Highly enantio- and diastereoselective synthesis of β-methyl-γ- monofluoromethyl-substituted alcohols

Article abstract of DOI:10.1002/chem.201100929

Enanatiopure β-methyl-γ-monofluoromethyl alcohols were prepared from the allylic alkylation between fluorobis(phenylsulfonyl)methane with Morita-Baylis-Hillman carbonates. The reaction was catalyzed by using the Cinchona alkaloid derivative, (DHQD)₂AQN. The origin of the stereoselectivity was verified by DFT methods. Calculated geometries and relative energies of various transition states strongly support the observed stereoselectivity.

Full text of DOI:10.1002/chem.201100929

DOI: 10.1002/chem.201100929
Highly Enantio- and Diastereoselective Synthesis of b-Methyl-g-
monofluoromethyl-Substituted Alcohols
Wenguo Yang,[a] Xinle Wei,[a] Yuanhang Pan,[b] Richmond Lee,[c] Bo Zhu,[a]
Hongjun Liu,[b] Lin Yan,[a] Kuo-Wei Huang,*[c] Zhiyong Jiang,*[a] and
Choon-Hong Tan*[a, b]
Abstract: Enanatiopure b-methyl-g-monofluoromethyl alcohols were prepared
from the allylic alkylation between fluorobis(phenylsulfonyl)methane with
Keywords: alcohols
catalysis · FBSM · Morita–Baylis–
Hillman reactions · organocatalysis
· asymmetric
Morita–Baylis–Hillman carbonates. The reaction was catalyzed by using the Cin-
chona alkaloid derivative, (DHQD)2AQN. The origin of the stereoselectivity was
verified by DFT methods. Calculated geometries and relative energies of various
transition states strongly support the observed stereoselectivity.
Introduction
ral products and drugs.[4] For instance, (+)-pinnatoxin A
(Scheme 1) was reported to be an activator of calcium chan-
nels.[4 g] Other examples include, (2R,3R)-lasiol, which was
À
The highly polarized C F bond has unique properties that
are understood by considering its stereoelectronic interac-
tions with neighboring bonds or lone pairs of electrons.[1]
Monofluorinated analogues of biologically active com-
pounds are often evaluated as bioisosteres of their parent
molecules.[2] Fluorinated compounds containing a mono-
fluoromethyl group have been utilized for important appli-
cations in biological systems.[2] Thus, there is a strong
demand to increase synthetic capabilities to construct build-
ing blocks containing a monofluoromethyl group, particular-
ly enantiopure ones.[3]
Alcohols bearing b,g-dimethyl groups are important struc-
tural features in a large number of biologically active natu-
Scheme 1. Biologically active natural products containing the b,g-dimeth-
yl moiety.
[a] W. Yang,+ X. Wei,+ B. Zhu, Dr. L. Yan, Prof. Dr. Z. Jiang,
Prof. Dr. C.-H. Tan
one of new monoterpene alcohols isolated from mandibular
glands of the male ants (Lasius meridionalis).[4 h] Also, one
of the cytotoxic sterols extracted from starfish Certonardoa
semiregularis exhibited unique biological activity.[4d] Meth-
ods to introduce a fluorine atom on the ꢀnakedꢁ methyl
group of b,g-dimethyl-substituted alcohols in a stereoselec-
tive and diastereoselective manner will be highly desirable.
The established protocol for the preparation of b,g-dimethyl
substituted alcohols utilized tandem conjugate addition/a-al-
kylation reactions employing chiral auxiliaries or chiral re-
agents.[5] Other methods include the use of bakerꢁs yeast to
mediate the reduction of the trisubstituted double bonds in
cinnamaldehydes[6] and silylated biarylprolinol-catalyzed
enantioselective Michael addition of aldehydes to vinyl sul-
fones.[7] However, these methods cannot be easily modified
for the preparation of monofluorinated derivatives.
Key Laboratory of Natural Medicine and
Immuno-Engineering of Henan Province
Henan University, Jinming Campus
Kaifeng, Henan, 475004 (P.R. China)
Fax : (+86)378-2864-665
E-mail: chmjzy@henu.edu.cn
[b] Y. Pan, Dr. H. Liu, Prof. Dr. C.-H. Tan
Department of Chemistry
National University of Singapore (NUS)
3 Science Drive 3, Singapore 117543
Fax : (+65)6779-1691
E-mail: chmtanch@nus.edu.sg
[c] R. Lee, Prof. Dr. K.-W. Huang
KAUST Catalysis Center and Divison
of Chemical and Life Sciences and Engineering
King Abdullah University of Science and Technolog
Thuwal, 23955-6900 (Kingdom of Saudi Arabia)
Fax : (+996)28081025
E-mail: hkw@kaust.edu.sa
À
[+] W. Yang and X. Wei made equal contributions to this work.
