Oxidative Kinetic Resolution of Some Naphtholic Alcohols Mediated by a Chiral Hypervalent Iodine Reagent

Article abstract of DOI:10.1055/s-0037-1610214

A chiral aryl iodide enables the catalytic, oxidative kinetic resolution of various 2-[(3-hydroxy-2-alkyl)propyl]naphthalen-1-ols.

Full text of DOI:10.1055/s-0037-1610214

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
feature
A
en
N. Jain et al.
Feature
Synthesis
Oxidative Kinetic Resolution of Some Naphtholic Alcohols Mediated
by a Chiral Hypervalent Iodine Reagent
R1
NHCOMes
I
NHCOMes
Nikita Jain
O
O
HO
Marco A. Ciufolini*
i-Pr
i-Pr
(20 mol%)
OH
Department of Chemistry, The University of British Columbia,
2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
ciufi@chem.ubc.ca
MCPBA (60 mol%)
racemic
R1 = alkyl, aryl
R2 = H, Cl, Br
CH2Cl2, –20 °C, ~ 12 h
50% conversion
14 examples
R2
syn
R1
H
R1
H
HO
O
OH
O
+
R2
R2
40–80% ee; 28–44% yield
(out of ~ 50% maximum)
+ anti diast.; dr ~ 4:1; 70–96% ee
for each diast.; 37–50% yield
(out of ~ 50% maximum)
Received: 22.05.2018
Accepted after revision: 21.06.2018
Published online: 02.08.2018
R
R
HO
O
X
MCPBA
CH2Cl2
OH
O
DOI: 10.1055/s-0037-1610214; Art ID: ss-2018-z0334-fa
3 (20 mol%)
–20 °C
1
2
Abstract A chiral aryl iodide enables the catalytic, oxidative kinetic
resolution of various 2-[(3-hydroxy-2-alkyl)propyl]naphthalen-1-ols.
X
median
range
90% 69–93%
63% 15–79%
ee =
yield =
Key words alcohols, asymmetric catalysis, hypervalent iodine, kinetic
resolution
O
Z
I
Z
O
3
4
Z = t-Bu
Z = i-Pr
O
O
Mes
Mes
N
N
Mes
Mes
A recent contribution from these laboratories describes
the catalytic, enantioselective oxidative cyclization of naph-
tholic alcohols 1 to spirocycles 2 (Scheme 1; R = H).1 This
process is mediated by a hypervalent2 form of chiral aryl io-
dide3 3, which is recognized as a structural variant of the
Uyanik–Ishihara catalyst, 6.4 Unlike the related reaction of
carboxylic acids,4 the rate of cyclization of 1 is rather slow,
typically requiring from 12 hours (X ≠ acyl) to as long as
some days (X = acyl). Attempts to accelerate the reaction by
introducing a gem-dialkyl motif on the hydroxypropyl
chain (Thorpe–Ingold effect)5 resulted in even slower rates.
Evidently, in the present case, unfavorable steric interac-
tions between substrate and catalyst override rate-enhanc-
ing effects. This observation led to the surmise that the
same interactions could promote the kinetic resolution of
alcohols 1,6 wherein R is a single alkyl group. Indeed, our
publication illustrated one such example.
Examples of kinetic resolution mediated by hypervalent
iodine species are known,7 but systematic studies of the
process appear to be unrecorded. This provided an incen-
tive to further research the kinetic resolution of alcohols 1,
in that results of such investigations may well assist in the
future development of more effective hypervalent iodine
catalysts.
H
H
O
R1
I
R1
O
5 R1 = Me, R2 = H
6 R1 = H, R2 = Me
O
O
N
N
H
H
R2
R2
Scheme 1 Enantioselective oxidative cyclization of alcohols 1 cata-
lyzed by aryl iodide 3
The pursuit of the foregoing objective commenced with
an exploration of the behavior of substrates (±)-1a–d
(Scheme 2). The presence of a chlorine atom at the naphth-
olic 4-position ensured that no oxidation to naphthoqui-
nones would occur upon exposure of these materials to io-
2'
2'
R
R
R3'
R1'
R3'
R1'
O
[ O ]
chiral
iodide
HO
O
+
enantio-
enriched
1a–d
OH
ca.
50%
conv.
