Recyclable Organocatalysts for a One-Pot Asymmetric Synthesis of 2-Fluorocyclohexanols Bearing Six Contiguous Stereocenters

Article abstract of DOI:10.1002/adsc.201700129

A recyclable fluorous bifunctional Cinchona alkaloid/thiourea-catalyzed quadruple fluorination/Michael/Michael/aldol sequence has been developed for the one-pot synthesis of cyclohexanols bearing six contiguous stereocenters including a fluorinated tertiary carbon. By using readily available starting materials including β-keto esters, β-nitrostyrenes, and α,β-unsaturated aldehydes, fully functionalized cyclohexanols were synthesized in 52–80% yields with up to 99% ee and >20:1 dr. The fluorous catalyst could be easily recovered by fluorous solid-phase extraction in 94–97% yield and >98% purity. In addition to the high synthetic efficiency achieved through the pot economic reactions, other green techniques such as transition metal-free catalysis and catalyst recovery are also employed. (Figure presented.).

Full text of DOI:10.1002/adsc.201700129

Title: Recyclable Organocatalysts for a One-Pot Asymmetric Synthesis
of 2-Fluorocyclohexanols Bearing Six Contiguous Stereocenters
Authors: Xin Huang, Miao Liu, Jerry P. Jasinski, and Bo Peng
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700129
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10.1002/adsc.201700129
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201xxx
Recyclable Organocatalysts for a One-Pot Asymmetric Synthesis of
2-Fluorocyclohexanols Bearing Six Contiguous Stereocenters
Xin Huang,a,* Miao Liu,b Jerry P. Jasinski,c Bo Penga and Wei Zhangb,*
a
College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China; e-mail: xin.huang@zjnu.cn
Department of Chemistry, University of Massachusetts, 100 Morrissey Boulevard, Boston, MA 02125, USA; e-mail:
b
wei2.zhang@umb.edu
c
Department of Chemistry, Keene State College, 229 Main Street, Keene, NH 03435, USA
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201
Abstract.
A
recyclable
fluorous
bifunctional
cinchona
alkaloid/thiourea-catalyzed
quadruple
fluorination/Michael/Michael/aldol sequence has been developed for the one-pot synthesis of cyclohexanols bearing six
contiguous stereocenters including a fluorinated tertiary carbon. By using readily available starting materials including -
keto esters, β-nitrostyrenes, and α,β-unsaturated aldehydes, fully functionalized cyclohexanols were synthesized in 52-
80% yields with up to 99% ee and >20:1 dr. The fluorous catalyst could be easily recovered by fluorous solid-phase
extraction in 94-97% yield and >98% purity. In addition to the high synthetic efficiency achieved through the pot economic
reactions, other green techniques such as transition metal-free catalysis and catalyst recovery are also employed.
Keywords: asymmetric organocatalysis; one-pot synthesis; fluorous; recyclable catalyst; 2-fluorocyclohexanols
cyclohexanes bearing multiple stereogenic centers.[11]
Despite significant progresses have been made on this
Introduction
topic, the synthesis of fluorinated cyclohexanols still
It has become a common practice in medicinal
chemistry to incorporate fluorine atom(s) to modify
the biological activity, bioavailability and metabolic
remains less explored.[12,13] As part of our ongoing
effort to develop recyclable organocatalysts[14-16] and
properties of the target molecules.[1] The special effect
of organofluorine compounds has made fluorination,
especially asymmetric fluorination, an active research
topic in the development of new medicinal and
agricultural chemicals.[2] Shown in Figure 1 are
diterpenoid alkaloids[3] and bioactive compounds such
as antimalarial candidate A,[4] hypogonadism drug B,[5]
cytotoxic agent COTC intermediate C[6] and
aminopeptidase inhibitor D.[7] They all have an
asymmetric 2-fluorocyclohexanol moiety.
Figure 1. Biologically active 2-fluorocyclohexanols
Besides asymmetric Diels–Alder reactions,[8]
Michael addition-based organocatalytic reaction
sequences are also an important approach for making
enantiomerically enriched and highly functionalized
cyclohexanes and cyclohexenes.[9,10] The Enders and
other groups have reported Michael/Michael/aldol and
Scheme 1. Michael addition-initiated one-pot reactions
related sequences for the asymmetric synthesis of
1
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10.1002/adsc.201700129
Advanced Synthesis & Catalysis
new methods for the synthesis of organofluorine
compounds,[17] We recently introduced fluorous
bifunctional cinchona alkaloid–thiourea catalysts cat-
1 and cat-2, which have different configurations at C9.