We recently reported the formation of chiral C F bonds
by using fluorocarbon nucleophiles in highly enantio- and
diasteroselective conjugate-addition and Mannich reac-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100929.
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Chem. Eur. J. 2011, 17, 8066 – 8070

FULL PAPER
Table 1. Allylic alkylation of BSM 1 with MBH carbonate 2a.[a]
tions.[8] Herein, we would like to report the first highly enan-
tio- and diastereoselective synthesis of b-methyl-g-mono-
fluoromethyl-substituted alcohols based on the allylic alkyla-
tions between bis(phenylsulfonyl)methane (BSM) or fluoro-
bis(phenylsulfonyl)methane (FBSM) with Morita-Baylis–
Hillman (MBH) carbonates.
Entry Catalyst
Solvent
t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
quinidine
hydroquinine
toluene
toluene
toluene
toluene
60
63
26
26
26
26
20
33
20
33
72
43
79
99
75
88
83
93
81
90
66
87
68
74
60
76
57
57
À65
À55
53
A
Results and Discussion
(DHQ)2AQN[d]
ACHTUNGTRENNUNG
(DHQD)2PHAL[d] toluene
Sulfone reagents, such as BSM, are sufficiently acidic to be
activated by mild bases and can give terminal ꢀnakedꢁ alkyl
groups with the removal of sulfonyl groups through reduc-
tion with Mg or Hg/Na.[9,10] FBSM, a fluorocarbon nucleo-
phile derived from BSM, was demonstrated as an efficient
precursor of the monofluoromethyl group.[10] Retrosynthetic
analysis revealed that FBSM is a viable synthon to prepare
enantiopure b-methyl-g-monofluoromethyl-substituted alco-
hols from asymmetric allylic alkylation (Scheme 2).[11]
E
toluene
toluene
DCE
PhCF3
xylene
mesitylene
toluene
mesitylene
80
R
91 (93)[e]
U
80
89
84
95
9
N
10
11
12[f]
13[f]
G
R
G
95 (97)[g]
97
AHCTUNGTRENNUNG
[a] Unless otherwise noted, reactions were performed with 0.05 mmol of
1, 0.075 mmol of 2a, and 0.005 mmol of catalyst in 0.5 mL solvent.
[b] Yield of isolated product. [c] Determined by HPLC methods.
[d] (DHQ)2PYR=hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether,
(DHQ)2AQN =hydroquinine
(DHQ)2PHAL=hydroquinine
anthraquinone-1,4-diyl
1,4-phthalazinediyl
diether,
diether,
(DHQD)2PYR=hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether,
(DHQD)2AQN =hydroquinidine (anthraquinone-1,4-diyl) diether.
[e] 5 mol% catalyst, 24 h, 99% yield. [f] Reaction was conducted at
Scheme 2. Retrosynthetic analysis of b,g-dimethyl-substituted alcohols.
308C. [g] 0.2 mmol scale, 96 h, 73% yield.
Table 2. Highly enantioselective allylic alkylation between BSM 1 and
MBH carbonates 2b–m.[a]
BSM is commercially available and its reactivity is similar
to FBSM.[10a–b] For the initial investigation, we selected BSM
as a model for FBSM. Cinchona alkaloids were investigated
as catalysts as they have been shown to be excellent chiral
Lewis bases.[12] The allylic alkylation between BSM 1 and
MBH carbonate 2a was shown to work well with quinidine
and hydroquinine, providing moderate reactivities and enan-
tioselectivies (Table 1, entries 1–3). C2-Symmetric (bis)cin-
chona alkaloid derivatives, such as (DHQD)2AQN,[11g–h,k] im-
proved the ee (ee=enantiomeric excess) values significantly
(entries 3–7). Their rigid enzyme-like pockets help to in-
crease the enantioselectivities.[12b] Catalyst loading can also
be lowered to 5 mol% (entry 7). Next, we investigated the
effects of solvent and temperature (entries 8–13). Mesitylene
was found as the most suitable solvent, giving 3a in 95% ee
at 508C after 72 h (entry 11). By lowering the reaction tem-
perature to 308C, the ee of 3a was improved to 97%
(entry 13).
By using the established conditions, allylic alkylations of
BSM 1 with various MBH carbonates (2b–m) was found to
afford the products 3b–m with excellent ee values (Table 2).