Cl
Cl
1a R1' = Me, R2' = R3' = H
1' = Ph, R2' = R3' = H
1c R1' = R2' = H, R3' = Ph
1d R1' = R3' = H, R2' = i-Pr
2a
2b
R
1' = Me, R2' = R3'= H
R
1' = Ph, R2' = R3'= H
2c R1' = R2' = H, R3' = Ph
2d R1' = R3' = H, R2' = i-Pr
1b
R
Scheme 2 Model substrates employed in the initial phase of this study
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
N. Jain et al.
Feature
Synthesis
dine-based oxidants. This process consumes significant
amounts of 4-unsubstituted naphthol substrates, to the
detriment of overall efficiency.1
and the minor ones as (±)-syn-2a and (±)-syn-2b. The oxi-
dative cyclization of 1c returned only (±)-anti-2c.1 In con-
trast to the above cases, the cyclization of 1d returned (±)-
syn-2d as the dominant product (d.r. ≈ 4:1; see Table 3). Al-
so, yields of spiroethers 2d were higher compared to 2a–c.
Alcohol 1d was thus chosen as the test substrate for oxida-
tive cyclization/kinetic resolution.1
The action of a chiral oxidant on (±)-1a–d could not only
promote selective cyclization of one enantiomer to 2, pro-
viding enantioenriched residual alcohol (= kinetic resolu-
tion), but also alter the diastereoselectivity of the process.
Accordingly, the oxidative cyclization of 1a–d was first exe-
cuted with an achiral iodine oxidant, so as to evaluate the
innate (substrate-controlled) selectivity of the reaction.
Past experience had shown that the chiral iodides in
Scheme 1 perform best in CH2Cl2 and that the stereochemi-
cal course of the reaction was quite solvent-dependent. It
thus seemed advisable to carry out the spiroetherification
of 1a–d in CH2Cl2. To that end, [bis(trifluoroacetoxy)io-
do]benzene (PIFA) was chosen as the oxidant, because it is
known to perform well in CH2Cl2. In all cases, the four ste-
reoisomers of each product (two enantiomers of each dia-
stereomer), were separable by chiral supercritical fluid
chromatography (SFC). Integration of the SFC trace enabled
the determination of diastereomeric ratios and, later, of en-
antiomeric excess values. However, the diastereomers were
difficult to separate by flash column chromatography. For-
tunately, their 1H NMR signals were well resolved, enabling
the assignment of relative configurations by NOESY-2D
NMR spectrometry.1
The process in question was initially studied with cata-
lysts 3–6 under the conditions optimized earlier for the
asymmetric cyclization of unsubstituted alcohols 1.1 Reac-
tions were run to about 50% conversion in order to assess
the enantiomeric enrichment of recovered 1d and of prod-
ucts. To that end, only 0.6 equivalents of MCPBA were used
in each experiment (Table 1). The diastereoselectivity of the
process was largely unaffected by the nature of the chiral
catalyst. With regard to optical enrichment of residual 1d,
iodoarenes 3 and 6 afforded material of a moderate 54–57%
ee. Much better results were obtained with 4, which re-
turned unreacted 1d of 79% ee. Catalyst 4 also exhibited a
higher selectivity factor (S = 10) relative to its congeners
(S = 4.5–5.6). Furthermore, reactions run with 4 proceeded
at a faster rate relative to 3 (13.5 vs. 20 h). Finally, reactions
run with iodides 3 and 4 returned (+)-1d, later shown to be
of S-configuration, while 6 afforded (R)-(–)-1d (vide infra).
That catalysts 3 and 4 promote the opposite sense of induc-
tion relative to 5 is consistent with earlier findings.1
Substrates bearing a group at the 1′-position 1a,b react-
ed with poor diastereoselectivity (d.r. ≈ 1.5:1 for 1a, 1.8:1
for 1b). In either case, the 1′-substituent in the major dias-
tereomer was anti to the naphthol-derived carbonyl group
within the newly formed tetrahydrofuran ring. The major
products are thus described as (±)-anti-2a and (±)-anti-2b,
An opposite sense of asymmetric induction was also ob-
served for spiroethers 2 (Table 1). It subsequently trans-
pired that iodide 4 induced formation of syn-2d of R,R-con-
figuration, and of anti-2d of R-configuration at the spiro-
center and S-configuration at the isopropyl-bearing carbon.
Biographical Sketches
Nikita Jain (Siliguri, India,
1988), received her B.Sc. in
2010 from St. Xavier’s College
(India) and her M.Sc. in 2012
from IIT Kanpur (India), where
she synthesized 2,2-diarylethyl-
amines and various γ-aminobu-
tyric acid derivatives in the
group of Prof. Manas K. Ghorai.
She pursued her Ph.D. (2012–
2017) in the group of Prof. Marco
A. Ciufolini at The University of
British Columbia, Vancouver.
There, she developed method-
ologies for enantioselective
oxidative amidation and cy-
cloetherification of naphthols
using chiral hypervalent iodine
reagents. She is currently work-
ing as a Research Scientist at
SWITCH Materials Inc., Burnaby,
Canada.