They have been used for one-pot fluorination/Michael
addition reactions for compounds 1 bearing two
stereocenters[15] and also for one-pot Michael/aza
Henry/lactamization reactions for lactams 2 bearing
four stereocenters (Scheme 1, a & b).[16a,b] Introduced
Table 1: One-pot Michael/aldol reactions[a]
catalyst
Pyrrolidine Yield[b] dr[c]
(equiv.)
ee
Entry
(%)[d]
1
2
3
4
0.25
0.5
1.0
1.0
45
69
82
76
>20:1
>20:1
>20:1
>20:1
99
99
99
99
cat-1
cat-1
cat-1
-
in this paper is
a
one-pot and quadruple
fluorination/Michael/Michael/aldol reaction sequence
for fluorocyclohexanols 3 bearing six contiguous
stereocenters (Scheme 1, c). Green chemistry
techniques such as toxic transition metal-free catalysis,
pot economic synthesis, and catalyst recovery are
successfully implemented.
[a] 0.2 mmol of 4a and 0.4 mmol of 7a in 0.4 mL of PhMe
[b] Isolated yield of 3a
[c] Determined by 1H NMR of the crude reaction mixture
[d] Determined by HPLC with a chiral OD-H column
Results and Discussion
Following our previous work,[15] asymmetric
Michael reaction of fluorinated -keto ester 5a and 6a
was carried out using cat-1 as a catalyst to afford 4a
and 4a’ as a 6:1 diastereomeric mixture with 99% and
96% ee, respectively (Scheme 2). The major
diastereomer 4a with 99% ee was isolated and used for
the Michael and sequential aldol reactions for
fluorocyclohexanol 3a, which are the last two steps of
the quadruple reaction sequence. The reaction
condition reported by the Enders group was modified
for a reaction shown in Table 1.[11] The reaction of 4a
bearing (2S,3S)-stereocenters with 7a was carried out
using cat-1 as a catalyst and pyrrolidine as a base. It
was found that the amount of pyrrolidine has a
significant influence on yield of the product (entries 1-
3). A reaction using 20 mol% of cat-1 and 1.0 equiv.
of pyrrolidine at room temperature for 12 h gave 3a in
82% yield and high stereoselectivity (99% ee, >20:1
dr) (Table 1, entry 3). A reaction without using a
chiral catalyst also produced 3a in 76% yield and
excellent stereoselectivity (entry 4), which indicated
that the stereochemical outcomes of the Michael and
aldol reactions shown in Table 1 are controlled by
substrate 4a instead of cat-1.
Scheme 3. Control reactions of ent-4a, 4a and 4a’
substrate 4a controlled the stereochemistry of the
Michael and the aldol reactions via iminium-enamine
activation of the complex generated from 4a and
secondary amine pyrrolidine.[18] The minor
diastereomer 4a’ bearing (2R,3S)-stereocenters was
also used for the Michael and the aldol reactions. LC-
MS analysis of the reaction mixture indicated that the
molecular weight of the product is 18-units smaller
than that of 3a. Therefore, we expect that 9a’ is a
dehydrated compound (Scheme 3, c).
With the understanding of the stereochemistry of the
Michael/aldol reactions of compounds 4, our effort
was then shifted to the development of a one-pot
synthesis starting from 1,3-dicarbonyl compounds 10.
The fluorination reaction of
a 1,3-dicarbonyl
compound 10 with SelectfluorTM was conducted under
o
microwave heating at 120 C for 20 min without a
Scheme 2. Asymmetric synthesis of 4a and 4a’
catalyst to form 5. β-Nitrostyrene 6 and cat-1 were
added to the reaction mixture at room temperature for
the asymmetric Michael addition. After the Michael
adduct 4 was generated by reacting at 25 oC for 24 h,
2 equiv. of α,β-unsaturated aldehyde 7 and 1 equiv. of
pyrrolidine were added and the reaction mixture was
stirred for additional 12 h for the second Michael and
A control reaction using ent-4a as a starting material
and cat-2 as a catalyst gave expected product ent-3a
in 80% yield with ee 99% and 20:1 dr (Scheme 3, a).
