Asymmetric Synthesis of Chiral Spiroketal Bisphosphine Ligands and Their Application in Enantioselective Olefin Hydrogenation

Article abstract of DOI:10.1021/acs.joc.8b01693

A series of chiral spiroketal bisphosphine ligands containing 1,1′-spirobi(3H,3′H)isobenzofuran backbones was accessed through asymmetric synthesis and subsequently tested in enantioselective Rh-catalyzed hydrogenation of α-dehydroamino acid esters. The l

Full text of DOI:10.1021/acs.joc.8b01693

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Note
Asymmetric Synthesis of Chiral Spiroketal Bisphosphine Ligands
and Their Application in Enantioselective Olefin Hydrogenation
Jian Huang, Mao Hong, Chuan-Chuan Wang, Søren Kramer, Guo-Qiang Lin, and Xing-Wen Sun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01693 • Publication Date (Web): 12 Sep 2018
Downloaded from http://pubs.acs.org on September 13, 2018
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Asymmetric Synthesis of Chiral Spiroketal Bisphosphine Ligands and
Their Application in Enantioselective Olefin Hydrogenation
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†
Jian Huang,† Mao Hong,† Chuan-Chuan Wang,† Søren Kramerξ,*, Guo-Qiang Lin†,‡ and Xing-Wen Sun*,
†Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China.
‡Shanghai Institute of Organic Chemistry, CAS, 345 Lingling Road, Shanghai, 200032, China
ξDepartment of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
Supporting Information Placeholder
ABSTRACT: A series of chiral spiroketal bisphosphine ligands containing 1,1’-spirobi(3H,3’H)isobenzofuran backbones was
accessed through asymmetric synthesis and subsequently tested in enantioselective Rh-catalyzed hydrogenation of α-
dehydroamino acid esters. The ligand providing the highest enantioselectivity (up to 99.5%) was obtained in seven steps in
an overall 38% yield. The synthesis could be performed on gram-scale and no kinetic resolution of enantiomers is required.
Overall, the developed ligand provides an easily accessible alternative to SDP ligands as well as other chiral bisphosphine
ligands.
Asymmetric catalysis is one of the most powerful and
atom-economical strategies for accessing enantiopure chi-
ral organic molecules, such as pharmaceuticals, fragrances,
and agrochemicals.1 Since asymmetric transition-metal
catalysis is highly dependent on chiral non-racemic ligands,
the development of new ligands, which are easily accessi-
ble in high enantiopurity and which provide high levels of
enantioselectivity in catalytic reactions, is an important
task. Across a range of reactions, C2-symmetric bisphos-
phines, such as DIOP and BINAP, have demonstrated the
ability to provide high enantioselectivities.2,3 However,
there is still a need for alternatives to the well-established
ligands for further improving reaction conditions, yields,
and enantioselectivities.
(Figure 1).8,9 Examples of related spiroketal-based ligands
have also been developed and successfully applied in
asymmetric catalysis. Most notable are the SKP ligands
which contain a spirobichroman skeleton, as first reported
by Ding et al. (Figure 1).10 These ligands were efficient in
Pd-catalyzed asymmetric allylic amination of racemic
Morita–Baylis–Hillman adducts, obtaining good yields and
excellent enantioselectivities. Importantly, the spiroketal
moiety is stable and maintains stereochemical integrity
under basic, neutral, and mildly acidic conditions.
Since 2003, C2-symmetric bisphosphines based on spiro-
fused carbocyclic backbones have been identified as a new
privileged ligand class.4 The first example of these ligands
was described by Zhou and coworkers who developed the
SPINOL-based SDP ligands (Figure 1).5 SDP ligands have
since then been applied in a number of asymmetric trans-
formations where they induced high levels of enantioselec-
tivity.6,7 Later, SFDP ligands based on a spirobifluorene
structure was developed and applied in Ru-catalyzed
asymmetric hydrogenation of unsaturated carboxylic acids
Figure 1. Examples of previously reported chiral spiro-
bisphosphines.
Although SDP ligands have been highly successful in
asymmetric catalysis, their high price prevents widespread
use and makes large-scale applications less attractive.11
The synthesis of SDP ligands starting from SPINOL in-
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volves resolution of enantiomers and multistep synthe-
amine (DIPEA) afforded ether 3 in 96% yield. Compound 3
sis.5a,5b Due to the ability of SDP ligands to induce high lev-
els of enantioselectivity in combination with high price and
difficult access routes, easily accessible ligand analogues
are highly warranted. As a result, this year, three promi-
nent routes to SDP analogues and precursors have been
reported.12 Ding et. al demonstrated the facile synthesis of
cyclohexyl-fused spirobiindane scaffolds, which can serve
as SDP-analogue precursors.12c Yin, Zhang, and coworkers
was subjected to lithium-bromide exchange, followed by
formylation to give aldehyde 4 in 93% yield. In the key
step, after a lithium–bromide exchange, compound 3 was
reacted with the previously accessed aldehyde 4 to give
the symmetrical alcohol, 5. Oxidation with manganese di-
oxide provided ketone 6 in an excellent yield. In the pres-
ence of dry zinc bromide, intermediate 6 undergoes depro-
tection and cyclization affording racemic spiroketal difluo-
ride 7. At this point, enantiomerically pure isomers of 7
were obtained by separation of enantiomers using an
HPLC with a chiral stationary phase. One of the enantio-
mers, (+)-7, was converted to the spiroketal-bisphosphine
ligand (+)-8 by addition of KPPh2.
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reported
a
large
scale
synthesis
of
3,3’-
spirobi(2H,2’H)isobenzofuran scaffolds, which can also
serve as SDP-analogue precursors.12b Finally, Nagorny and
coworkers
reported
the
first
1,1’-
spirobi(3H,3’H)isobenzofuran analogues of the SDP-ligand
in a synthesis affording 23% overall yield of the best-
performing ligand.12a,13 We had also envisioned that 1,1’-
spirobi(3H,3’H)isobenzofuran analogues of the SDP-
ligands could be obtained in a straightforward fashion re-
lying on robust chemical transformations. Herein, we re-
port the asymmetric synthesis of these chiral spiroketal
bisphosphine ligands as well as their application in enanti-
oselective rhodium-catalyzed hydrogenation of α-
dehydroamino acid esters. The ligand providing the high-
est enantioselectivity (up to 99.5%) was obtained in just
seven steps in an overall 38% yield.
The facile synthesis of (+)-8 demonstrated that spiro-
ketal analogues of SDP could indeed be accesses in high
yields using straightforward and robust chemical trans-
formations. However, the route still suffers from the need
for separation of enantiomers by HPLC. To avoid this reso-
lution, we hypothesized that the installation of stereogenic,
homochiral methyl groups at the 3,3’-positions, leading to
diastereomers during spiroketal formation, would facili-
tate purification by normal column chromatography.
The synthesis the 3,3’-methyl-substituted ligand was ini-
tiated from 1-(2-bromo-3-fluorophenyl)-ethanone
9
Initially, the direct spiroketal analogue of SDP was tar-
(Scheme 2).14 Asymmetric reduction of the ketone was
effectuated by (+)-B-chlorodiisopinocampheylborane ((+)-
DIPCl) affording the (R)-enantiomer of alcohol 10 in 96%
ee and 96% yield.15 Treatment of the chiral alcohol 10 with
MEMCl in the presence of DIPEA produced ether 11 in 93%
yield. Compound 11 was subjected to lithium bromide ex-
change followed by formylation to give aldehyde 12 in 93%
yield. After another lithium–bromide exchange on com-
pound 11, it was reacted with the aldehyde 12 affording
alcohol 13, which was oxidized with manganese dioxide to
ketone 14 in 87% yield over two steps. The deprotec-
tion/spiroketal formation mediated by dry zinc bromide
also proceeded smoothly forming both diastereomers of
spiroketal 15. However, the cyclization is diastereoselec-
tive leading to a 3:1 ratio of 15a:15b. The separation of
diastereomers by column chromatography on normal silica
gel was straightforward, thus avoiding the need for purifi-
cation by chiral HPLC. Finally, each of the diastereomers
were reacted with KPPh2 affording enantiopure bisphos-
phine ligands 16a and 16b in 38% and 12% overall yield,
respectively.
geted
(Scheme
1).
Starting
from
2-bromo-3-
fluorobenzaldehyde (1), sodium borohydride reduction
afforded the benzylic alcohol 2, quantitatively. Treatment
of 2 with MEMCl in the presence of N,N-diisopropylethyl
Scheme
1.