Marco A. Ciufolini (Rome, Ita-
ly, 1956; B.Sc. 1978, Spring Hill
College, Mobile, AL, USA; Ph.D.
1981, University of Michigan,
Prof. M. Koreeda; postdoctoral
fellow, 1982–1984, Yale Univer-
sity, Prof. S. Danishefsky) is the
Canada Research Chair in Syn-
thetic Organic Chemistry at the
University of British Columbia.
He started his independent ca-
reer in 1984 at Rice University,
Houston, TX, where he rose
through the ranks and was pro-
moted to Professor in 1997. In
the same year, he was offered a
professorship at the ESCPE Lyon
and the University Claude
Bernard Lyon and moved to
France, but in 2004 he returned
to North America to accept his
current position. His research
interests center on the chemical
synthesis of nitrogenous natural
products and span natural prod-
ucts chemistry, synthetic meth-
odology,
and
medicinal
chemistry.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

C
N. Jain et al.
Feature
Synthesis
Henceforth, the configurations of cyclic products are re-
ported so that the first one relates to the spirocenter; the
second one, to the alkyl-bearing carbon.
scalemic 1d of lower ee relative to CH2Cl2. On the other
hand, the spiroether products still exhibited an excellent
enantiomeric enrichment. Polar solvents, either neat or ad-
mixed with CH2Cl2, were damaging. Thus, substantial loss of
asymmetric induction was observed when the reaction was
run in a mixture of CH2Cl2 and nitromethane, while no en-
antioselectivity at all ensued upon operation in neat trifluo-
roethanol (TFE).9 Nonpolar solvents such as toluene were
also unsatisfactory. Finally, reactions run in a mixture of
CH2Cl2 and methyl tert-butyl ether were found to be ex-
tremely slow, resulting in hardly any conversion after 6
hours. Perhaps unsurprisingly, the best conditions for effec-
tive cycloetherification/kinetic resolution were the same as
those employed earlier for the enantioselective cyclization
of 1.
Table 1 Enantioselective Cyclization/Kinetic Resolution of Test Alcohol
1d Mediated by Catalysts 3–6a
O
O
chiral
iodide
i-Pr
O
O
H
recovered
1d
*
(
)-1d
*
+
+
MCPBA
CH2Cl2
i-Pr
H
Cl
Cl
syn-2d: major
anti-2d: minor
Iodide
3
4
5
6
Reaction time (h)
Conversionb (%)
d.r.c
20
13.5
56
6.5
6
The absolute configurations of unreacted 1d and of syn-
and anti-2d thus produced were determined as reported by
us earlier.1
52
53
54
80:20
49
83:17
52
83:17
47
77:23
50
Yield (%) syn + anti 2dd
ee (%) syn-2de
Alcohol (+)-1d of 79% ee, retrieved from a reaction run
with 4, was subjected to a second round of oxidative cy-
clization mediated by the same catalyst (Scheme 3). This re-
action was halted at 43% conversion, whereupon residual
(+)-1d was found to be of 96% ee. This highly enantioen-
riched material was converted into the crystalline bis-p-
bromobenzoate ester (–)-7, which proved to be of S-config-
uration upon X-ray crystallographic analysis. This means
that (S)-(+)-1d is the slow reacting alcohol enantiomer
when (±)-1d cyclizes in the presence of iodide 4 (or 3), and
(R)-(–)-1d is the fast reacting one. Consequently, the abso-
lute configuration of the carbon atom bearing the i-Pr
group in major diastereomer syn-2d (94% ee, Table 1) must
be R. But the relative configuration of syn-2d requires that
the spirocenter of the molecule also be of R-configuration.
Therefore, syn-2d obtained with catalysts 3 and 4 must be
of R,R configuration.
Furthermore, (S)-(+)-1d of 96% ee was again subjected
to cyclization in the presence of 4, thereby yielding a 1:4
mixture of syn-2d (minor in this case) and anti-2d (major).