Another control reaction of 4a using cat-2 as a catalyst
gave 3a in 80% yield with 99% ee and 20:1 dr
(Scheme 3, b). It further confirms that the chiral
2
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10.1002/adsc.201700129
Advanced Synthesis & Catalysis
sequential aldol reactions. Under the optimized one-
pot reaction conditions, a series of 1,3-dicarbonyl
compounds 10 and β-nitrostyrenes 6 were employed
for the quadruple sequential reactions to explore the
scope for the synthesis of fully substituted
fluorocyclohexanols 3 (Table 2). The reactions of
cinnamaldehyde (Ar = Ph) gave products 3a-k in 52-
78% yields with excellent ee (89-99%) and dr (>20:1)
(entries 1-11). The variation of the R group (MeO, EtO
and tBuO, and Me) only had a small influence on the
product yields of 3a-d (entries 1-3). The electron-
donating or -withdrawing groups on the phenyl group
of nitroalkenes 6 also have some influence on the
yields, but not on the ee and dr of products 3e-j (entries
yield and a good stereoselectivity (entries 11).
Besides nitroalkenes, such as 6a, other active olefins
were also explored for the first Michael additions
(Table 3). Interestingly, β-methyl-β-nitrostyrene 6b
didn’t give product unless co-catalyst L-alanine was
added to generate 3l in 12% yield with 93% ee and
12:1 dr (entry 2). The low yield may be caused by the
reduced reactivity of 6b which is a disubstituted
nitroolefin.[19] Some β-disubstituted styrenes were also
investigated. Due to unfavorable electronic and steric
effects, both 6c and 6d only gave corresponding
intermediates 4m and 4n in 95% and 90% yields, but
fluorocyclohexanols 3m and 3n were not observed.
The reaction of 6e gave good yields for both 4o and 3o,
5-10). A reaction with furyl as the Ar resulted 3k in 58% but the ee of 3o is only 27%.
Table 2: Scope of the one-pot fluorination and asymmetric Michael/Michael/aldol reactions[a,b]
Entry
R
Ar
Product
Yield (%)[c]
dr[d]
ee (%)[e]
1
2
3
4
5
6
7
8
MeO
EtO
tBuO
Me
MeO
MeO
MeO
MeO
MeO
MeO
MeO
Ph
Ph
Ph
Ph
78
65
67
80
63
66
52
52
57
55
58
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
99
93
89
99
99
96
96
99
99
93
93
3a
3b
3c
3d
3e
3f
3g
3h
3i
2-BrC6H4
3-ClC6H4
4-MeC6H4
4-BrC6H4
4-CF3C6H4
4-OMeC6H4
2-furyl
9
10
11
3j
3k
[a]
[b]
[c]
Reaction of 0.25 mmol of 10 and 0.25 mmol of SelectfluorTM in 0.5 mL of CH3CN
Add 0.5 mL of PhMe, 1:1:2:1 of 10:6:7:pyrrolidine
Isolated yield of major diastereomer 3
[d] Determined by 1H NMR analysis of the crude sample. The amount of the dehydrated products 9 generated from
the minor diastereomer 4’ were not determined
[e]
Determined by HPLC with a chiral OD-H column
Table 3: One-pot reactions with different olefins 6[a,b]
Entry
R1
R2
Yield (%)[c]
Yield (%)[d]
dr[e]
ee (%)[f]
6
4
3
1
NO2
NO2
NO2
SO2Ph
CO2Et
H
Me
CO2Et
CN
CN
92
30
95
90
82
78
12
nr
nr
79
>20:1
12:1
nd
nd
>20:1
99
93
nd
nd
27
6a
6b
6c
6d
6e
4a
4l
4m
4n
4o
3a
3l
3m
3n
3o
2[g]
3
4
5
Reaction of 0.25 mmol of 9a and 0.25 mmol of SelectfluorTM in 0.5 mL of CH3CN
Add 0.5 mL of PhMe, 1:1:2:1 of 10a:6:7a:pyrrolidine
GC-MS yield of 4
[a]
[b]
[c]
[d] Isolated yield of 3
Determined by 1H NMR analysis of the crude reaction mixture
[e]
[f]
Determined by HPLC with a chiral OD-H column
[g] Added 20 mol% L-alanine as a co-catalyst, 40 oC
3
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10.1002/adsc.201700129
Advanced Synthesis & Catalysis
Proposed in Scheme 4 is the stereoselective
transformations in the synthesis of
in Scheme 3, the catalyst only controls the formation
of the first two stereocenters of the first Michael
addition. Highly enantiomerically pure fluorinated
Michael adducts 4 induce the formation of the
remaining four stereocenters from the second Michael
and the aldol reactions.
