, we have developed the substrate-controlled
1,3-stereoselective conjugate addition of alkenylboronic acids
and potassium alkenyltrifluoroborates in the presence of
trifluoroacetic anhydride (TFAA) under metal-free conditions,
following a very simple experimental procedure. The reaction is
highly stereoselective for the generation of 6,8-dioxa[3.2.1]-
bicycles and constitutes a versatile method for the stereo-
divergent synthesis of optically pure di- and trisubstituted
tetrahydropyrans.
EXPERIMENTAL SECTION
■
(1S,3S,5S)-5-Phenyl-3-((E)-styryl)-6,8-dioxabicyclo[3.2.1]octane
4a. Following the general procedure, reaction of 2a (32 mg, 0.13
mmol) with trans-2-phenylvinylboronic acid 5a (38 mg, 0.26 mmol)
and TFAA (54 μL, 0.39 mmol) in CH2Cl2 (0.8 mL) yielded after flash
General Considerations. All commercially available reagents
including anhydrous solvents were used without purification.
Analytical thin-layer chromatography (TLC) was performed on
commercial silica gel plates (0.25 mm) precoated with a fluorescent
indicator. Flash chromatography (FC) was performed on silica gel F-
60. Visualization was effected with ultraviolet light and ethanolic
vanillin solution. NMR spectra were recorded on a 300 MHz
1
chromatography (Hexane/AcOEt 8/2) 4a (26 mg, 69%): H NMR
(CDCl3, 500 MHz) δ 1.70−1.87 (m, 3H), 2.11 (dd, J = 13.3 Hz, J =
5.4 Hz, 1H), 2.95 (m, 1H), 3.96 (m, 1H), 4.05 (d, J = 6.9 Hz, 1H),
4.70−4.74 (m, 1H), 6.04 (dd, J = 15.9 Hz, J = 7.3 Hz, 1H), 6.36 (d, J =
15.9 Hz, 1H), 7.11−7.34 (m, 8H), 7.48−7.52 (m, 2H); 13C NMR
(CDCl3, 125 MHz) δ 33.3, 34.8, 42.8. 69.5, 75.0, 107.7, 125.2 (2C),
126.2 (2C), 127.4, 128.3 (2C), 128.5, 128.7 (2C), 129.2, 133.5, 137.5,
141.0. Anal. Calc. for C20H20O2: C, 82.16; H, 6.89. Found: C, 82.13;
H, 6.80.
(1S,3S,5S)-3-((E)-4-Methylstyryl)-1-phenyl-6,8-dioxabicyclo[3.2.1]-
octane 4b. Following the general procedure, reaction of 2a (33 mg,
0.13 mmol) with trans-2-(4-methylphenyl)vinylboronic acid 5b (43
mg, 0.27 mmol) and TFAA (56 μL, 0.40 mmol) in CH2Cl2 (0.8 mL)
yielded after flash chromatography (Hexane/AcOEt 8/2) 4b (26 mg,
64%): 1H NMR (CDCl3, 300 MHz) δ 1.66−1.88 (m, 3H), 2.10 (dd, J
= 13.5 Hz, J = 5.5 Hz, 1H), 2.25 (s, 3H), 2.93 (m, 1H), 3.95 (m, 1H),
4.05 (d, J = 6.9 Hz, 1H), 4.69−4.76 (m, 1H), 5.98 (dd, J = 15.9 Hz, J =
7.4 Hz, 1H), 6.33 (d, J = 15.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 2H), 7.13−
7.35 (m, 5H), 7.46−7.52 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ
1
spectrometer. Chemical shifts are given in ppm. H NMR chemical
shifts were referenced to the residual solvent signal; 13C NMR
chemical shifts were referenced to the deuterated solvent signal.
Multiplicity was defined by DEPT 135 analysis. Data are presented as
follows: chemical shift δ (ppm), multiplicity (s = singlet, d = doublet, t
= triplet, m = multiplet, br = broad), coupling constant J (Hz),
integration.