The 4:1 mixture of syn-2d (major) and anti-2d (minor) pro-
duced in the reaction of Table 2, and the 1:4 one of syn-2d
(minor) and anti-2d (major) obtained as per Scheme 4,
were independently subjected to NOESY 2D NMR study,
which nicely confirmed the relative configuration of each
product. Furthermore, anti-2d arising as the major product
from the cyclization of (S)-(+)-1d of 96% ee was identical
(chiral SFC; NMR) to the major enantiomer of anti-2d ob-
tained earlier from the reactions in Table 2. Therefore, the
absolute configuration of the carbon atom bearing the i-Pr
group in anti-2d produced with catalysts 3 and 4 is S. But
the relative configuration of the molecule requires that the
spirocenter be of R-configuration. The absolute configura-
tion of anti-2d must then be R,S. Chiral iodides 3 and 4 thus
operate preferentially on the R-enantiomer of 1d and pro-
90
94
77
89
Config. syn-2df
ee (%) anti-2de
Config. anti-2df
ee (%) recov. 1de
Config. recov. 1dg
Yield (%) recov. 1dd
S-factorh
R,R
97
R,R
98
S,S
S,S
97
79
R,S
57
R,S
79
S,R
S,R
54
57
(S)-(+)-
30
(S)-(+)-
(R)-(–)-
29
(R)-(–)-
30
35
5.6
10.0
5.3
4.5
a Reaction conditions: 20 mol% chiral iodide, 60 mol% MCPBA, 0.02 M solu-
tion, –20 °C.
b Determined by 1H NMR spectroscopy using 3,5-dimethoxybenzaldehyde
as the internal standard.
c Diastereomeric ratio: determined by integration of the chiral SFC trace of
the mixture of products after column chromatography.
d Isolated yields after chromatography.
e Enantiomeric excess: determined by chiral SFC.
f In all cases, the first configuration is that of the spirocenter, the second
one, that of the alkyl-bearing carbon.
g Determined by X-ray diffractometry (see text).
h Selectivity factor, S = ln[(1 – c)(1 – eeSM)]/ln[(1 – c)(1 + eeSM)]; eeSM = ee
of recovered starting material, c = conversion.
The observation that a decrease in the steric demand of
the alkyl group in 3 versus 4 (t-Bu vs i-Pr) resulted in better
catalytic performance induced us to evaluate the methyl
analogue, 5.8 However, this catalyst proved to be inferior:
the ee’s of recovered 1d and of cyclic products, as well as
the selectivity factor (S = 5.3), were markedly lower com-
pared to 4. Overall, the latter iodide seemed to be optimal
for kinetic resolution.
Just as observed earlier for the reaction 1 → 2,1 kinetic
resolutions orchestrated by iodoarene 4 occurred best in a
0.02 M solution in CH2Cl2 at –20 °C (Table 2). Changes in
temperature or concentration had no major effect on effi-
ciency, except for a slight lowering of the S-factor. However,
the nature of the solvent was critical. Among the alternative
solvents that were tested, only CHCl3 proved to be moder-
ately competent. Yet, reactions run in this medium returned
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

D
N. Jain et al.
Feature
Synthesis
Table 2 Effect of Solvent on the Performance of Catalyst 4 with Test Substrate 1da
O
O
4
HO
i-Pr
O
O
H
(20 mol%)
recovered
(S)-(+)-1d
+
OH
+
MCPBA
solvent
H
i-Pr
Cl
Cl
(
)-1d
Cl
(R,R)-syn-2d: major
(R,S)-anti-2d: minor
1:3 CH2Cl2/ MeNO2 4:3 CH2Cl2/ MTBEe CHCl3
Toluene
TFEf
b
c
d
Solvent:
CH2Cl2
CH2Cl2
CH2Cl2
Reaction time (h)
Conversiong (%)
d.r.h
13.3
56
7.3
58
9.7
60
18.5
50
6
<5
–
16.5
51
14.3
53
13.5
59
83:17
52
84:16
53
80:20
52
82:18
44
82:18
50
88:12
34
75:25
48
Yield (%) syn + anti 2di
ee (%) (R,R)-syn-2dj
ee (%) (R,S)-anti-2dj
ee (%) recov. (S)-1dj
Yield (%) recov. (S)-1di
S-factork
–
94
89
90
80
–
94
90
32
98
92
97
79
–
98
71
<5
79
80
78
48
–
62
45
<5
35
36
35
30
–
35
38
<5
10.0
8.9
7.2
4.5
–
7.3
3.5
–
a Reaction conditions: 0.6 equiv MCPBA, 0.02 M solution.
b Reaction performed at –20 °C.
c Reaction performed at 0 °C.
d Reaction performed at –20 °C at a concentration of 0.05 M.
e MTBE: methyl tert-butyl ether.
f TFE: 2,2,2-trifluoroethanol.
g Determined by 1H NMR spectroscopy using 3,5-dimethoxybenzaldehyde as the internal standard, (c = 100% yield of starting material).
h Determined by integration of the chiral SFC trace of the mixture of products after column chromatography.
i Isolated yields after column chromatography.
j Determined by chiral SFC.
k Selectivity factor, S = ln[(1 – c)(1 – eeSM)]/ln[(1 – c)(1 + eeSM)]; eeSM = ee of recovered starting material, c = conversion.