Synthesis
of
a
1,1’-spirobi-
(3H,3’H)isobenzofuran bisphosphine ligand.
Scheme 2. Synthesis of 3,3'-dimethyl-1,1’-spirobi-
(3H,3’H)isobenzofuran bisphosphine ligands.
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With five different new chiral ligands in hand, their abil-
ity to induce enantioselectivity in rhodium-catalyzed hy-
drogenation of α-dehydroamino acid esters was investi-
gated. In order to compare the ligands, they were tested
under the same reaction conditions with α-dehydroamino
acid ester 19a (Table 1). The direct spiroketal analogue of
SDP, (+)-8, led to full conversion to hydrogenated product
20a but with modest 59% ee (entry 1). The major dia-
stereomer of the 3,3’-dimethyl substituted ligand, 16a,
dramatically increased the enantioselectivity to 94.5% ee
(entry 2). Hence, the 3,3’-methyl substituents not only
simplify the ligand synthesis, they are also highly beneficial
for enantioselectivity during catalysis. However, the minor
diastereomer of the 3,3’-substituted ligand, 16b, afforded
the opposite enantiomer of 20a and only in 65% ee (entry
3). It is evident that the stereochemistry of the spiroketal
stereocenter controls which enantiomer is predominantly
formed; the (S,R,R)-configuration of 16a provides the R-
enantiomer of product while the (R,R,R)-configuration of
16b gives the S-enantiomer. In addition, the spiroketal
stereocenter and the methyl stereocenters must be
matched in order to enhance the enantioselectivity (com-
pare entries 2 and 3). The same trends are observed for
mono-methyl ligands 18a and 18b which afforded 88%
and 52% ee, respectively (entries 4-5). To our surprise,
using the original SDP ligand under the same reaction con-
ditions led to a sluggish reaction affording almost racemic
product (entry 6).
While the installation of 3,3’-methyl groups on the 1,1’-
spirobi(3H,3’H)isobenzofuran backbone was mainly done
for to facilitate easy purification, the substituents could
potentially also affect ketal stability as well as stereoselec-
tivity when applied in catalysis. To investigate the latter
point, the mono-methyl analogues were prepared in an
analogous manner to the 3,3’-methyl substituted ligands
by reacting compound 4 and 11.16 The spiroketal for-
mation afforded a 2:1 ratio of diastereomers 17a:17b.
Finally, reaction with KPPh2 provided the bisphosphine
ligands 18a and 18b, respectively (Scheme 3).
Table 1 Optimization for asymmetric hydrogenation of
methyl (Z)-2-acetamido-3-phenylacrylate.
All the synthesized ligands are stable and can be stored
in ambient atmosphere without oxidation or erosion of
enantio- and diastereomeric purity. The absolute and rela-
tive stereochemistry of ligands 16a, 16b, and 18a were
confirmed by single-crystal X-ray diffraction.
Scheme
3.
Synthesis
of
3-methyl-
1,1’spirobi(3H,3’H)isobenzofuran bisphosphine lig-
ands.
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(Table 2). For all the substrates, the observed enantiose-
lectivities (96.5–99.5% ee) match the best-performing
ligands (e.g. DuPHOS17: 99–99.4%; MonoPHOS18: 93.2–
99.8%; SIPHOS19: 95.6%-99.3%) and they are better than
those reported for BINAP3a (92-93%).
6
7
8
9
Table
2
Asymmetric
hydrogenation
of
α-
dehydroamino acid esters
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11
12
13
14
15
16
17
18
19
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entrya
Substrate (19)
(R = Ph)
ee (%)b
96.5
97.6
98.8
97.8
97.0
99.4
99.5
Config. c
1
2
3
4
5
6
7
R
R
R
R
R
R
R
(R = 4-ClPh)
(R = 2-OMePh)
(R = 3-OMePh)
(R = 4-CH3Ph)
(R = H)
en-
L
solvent temp time conv
ee
(%) c
trya
(oC)
(h) b
(%)
1
2
3
4
5
6
(+)-8d
16a
DCM
DCM
DCM
DCM
DCM
DCM
rt
rt
rt
rt
rt
rt
3
3
100
100
100
100
100
10
-59
94.5
-65
88
16b
18a
3
(R = Me)
3
a The reaction was performed at 15 °C with 0.5 mmol of
substrate and 1 mol% of catalyst {[Rh(COD)2BF4]:L =
1:1.1} in 5 mL of DCE; 100% conversion was observed for
all substrates by H NMR of the crude reaction mixture.
Determined by chiral stationary phase HPLC. c Assigned by
comparing the optical rotation with reported values.
18b
3
-52
-10
(R)-
SDP
24
1
b
7
8
16a
16a
16a
16a
16a
16a
16a
16a
CHCl3
DCE
rt
rt
rt
rt
rt
rt
0
3
3
100
100
100
100
100
100
83
93.9
95.5
93.6
93.1
90.2
95.1
98.1
96.5
9
EtOH
i-PrOH
THF
3
In summary, we have developed a new chiral bisphos-
phine
10
11
12e
13
14
3
ligand,
16a,
which
contains
a
1,1’-
3
spirobi(3H,3’H)isobenzofuran backbone. The ligand is ac-
cessed in 7 steps in an overall 38%. The synthesis does not
involve separation of enantiomers and the chemical trans-
formations are robust and can be performed on gram-scale.
The ligand was evaluated in rhodium-catalyzed hydro-
genation of α-dehydroamino acid esters where it provided
excellent enantioselectivities (96.5%-99.5% ee). Interest-
ingly, when compared head-to-head under the same condi-
tions for this reaction, ligand 16a significantly outperforms
the original SDP ligand.
DCE
9
DCE
24
DCE
15
8
100
a The reaction was performed at room temperature with
0.5 mmol of substrate and mol% of catalyst
{[Rh(COD)2BF4]:L = 1:1.1} in 5 mL of solvent unless stated
otherwise. b Time taken for 100% conversion of substrate.
c Determined by chiral stationary phase HPLC. d The stere-
ochemistry of (+)-8 was tentatively assigned based on the
1
e
stereoselectivity. 0.5 mol% of catalyst {[Rh(COD)2BF4]:L
= 1:1.1} was used.
EXPERIMENTAL SECTION
General Information. NMR spectra were all recorded
on a Bruker AM400 (400 MHz) spectrometer. Chemical
shifts are reported in δ ppm referenced to an internal
SiMe4 standard for 1H NMR and chloroform-d (δ 77.16) for
13C NMR. Optical rotations were measured in CH2Cl2 or
CHCl3 on a Perkin-Elmer 241MC automatic polarimeter.
HRMS were recorded on a Bruker ApeXIII 7.0 TESLA FTMS
(TOF) Mass Spectrometer. Flash column chromatography
was performed using silica gel (300-400 mesh). Analytical
thin-layer chromatography was performed using glass
plates precoated with 0.25 mm 300–400 mesh silica gel
impregnated with a fluorescent indicator (254 nm). Thin
layer chromatography plates were visualized by exposure
With 16a identified as the superior ligand, different sol-
vents were examined and dichloroethane (DCE) afforded
the highest enantioselectivity (Table 1, entry 7-11). No loss
of enantioselectivity was observed when the catalyst load-
ing was reduced to 0.5 mol% (entry 12). Reducing the
temperature improved the enantioselectivity of the reac-
tion. At 0 °C, 98.1% ee was obtained but the reaction was
sluggish (entry 13). However, at 15 °C, full conversion was
observed in 8 h and the product obtained in 96.5% ee (en-
try 14).
Next, a variety of aryl and alkyl dehydroamino acid es-
ters were subjected to the optimized reaction conditions
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to ultraviolet light (254 nm). Enantioselectivities were
Hz), 114.8 (d, J = 21.4 Hz), 95.2, 71.6, 66.9 (d, J = 14.6 Hz),
58.8. HRMS: (ESI+, m/z) calculated for [C12H15FNaO4]+
(M+Na)+: 265.0852, found: 265.0868. IR (KBr) 2923, 2887,
2789, 1694, 1613, 1574, 1473, 1411, 1242, 1118, 1055,
831, 792, 519 cm-1.
determined by high-performance liquid chromatography
(HPLC) with a Aglilent-1100 or Aglilent-1260 intelligent
uv/vis detector (λ = 214 nm, 220nm or 254 nm) and a
Daicel IC or Daicel AD-H column. KPPh2 (0.5 M in THF) was
purchased from Sigma-Aldrich.