General Procedure for the Preparation of Compounds 2.
(S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol (500 mg, 3.42 mmol)
was dissolved in 7.2 mL of anhydrous dichloromethane followed by
slow addition of pyridinium chlorochromate (885 mg, 4.10 mmol) and
powdered 4 Å molecular sieves (750 mg). The suspension was stirred
vigorously overnight at room temperature. Hexane/ethyl acetate (1:1,
6.2 mL) was added to the reaction mixture that was then stirred for 30
min. The black suspension was filtered through a short flash silica gel
column to remove excess PCC and its reduced forms. The organic
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Note
21.3, 33.3, 34.9, 42.9. 69.5, 75.0, 107.7, 125.2 (2C), 126.1 (2C), 128.3
(2C), 128.4, 129.0, 129.4 (2C), 132.4, 134.7, 137.1, 141.0. Anal. Calc.
for C21H22O2: C, 82.32; H, 7.24. Found: C, 82.38; H, 7.12.
TFAA (81 μL, 0.58 mmol) in CH2Cl2 (1.2 mL) yielded after flash
chromatography (Hexane/AcOEt 8/2) 4h (22 mg, 52%): H NMR
1
(CDCl3, 300 MHz) δ 1.39−2.01 (m, 5H), 2.77 (m, 1H), 3.74 (m,
1H), 3.92 (d, J = 7.1 Hz, 1H), 4.46−4.56 (m, 1H), 5.51 (s, 1H), 5.98
(dd, J = 15.9 Hz, J = 7.4 Hz, 1H), 6.31 (d, J = 15.9 Hz, 1H), 7.06−7.36
(m, 5H); 13C NMR (CDCl3, 75 MHz) δ 31.6, 35.4, 38.0, 68.5, 73.3,
101.4, 126.2 (2C), 127.4, 128.7 (2C), 129.0, 133.6, 137.4. Anal. Calc.
for C14H16O2: C, 77.75; H, 7.46. Found: C, 77.62; H, 7.30.
General Procedure for the Preparation of Compounds 7
Using BF3·Et2O/Et3SiH. To a stirred solution of the corresponding
bicycle 4 (1.0 equiv) in anhydrous CH2Cl2 (28 mL/mmol) at −40 °C
was added dropwise BF3·Et2O (2.5 equiv) and Et3SiH (5.0 equiv)
successively. After stirring overnight, a saturated solution of NaHCO3
was added. The layers were separated, and the aqueous one was
extracted with CHCl3. The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The crude product was
chromatographed on silica gel (CH2Cl2:AcOEt 95:5) to afford the
title compounds.
(2S,4S,6R)-6-Phenyl-4-((E)-styryl)tetrahydro-2H-pyran-2-yl)-
methanol 7a. Following the general procedure, reaction of 4a (19 mg,
0.07 mmol) with BF3·Et2O (20 μL, 0.16 mmol) and Et3SiH (52 μL,
0.32 mmol) in CH2Cl2 (1.8 mL) yielded after flash chromatography
(CH2Cl2:AcOEt 95:5) 7a (15 mg, 81%): 1H NMR (CDCl3, 300
MHz) δ 1.64 (d, J = 13.4 Hz, 1H), 1.76 (ddd, J = 13.4 Hz, J = 11.8 Hz,
J = 5.1 Hz, 1H), 1.85−1.92 (m, 2H), 2.88−2.96 (m, 1H), 3.54 (dd, J =
11.5 Hz, J = 7.0 Hz, 1H), 3.61 (dd, J = 11.5 Hz, J = 3.3 Hz, 1H), 3.88−
3.99 (m, 1H), 4.66 (dd, J = 9.0 Hz, J = 5.0 Hz, 1H), 6.40−6.54 (m,
2H), 7.13−7.39 (m, 10H); 13C NMR (CDCl3, 75 MHz) δ 31.6, 34.2,
38.7, 66.6, 74.0, 75.1, 126.1 (2C), 126.2 (2C), 127.5, 127.7, 128.5
(2C), 128.8 (2C), 130.9, 132.4, 137.5, 143.0. Anal. Calc. for C20H22O2:
C, 81.60; H, 7.53. Found: C, 81.71; H, 7.44.