O
H
mote the formation of spirocenters of R-configuration
(Scheme 4). This is consistent with the sense of induction
observed earlier with substrates 1 (R = H).1
PMBO
Br
Cl
OPMB
DMAP, Py
79%
(–)-(S)-7
96% ee
(X-rays)
Cl
HO
Cl
H
4
4 (20 mol%)
MCPBA
(0.6 equiv)
i-Pr
(
)-1d
*
HO
O
MCPBA
syn-2d
major
61% ee
anti-2d
minor
99% ee
(+)-1d
52%
96% ee
8
Cat*
OH
+
+
CH2Cl2
(0.02 M)
–20 °C, 6 h
43% conv.
i-Pr
i-Pr
i-Pr
H
O
H
O
H
36% yield
d.r. = 51:49
O
O
HO
(+)-1d Cl
79% ee
OH
+
+
O
O
4 (20 mol%)
MCPBA
(S)
(S)
Cl
Cl
Cl
(1.3 equiv)
(R)
(S)
O
+
O
(S)-(+)-1d
(R,R)-syn-2d
(R,S)-anti-2d
major
minor
CH2Cl2
(0.02 M)
–20 °C
16 h
Cl
Cl
Scheme 4 Preferred stereochemical course of the oxidative cycliza-
tion/kinetic resolution of alcohol 1d with catalyst 4
d.r. = 4 :1
(S,S)-2d
minor
(R,S)-2d
major, 99% ee
identical to
anti-2d obtained
with 3 or 4 (Table 2)
In contrast, the kinetic resolution of compounds 1a–c
mediated by catalyst 4 was inefficient: recovered alcohols
were of uniformly low (<10%) ee.1 Moreover, (±)-1a,b af-
forded highly enantioenriched spirocyclic products (config-
urations not determined), but with low diastereoselectivity,
Scheme 3 Determination of the absolute configurations of enantioen-
riched spirocycle (R,S)-anti-2d (minor product obtained upon cycliza-
tion of 1d in the presence of 4) and of recovered alcohol 1d
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

E
N. Jain et al.
Feature
Synthesis
while (±)-1c provided (+)-2c as a single diastereomer of
only 34% ee. Therefore, no further work was done with 1′-
or 3′-substituted materials.
The encouraging results obtained with 1d warranted
further investigation of analogous 2′-substituted substrates.
Indeed, the resolution of primary alcohols bearing a stereo-
genic center at the β-position (such as 1d) is challenging.10
Kinetic resolution mediated by 4 offered an interesting and
novel opportunity.
meric enrichments of unreacted (+)-1 were observed in the
4-Cl series (ee >70%), as were the best selectivity factors, S.
An especially high S-value of 19 was attained with 1f. Sub-
strates with R = Me consistently returned (+)-1 of less than
50% ee. Contrary to what was observed earlier with 1d, cat-
alyst 4 generally enhanced the diastereoselectivity of the
reaction of 1e–p in favor of the syn-isomer. The most nota-
ble effect in that sense was recorded with 1f, for which the
syn-selectivity increased from 74:26 with PIFA (Table 3) to
91:9 with 4. Spiroethers obtained from 4-H and 4-Cl sub-
strates were of generally good to excellent ee, except for
anti-2i, while those resulting from 4-Br alcohols tended to
be of slightly lower ee. As seen in Table 4, in some cases chi-
ral SFC failed to separate the enantiomers of the spirocycles.
This was especially distressing in the context of 1q (Scheme
5), because, unlike other cyclic products, diastereomers
syn-2q and anti-2q were readily separable by flash column
chromatography and exhibited large positive rotations
(> +100; Scheme 5). The failure of chiral SFC to separate
their enantiomers prevented a straightforward determina-
tion of their ee.
The compounds thus examined are alcohols 1e–p,8
which, as before, were first subjected to oxidative cycliza-
tion with PIFA in CH2Cl2 (Table 3). This consistently resulted
in preferential (3–4:1) formation of syn-2e–p.
Table 3 Diastereoselectivity in the Oxidative Cyclization of 2′-Mono-
substituted Alcohols 1 Mediated by PIFAa
O
O
R
HO
O
O
R
+
H
OH
)-1
H
R
X
X
(
(
)-syn-2: major
( )-anti-2: minor
X
CH2CF3
CH2CF3
4 (20 mol%)
MCPBA
(0.6 equiv)
Entry
X
R
dr
Yield (%)b
HO
HO
*
+
OH
OH
d
e
f
Cl
i-Pr
77:23c
68:32d
74:26c
69:31c
75:25c
68:32c
68:32d
73:27c
78:22c
79:21c
68:32d
77:23c
77:23c
49
45
46
48
50
39
48
33
44
43
18
28
20
CH2Cl2
(0.02 M)
–20 °C, 6 h
48% conv.