The recovery of fluorous catalyst was performed by
loading the concentrated reaction mixture onto a
fluorous silica gel cartridge for fluorous solid-phase
extraction (F-SPE).[21] The cartridge was first eluted
with 80:20 MeOH/H2O to collect the product and other
nonfluorous components. The fluorous catalyst
remained on the cartridge was eluted with MeOH. The
concentration of the MeOH fraction gave recovered
cat-1 in 94-97% yields and >98% purity. It could be
fluorocyclohexanols 3 from the major diastereomer 4
and for the dehydrated product 9’ from the minor
diastereomer 4’ through the Michael/Michael/aldol
reaction process. The reaction with cat-1 bearing an
(S)-C9 stereocenter induces the first Michael addition
to form a mixture of major diastereomer 4 with
(2S,3S)-stereocenters and minor diastereomer 4’ with
(2R,3S)-stereocenters. The second Michael additions
of 4 and 4’ with 7 afford 8 and 8’, respectively. They
undergo aldol reactions to form corresponding 3 and
3’. Fluorocyclohexanol 3 could be isolated due to the
stabilization through intramolecular H-bonding
between the hydroxyl group and the ester alkoxy group
as revealed by the X-ray structure of 3h (Figure 2).[11,12] reused without further purification.
However, 3’ derivatized from the minor diastereomer
4’ is ended as dehydrated fluorocyclohexene 9’
because there is no effective intramolecular H-bonding
Conclusions
in 3’. As indicated by the control reactions presented
We have developed an organocatalytic quadruple
fluorination/Michael/Michael/aldol reaction sequence
for one-pot synthesis of fully functionalized
cyclohexanols bearing six contiguous stereocenters
including a fluorinated tertiary carbon. The results
obtained from the control reactions indicated that the
bifunctional cinchona alkaloid–thiourea catalyst
controls the formation of the first two stereocenters
during the first Michael addition. The formations of
remaining four stereocenters are controlled by the
enantioenriched substrates instead of the catalyst. The
one-pot reactions promoted by the recyclable
organocatalyst cat-1 gave products in 52-80%
yields, >20:1 dr and up to 99% ee. However, reactions
with sterically hindered Michael acceptors
significantly reduced the product yield and the
stereoselectivity.
In addition to high synthetic
efficiency achieved through pot economic reactions,
other green techniques such as transition metal-free
catalysis and catalyst recovery have also been
employed in the development of this new synthetic
method.
Scheme 4. Stereochemistry of the one-pot reactions
Experimental Section
Typical procedures for the asymmetric synthesis of
2-fluorinated cyclohexanols 3 and the catalyst
recovery
To a solution of a β-keto ester 10 (0.25 mmol) in
CH3CN (0.5 mL) was added SelectfluorTM (0.25
o
mmol). After being stirred and heated at 120 C in
microwave reaction station for 20 min, the reaction
mixture was allowed to cool to room temperature and
a nitroolefin 6 (0.25 mmol) and 20 mol% of catalyst
Figure 2. X-ray crystal structure of 3h[20]
4
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10.1002/adsc.201700129
Advanced Synthesis & Catalysis
cat-1 in PhMe (0.5 mL) were added. After the reaction
mixture was stirred for 24 h, α,β-unsaturated aldehyde
7 (0.5 mmol) and pyrrolidine (0.25 mmol) were added
and the reaction mixture was stirred for another 12 h.