(1S,3S,5S)-3-((E)-4-Fluorostyryl)-1-phenyl-6,8-dioxabicyclo[3.2.1]-
octane 4c. Following the general procedure, reaction of 2a (31 mg,
0.13 mmol) with trans-2-(4-fluorophenyl)vinylboronic acid 5c (42 mg,
0.25 mmol) and TFAA (52 μL, 0.38 mmol) in CH2Cl2 (0.8 mL)
yielded after flash chromatography (Hexane/AcOEt 8/2) 4c (24 mg,
61%): 1H NMR (CDCl3, 300 MHz) δ 1.69−1.88 (m, 3H), 2.10 (dd, J
= 13.4 Hz, J = 5.5 Hz, 1H), 2.92 (m, 1H), 3.96 (m, 1H), 4.05 (d, J =
7.0 Hz, 1H), 4.69−4.76 (m, 1H), 5.96 (dd, J = 15.9 Hz, J = 7.3 Hz,
1H), 6.32 (d, J = 15.9 Hz, 1H), 6.91 (t, J = 8.7 Hz, 2H), 7.16−7.36 (m,
6H), 7.45−7.52 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 33.3, 34.8,
42.8. 69.5, 75.0, 107.7, 115.4, 115.7, 125.2 (2C), 127.6, 127.7, 128.0,
128.3 (2C), 128.5, 133.2, 141.0. Anal. Calc. for C20H19FO2: C, 77.40;
H, 6.17. Found: C, 77.44; H, 6.06.
(1S,3S,5S)-3-((E)-4-Chlorostyryl)-1-phenyl-6,8-dioxabicyclo[3.2.1]-
octane 4d. Following the general procedure, reaction of 2a (30 mg,
0.12 mmol) with trans-2-(4-chlorophenyl)vinylboronic acid 5d (44
mg, 0.24 mmol) and TFAA (51 μL, 0.36 mmol) in CH2Cl2 (0.7 mL)
yielded after flash chromatography (Hexane/AcOEt 8/2) 4d (26 mg,
66%): 1H NMR (CDCl3, 300 MHz) δ 1.69−1.88 (m, 3H), 2.10 (dd, J
= 13.3 Hz, J = 5.5 Hz, 1H), 2.94 (m, 1H), 3.96 (m, 1H), 4.05 (d, J =
7.0 Hz, 1H), 4.68−4.76 (m, 1H), 6.02 (dd, J = 15.9 Hz, J = 7.3 Hz,
1H), 6.31 (dd, J = 15.9 Hz, J = 1.1 Hz, 1H), 7.14−7.36 (m, 7H), 7.45−
7.54 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 33.3, 34.7, 42.7. 69.5,
74.9, 107.7, 125.2 (2C), 127.4 (2C), 128.0, 128.3 (2C), 128.5, 128.8
(2C), 132.9, 134.2, 136.0, 140.9. Anal. Calc. for C20H19ClO2: C, 73.50;
H, 5.86. Found: C, 73.59; H, 5.79.