Bis(2-fluoro-6-(((2-
Experimental
Procedures.
(2-bromo-3-
methoxyethoxy)methoxy)methyl)phenyl)methanol
(5).
fluorophenyl)methanol (2). To a solution of compound 1
(6.0 g, 30.0 mmol) in MeOH (100 mL) was added NaBH4
(1.1 g, 30.0 mmol) slowly at 0 °C. The mixture was stirred
at 0 °C for an additional 1 h. After quenching with 10 mL of
saturated aqueous solution of ammonium chloride, the
mixture was concentrated and extracted with EtOAc
(3×100 mL). The combined extracts were washed with 50
mL of brine, dried over Na2SO4, filtered, and concentrated
to give 2 (6.0 g, 99%) as a white solid. The product was
used directly for the next step without further purification.
1H NMR (400 MHz, CDCl3): δ 7.28-7.32 (m, 2H), 7.04-7.09
(m, 1H), 4.78 (s, 2H).
Compound 3 (2.2 g, 7.6 mmol) was dissolved in 40 mL THF
and cooled to –78 °C under argon. n-BuLi (4.8 mL, 7.6
mmol) was added dropwise and the mixture was stirred
for an additional 1 h. A solution of compound 4 (1.5 g, 6.3
mmol) in THF (10 mL) was added dropwise. After com-
pleted addition, the mixture was stirred for 1.5 h while the
temperature rose to –60 °C. The reaction mixture was then
allowed to warm to 0 °C (about 4 h). The reaction mixture
was treated with 10 mL of saturated aqueous solution of
ammonium chloride and extracted with EtOAc (3×30 mL).
The combined organic extracts were washed with 20 mL of
brine, dried over Na2SO4, filtered, and concentrated and
the crude product was purified by flash chromatography
(silica gel, PE/EA = 2:1) to give the product 5 (2.5 g, 87%)
as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.17-7.26 (m,
4H), 6.87-6.92 (m, 2H), 6.54 (d, J = 5.6 Hz, 1H), 4.93 (q, J =
12.4 Hz, 4H), 4.78 (s, 4H), 4.20 (d, J = 5.6 Hz, 1H), 3.69-3.72
(m, 4H), 3.56 – 3.44 (m, 4H), 3.35 (s, 6H). 19F NMR (376
MHz, CDCl3): δ -114.26. 13C NMR (100 MHz, CDCl3): δ 161.9,
159.4, 138.2, 128.6, 128.5, 128.4, 128.3, 125.5, 115.7, 115.4,
94.6, 71.6, 67.4, 67.0, 65.9 (t, J = 3.8 Hz), 58.9. HRMS: (ESI+,
m/z) calculated for [C23H30F2NaO7]+ (M+Na)+: 479.1857,
found: 479.1851. IR (KBr) 2931, 2886, 1696, 1614, 1579,
1468, 1243, 1113, 1048, 851, 786 cm-1.
9
10
11
12
13
14
15
16
17
18
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28
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41
42
43
44
45
46
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59
60
2-Bromo-1-fluoro-3-(((2-
methoxyethoxy)methoxy)methyl)benzene (3). DIPEA (10.3
mL, 60 mmol) was added to a solution of compound 2 (6.0
g, 29.3 mmol) in anhydrous CH2Cl2 (80 mL) at 0 °C under
argon. MEMCl (6.1 mL, 52.7 mmol) was added dropwise
and the mixture was stirred at 0 °C for 1 h. It was then al-
lowed to warm to room temperature and stirred for 24 h.
The mixture was concentrated, and the crude product was
purified by flash chromatography (silica gel, PE/EA = 7:1)
to give the product 3 (8.3 g, 96%) as a colorless oil. 1H
NMR (400 MHz, CDCl3): δ7.25-7.31 (m, 2H), 7.03-7.09
(m,1H), 4.87 (s, 2H), 4.71 (s, 2H), 3.76-3.78 (m, 2H), 3.57-
3.59 (m, 2H), 3.40 (s, 3H). 19F NMR (376 MHz, CDCl3): δ -
106.14. 13C NMR (100 MHz, CDCl3): δ 158.9 (d, J = 246.7.2
Hz), 13.7, 128.2 (d, J = 8.7 Hz), 124.2 (d, J = 3.1 Hz), 115.1
(d, J = 22.2 Hz), 109.4 (d, J = 17.6 Hz), 95.1, 71.6, 68.4, 67.0,
58.0. HRMS: (ESI) calcd for C11H14BrFNaO3 (M+Na)+:
315.0008, found 315.0019. IR (KBr) 2927, 2886, 1602,
1578, 1467, 1445, 1263, 1173, 1055, 993, 779 cm-1.
Bis(2-fluoro-6-(((2-
methoxyethoxy)methoxy)methyl)phenyl)methanone (6). To
a solution of compound 5 (2.5 g, 5.5 mmol) in anhydrous
CH2Cl2 (30 mL) was added activated manganese dioxide
(6.2 g, 71.7 mmol). The mixture was stirred at room tem-
perature overnight. The reaction mixture was filtered and
the retained solid rinsed with 50 mL of CH2Cl2. The com-
bined filtrates were concentrated to give the crude product
6 (2.4 g, 97%) as a pale yellow oil. The crude product was
used directly for the next step without further purification.
1H NMR (400 MHz, CDCl3): δ 7.38-7.48 (m, 4H), 6.99 (t, J =
8.8 Hz, 2H), 4.79 (s, 4H), 4.74 (s, 4H), 3.71 (t, J = 4.8 Hz, 4H),
3.54 (t, J = 4.4 Hz, 4H), 3.37 (s, 6H). 19F NMR (376 MHz,
CDCl3): δ -113.51. 13C NMR (100 MHz, CDCl3): δ 191.4,
161.9, 159.4, 140.0, 132.3, 132.2, 127.1, 127.0, 123.9, 115.0,
114.7, 94.8, 71.5, 66.8, 66.3, 58.7. HRMS: (ESI+, m/z)
calculated for [C23H28F2NaO7]+ (M+Na)+: 477.1701, found:
477.1695. IR (KBr) 2927, 2886, 2815, 1673, 1611, 1577,
1469, 1251, 1115, 1052, 924, 794 cm-1.
2-Fluoro-6-(((2-
methoxyethoxy)methoxy)methyl)benzaldehyde (4). Com-
pound 3 (11.8 g, 40.0 mmol) was dissolved in 85 mL THF
and cooled to –78 °C under argon. n-BuLi (20.0 mL, 48
mmol) was added dropwise and the mixture was stirred
for an additional 40 minutes. DMF (6.21 mL, 80.0 mmol)
was added. The mixture was stirred for 30 minutes while
the temperature rose to –70 °C. The reaction mixture was
then allowed to warm to 0 °C (about 4 h). The reaction
mixture was quenched with 20 mL of saturated aqueous
solution of ammonium chloride and extracted with EtOAc
(3×100 mL). The combined organic extracts were washed
with 50 mL of brine, dried over Na2SO4, filtered, and con-
centrated, and the crude product was purified by flash
chromatography (silica gel, PE/EA = 5:1) to give the prod-
(+)-7,7'-Difluoro-3H,3'H-1,1'-spirobi[isobenzofuran] ((+)-
7). To a solution of compound 6 (2.4 g, 5.3 mmol) in anhy-
drous CH2Cl2 (30 mL) was added extra dry ZnBr2 (3.6 g,
32.0 mmol). The mixture was stirred at room temperature
overnight. Then, the reaction mixture was filtered, the re-
tained solid washed with 30 mL of CH2Cl2, and the com-
bined filtrates concentrated to give the crude product
which was purified by flash chromatography (silica gel,
PE/EA = 15:1) to give the racemic product 7 (1.1 g, 80%)
1
uct 4 (9.0 g, 93%) as a pale yellow oil. H NMR (400 MHz,
CDCl3): δ 10.51 (s, 1H), 7.52-7.62 (m, 2H), 7.11 (t, J = 9.2 Hz,
1H), 5.02 (s, 2H), 4.88 (s, 2H), 3.74-3.77 (m, 2H), 3.56-3.59
(m, 2H), 3.40 (s, 3H). 19F NMR (376 MHz, CDCl3): δ -120.89.