Upon the completion of the reaction, the reaction
mixture was concentrated and loaded on to a 10 g
fluorous silica gel cartridge with a minimal amount
(<0.5 mL) of MeOH. The cartridge was first eluted
with 10 mL 80:20 MeOH/H2O for the nonfluorous
components including product 3. The fluorous catalyst
remaining on the cartridge was eluted out with 10 mL
of MeOH. The MeOH fraction from the F-SPE was
concentrated under a reduced pressure to afford cat-1
in 94-97% yield (41-43 mg) and >98% purity as
analyzed by LC-MS. It could be reused directly
without further purification. The MeOH/H2O fraction
from the F-SPE was concentrated and then purified by
a prep-HPLC system with a C18 column. The
enantiomeric excess (ee) was determined by HPLC
with a Venusil Chiral OD-H column.
Methyl 1-fluoro-3-formyl-2-hydroxy-2-methyl-5-
nitro-4,6-diphenylcyclohexane-1-carboxylate (3a):
White solid (80 mg, 78% yield), >20:1 dr, 93% ee. 1H
NMR (300 MHz, CDCl3): δ = 9.52 (d, J = 5 Hz, 1H),
7.31-7.16 (m, 10H), 5.16 (t, J = 5 Hz, 1H), 4.37 (dd, J
= 5, 12 Hz, 1H), 4.25 (d, 5 Hz, 1H) ,4.10 (m, 1H), 50
(s, 3H), 1.45 (d, 3H); 13C NMR (75 MHz, CDCl3): δ =
23.1, 40.6, 46.2, 46.5, 50.9, 53.1, 90.9, 128.4, 128.9,
129.0, 129.1, 129.2, 129.3, 202.6; 19F NMR (284 MHz,
CDCl3): δ = 171.6 ppm. MS (ACPI) m/z: 416.1 (M+1);
HRMS (ESI-TOF, m/z): calcd. for C22H22FNO6:
416.1509 [M+H]+, Found: 416.1493.
(m, 1H), 4.34 (dd, J = 5, 12 Hz, 1H), 4.22 (d, J = 6 Hz,
1H), 4.00-4.10 (m, 3H), 3.97 (s, 1H), 1.45 (d, 3H),
1.15(d, J = 6 Hz, 3H), 0.67 (d, J = 5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): δ = 20.6, 21.4, 23.0, 40.6, 46.3,
46.6, 51.1, 71.1, 73.6, 74.0, 90.9, 128.3, 128.7, 128.9,
129.0, 129.1, 129.5, 129.6, 134.8, 202.6. MS (ACPI)
m/z: 444.1 (M+1); HRMS (ESI-TOF, m/z): calcd. for
C24H26FNO6: 444.1822 [M+H]+, Found: 444.1818.
3-Acetyl-3-fluoro-2-hydroxy-2-methyl-5-nitro-
4,6-diphenylcyclohexane-1-carbaldehyde
(3d):
White solid (88 mg, 80% yield), >20:1 dr, 99% ee. 1H
NMR (300 MHz, CDCl3): δ = 9.52 (d, J = 5 Hz, 1H),
7.31-7.16 (m, 10H), 5.16 (t, J = 5 Hz, 1H), 4.37(dd, J
= 5, 12 Hz, 1H), 4.22 (d, J =5 Hz, 1H) ,4.10 (m, 1H),
13
3.93 (s, 1H), 1.95 (d, J = 5 Hz, 3H) 1.42 (d, 3H); C
NMR (75 MHz, CDCl3): δ = 23.0, 29.5, 40.4, 46.3,
46.5, 51.4, 91.2, 128.4, 128.9, 129.1, 129.2, 129.3,
129.5, 129.6, 134.4, 202.5. MS (ACPI) m/z: 400.1
(M+1); HRMS (ESI-TOF, m/z): calcd. for
C22H22FNO5: 400.1560 [M+H]+, Found: 400.1557.
Methyl 6-(2-bromophenyl)-1-fluoro-3-formyl-2-
hydroxy-2-methyl-5-nitro-4-phenylcyclohexane-1-
carboxylate (3e): White solid (78 mg 63%
yield), >20:1 dr, 99% ee. 1H NMR (300 MHz, CDCl3):
δ = 9.52 (d, J = 5 Hz, 1H), 7.31-7.16 (m, 9H), 5.13 (t,
J = 5 Hz, 1H), 4.37(dd, J = 5, 12 Hz, 1H), 4.25 (d, J =
5 Hz, 1H), 4.10 (m, 1H), 3.59 (s, 3H), 1.45 (d, 3H); 13C
NMR (75 MHz, CDCl3): δ = 22.9, 45.8, 40.6, 46.2,
50.9, 53.3, 90.6, 128.5, 128.9, 129.1, 130.5, 132.2,
132.4, 134.5, 202.4. MS (ACPI) m/z: 493.9 (M+1);
HRMS (ESI-TOF, m/z): calcd. for C22H21BrFNO6:
494.0614 [M+H]+, Found: 494.0601.