(1S,3S,5S)-1-Phenyl-3-((E)-4-(trifluoromethyl)styryl)-6,8-
dioxabicyclo[3.2.1]-octane 4e. Following the general procedure,
reaction of 2a (33 mg, 0.12 mmol) with trans-2-(4-
trifluoromethylphenyl)vinylboronic acid 5e (57 mg, 0.27 mmol) and
TFAA (56 μL, 0.40 mmol) in CH2Cl2 (0.8 mL) yielded after flash
(2S,4S,6R)-4-((E)-4-Methylstyryl)-6-phenyltetrahydro-2H-pyran-2-
yl)methanol 7b. Following the general procedure, reaction of 4b (21
mg, 0.07 mmol) with BF3·Et2O (22 μL, 0.17 mmol) and Et3SiH (56
μL, 0.35 mmol) in CH2Cl2 (2.0 mL) yielded after flash
1
chromatography (Hexane/AcOEt 8/2) 4e (32 mg, 66%): H NMR
(CDCl3, 300 MHz) δ 1.71−1.91 (m, 3H), 2.12 (dd, J = 13.3 Hz, J =
5.4 Hz, 1H), 2.98 (m, 1H), 3.97 (m, 1H), 4.06 (d, J = 7.0 Hz, 1H),
4.70−4.79 (m, 1H), 6.15 (dd, J = 15.9 Hz, J = 7.2 Hz, 1H), 6.39 (d, J =
15.9 Hz, 1H), 7.16−7.39 (m, 5H), 7.44−7.55 (m, 4H); 13C NMR
(CDCl3, 75 MHz) δ 33.4, 34.6, 42.6. 69.5, 74.9, 107.7, 125.2 (2C),
125.6, 125.7, 126.4 (2C), 128.0, 128.4 (2C), 128.5, 136.2, 140.9. Anal.
Calc. for C20H19F3O2: C, 69.99; H, 5.31. Found: C, 70.06; H, 5.42.
(1S,3S,5S)-3-((E)-2-([1,1′-Biphenyl]-4-yl)vinyl)-1-phenyl-6,8-
dioxabicyclo[3.2.1]-octane 4f. Following the general procedure,
reaction of 2a (27 mg, 0.11 mmol) with trans-2-(4-biphenyl)-
vinylboronic acid 5f (49 mg, 0.22 mmol) and TFAA (46 μL, 0.33
mmol) in CH2Cl2 (0.6 mL) yielded after flash chromatography
(Hexane/AcOEt 8/2) 4f (24 mg, 59%): 1H NMR (CDCl3, 300 MHz)
δ 1.71−1.91 (m, 3H), 2.13 (dd, J = 13.5 Hz, J = 5.5 Hz, 1H), 2.96 (m,
1H), 3.97 (m, 1H), 4.07 (d, J = 6.9 Hz, 1H), 4.70−4.77 (m, 1H), 6.09
(dd, J = 15.9 Hz, J = 7.3 Hz, 1H), 6.40 (d, J = 15.9 Hz, 1H), 7.15−7.59
(m, 14H); 13C NMR (CDCl3, 75 MHz) δ 33.4, 34.8, 42.8. 69.5, 75.0,
107.7, 125.3 (2C), 126.6 (2C), 127.0 (2C), 127.4 (3C), 128.3 (2C),
128.5, 128.8, 128.9 (2C), 133.6, 136.5, 140.2, 140.9, 141.0. Anal. Calc.
for C26H24O2: C, 84.75; H, 6.57. Found: C, 84.82; H, 6.62.
(1R,3S,5S)-1-Methyl-3-((E)-styryl)-6,8-dioxabicyclo[3.2.1]octane
4g. Following the general procedure, reaction of 2b (29 mg, 0.16
mmol) with potassium trans-β-styryltrifluoroborate 5i (66 mg, 0.31
mmol) and TFAA (65 μL, 0.47 mmol) in CH2Cl2 (0.9 mL) yielded
after flash chromatography (Hexane/AcOEt 8/2) 4g (26 mg, 71%):
1H NMR (CDCl3, 300 MHz) δ 1.41 (s, 3H), 1.43−1.55 (m, 2H),
1.58−1.70 (m, 1H), 1.82 (dd, J = 13.4 Hz, J = 5.6 Hz, 1H), 2.76 (m,
1H), 3.78−3.90 (m, 2H), 4.49−4.58 (m, 1H), 5.98 (dd, J = 15.9 Hz, J
= 7.4 Hz, 1H), 6.32 (d, J = 15.9 Hz, 1H), 7.06−7.38 (m, 5H); 13C
NMR (CDCl3, 75 MHz) δ 24.4, 33.0, 34.8, 42.0. 69.2, 74.6, 107.0,
126.2 (2C), 127.3, 128.7 (2C), 129.0, 133.7, 137.5. Anal. Calc. for
C15H18O2: C, 78.23; H, 7.88. Found: C, 78.31; H, 7.95.