(+)-1q
44%
57% ee
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
H
Me
(
)-1q
CH2CF3
Bn
O
O
O
O
g
h
i
H
CH2CF3
+
c-C6H11
Ph
CH2CF3
H
syn-2q
anti-2q
minor, 4%
d.r = 83:17
(text)
major, 36%
[α]D25 +132.7°
[α]D25 +190.1°
j
Me
(c 0.93, CHCl3)
(c 0.31, CHCl3)
k
l
Bn
Scheme 5 Behavior of alcohol 1q
i-Pr
m
n
o
p
c-C6H11
Me
In summary, chiral iodide 4 appears to be a competent
catalyst for the kinetic resolution of alcohols 1d–p, afford-
ing improved selectivity factors relative to structurally re-
lated catalysts. This work illustrates a new application of
chiral hypervalent iodine species as mediators of the kinetic
resolution of primary alcohols bearing a stereogenic center
at the β-position.
H
i-Pr
H
c-C6H11
a Reaction conditions: PIFA, CH2Cl2.
b Isolated yields (non-optimized) after silica gel column chromatography.
c Determined by integration of chiral SFC trace.
d Determined by integration of the 1H NMR spectrum of the crude reaction
mixture.
Diastereomeric ratios were once again measured by in-
tegration of 1H NMR spectra of product mixtures or of chro-
matograms obtained by chiral SFC, and the relative configu-
ration of syn- and anti-2e–p was determined by 2D NOESY
NMR.8 Notice how substrates incorporating halogen at the
naphtholic 4-position cyclized in generally higher yields
relative to their unsubstituted analogues 1n–p, a significant
fraction which was lost to naphthoquinone formation.
Kinetic resolution of 1e–p in the presence of 4 yielded
the results summarized in Table 4. In all cases, recovered
starting alcohol was dextrorotatory. The highest enantio-
Most commercial reagents and solvents were used as received, but
CH2Cl2 was freshly distilled from CaH2 under argon. All reactions were
performed under argon in flame- or oven-dried flasks equipped with
Teflon stirring bars and fitted with rubber septa for the introduction
of materials via syringe. Reactions were monitored by TLC using silica
gel 60 F254 precoated plates. Spots were visualized by UV or with
KMnO4 or vanillin stains. Flash chromatography utilized Silicycle®
1
230–400 mesh silica gel. Unless otherwise stated, H (300 MHz) and
13C (75 MHz) NMR spectra were recorded from CDCl3 solutions at r.t.
Chemical shifts are reported in parts per million (ppm) on the δ scale
and coupling constants, J, in hertz (Hz). Standard abbreviations are
used to indicate multiplicities. IR spectra (cm–1) were recorded from
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

F
N. Jain et al.
Feature
Synthesis
Table 4 Kinetic Resolution of Alcohols 1 Mediated by Catalyst 4a
R
O
X
O
X
4
HO
(20 mol%)
R
O
O
H
unreacted
(+)-1
*
*
+
OH
)-1
+
MCPBA
solvent
H
R
(
X
syn-2: major
anti-2: minor
Entry
X
R
Conv.b (%)
Yield (%) recov. 1c,d ee (%) recov. d.r.e syn/anti Yield (%) 2c (syn + anti) ee (%)syn-2e ee (%) anti-2e S-factorf
1e
h
h
e
f
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
H
Me
44
47
50
58
42
59
52
57
60
55
60
57
48
40
37
40
38
40
35
42
35
28
40
35
33
44
47
71
72
76
51
49
71
67
65
48
62
41
57
79:21g
91:9
42
–
–
6.2
19.0
13.0
7.6
CH2CF3
Bn
45
94
94
92
93
79
91
95
59
g
h
i
87:13
80:20
86:14
81:19g
88:12
86:14
83:17
86:14g
82:18
81:19
83:17
47
c-C6H11
Ph
53
37
9.5
h
h
j
Me
45
–
–
3.2
k
l
Bn
45
86
73
72
82
87
86
10.0
5.9
i-Pr
51
m
n
o
p
q
c-C6H11
Me
53
4.7
h
h
50
–
–
3.6
h
H
i-Pr
48
96
94
–
4.3
h
H
c-C6H11
CH2CF3
45
–
2.7
h
h
H
36 + 4
–
–
7.4
a Reaction conditions: 0.6 equiv MCPBA, 0.02 M solution, 13 h.
b Determined by 1H NMR spectroscopy using 3,5-dimethoxybenzaldehyde as the internal standard, (c = 100% yield of starting material).
c Isolated yields after column chromatography.
d The maximum theoretical yield of recovered 1e–q is 50%.
e Determined by chiral SFC.
f Selectivity factor, S = ln[(1 – c)(1 – eeSM)]/ln[(1 – c)(1 + eeSM)]; eeSM = ee of recovered starting material, c = conversion.
g Determined by integration of the 1H NMR spectrum of the crude reaction mixture.
h The enantiomers were inseparable by chiral SFC under all conditions tried.
films (PerkinElmer Universal ATR Sampling Accessories). Low and
high-resolution mass spectra (m/z) were obtained in the electron im-
pact (EI) or electrospray (ESI; MeOH solutions) mode, as specified.