MBH carbonates (Table 2, 2b–d, f–i) with electron-with-
drawing groups appended on the aromatic rings were more
active than those (Table 2, 2j–k, m) with electron-neutral
and donating groups. However, the fluorinated 2e deviated
from this trend. The absolute configurations of the allylic al-
kylation products were assigned based on X-ray crystallo-
graphic analysis of a single crystal of 3j.[13]
Entry R1
R2
2
t [h]
3
Yield [%][b] ee [%][c]
1
2
3
4-NO2C6H5
CO2Me 2b
CO2Me 2c
CO2Me 2d
CO2Me 2e
CO2Me 2 f
CO2Me 2g
CO2Me 2h
CO2Me 2i
CO2Me 2j
48 3b
47 3c
47 3d
75 3e
44 3 f
47 3g
47 3h
59 3i
48 3j
36 3k
20 3l
99
96
80
84
80
96
83
97
97
99
71
85
94
90
92
90
92
95
96
93
94
94
92
94
3-NO2C6H5
4-CF3C6H5
4-FC6H5
2-ClC6H5
3,4-Cl2C6H5
4-BrC6H5
3-BrC6H5
4-iPrC6H5
4[d]
5
6
7
8
9[d]
10[d]
11[d]
12[d]
4-MeOC6H5 CO2Me 2k
3-thiophenyl CO2Me 2l
2-naphthyl
CO2Me 2m 75 3m
[a] Reactions were performed with 0.1 mmol of 1, 0.15 mmol of 2b–m,
and 0.01 mmol of catalyst in 1.0 mL mesitylene. [b] Yield of isolated
product. [c] Determined by HPLC methods. [d] Reaction was conducted
at 508C.
carbonate 2 in the presence of 10 mol% of (DHQD)2AQN
in mesitylene at 308C (Table 3, entry 1). The reaction was
very slow and it indicated that the reactivity of FBSM 4 was
lower than BSM 1 in this reaction. When the temperature
was increased to 508C, the desired product 5a was obtained
with 52% yield and 91% ee (entry 2). Subsequently, mesity-
lene-like solvents were screened under the same reaction
conditions (entries 2–7). The best solvent was found to be
With the excellent results in hand, we conducted the
asymmetric allylic alkylation between FBSM 4 and MBH
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C.-H. Tan, K.-W. Huang, Z. Jiang et al.
Table 3. Allylic alkylation of FBSM 4 with MBH carbonate 2a.[a]
Table 4. Highly enantioselective allylic alkylation between FBSM 4 and
MBH carbonates 2.[a]
Entry
1[d]
2
3
4
Solvent
Yield [%][b]
n.d.[e]
52
64
43
67
68
58
72
ee [%][c]
n.d.[e]
91
89
91
90
90
91
>99.9
Entry
1[d]
2
R1
2
t [h]
5
Yield [%][b]
ee [%][c]
mesitylene
mesitylene
PhCF3
4-NO2C6H5
4-CF3C6H5
4-FC6H5
2-FC6H5
2-ClC6H5
3,4-Cl2C6H5
4-BrC6H5
4-MeC6H5
4-iPrC6H5
4-MeOC6H5
3-thiophenyl
2b
2d
2e
2n
2 f
2g
2h
2o
2j
24
94
72
46
48
48
42
71
48
94
48
5b
5c
5d
5e
5 f
5g
5h
5i
67
60
71
69
72
65
70
59
58
68
60
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
>99.9
3
4
xylene
5
6
o-xylene
p-xylene
toluene
5[e]
6[f]
7
7
8[f]
toluene
8
9
[a] Unless otherwise noted, reactions were performed with 0.05 mmol of
4, 0.075 mmol of MBH 2a, and 0.005 mmol of catalyst in 0.5 mL solvent.
The reactions were stopped after 13 h. [b] Yield of isolated product.
[c] Determined by HPLC methods. [d] 308C. [e] n.d.=not determined.
[f] 0.5 mmol scale, reaction was stopped after 72 h. Filtration yield. The
reaction was repeated three times.
5j
5k
5l
10[g]
11
2k
2l
[a] Unless otherwise noted, reactions were performed with 0.1 mmol of 4,
0.15 mmol of 2, and 0.01 mmol of catalyst in 1.0 mL toluene. The reac-
tions were repeated more than twice. [b] Filtration yield. [c] Determined
by HPLC methods. [d] FC yield=81%, ee=86%. [e] FC yield=85%,
ee=90%. [f] FC yield=83%, ee=90%. [g] Flash chromatography
yield=85%, ee=95%.
toluene as the reaction was faster in this solvent (entry 7).
Recently, a filtration approach was used by List et al. to ach-
ieve enantiopure products in a convenient manner.[14] The
product 5a precipitated progressively from the initial homo-
genous reaction mixture of starting materials consisting of
FBSM 4, MBH carbonate 2, and (DHQD)2AQN (Figure 1).