13C NMR (100 MHz, CDCl3): δ 188.5 (d, J = 10.7 Hz), 167.1,
164.5, 142.7, 135.4 (d, J = 10.7 Hz), 122.9, 120.9 (d, J = 6.1
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9
as a white solid. Resolution of the enantiomers was per-
(R)-2-Bromo-1-fluoro-3-(1-((2-
formed by HPLC using a chiral column. (Separation condi-
tions: Daicel Chiralpak OJ-H column, EtOH=100%, flow
rate 0.5 mL/min, λ = 214 nm: tR1 = 7.62 min., tR2 = 9.95 min.
methoxyethoxy)methoxy)ethyl)benzene (11). DIPEA (21.3
mL, 123.2 mmol) was added to a solution of compound 10
(13.5 g, 61.6 mmol) in anhydrous CH2Cl2 (200 mL) at 0 °C
under argon. MEMCl (12.7 mL, 110.9 mmol) was added
dropwise and the mixture was stirred at 0 °C for 1 h. It was
then allowed to warm to room temperature and stirred for
24 h. The mixture was concentrated, and the crude product
was purified by flash chromatography (silica gel, PE/EA =
10:1) to give the product 11 (17.6 g, 93%) as a colorless oil.
(+)-7: [α]20 = 19 (c = 1.0, CH2Cl2). 1H NMR (400 MHz,
D
CDCl3): δ 7.37-7.42 (m, 2H), 7.10 (d, J = 7.2 Hz, 2H), 6.95 (t J
= 8.8 Hz, 2H), 5.34 (d, J = 12.8 Hz, 2H), 5.23 (d, J = 12.8 Hz,
2H). 19F NMR (376 MHz, CDCl3): δ -121.31. 13C NMR (100
MHz, CDCl3): δ 159.3, 156.8, 143.0, 142.9, 131.9, 131.4,
125.4, 125.2, 116.9, 116.8, 116.7, 114.7, 114.5, 72.1. HRMS:
(ESI+, m/z) calculated for [C15H11F2O2]+ (M+H)+: 261.0727,
found: 261.0733. IR (KBr) 2953, 2873, 1629, 1597, 1475,
1364, 1294, 1256, 1023, 968, 932, 776, 735, 588 cm-1.
HPLC: Daicel OJ-H column (EtOH = 100%), flow rate = 0.5
mL/min; λ = 214 nm; tR(minor) = 7.62min, tR(major) = 9.95 min,
ee = 99%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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30
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32
33
34
35
36
37
38
39
40
41
42
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47
48
49
50
51
52
53
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58
59
60
[α]20 = 143 (c = 1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ
D
7.27-7.32 (m, 2H)，7.00-7.05 (m,1H)，5.18 (q, J = 6.4 Hz,
1H), 4.75 (d, J = 7.2 Hz, 1H), 4.63 (d, J = 6.8 Hz, 1H), 3.77-
3.82 (m, 1H), 3.59-3.65 (m, 1H), 3.47-3.64 (m, 2H), 3.38 (s,
3H), 1.44 (d, J = 6.4 Hz, 3H). 19F NMR (376 MHz, CDCl3): δ -
105.31. 13C NMR (100 MHz, CDCl3): δ 158.7 (d, J = 45.2 Hz),
145.4, 128.6 (d, J = 7.7 Hz), 123.3 (d, J = 3.1 Hz), 114.8 (d, J
= 22.2 Hz), 109.2 (d, J = 20.7 Hz), 93.7, 72.7 (d, J = 3.1 Hz),
71.7, 67.1, 59.0, 22.3. HRMS: (ESI+, m/z) calculated for
[C12H20BrFNO3]+ (M+NH4)+: 324.0611, found: 324.0604. IR
(KBr) 2930, 2887, 1674, 1575, 1465, 1261, 1119, 1041,
929, 848, 791, 715 cm-1.
(+)-7,7'-Bis(diphenylphosphanyl)-3H,3'H-1,1'-
spirobi[isobenzofuran] ((+)-8). To a 15 mL pressure tube
equipped with magnetic stirring bar were added com-
pound (+)-7 (130 mg, 0.5 mmol) and KPPh2 (3.0 mL, 1.5
mmol, 0.5 M in THF), and the tube sealed under argon. The
mixture was heated to reflux for 6 h and then cooled and
filtered. The retained solid was washed with CH2Cl2 and
the combined filtrates were concentrated to give the crude
product which was purified by flash chromatography (sili-
ca gel, PE/EA/CH2Cl2 = 20:1:1) to give the product (+)-8
(250 mg, 84%, > 99% ee) as a white solid. m. p. 212 ~ 214
oC. [α]20D = 255(c = 1.0, CH2Cl2). m. p. 212 ~ 214 oC. 1H NMR
(400 MHz, CDCl3): δ 7.34 (t J = 8.8 Hz, 2H), 7.21-7.26 (m,
10H), 7.18 (t J = 7.2 Hz, 4H), 7.03-7.13 (m, 4H), 6.91-6.95
(m, 2H), 6.88 (t J = 7.6 Hz, 4H), 5.12 (d, J = 12.4 Hz, 2H),
4.71 (d, J = 12.4 Hz, 2H). 31P NMR (162 MHz, CDCl3): δ -
18.60. 13C NMR (100 MHz, CDCl3): δ 144.2, 143.9, 140.9,
140.8, 137.7, 137.6, 136.7, 136.6, 134.0, 133.8, 133.7, 133.4,
133.2, 133.0, 129.5, 128.3, 128.2, 128.1, 128.0, 121.5, 120.7,
71.3. HRMS: (ESI+, m/z) calculated for [C39H31O2P2]+
(M+H)+: 593.1799, found: 593.1791. IR (KBr) 3067, 2912,
2860, 1584, 1479, 1433, 1357, 1281, 1091, 1025, 947, 744,
695, 506 cm-1. HPLC: Daicel IA column (hexane/i-PrOH =
(R)-2-Fluoro-6-(1-((2-
methoxyethoxy)methoxy)ethyl)benzaldehyde (12). Com-
pound 11 (9.0 g, 29.3 mmol) was dissolved in 130 mL THF
and cooled to –78 °C under argon. n-BuLi (22.0 mL, 35.2
mmol) was added dropwise and the mixture was stirred
for an additional 40 minutes. DMF (4.6 mL, 58.6 mmol)
was added. The mixture was stirred for 30 minutes while
the temperature rose to –70 °C. The reaction mixture was
then allowed to warm to 0 °C (about 4 h). The reaction
mixture was quenched with 20 mL of saturated aqueous
solution of ammonium chloride and extracted with EtOAc
(3×60 mL). The combined organic extracts were washed
with 50 mL of brine, dried over Na2SO4, filtered, and con-
centrated, and the crude product was purified by flash
chromatography (silica gel, PE/EA = 5:1) to give the prod-
uct 12 (7.0 g, 93%) as a pale yellow oil. [α]20D = 205 (c = 1.0,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 1H NMR (400 MHz,
CDCl3) δ 10.47 (s, 1H), 7.41-7.61 (m, 2H), 6.93-7.12 (m,
1H), 5.60 (q, J = 5.6 Hz, 1H), 4.70 (d, J = 6.8 Hz, 1H), 4.56 (d,
J = 5.6 Hz, 1H), 3.65-3.79 (m, 1H), 3.40-3.58 (m, 3H), 3.32
(s, 3H), 1.41 (d, J = 8.4 Hz, 3H). 19F NMR (376 MHz, CDCl3):
δ -120.79. 13C NMR (100 MHz, CDCl3): δ 188.8 (d, J = 11.5
Hz), 165.6 (d, J = 256.6 Hz), 148.7, 135.5 (d, J = 9.9 Hz),
122.1 (d, J = 3.8 Hz), 121.2 (d, J = 6.2 Hz), 114.6 (d, J = 21.5
Hz), 93.8, 71.5, 70.2 (d, J = 2.3 Hz), 67.0, 58.9, 23.6. HRMS:
(ESI+, m/z) calculated for [C13H21FNO4]+ (M+NH4)+:
274.1455, found: 274.1468. IR (KBr) 2931, 2886, 1697,
1611, 1573, 1470, 1241, 1118, 1038, 801, 730 cm-1.
95/05), flow rate = 1.0 mL/min; λ = 254 nm; tR(major)
7.52min, tR(minor) = 10.72 min.