Optical rotations were measured at the NaD line (589 nm) with a
PerkinElmer 241 polarimeter. Enantiomeric excesses reported in this
experimental section were determined using a Thar SFC station
(Model 840) equipped with chiral columns OD-H (0.46 cm × 25 cm 5
μm), AD-H (0.46 cm × 25 cm 5 μm), AS-H (0.46 cm × 25 cm 5 μm), OJ-
H (0.46 cm × 25 cm 5 μm) and Lux 3u Cellulose 2 (50 × 4.60 mm). The
operating pressure was 120 bar and the column temperature was 33–
34 °C. The intensities of the signals of each enantiomer in enantioen-
riched products were corrected on the basis the ratios of the signal
intensities observed for the racemates. More detailed experimental
protocols are provided as Supporting Information.8
(±)-4′-Chloro-4-isopropyl-4,5-dihydro-1′H,3H-spiro[furan-2,2′-
naphthalen]-1′-one (2d)
Eluent: 1:19 EtOAc/hexanes; yield: 24 mg (49%) from 50 mg of (±)-1d;
colorless oil; 3:1 mixture of syn- and anti-2d.
IR (film): 1693 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.04–7.99 (m, 1 H), 7.72–7.64 (m, 2 H),
7.48–7.43 (m, 1 H), 6.42 (s, 0.75 H), 6.37 (s, 0.25 H), 4.42 (app t, J = 7.5
Hz, 0.25 H), 4.26 (app t, J = 7.5 Hz, 0.75 H), 3.86 (app t, J = 9.0 Hz, 0.75
H), 3.76 (app t, J = 7.5 Hz, 0.25 H), 2.43–1.99 (m, 3 H), 1.70–1.49 (m, 1
H), 0.95–0.88 (m, 6 H).
13C NMR (CDCl3, 75 MHz): δ = 199.6, 135.1 (2 C), 135.0, 134.9, 133.8,
133.7, 129.4, 129.3, 129.2, 129.0, 128.9 (2 C), 127.7, 125.6, 125.5, 86.3,
84.6, 48.4, 45.3, 43.4, 40.9, 32.1, 31.5, 22.1, 22.0, 21.9, 21.7.
HRMS: m/z [M – H]– calcd for C16H16ClO2: 275.0844; found: 275.0816.
Diastereoselective Cyclization of Alcohols 1 with PIFA in CH2Cl2;
General Procedure
(±)-4′-Chloro-4-methyl-4,5-dihydro-1′H,3H-spiro[furan-2,2′-
naphthalen]-1′-one (2e)
A solution of an alcohol 1 (0.36 mmol, 1.0 equiv) in CH2Cl2 (12.0 mL)
was slowly added at r.t. over a period of 2 min to a solution of PIFA
(170 mg, 0.4 mmol, 1.1 equiv) in CH2Cl2 (8.0 mL). The final concentra-
tion of substrate was then nominally 0.02 M. The solution was stirred
for 1 to 2 h, whereupon TLC showed that the reaction was complete.
The mixture was evaporated to dryness and the residue was purified
by flash column chromatography to afford spiroethers 2.
Eluent: 1:19 EtOAc/hexanes; yield: 9 mg (45%) from 20 mg of (±)-1e;
colorless oil; 7:3 mixture of syn- and anti-2e.
IR (film): 1692 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