Ethyl 1-fluoro-3-formyl-2-hydroxy-2-methyl-5-
nitro-4,6-diphenylcyclohexane-1-carboxylate (3b):
White solid (70 mg, 65% yield), >20:1 dr, 99% ee. 1H
NMR (300 MHz, CDCl3): δ = 9.52 (d, J = 5 Hz, 1H),
7.31-7.16 (m, 10H), 5.16 (t, J = 5 Hz, 1H), 4.34 (dd, J
= 5, 12 Hz, 1H), 4.24 (d, J = 6 Hz, 1H), 3.95-4.10 (m,
3H), 1.45 (d, 3H), 0.85 (t, J = 5 Hz, 3H); 13C NMR (75
MHz, CDCl3): δ = 13.4, 23.1, 40.6, 46.3, 46.5, 51.0,
62.7, 90.9, 128.4, 128.8, 128.9, 129.0, 129.3, 129.4,
134.7, 202.6. MS (ACPI) m/z: 430.1 (M+1); HRMS
(ESI-TOF, m/z): calcd. for C23H24FNO6: 430.1666
[M+H]+, Found: 430.1668.
Isopropyl 1-fluoro-3-formyl-2-hydroxy-2-methyl-
5-nitro-4,6-diphenylcyclohexane-1-carboxylate
(3c): White solid (74 mg, 67% yield ), >20:1 dr, 89%
ee. 1H NMR (300 MHz, CDCl3): δ = 9.52 (d, J = 5 Hz,
1H), 7.33-7.16 (m, 10H), 5.16 (t, J = 5 Hz, 1H),4.86
Methyl 6-(3-chlorophenyl)-1-fluoro-3-formyl-2-
hydroxy-2-methyl-5-nitro-4-phenylcyclohexane-1-
carboxylate (3f): White solid (74 mg, 66%
yield), >20:1 dr, 99% ee. 1H NMR (300 MHz, CDCl3):
δ = 9.52 (d, J = 5 Hz, 1H), 7.31-7.16 (m, 9H), 5.14 (t,
J = 5 Hz, 1H), 4.36 (dd, J = 5, 12 Hz, 1H), 4.25 (d, J =
5 Hz, 1H), 4.10 (m, 1H), 3.59 (s, 3H), 1.45 (d, 3H); 13C
NMR (75 MHz, CDCl3): δ = 22.9, 40.5, 45.8, 46.1,
50.8, 53.3, 90.6, 127.1, 127.2, 128.5, 128.9, 129.1,
129.2, 129.4, 129.5, 130.2, 134.5, 202.5. MS (ACPI)
m/z: 450.1 (M+1); HRMS (ESI-TOF, m/z): calcd. for
C22H21ClFNO6: 450.1119 [M+H]+, Found: 450.1118.
Methyl 1-fluoro-3-formyl-2-hydroxy-2-methyl-5-
nitro-4-phenyl-6-(p-tolyl)cyclohexane-1-
carboxylate (3g): White solid (56 mg, 52% yield), >
20:1 dr, 99% ee. 1H NMR (300 MHz, CDCl3): δ = 9.52
(d, J = 5 Hz, 1H), 7.31-7.16 (m, 9H), 5.14 (t, J = 5 Hz,
5
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10.1002/adsc.201700129
Advanced Synthesis & Catalysis
1H), 4.36 (dd, J = 5, 12 Hz, 1H), 4.25 (d, J = 5 Hz, 1H),
4.10 (m, 1H), 3.59 (s, 3H), 2.30 (s, 1H), 1.45 (d, 3H);
13C NMR (75 MHz, CDCl3): δ = 21.1, 23.0, 40.6, 45.8,
46.1, 50.9, 53.1, 91.1, 128.3, 128.9, 129.0, 129.1,
129.6, 129.7, 129.8, 134.7, 138.7, 202.7. MS (ACPI)
m/z: 430.1 (M+1); HRMS (ESI-TOF, m/z): calcd. for
C23H24FNO6: 430.1666 [M+H]+, Found: 430.1669.