=
R)-1-(2-Bromo-3-fluorophenyl)ethan-1-ol (10). With ref-
erence to the known literature15, (+)-DIPCl (50.0 mL, 84
mmol) was dissolved in 400 mL THF and cooled to –35 °C
under argon. A solution of compound 9 (14.0 g, 64.4 mmol)
in 140 mL THF was added dropwise. After completed addi-
tion, the mixture was stirred for 18 h at –35 °C. Then, di-
ethanolamine (20.2 g, 193.2 mmol) was added and the
reaction mixture stirred for 3 h. The mixture was concen-
trated, solvent added (400 mL, n-hexane/MTBE = 7:1), and
the mixture filtered, rinsing the retained solid with 100 mL
n-hexane. The concentrated filtrates were purified by flash
chromatography (silica gel, PE/EA = 10:1) to give the
Bis(2-fluoro-6-((R)-1-((2-
methoxyethoxy)methoxy)ethyl)phenyl)methanone
(14).
Compound 11 (8.6 g, 28.0 mmol) was dissolved in 130 mL
THF and cooled to –78 °C under argon. n-BuLi (17.5 mL,
28.0 mmol) was added dropwise and the mixture was
stirred for an additional 1 h. A solution of compound 12
(6.0 g, 23.3 mmol) in 50 mL THF was added dropwise. Af-
ter completed addition, the mixture was stirred for 1.5 h
while the temperature rose to –60 °C. The reaction mixture
product 10 (13.5 g, 96%, 96% ee) as a colorless oil. [α]20
=
D
60 (c = 1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.37-7.40
(m, 1H), 7.30 (dt, J = 5.6 Hz, J = 8.0 Hz, 1H), 7.03 (dt, J = 1.6
Hz, J =9.6 Hz, 1H), 5.22-5.28 (m, 1H), 2.22 (d, J = 3.2 Hz, 1H),
1.47 (d, J = 6.4 Hz, 3H).
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was then allowed to warm to 0 °C (about 4 h). The reaction
mixture was treated with 10 mL of saturated aqueous solu-
tion of ammonium chloride and extracted with EtOAc
(3×100 mL). The combined organic extracts were washed
with 50 mL of brine, dried over Na2SO4, filtered, and con-
centrated to give 12.5 g of the crude product 13, which
was used directly for the next step without further purifi-
cation: To a solution of compound 13 (12.5 g, 23.3 mmol)
in anhydrous CH2Cl2 (150 mL) was added activated man-
ganese dioxide (30.5 g, 349.5 mmol). The mixture was
stirred at room temperature overnight. Then, the mixture
was filtered, the retained solid rinsed with 100 mL of
CH2Cl2, and the combined filtrates concentrated to give the
crude product which was purified by flash chromatog-
raphy (silica gel, PE/EA = 3:1) to give the product 14 (9.8 g,
cm-1. HPLC: Daicel Chiralpak IC column, hexane/i-PrOH
99:01, flow rate 0.7 mL/min, λ = 220 nm: tR(minor)= 7.49
min., tR (major) = 9.18 min.
2
3
4
5
6
7
8
9
((1S,3R,3'R)-3,3'-dimethyl-3H,3'H-1,1'-
spirobi[isobenzofuran]-7,7'-diyl)bis(diphenylphosphane)
(16a). To a 48 mL pressure tube was added compound
15a (0.500 g, 1.74 mmol) and KPPh2 (12.0 mL, 6.00 mmol,
0.5 M in THF), and the tube sealed under argon. The mix-
ture was heated at 85 °C for 30 h and then cooled to room
temperature. The mixture was filtered, the retained solid
rinsed with CH2Cl2, and the combined filtrates concentrat-
ed to give the crude product which was purified by flash
chromatography (silica gel, PE/EA/CH2Cl2 = 25:1:1) to give
10
11
12
13
14
15
16
17
18
19
20
21
22
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the product 16a (0.930 g, 86%, >99% ee) as a white solid.
[α]20 = -318 (c = 1.0, CH2Cl2). m. p. 264 ~ 266 C. 1H NMR
o
D
87%) as a colorless viscous liquid. [α]20 = 170 (c = 1.0,
D
(400 MHz, CDCl3): δ 7.37 (t, J = 7.6 Hz, 2H), 7.18-7.30 (m,
14H), 6.93-7.03 (m, 10H), 5.36 (q, J = 6.4 Hz, 2H), 1.06 (d, J
= 6.4Hz, 6H). 31P NMR (162 MHz, CDCl3): δ -20.47.13C NMR
(100 MHz, CDCl3): δ 145.2, 145.1, 144.6, 144.3, 138.0, 137.9,
137.4, 137.2, 134.5, 134.1, 134.0, 133.9, 133.2, 133.1, 133.0,
132.4, 132.2, 129.5, 128.3, 128.2, 128.2, 128.2, 128.1, 128.0,
128.0, 128.0, 127.7, 121.6, 117.4, 77.3, 18.7.HRMS: (ESI+,
m/z) calculated for [C41H35O2P2]+ (M+H)+: 621.2112, found:
621.2119. IR (KBr) 3050, 2924, 2854, 1583, 1480, 1432,
1371, 1322, 1280,1092, 1032, 998, 948, 775, 695, 511 cm-1.
HPLC: Daicel Chiralpak IC column, hexane/i-PrOH 99:01,
flow rate 0.7 mL/min, λ = 220 nm: tR(minor) = 6.03 min., tR
(major) = 7.48 min.
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ7.42-7.53 (m, 4H),
6.92 (t, J = 8.8 Hz, 2H), 5.01 (q, J = 6.4 Hz, 2H), 4.67 (d, J =
6.8 Hz, 2H), 4.59 (d, J = 6.8 Hz, 2H), 3.71-3.77 (m, 2H), 3.56-
3.62 (m, 2H), 3.43-3.53 (m, 4H), 3.33 (s, 6H), 1.58 (d, J = 6.4
Hz, 6H). 19F NMR (376 MHz, CDCl3): δ -113.31. 13C NMR
(100 MHz, CDCl3): δ 192.0, 161.5, 158.9, 146.8, 132.6,
132.5, 127.8, 127.7, 122.6, 114.4, 114.1, 93.6, 71.6, 70.9,
66.9, 58.8, 24.5. HRMS: (ESI+, m/z) calculated for
[C25H36F2NO7]+ (M+NH4)+: 500.2460, found: 500.2459. IR
(KBr) 2931, 2887, 1668, 1612, 1574, 1470, 1294, 1245,
1119, 1035, 922, 805 cm-1.
(1S,3R,3'R)-7,7'-Difluoro-3,3'-dimethyl-3H,3'H-1,1'-
spirobi[isobenzofuran](15a) and (1R,3R,3'R)-7,7'-difluoro-
3,3'-dimethyl-3H,3'H-1,1'-spirobi[isobenzofuran] (15b). To a
solution of compound 14 (9.0 g, 18.6 mmol) in anhydrous
CH2Cl2 (90 mL) was added extra dry ZnBr2 (30.0 g, 130.2
mmol). The mixture was stirred at room temperature
overnight. Then, the reaction mixture was filtered, the re-
tained solid rinsed with 100 mL of CH2Cl2, and the com-
bined filtrates concentrated to give the crude product
which was purified by flash chromatography (silica gel,
PE/EA = 25:1) to obtain two diastereoisomers 15a and
15b. 15a: 3.3 g (61%, > 99% ee), white solid. m. p. 141 ~
((1R,3R,3'R)-3,3'-dimethyl-3H,3'H-1,1'-
spirobi[isobenzofuran]-7,7'-diyl)bis(diphenylphosphane)
(16b). To a 15 mL pressure was added compound 15b
(144 mg, 0.5 mmol) and KPPh2 (4.0 mL, 2.0 mmol, 0.5 M in
THF), and the tube sealed under argon. The mixture was
heated at 85 °C for 30 h and then cooled to room tempera-
ture. The mixture was filtered, the retained solid rinsed
with with CH2Cl2, and the combined filtrates concentrated
to give the crude product which was purified by flash
chromatography (silica gel, PE/EA/CH2Cl2 = 25:1:1) to give
the product 16b (270 mg, 87%, >99% ee) as a white solid.
143 oC. [α]20 = 32 (c = 1.0, CH2Cl2). 1H NMR (400 MHz,
D
m. p. 168 ~ 171 oC. [α]20 = 230 (c = 1.0, CH2Cl2). 1H NMR
D
CDCl3): δ 7.37-7.43 (m, 2H), 7.04 (d, J = 7.2 Hz, 2H), 6.95 (t J
= 8.8 Hz, 2H), 5.57 (q, J = 6.4 Hz, 2H), 1.58 (d, J = 6.4 Hz,
6H). 19F NMR (376 MHz, CDCl3): δ -121.13. 13C NMR (100
MHz, CDCl3): δ 159.1, 156.6, 147.6, 147.6, 132.0, 132.0,
126.0, 125.4, 116.6, 116.6, 114.9, 114.7, 114.0, 79.1, 21.0.