Scheme 3. Synthesis of the b-methyl-g-monofluoromethyl alcohols.
To shed light on the origin of the enantioselectivity of the
alkylation reaction of FBSM 1/BSM 4 with MBH carbonates
catalyzed by (DHQD)2AQN, computational modeling was
conducted by using DFT at the B3LYP level of theory[17] to
investigate the transition states for the generation of R and
S enantiomers through the nucleophilic attack from the si
(CS1) or re-face (CS2) rotamers of the catalyst–MBH sub-
strate adduct, respectively, by the BSM nucleophile in either
cis or trans forms (Figure 2).[18] Preliminary results indicate
that the transition state for the generation of the R product
is lower than those for the S product by 11.4 to 13.8 kcal
molÀ1, owing to the increased steric interaction in the re-
face approach in which both MBH substrate and nucleo-
phile are buried internally within the anthraquinone back-
bone. The observation that the cis-BSM attack to afford the
R enantiomer is preferred may be attributed to the stabiliza-
tion effect of the p–p orbital interaction between the two
phenyl rings on the nucleophile.[18] Since the calculated spe-
cies are charge-separated zwitterions, solvent effects on the
structures by using toluene were also evaluated by single-
point calculations on the optimized gas-phase structures by
employing a polarizable continuum model with the default
integral equation formalism variant (IEFPCM).[19] It was
found that the computed energy of the transition state lead-
ing to the R enantiomer was more stable than those leading
Figure 1. Allylic alkylation of MBH carbonate 2a and FBSM 4 in the
presence of 10 mol% (DHQD)2AQN in toluene. Left: picture of homo-
genous reaction mixture after mixing all components. Right: picture of
reaction mixture after completion of the reaction (72 h).
After a simple filtration, the product 5a was rinsed with
cold toluene/petroleum ether (60–908C) 1:10 and 5a was ob-
tained with >99.9% ee (entry 11).[15] Different MBH carbo-
nates were investigated under the optimal reaction condi-
tions and enantiopure products 5b–l were obtained with ex-
cellent ee values by using the filtration protocol (Table 4).
We then proceeded to synthesize the b-methyl-g-mono-
fluoromethyl alcohols from the monofluorinated allylic alky-
lation adducts (Scheme 3). After attempting several reduc-
tive protocols, hydrogen gas on Pd/C in ethyl acetate at
room temperature was found as the most effective method;
only one diastereoisomer 6a was obtained with 99%
yield.[15] The structure of 6a was confirmed by using X-ray
crystallographic analysis.[16] Diastereoisomer 6a was subject-
ed to LiBH4 reduction and desulfonation with magnesium/
iodine in THF. Enantiopure monofluoromethylated 7a was
obtained (>99.9% ee and >99:1 d.r. (d.r.=diastereomeric
ratio)) in good overall yield.
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Synthesis of b-Methyl-g-monofluoromethyl-Substituted Alcohols
FULL PAPER
0.1 equiv) were dissolved in toluene (5.0 mL). The reaction mixture was
stirred at 508C and monitored by using TLC analysis. After 72 h, the re-
action was completed and cooled down to 08C. Then the precipitate was
filtered through a Buchner funnel and washed with a cooled solvent (tol-
uene/petroleum ether (60–908C) 1:10, 08C). Finally, 5a (176.1 mg, 72%
yield) was obtained as a white solid after drying.
Acknowledgements
We are grateful for the financial support from NSFC (21072044) to Z.J.,
Henan Province International Cooperation Foundation (104300510062)
to Z.J. and C.-H.T., and KAUST (4000000076) to K.-W.H.
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Conclusion
We have successfully developed practical and highly enan-
tioselective allylic alkylations to construct enantiopure b-
methyl-g-monofluoromethyl-substituted alcohols. The origin
of stereoselectivity was elucidated by DFT calculations. Fur-
ther work is ongoing to illustrate a more coherent picture of
the reaction mechanism and to extend the scope of applica-
tions.
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Experimental Section
Representative procedure for the synthesis of 5a: FBSM 4 (157.2 mg,
0.5 mmol, 1.0 equiv), MBH carbonate 2a (219.2 mg, 0.75 mmol,
1.5 equiv), and (DHQD)2AQN (95% purity) (45.1 mg, 0.05 mmol,
À
3631; for selected examples to the synthesis of chiral C F bonds
Chem. Eur. J. 2011, 17, 8066 – 8070
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C.-H. Tan, K.-W. Huang, Z. Jiang et al.
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Received: March 26, 2011
Published online: June 7, 2011
8070
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8066 – 8070