Methyl 6-(4-bromophenyl)-1-fluoro-3-formyl-2-
hydroxy-2-methyl-5-nitro-4-phenylcyclohexane-1-
carboxylate (3h): White solid (64 mg, 52% yield), >
20:1 dr, 99% ee. 1H NMR (300 MHz, CDCl3): δ = 9.52
(d, J = 5 Hz, 1H), 7.31-7.16 (m, 9H), 5.13 (t, J = 5 Hz,
1H), 4.37 (dd, J = 5, 12 Hz, 1H), 4.25 (d, J = 5 Hz,
1H) ,4.10 (m, 1H), 3.59 (s, 3H), 1.45 (d, 3H); 13C NMR
carboxylate (3k): White solid (59 mg, 58% yield), >
20:1 dr, 93% ee. 1H NMR (300 MHz, CDCl3): δ = 9.52
(d, J = 5 Hz, 1H), 7.24-7.16 (m, 6H), 6.21-6.14 (m,
2H), 5.07 (t, J = 5 Hz, 1H), 4.37 (dd, J = 6, 36 Hz, 1H),
4.17 (dd, J = 6, 12 Hz, 1H), 3.92 (m, 1H), 3.60 (s, 3H),
13
1.30 (d, 3H); C NMR (75 MHz, CDCl3): δ = 22.9,
40.6, 40.8, 41.1, 50.7, 53.5, 88.7, 110.1, 110.2, 110.8,
128.4, 129.0, 129.1, 134.6, 142.9, 202.6; 19F NMR
(284 MHz, CDCl3): δ = -173.6. MS (ACPI) m/z: 406.1
(M+1); HRMS (ESI-TOF, m/z): calcd. for
C20H20FNO7: 406.1302 [M+H]+, Found: 406.1315.
Methyl1-fluoro-3-formyl-2-hydroxy-2,5-
dimethyl-5-nitro-4,6-diphenylcyclohexane-1-
carboxylate (3l): colorless oil (31 mg, 29% yield), 4:1
(75 MHz, CDCl3): δ = 22.9, 40.6, 45.8, 46.2, 50.9, 53.3, dr, 97% ee. 1H NMR (300 MHz, CDCl3): δ = 9.33 (d,
90.6, 128.5, 128.9, 129.1, 130.5, 132.2, 132.4, 134.5,
202.4. MS (ACPI) m/z: 494.1 (M+1); HRMS (ESI-
TOF, m/z): calcd. for C22H21BrFNO6: 494.0614
[M+H]+, Found: 494.0611.
Methyl 1-fluoro-3-formyl-2-hydroxy-2-methyl-5-
nitro-4-phenyl-6-(4-(trifluoromethyl)phe
J = 5 Hz, 1H), 7.23-7.18 (m, 10H), 4.12 (d, J = 5 Hz,
1H), 3.94 (s, 1H) 3.82 (s, 1H) ,3.34 (s, 3H),1.99 (s, 3H),
1.45 (d, 3H); 13C NMR (75 MHz, CDCl3): δ = 23.2,
25.0, 47.2, 52.0, 52.3, 53.0, 53.9, 90.4, 118.7, 128.7,
129.0, 133.6, 202.8; 19F NMR (284 MHz, CDCl3): δ =
-172. MS (ACPI) m/z: 430.1 (M+1); HRMS (ESI-TOF,
m/z): calcd. for C23H24FNO6: 430.1666 [M+H]+,
nyl)cyclohexane-1-carboxylate (3i): White solid, (69
mg, 57% yield), >20:1 dr, 99% ee. 1H NMR (300 MHz, Found: 430.1678.