HRMS: (ESI+, m/z) calculated for [C17H15F2O2]+ (M+H)+:
289.1040, found: 289.1028. IR (KBr) 2986, 2865, 1626,
1601, 1478, 1351, 1301, 1253, 1084, 1013, 944, 779, 744
cm-1. HPLC: Daicel Chiralpak IC column, hexane/i-PrOH
99:01, flow rate 0.7 mL/min, λ = 220 nm: tR(minor) = 8.66
min., tR(major) = 10.17 min. 15b: 1.0 g (19%, > 99% ee), white
(400 MHz, CDCl3): δ 7.32 (t, J = 7.2 Hz, 2H), 7.19-7.26 (m,
10H), 7.05-7.14 (m, 8H), 6.93-6.96 (m, 2H), 6.78 (t, J = 7.6
Hz, 4H), 5.19 (q, J = 6.4 Hz, 2H), 1.52 (d, J = 6.4Hz, 6H).31
P
NMR (162 MHz, CDCl3): δ -19.14. 13C NMR (100 MHz,
CDCl3): δ 145.6, 145.5, 145.0, 144.8, 138.1, 138.0, 136.9,
136.7, 134.0, 133.8, 133.1, 133.0, 132.7, 132.5, 129.3, 128.3,
128.1, 128.0, 128.0, 127.9, 121.5, 119.1, 78.7, 78.6, 23.3.
HRMS: (ESI+, m/z) calculated for [C41H35O2P2]+ (M+H)+:
621.2112, found: 621.2121. IR (KBr) 3050, 2968, 2921,
1584, 1478, 1433, 1343, 1268, 1027, 946, 742, 695, 502
cm-1. HPLC: Daicel Chiralpak IC column, hexane/i-PrOH
99.6:0.4, flow rate 0.4 mL/min, λ = 220 nm: tR(major) = 11.23
min., tR (minor) = 12.41 min.
solid. m. p. 149 ~ 152 oC. [α]20 = -43 (c = 1.0, CH2Cl2). 1H
D
NMR (400 MHz, CDCl3): δ 7.35-7.40 (m, 2H), 7.03 (d, J = 7.6
Hz, 2H), 6.93 (t, J = 8.8 Hz, 2H), 5.48 (q, J = 6.4 Hz, 2H), 1.64
(R)-(2-fluoro-6-(((2-
methoxyethoxy)methoxy)methyl)phenyl)(2-fluoro-6-(1-((2-
(d, J = 6.4 Hz, 6H). 19F NMR (376 MHz, CDCl3): δ -121.15. 13
C
NMR (100 MHz, CDCl3): δ 159.0, 156.5, 147.4, 147.3, 131.8,
131.7, 125.7, 125.5, 116.7, 116.6, 114.8, 114.6, 113.0, 79.5,
21.0. HRMS: (ESI, m/z) calculated for [C17H15F2O2]+ (M+H)+:
289.1040, found: 289.1051. IR (KBr) 2984, 2894, 1627,
1598, 1476, 1368, 1285, 1245, 1076, 1009, 935, 794, 745
methoxyethoxy)methoxy)ethyl)phenyl)methanone
(22).
Compound 11 (11.0 g, 36.0 mmol) was dissolved in 160
mL THF and cooled to –78 °C under argon. n-BuLi (15.0 mL,
36.0 mmol) was added dropwise and the mixture was
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stirred for an additional 1 h. A solution of compound 4 (7.3
738 cm-1. HPLC: Daicel Chiralpak IC column, hexane/i-
PrOH 97:03, flow rate 0.7 mL/min, λ = 254 nm: tR(major)
g, 30.0 mmol) in 50 mL THF was added dropwise. After
completed addition, the mixture was stirred for 1.5 h while
the temperature rose to –60 °C. The reaction mixture was
then allowed to warm to 0 °C (about 4 h). The reaction
mixture was treated with 10 mL of saturated aqueous solu-
tion of ammonium chloride and extracted with EtOAc
(3×100 mL). The combined organic extracts were washed
with 50 mL of brine, dried over Na2SO4, filtered, and con-
centrated to give 15.9 g of the crude product 21. The crude
product was used directly for the next step without further
purification: To a solution of compound 21 (15.9 g, 30.0
mmol) in anhydrous CH2Cl2 (150 mL) was added activated
manganese dioxide (39.2 g, 450.0 mmol). The mixture was
stirred at room temperature overnight. Then, the reaction
mixture was filtered, the retained solid rinsed with 100 mL
of CH2Cl2, and the combined filtrates concentrated to give
the crude product which was purified by flash chromatog-
raphy (silica gel, PE/EA = 3:1) to give the product 22 (12.0
=
10.02 min., tR(minor) = 12.83 min. 17b: 737 mg (recrystalliza-
tion from hexane, 21% yield, > 99% ee), white solid. m. p.
103 ~ 104 oC. [α]20 = -12 (c = 1.0, CH2Cl2). 1H NMR (400
D
MHz, CDCl3): δ 7.35-7.42 (m, 2H), 7.06 (dd, J = 7.6 Hz, J =
18.8 Hz, 2H), 6.91-6.96 (m, 2H), 5.49 (q, J = 6.4 Hz, 1H),
5.37 (d, J = 12.8 Hz, 1H), 5.23 (d, J = 12 .8Hz, 1H), 1.64 (d, J
= 6 .4Hz, 3H). 19F NMR (376 MHz, CDCl3): δ -121.28, -
121.45. 13C NMR (100 MHz, CDCl3): δ 159.2 (d, J = 13.8 Hz),
156.7 (d, J = 13.8 Hz), 147.3 (d, J = 3.1 Hz), 142.9 (d, J = 3.8
Hz), 132.0 (d, J = 6.9 Hz), 131.8 (d, J = 6.9 Hz), 125.6 (d, J =
13.7 Hz), 125.4 (d, J = 13.8 Hz), 116.9 (d, J = 3.8 Hz), 116.7
(d, J = 3.8 Hz), 115.8, 114.8 (d, J = 13.8 Hz), 114.6 (d, J =
14.6 Hz), 79.6, 72.2, 22.9. HRMS: (ESI+, m/z) calculated for
[C16H13F2O2]+ (M+H)+: 275.0884, found: 275.0887. IR (KBr)
2987, 2869, 1630, 1599, 1477, 1363, 1334, 1246, 1082,
994, 937, 797, 742 cm-1. HPLC: Daicel Chiralpak IC column,
hexane/i-PrOH 97:03, flow rate 0.7 mL/min, λ = 254 nm: tR
(minor)= 8.79 min., tR(major) = 12.86 min.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
g, 85%) as a colorless viscous liquid. [α]20 = 71 (c = 1.0,
D
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.41-7.48 (m, 4H)，
6.92-7.00 (m,2H)，5.03 (q, J = 6.4 Hz, 1H), 4.85 (s, 2H),
4.80 (s, 2H), 4.61 (dd, J = 6.8 Hz, J = 18.4 Hz, 2H), 3.70-3.75
(m, 3H), 3.54-3.60 (m, 3H), 3.47 (t, J = 4.8 Hz, 2H), 3.37 (s,
3H), 3.32 (s, 3H) 1.51 (d, J = 6.4 Hz, 3H). 19F NMR (376 MHz,
CDCl3): δ -112.69, -114.16. 13C NMR (100 MHz, CDCl3): δ
191.8, 161.7 (d, J = 98.1 Hz), 159.2 (d, J = 95.8 Hz), 146.1,
140.5, 132.6 (d, J = 9.2 Hz), 132.2 (d, J = 9.2 Hz), 127.7 (d, J
= 13.8 Hz), 126.9 (d, J = 12.3 Hz), 124.0 (d, J = 2.3 Hz),
122.4 (d, J = 3.1 Hz), 114.9 (d, J = 22.2 Hz), 114.2 (d, J =
21.5 Hz), 94.9, 93.4, 71.6, 71.5, 70.7, 66.9, 66.8, 66.3, 58.8,
58.7, 24.1. HRMS: (ESI+, m/z) calculated for [C24H34F2NO7]+
(M+NH4)+: 486.2303, found: 486.2323. IR (KBr) 2930,
2887, 1671, 1611, 1576, 1470, 1247, 1116, 1042, 923, 803
cm-1.