1
chromatography (CH2Cl2:AcOEt 95:5) 7b (16 mg, 77%): H NMR
(CDCl3, 300 MHz) δ 1.63 (d, J = 13.5 Hz, 1H), 1.75 (ddd, J = 13.5
Hz, J = 12.0 Hz, J = 5.1 Hz, 1H), 1.84−1.90 (m, 2H), 2.28 (s, 3H),
2.88−2.94 (m, 1H), 3.54 (dd, J = 11.5 Hz, J = 6.9 Hz, 1H), 3.61 (dd, J
= 11.5 Hz, J = 3.2 Hz, 1H), 3.88−3.99 (m, 1H), 4.66 (dd, J = 9.2 Hz, J
= 5.0 Hz, 1H), 6.40−6.45 (m, 2H), 7.03−7.34 (m, 9H); 13C NMR
(CDCl3, 75 MHz) δ 21.3, 31.7, 34.2, 38.7, 66.7, 74.0, 75.1, 126.0 (2C),
126.1 (2C), 127.6, 128.5 (2C), 129.5 (2C), 130.7, 131.3, 134.7, 137.3,
143.0. Anal. Calc. for C21H24O2: C, 81.78; H, 7.84. Found: C, 81.88;
H, 7.71.
(2S,4S,6R)-4-((E)-4-Fluorostyryl)-6-phenyltetrahydro-2H-pyran-2-
yl)methanol 7c. Following the general procedure, reaction of 4c (27
mg, 0.09 mmol) with BF3·Et2O (26 μL, 0.21 mmol) and Et3SiH (70
μL, 0.43 mmol) in CH2Cl2 (2.4 mL) yielded after flash
1
chromatography (CH2Cl2:AcOEt 95:5) 7c (19 mg, 71%): H NMR
(CDCl3, 300 MHz) δ 1.62 (d, J = 13.4 Hz, 1H), 1.75 (ddd, J = 13.4
Hz, J = 12.0 Hz, J = 5.2 Hz, 1H), 1.84−1.92 (m, 2H), 2.86−2.94 (m,
1H), 3.54 (dd, J = 11.3 Hz, J = 6.9 Hz, 1H), 3.61 (dd, J = 11.3 Hz, J =
2.3 Hz, 1H), 3.86−3.97 (m, 1H), 4.65 (t, J = 6.3 Hz, 1H), 6.33−6.48
(m, 2H), 6.96 (t, J = 8.5 Hz, 2H), 7.15−7.36 (m, 7H); 13C NMR
(CDCl3, 75 MHz) δ 31.6, 34.2, 38.6, 66.6, 74.0, 75.1, 115.5, 115.8,
126.1 (2C), 127.6, 127.6, 127.7, 128.5 (2C), 129.7, 132.1, 132.2, 133.6,
133.7, 142.9, 160.7, 164.0. Anal. Calc. for C20H21FO2: C, 76.90; H,
6.78. Found: C, 76.81; H, 6.91.
(2S,4S,6R)-4-((E)-4-Chlorostyryl)-6-phenyltetrahydro-2H-pyran-2-
yl)methanol 7d. Following the general procedure, reaction of 4d (21
mg, 0.06 mmol) with BF3·Et2O (20 μL, 0.16 mmol) and Et3SiH (52
μL, 0.32 mmol) in CH2Cl2 (1.8 mL) yielded after flash
1
chromatography (CH2Cl2:AcOEt 95:5) 7d (16 mg, 77%): H NMR
(CDCl3, 300 MHz) δ 1.63 (d, J = 13.4 Hz, 1H), 1.76 (ddd, J = 13.4
Hz, J = 12.4 Hz, J = 5.3 Hz, 1H), 1.85−1.92 (m, 2H), 2.86−2.96 (m,
1H), 3.48−3.68 (m, 2H), 3.85−4.02 (m, 1H), 4.64 (t, J = 6.6 Hz, 1H),
6.35−6.52 (m, 2H), 7.04−7.36 (m, 9H); 13C NMR (CDCl3, 75 MHz)