CDCl3): δ = 9.52 (d, J = 5 Hz, 1H), 7.49 (d, J = 8 Hz,
2H), 7.36 (d, J = 8 Hz, 2H), 7.26-7.16 (m, 5H), 5.07 (t,
J = 5 Hz, 1H), 4.37(dd, J = 5, 12 Hz, 1H), 4.25 (m,
1H) ,4.05 (m, 1H), 3.47 (s, 3H), 1.38 (d, 3H); 13C NMR
Ethyl 3-methyl 1-cyano-3-fluoro-5-formyl-4-
hydroxy-4-methyl-2,6-diphenylcyclohexane-1,3-
dicarboxylate (3o): White solid (95 mg, 82%
yield), >20:1 dr, 27% ee. 1H NMR (300 MHz, CDCl3):
(75 MHz, CDCl3): δ = 22.9, 40.6, 45.8, 46.2, 50.9, 53.3, δ = 9.52 (d, J = 5 Hz, 1H), 7.38-7.26 (m, 10H), 4.56 (d,
90.6, 125.8, 125.9, 128.6, 128.9, 129.1, 129.6, 129.7,
134.4, 202.4; 19F NMR (284 MHz, CDCl3): δ = -63.5,
-171.6. MS (ACPI) m/z: 484.1 (M+1); HRMS (ESI-
J = 13 Hz, 1H), 4.47(s, 1H), 4.35 (s, 1H) ,3.74 (m, 2H),
3.48 (s, 3H), 1.39 (d, 3H) 0.70 (t, J = 6 Hz, 3H); C
NMR (75 MHz, CDCl3): δ = 13.3, 22.9, 44.6, 46.0,
13
TOF, m/z): calcd. for C23H21F4NO6: 484.1383 [M+H]+, 49.0, 49.2, 53.0, 54.3, 55.8, 62.9, 73.3, 73.6, 116.2,
Found: 484.1383.
Methyl
methoxyphenyl)-2-methyl-5-nitro-4-phenylcycl
ohexane-1-carboxylate (3j): White solid (61 mg, 55% 468.1822 [M+H]+, Found: 468.1827.
yield), 20:1 dr, 93% ee. 1H NMR (300 MHz, CDCl3):
128.6, 128.7, 128.9, 129.0, 129.1, 129.7, 130.4, 132.2,
133.7, 166.3, 201.0. MS (ACPI) m/z: 468.1 (M+1);
HRMS (ESI-TOF, m/z): calcd. for C26H26FNO6:
1-fluoro-3-formyl-2-hydroxy-6-(4-
δ = 9.52 (d, J = 5 Hz, 1H), 7.31-7.20 (m, 6H), 6.84 (d,
J = 5 Hz, 2H), 5.12 (t, J = 5 Hz, 1H), 4.37 (dd, J = 5,
Acknowledgements
12 Hz, 1H), 4.19 (d, J = 5 Hz, 1H), 4.07 (m, 1H), 3.77
We thank Joseph P. Healey Research Grant and the
(s, 3H), 3.54 (s, 3H), 1.44 (d, 3H); 13C NMR (75 MHz,
CDCl3): δ = 23.1, 40.6, 45.5, 45.7, 50.9, 53.2, 55.1,
91.2, 114.2, 128.4, 128.7, 128.9, 129.0, 129.4, 130.4,
130.5, 134.7, 202.8; 19F NMR (284 MHz, CDCl3): δ =
-171.8. MS (ACPI) m/z: 446.1 (M+1); HRMS (ESI-
TOF, m/z): calcd. for C23H24FNO7: 446.1615 [M+H]+,
Found: 446.1613.
Center for Green Chemistry at the University of
Massachusetts Boston, Zhejiang Normal University
Research Funds (ZZ323205020516001122) to support
this work. Jerry P. Jasinski acknowledges the NSF-
MRI program (CHE-1039027) for funds to purchase
the X-ray diffractometer. We also acknowledge Kenny
Pham and Jeremy H. Hyatt for their involvement in
this project.
Methyl
1-fluoro-3-formyl-6-(furan-2-yl)-2-
hydroxy-2-methyl-5-nitro-4-phenylcyclohexane-1-
6
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10.1002/adsc.201700129
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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FULL PAPER
Recyclable Organocatalysts for the One-pot Asymmetric Synthesis of 2-
Fluorocyclohexanols Bearing Six Contiguous Stereocenters
Adv. Synth. Catal. Year, Volume, Page – Page
Xin Huang, Miao Liu, Jerry P. Jasinsk, Bo Peng and Wei Zhang
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