((1S,3R)-3-methyl-3H,3'H-1,1'-spirobi[isobenzofuran]-
7,7'-diyl)bis(diphenylphosphane) (18a). To a 15 mL pres-
sure tube was added compound 17a (137 mg, 0.5 mmol)
and KPPh2 (4.0 mL, 2 mmol, 0.5 M in THF), and the tube
sealed under argon. The mixture was heated at 85 °C for 8
h and then cooled, filtered, and concentrated to give the
crude product which was purified by flash chromatog-
raphy (silica gel, PE/EA/CH2Cl2 = 20:1:1) to give the prod-
uct 18a (225 mg, 74%, >99% ee) as a white solid. m. p. 249
~ 251 oC. [α]20 = -217 (c = 1.0, CH2Cl2). 1H NMR (400 MHz,
D
CDCl3): δ 6.87-7.39 (m, 26H), 5.39 (q, J = 6.4 Hz, 1H), 4.99
(d, J = 12.4 Hz, 1H), 4.16 (d, J = 12.8Hz, 1H), 1.21 (d, J =
6.4Hz, 3H). 31P NMR (162 MHz, CDCl3): δ -17.60, -20.89. 13
C
NMR (100 MHz, CDCl3): δ 144.7, 144.6, 143.2, 142.9, 141.6,
141.5, 138.0, 137.9, 137.5, 137.4, 137.2, 137.1, 136.7, 136.5,
134.7, 134.1, 134.0, 133.9, 133.8, 133.2, 133.0, 132.8, 132.5,
132.3, 129.7, 129.3, 128.3, 128.2, 128.2, 128.2, 128.0, 128.0,
127.9, 127.6, 121.7, 121.3, 118.9, 77.8, 70.8, 1.8. HRMS:
(ESI+, m/z) calculated for [C40H33O2P2]+ (M+H)+: 607.1956,
found: 607.1976. IR (KBr) 3051, 2923, 2855, 1583, 1479,
1433, 1353, 1281, 1089, 1025, 946, 774, 695, 505 cm-1.
HPLC: Daicel Chiralpak IC column, hexane/i-PrOH 97:03,
flow rate 0.7 mL/min, λ = 220 nm: tR (minor)= 6.62 min.,
(1S,3R)-7,7'-difluoro-3-methyl-3H,3'H-1,1'-
spirobi[isobenzofuran] (17a) and (1R,3R)-7,7'-difluoro-3-
methyl-3H,3'H-1,1'-spirobi[isobenzofuran] (17b). To a solu-
tion of compound 22 (6.0 g, 12.8 mmol) in anhydrous
CH2Cl2 (90 mL) was added extra dry ZnBr2 (17.3 g, 76.8
mmol). The mixture was stirred at room temperature
overnight. Then, the mixture was filtered, the retained sol-
id rinsed with 50 mL of CH2Cl2, and the combined filtrates
concentrated to give the crude product which was purified
by flash chromatography (silica gel, PE/EA = 30:1) to ob-
tain two diastereoisomers (dr = 2:1). 17a: 1.3 g (recrystal-
lization from hexane, 38% yield, > 99% ee), white solid. m.
tR(major) = 8.99 min.
((1R)-3-Methyl-3H,3'H-1,1'-spirobi[isobenzofuran]-7,7'-
diyl)bis(diphenylphosphane) (18b). To a 15 mL pressure
tube was added compound 17b (137 mg, 0.5 mmol) and
KPPh2 (4.0 mL, 2 mmol, 0.5 M in THF), and the tube sealed
under argon. The mixture was heated at 85 °C for 8 h and
then cooled, filtered, and concentrated to give the crude
product which was purified by flash chromatography (sili-
ca gel, PE/EA/CH2Cl2 = 20:1:1) to give the product 18b
(218 mg, 72%, >99% ee) as a white solid. m. p. 182 ~ 183
p. 109 ~ 111 oC. [α]20 = 5 (c = 1.0, CH2Cl2). 1H NMR (400
D
MHz, CDCl3): δ 7.36-7.43 (m, 2H), 7.07 (dd, J = 7.6 Hz, J =
21.6 Hz, 2H), 6.95 (t, J = 8.4 Hz, 2H), 5.58 (q, J = 6.0 Hz, 1H),
5.32 (d, J = 12.8 Hz, 1H), 5.19 (d, J = 12 .8Hz, 1H), 1.59 (d, J
= 6 .4Hz, 3H). 19F NMR (376 MHz, CDCl3): δ -121.13, -
121.28. 13C NMR (100 MHz, CDCl3): δ 159.3 (d, J = 27.5 Hz),
156.7 (d, J = 27.4 Hz), 147.5 (d, J = 2.8 Hz), 143.2 (d, J = 2.8
Hz), 132.0 (d, J = 6.3 Hz), 131.9 (d, J = 7.1 Hz), 125.5 (d, J =
8.5 Hz), 125.3 (d, J = 9.1 Hz), 116.8 (d, J = 3.5 Hz), 116.6 (d,
J = 3.5 Hz), 115.3, 114.8 (d, J = 19.7 Hz), 79.3, 71.9, 20.9.
HRMS: (ESI+, m/z) calculated for [C16H13F2O2]+ (M+H)+:
275.0884, found: 275.0879. IR (KBr) 2974, 2929, 2869,
1626, 1600, 1477, 1359, 1299, 1256, 1083, 1022, 950, 794,
oC. [α]20 = 205 (c = 1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3):
D
δ 6.89-7.36 (m, 22H), 6.83 (q, J = 7.2 Hz, 4H), 5.20 (d, J =
12.4 Hz, 1H), 5.04 (q, J = 6.4 Hz, 1H), 4.88 (d, J = 12.4 Hz,
1H), 1.49 (d, J = 6.4Hz, 3H). 31P NMR (162 MHz, CDCl3): δ -
18.81. 13C NMR (100 MHz, CDCl3): δ 145.4, 144.6, 144.3,
140.9, 137.9, 137.8, 136.7, 136.6, 134.0, 133.8, 133.2, 133.0,
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132.8, 132.6, 129.5, 129.4, 128.3, 128.3, 128.1, 128.1, 128.0,
128.0, 121.5, 121.4, 119.9, 78.6, 71.4, 23.2. HRMS: (ESI+,
m/z) calculated for [C40H33O2P2]+ (M+H)+: 607.1956, found:
607.1976. IR (KBr) 3050, 2923, 2863, 1583, 1458, 1433,
1351, 1271, 1091, 1026, 947, 742, 695, 503 cm-1. HPLC:
Daicel Chiralpak IB column, hexane/i-PrOH 99:01, flow
3H), 3.71 (s, 3H), 3.11 (d, J = 6.4 Hz, 2H), 1.93 (s, 3H). 13
C
2
3
4
5
6
7
8
9
NMR (100 MHz, CDCl3): δ 172.5, 169.8, 157.5, 130.9, 131.1,
128.6, 124.5, 120.8, 55.3, 53.0, 52.1, 32.3, 22.9. HRMS:
(ESI+, m/z) calculated for [C13H18NO4] (M+H)+: 252.1236,
found: 252.1241. HPLC: Daicel IA column (hexane/i-PrOH
= 90/10), flow rate = 1.0 mL/min; λ = 220 nm; tR(major)
=
rate 0.7 mL/min, λ = 254 nm: tR (minor)= 9.50 min., tR(major)
11.03 min.
=
11.94 min, tR(minor) = 16.36 min.
Methyl
(R)-2-acetamido-3-(4-chlorophenyl)propanoate
General procedure for asymmetric hydrogenation of
α-dehydroamino acid derivatives. Standard procedure
at S/C = 100: To a 25 mL Schlenk tube was added com-
pound 19a (110 mg, 0.5 mmol), Rh(COD)2BF4 (2 mg, 5
μmol) and ligand 16a (3.8 mg, 6 μmol) under argon in a
glove box. After four vacuum/hydrogen cycles, 5 mL of 1,2-
dichloroethane was added and the reaction mixture was
stirring at 15 °C under ambient H2 pressure for 8 h. The
conversion was determined by 1H NMR. The resulting mix-
ture was filtered through a short silica gel column and con-
centrated under reduced pressure to give hydrogenation
product in quantitative yield.