δ 31.5, 34.2, 38.5, 66.6, 74.0, 75.1, 126.1 (2C), 127.4 (3C), 127.7,
(1R,3S,5S)-3-((E)-Styryl)-6,8-dioxabicyclo[3.2.1]octane 4h. Follow-
ing the general procedure, reaction of 2c (33 mg, 0.19 mmol) with
potassium trans-β-styryltrifluoroborate 5i (82 mg, 0.39 mmol) and
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The Journal of Organic Chemistry
Note
128.5 (2C), 128.9 (2C), 129.7, 133.1, 136.0, 142.9. Anal. Calc. for
C20H21ClO2: C, 73.05; H, 6.44. Found: C, 72.91; H, 6.56.
CH2Cl2 (3 mL) yielded after flash chromatography (CH2Cl2:AcOEt
95:5) 8a (15 mg, 65%): H NMR (CDCl3, 300 MHz) δ 1.22 (d, J =
1
(2S,4S,6R)-6-Phenyl-4-((E)-4-(trifluoromethyl)styryl)tetrahydro-
2H-pyran-2-yl)methanol 7e. Following the general procedure,
reaction of 4e (16 mg, 0.04 mmol) with BF3·Et2O (14 μL, 0.11
mmol) and Et3SiH (37 μL, 0.22 mmol) in CH2Cl2 (1.3 mL) yielded
after flash chromatography (CH2Cl2:AcOEt 95:5) 7e (12 mg, 71%):
1H NMR (CDCl3, 300 MHz) δ 1.65 (d, J = 13.6 Hz, 1H), 1.78 (ddd, J
= 13.6 Hz, J = 11.8 Hz, J = 5.1 Hz, 1H), 1.86−1.95 (m, 2H), 2.89−
3.00 (m, 1H), 3.55 (dd, J = 11.5 Hz, J = 6.9 Hz, 1H), 3.62 (dd, J = 11.5
Hz, J = 3.4 Hz, 1H), 3.86−3.97 (m, 1H), 4.64 (t, J = 6.7 Hz, 1H), 6.49
(d, J = 16.1 Hz, 1H), 6.59 (dd, J = 16.1 Hz, J = 5.8 Hz, 1H), 7.15−7.34
(m, 5H), 7.43 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) δ 31.4, 34.3, 38.4, 66.6, 74.1, 75.1, 125.6, 125.7,
125.8, 126.1(2C), 126.4 (2C), 127.8, 128.5 (2C), 129.2, 129.8, 135.3,
141.0, 142.8. Anal. Calc. for C21H21F3O2: C, 69.60; H, 5.84. Found: C,
69.72; H, 5.73.
6.1 Hz, 3H), 1.68 (dd, J = 11.0 Hz, J = 5.4 Hz, 2H), 1.76 (dm, J = 13.3
Hz, 2H), 2.40−2.56 (m, 1H), 3.46 (dm, J = 7.3 Hz, 1H), 3.74−3.86
(m, 1H), 4.05 (d, J = 10.4 Hz, 1H), 4.07−4.12 (m, 1H), 6.06 (dd, J =
15.9 Hz, J = 6.8 Hz, 1H), 6.37 (d, J = 15.9 Hz, 1H), 7.17−7.38 (m,
5H); 13C NMR (CDCl3, 125 MHz) δ 22.3, 31.4, 34.4, 39.6, 61.1, 65.5,
73.3, 126.2 (2C), 127.4, 128.70 (2C), 128.72, 134.4, 137.5. Anal. Calc.
for C15H20O2: C, 77.55; H, 8.68. Found: C, 77.66; H, 8.51.
(2S,4S,6R)-6-Phenyl-4-((E)-styryl)tetrahydro-2H-pyran-2-yl)-
methyl benzoate 9a. To a solution of 7a (9.8 mg, 0.033 mmol) in
anhydrous CH2Cl2 (2 mL) was added BzCl (4 μL, 0.04 mmol), Et3N
(5 μL, 0.033 mmol) and DMAP (0.4 mg, 0.003 mmol). The reaction
mixture was stirred overnight at rt. The resulting solution was filtered
through a Celite plug and the filtrate was concentrated. The residue
was purified by flash cromatography (Hexane:AcOEt, 8:2) to yield 9a
1
(11.5 mg, 87%): H NMR (CDCl3, 300 MHz) δ 1.80−1.95 (m, 4H),
2.91−3.00 (m, 1H), 4.12−4.23 (m, 1H), 4.29−4.43 (m, 2H), 4.70 (dd,
J = 10.6 Hz, J = 3.5 Hz, 1H), 6.43−6.56 (m, 2H), 7.08−7.52 (m,
13H), 7.96−8.06 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 32.4, 34.2,
38.4, 68.0, 71.6, 75.0, 126.0 (2C), 126.3 (2C), 127.4, 127.5, 128.4
(2C), 128.5 (2C), 128.8 (2C), 129.9 (2C), 130.4, 131.0, 132.2, 133.1,
137.4, 143.0, 166.7. Anal. Calcd. for C27H26O3: C, 81.38; H, 6.58.
Found: C, 81.45; H, 6.44.
(2S,4S,6S)-6-Methyl-4-((E)-styryl)tetrahydro-2H-pyran-2-yl)-
methanol 7f. Following the general procedure, reaction of 4g (21 mg,
0.09 mmol) with BF3·Et2O (27 μL, 0.23 mmol) and Et3SiH (72 μL,
0.45 mmol) in CH2Cl2 (2.5 mL) yielded after flash chromatography
(CH2Cl2:AcOEt 95:5) 7f (14 mg, 66%): 1H NMR (CDCl3, 300 MHz)
δ 1.12 (d, J = 6.13 Hz, 3H), 1.46−1.70 (m, 4H), 2.70−2.84 (m, 1H),
3.44 (dd, J = 11.3 Hz, J = 7.2 Hz, 1H), 3.53 (dd, J = 11.3 Hz, J = 3.2
Hz, 1H), 3.70−3.81 (m, 2H), 6.26−6.45 (m, 2H), 7.07−7.34 (m, 5H);
13C NMR (CDCl3, 75 MHz) δ 22.3, 31.7, 34.0, 38.3, 66.6, 69.0, 73.4,
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
126.1 (2C), 127.4, 128.7 (2C), 130.4, 132.9, 137.6. Anal. Calc. for
C15H20O2: C, 77.55; H, 8.68. Found: C, 77.68; H, 8.51.
S
(2S,4S)-4-((E)-Styryl)tetrahydro-2H-pyran-2-yl)methanol 7g. Fol-
lowing the general procedure, reaction of 4h (12 mg, 0.06 mmol) with
BF3·Et2O (17 μL, 0.14 mmol) and Et3SiH (45 μL, 0.28 mmol) in
CH2Cl2 (1.6 mL) yielded after flash chromatography (CH2Cl2:AcOEt
AUTHOR INFORMATION
Corresponding Author
*E-mail: csaky@ucm.es.