(20e).22 100% conversion and 97.0% ee. [α]20 = -110 (c =
D
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
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52
53
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58
59
60
1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.25 (d, J = 7.6 Hz,
2H), 7.02 (d, J = 8.0 Hz, 2H), 5.93 (br d, J = 6.4 Hz, 1H),
4.84-4.90 (m, 1H), 3.73 (s, 3H), 3.14 (dd, J = 14.0 Hz, J = 6.0
Hz, 1H), 3.06 (dd, J = 14.0 Hz, J = 6.0 Hz, 1H), 2.00 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 171.9, 169.5, 134.3, 133.0,
130.5, 128.7, 53.0, 52.4, 37.2, 23.0. HRMS: (ESI+, m/z) cal-
culated for [C12H15ClNO3] (M+H)+: 256.0740, found:
256.0748. HPLC: Daicel IA column (hexane/i-PrOH =
90/10), flow rate = 1.0 mL/min; λ = 220 nm; tR(major)
12.17min, tR(minor) = 14.73 min.
Methyl (R)-2-acetamidobutanoate (20f).21 100% conver-
=
Methyl acetyl-D-phenylalaninate (20a).20,21 100% con-
1
sion and 99.5% ee. [α]20 = -29 (c = 1.0, CHCl3). H NMR
D
version and 96.5% ee. [α]20 = -105 (c = 1.0, CHCl3). 1H
D
(400 MHz, CDCl3): δ 6.47 (br s, 1H), 4.54-4.59 (m, 1H),
3.75 (s, 3H), 2.04 (s, 3H), 1.82-1.91 (m, 1H), 1.66-1.77 (m,
1H), 0.92 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
173.0, 170.0, 53.2, 52.1, 25.3, 22.9, 9.4. HRMS: (ESI+, m/z)
calculated for [C7H13NNaO3] (M+Na)+: 182.0793, found:
182.0795. HPLC: Daicel IA column (hexane/i-PrOH =
95/05), flow rate = 1.0 mL/min; λ = 220 nm; tR(major) = 12.7
min, tR(minor) = 16.94 min.
NMR (400 MHz, CDCl3): δ 7.24-7.31 (m, 3H), 7.09 (d, J = 7.2
Hz, 2H), 6.00 (br s, 1H), 4.86-4.91 (m, 1H), 3.73 (s, 3H),
3.06-3.17 (m, 2H), 1.98 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 172.1, 169.6, 135.8, 129.2, 128.6, 127.1, 53.1, 52.3, 37.8,
23.1. HPLC: Daicel IA column (hexane/i-PrOH = 90/10),
flow rate = 1.0 mL/min; λ = 220 nm; tR(major) = 10.10min,
t
R(minor) = 12.87 min.
Methyl (R)-2-acetamido-3-(p-tolyl)propanoate (20b).22,23
Methyl acetyl-D-alaninate (20g).24 100% conversion and
100% conversion and 97.0% ee. [α]20 = -100 (c = 1.0,
D
99.4% ee. [α]20 = -8 (c = 1.0, CHCl3). H NMR (400 MHz,
1
D
CHCl3). 1H NMR (400 MHz, CDCl3): δ 7.09 (d, J = 7.6 Hz, 2H),
CDCl3): δ 6.60 (br s, 1H), 4.54-4.62 (m, 1H), 3.75 (s, 3H),
2.02 (s, 3H), 1.40 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 173.5, 169.7, 52.2, 47.8, 22.8, 18.0. HRMS: (ESI+,
m/z) calculated for [C6H11NNaO3] (M+Na)+: 168.0637,
found: 168.0628. HPLC: Daicel IA column (hexane/i-PrOH
6.97 (d, J = 7.6 Hz, 2H), 5.98 (br d, J = 6.4 Hz, 1H), 4.83-
4.88 (m, 1H), 3.73 (s, 3H), 3.10 (dd, J = 14.0 Hz, J = 6.0 Hz,
1H), 3.05 (dd, J = 14.0 Hz, J = 6.0 Hz, 1H), 2.31 (s, 3H), 1.98
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.2, 169.7, 136.7,
132.6, 129.3, 129.1, 53.1, 52.2, 37.3, 23.1, 21.0. HRMS:
(ESI+, m/z) calculated for [C13H18NO3] (M+H)+: 236.1287,
found: 236.1313. HPLC: Daicel IA column (hexane/i-PrOH
= 95/05), flow rate = 1.0 mL/min; λ = 214 nm; tR(major)
15.57min, tR(minor) = 21.21 min.
=
= 90/10), flow rate = 1.0 mL/min; λ = 220 nm; tR(major)
9.79min, tR(minor) = 12.72 min.
=
ASSOCIATED CONTENT
Supporting Information
Methyl (R)-2-acetamido-3-(3-methoxyphenyl)propanoate
(20c).20 100% conversion and 97.8% ee. [α]20 = -105 (c =
The Supporting Information is available free of charge on the
ACS Publications website.
D
1
1.0, CHCl3). H NMR (400 MHz, CDCl3): δ 7.21 (t, J = 8.0 Hz,
1H), 6.79 (d, J = 7.6 Hz, 1H), 6.63-6.68 (m, 2H), 5.93 (br s,
1H), 4.85-4.91 (m, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.04-3.15
(m, 2H), 2.00 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.0,
169.8, 159.4, 137.3, 129.3, 121.3, 114.8, 112.1, 54.9, 53.0,
52.0, 37.4, 22.7. HRMS: (ESI+, m/z) calculated for
[C13H18NO4] (M+H)+: 252.1236, found: 252.1238. HPLC:
Daicel IA column (hexane/i-PrOH = 90/10), flow rate = 1.0
mL/min; λ = 220 nm; tR(major) = 27.13min, tR(minor) = 32.35
min.
HPLC traces and NMR spectra for all new compounds (PDF)
X-ray data for compound 16a, 16b, 18a (CIF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: sokr@kemi.dtu.dk, sunxingwen@fudan.edu.cn.
Methyl (R)-2-acetamido-3-(2-methoxyphenyl)propanoate
Notes
(20d).23 100% conversion and 98.8% ee. [α]20 = -64 (c =
D
The authors declare no competing financial interest.
1
1.0, CHCl3). H NMR (400 MHz, CDCl3): δ 7.24 (t, J = 8.0 Hz,
ACKNOWLEDGMENT
1H), 7.08 (d, J = 7.2 Hz, 1H), 6.86-6.92 (m, 2H), 6.23 (br d, J
= 6.0 Hz, 1H), 4.75 (dt, J = 10.4 Hz, J = 7.2 Hz, 1H), 3.84 (s,
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Zhou, Q.-L. Dynamic Kinetic Resolution Allows a Highly Enantiose-
The authors acknowledge the financial support from the Na-
tional Natural Science Foundation of China (21342009 and
21472019).
lective Synthesis of cis-α-Aminocycloalkanols by Ruthenium-
Catalyzed Asymmetric Hydrogenation. Angew. Chem. Int. Ed.
2007, 46, 7506–7508. (f) Liu, C.; Xie, J.-H.; Li, Y.-L.; Chen, J.-Q.;
Zhou, Q.-L. Asymmetric Hydrogenation of α,α’-Disubstituted Cy-
cloketones through Dynamic Kinetic Resolution: An Efficient Con-
struction of Chiral Diols with Three Contiguous Stereocenters.
Angew. Chem. Int. Ed. 2013, 52, 593–596.
(7) Xie, J. H.; Zhou, Q.-L. Chiral Diphosphine and Monodentate
Phosphorus Ligands on a Spiro Scaffold for Transition-Metal-
Catalyzed Asymmetric Reactions. Acc. Chem. Res. 2008, 41, 581–
593.
(8) (a) Cheng, X.; Zhang, Q.; Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L.
Highly Rigid Diphosphane Ligands with a Large Dihedral Angle
Based on a Chiral Spirobifluorene Backbone. Angew. Chem. Int. Ed.
2005, 44, 1118–1121. (b) Cheng, X.; Xie, J.-H.; Li, S.; Zhou, Q.-L.
Asymmetric Hydrogenation of α,β-Unsaturated Carboxylic Acids
Catalyzed by Ruthenium(II) Complexes of Spirobifluorene Di-
phosphine (SFDP) Ligands. Adv. Synth. Catal. 2006, 348, 1271–
1276.
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Catalyzed Hydrogenation and Spiroketalization of α,α’-Bis(2-
hydroxyarylidene Angew. Chem. Int. Ed. 2012, 51, 936–940. (b)
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aldrich.com.
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