■
1
95:5) 7g (10 mg, 77%): H NMR (CDCl3, 300 MHz) δ 1.52−1.73
(m, 2H), 1.83−2.00 (m, 2H), 2.69−2.76 (m, 1H), 3.48−3.58 (m, 2H),
3.60−3.80 (m, 3H), 6.29−6.42 (m, 2H), 7.09−7.33 (m, 5H); 13C
NMR (CDCl3, 75 MHz) δ 31.0, 32.3, 33.4, 63.4, 65.8, 73.3, 126.2
(2C), 127.4, 128.7 (2C), 130.4, 132.6, 137.6. Anal. Calc. for C14H18O2:
C, 77.03; H, 8.31. Found: C, 77.14; H, 8.42.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
General Procedure for the Preparation of Compounds 7g
and 8 Using DIBALH. To a stirred solution of the corresponding
bicycle 4 (1.0 equiv) in CH2Cl2 (30 mL/mmol) at 0 °C was added
dropwise DIBALH (1.5 M toluene, 8.0 equiv). After stirring overnight
at rt, a saturated solution of NaHCO3 was added. The layers were
separated, and the aqueous one was extracted with CHCl3. The
combined organic layers were dried over MgSO4 and concentrated in
vacuo. The crude product was chromatographed on silica gel
(CH2Cl2:AcOEt 95:5) to afford the title compounds.
(2S,4S)-4-((E)-Styryl)tetrahydro-2H-pyran-2-yl)methanol 7g. Fol-
lowing the general procedure, reaction of 4h (12 mg, 0.06 mmol) with
DIBAL (1.5 M toluene, 0.33 mL, 0.49 mmol) in CH2Cl2 (2 mL)
yielded after flash chromatography (CH2Cl2:AcOEt 95:5) 7g (8 mg,
63%). NMR data matched those previously obtained in the reaction of
4h with BF3·Et2O and Et3SiH in CH2Cl2. Anal. Calc. for C14H18O2: C,
77.03; H, 8.31. Found: C, 77.12; H, 8.25.
We are thankful for Grant CTQ-2010-16170 from the Spanish
government (MICINN). S. Roscales is thankful to the
government of Spain and for FPU Predoctoral Grant No.
AP20090051. Prof. J. Plumet (UCM) is thanked for useful
comments.
REFERENCES
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methanol 8a. Following the general procedure, reaction of 4a (18 mg,
0.06 mmol) with DIBAL (1.5 M toluene, 0.33 mL, 0.49 mmol) in
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1
95:5) 8a (12 mg, 63%): H NMR (CDCl3, 300 MHz) δ 1.41−1.56
(m, 1H), 1.71−1.82 (m, 2H), 1.93 (d, J = 13.5 Hz, 1H), 2.53−2.68
(m, 1H), 3.49 (dd, J = 10.8 Hz, J = 4.0 Hz, 1H), 4.13 (t, J = 10.8 Hz,,
1H), 4.18−4.28 (m, 1H), 4.64 (dd, J = 11.6 Hz, J = 2.0 Hz, 1H), 6.00
(dd, J = 16.0 Hz, J = 6.8 Hz, 1H), 6.34 (d, J = 16.0 Hz, 1H), 7.08−7.37
(m, 10H); 13C NMR (CDCl3, 75 MHz) δ 31.5, 34.8, 40.0, 61.1, 72.0,
73.9, 126.1 (2C), 126.2 (2C), 127.4, 127.8, 128.6 (2C), 128.7 (2C),
129.0, 134.0, 137.4, 142.7. Anal. Calc. for C20H22O2: C, 81.60; H, 7.53.
Found: C, 81.72; H, 7.41.
(2S,4S,6R)-6-Methyl-4-((E)-styryl)tetrahydro-2H-pyran-2-yl)-
methanol 8b. Following the general procedure, reaction of 4g (23 mg,
0.10 mmol) with DIBAL (1.5 M toluene, 0.53 mL, 0.80 mmol) in
12829
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Note
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This may arise from protodeborylation of an R2BF2 intermediate upon
TFA formation during workup.
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