G
N. Jain et al.
Feature
Synthesis
1H NMR (CDCl3, 300 MHz): δ = 8.04–7.99 (m, 1 H), 7.72–7.64 (m, 2 H),
7.48–7.43 (m, 1 H), 6.40 (s, 0.7 H), 6.39 (s, 0.3 H), 4.38 (app t, J = 7.6
Hz, 0.3 H), 4.23 (app t, J = 7.6 Hz, 0.7 H), 3.74 (app t, J = 9.9 Hz, 0.7 H),
3.65 (app t, J = 8.1 Hz, 0.3 H), 2.80–2.61 (m, 0.3 H), 2.59–2.45 (m, 0.7
H), 2.37 (dd, J = 12.9, 7.0 Hz, 0.3 H), 2.19 (dd, J = 12.5, 7.5 Hz, 0.7 H),
1.99 (dd, J = 11.5, 10.7 Hz, 0.7 H), 1.66–1.61 (m, 0.3 H), 1.13 (d, J = 6.5,
2.3 H), 1.09 (d, J = 6.7 Hz, 0.7 H).
13C NMR (CDCl3, 75 MHz): δ = 199.5, 135.1 (2 C), 135.0, 134.9, 133.9,
133.6, 129.4, 129.3, 129.2, 129.1, 128.9, 127.7, 125.6, 125.5, 85.8, 84.5,
77.1, 77.0, 46.0, 44.1, 35.2, 32.8, 16.8, 15.6.
1H NMR (CDCl3, 300 MHz): δ = 8.04–7.99 (m, 1 H), 7.72–7.64 (m, 2 H),
7.48–7.42 (m, 1 H), 6.40 (s, 0.75 H), 6.36 (s, 0.25 H), 4.42 (app t, J = 7.8
Hz, 0.25 H), 4.27 (app t, J = 7.5 Hz, 0.75 H), 3.86 (app t, J = 8.3 Hz, 0.75
H), 3.77 (app t, J = 8.5 Hz, 0.25 H), 2.46–1.99 (m, 3 H), 1.75–1.61 (m, 5
H), 1.37–1.13 (m, 4 H), 1.68–0.92 (m, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 199.7, 199.6, 135.1 (2 C), 135.0, 134.9,
133.9, 133.7, 129.4, 129.3, 129.2, 129.0 (2 C), 128.8, 127.7, 125.6,
125.5, 86.2, 84.4, 74.9, 74.8, 47.0, 44.0, 43.0, 41.8, 41.2, 40.6, 32.7,
32.6, 32.4, 32.1, 26.4, 26.2 (2 C).
HRMS: m/z [M + Na]+ calcd for C19H21ClO2Na: 339.1128; found:
339.1128.
HRMS: m/z calcd [M + Na]+ for C14H13ClO2Na: 271.0502; found:
271.0509.
(±)-4′-Chloro-4-phenyl-4,5-dihydro-1′H,3H-spiro[furan-2,2′-naph-
thalen]-1′-one (2i)
(±)-4′-Chloro-4-(2,2,2-trifluoroethyl)-4,5-dihydro-1′H,3H-
spiro[furan-2,2′-naphthalen]-1′-one (2f)
Eluent: 1:19 EtOAc/hexanes; yield: 20 mg (39%) as a mixture of dia-
stereomers from 50 mg of (±)-1i; light yellow oil; ca. 7:3 mixture of
syn- and anti-2i.
Eluent: 1:19 EtOAc/hexanes; yield: 23 mg (46%) as a mixture of dia-
stereomers from 50 mg of (±)-1f; light yellow oil; 3:1 mixture of syn-
and anti-2f.
IR (film): 1690 cm–1
.
IR (film): 1692 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.09–8.04 (m, 1 H), 7.76–7.67 (m, 2 H),
7.51–7.46 (m, 1 H), 7.37–7.32 (m, 4 H), 7.29–7.24 (m, 1 H), 6.51 (s, 0.7
H), 6.47 (s, 0.3 H), 4.66 (app t, J = 8.0 Hz, 0.3 H), 4.45 (app t, J = 7.9 Hz,
0.7 H), 4.22 (dd, J = 10.8, 8.5 Hz, 0.7 H), 4.10 (app t, J = 8.6 Hz, 0.3 H),
3.98–3.86 (m, 0.3 H), 3.71–3.59 (m, 0.7 H), 2.66–2.43 (m, 1.7 H), 2.16
(dd, J = 12.9, 10.6 Hz, 0.3 H,).
13C NMR (CDCl3, 75 MHz): δ = 199.2, 139.9, 138.7, 135.1 (2 C), 135.0,
133.2, 132.9, 129.9, 129.6, 129.5, 129.0, 128.9, 127.8 (2 C), 127.5,
127.4, 127.2, 125.8, 125.7, 85.8, 83.9, 76.4, 76.3, 46.1, 45.6, 43.6, 43.5.
1H NMR (CDCl3, 300 MHz): δ = 8.03 (app d, J = 7.6 Hz, 1 H), 7.74–7.67
(m, 2 H), 7.50–7.45 (m, 1 H), 6.36 (s, 0.75 H), 6.33 (s, 0.25 H), 4.49
(app t, J = 8.0 Hz, 0.25 H), 4.31 (app t, J = 7.8 Hz, 0.75 H), 3.88 (app t, J =
9.1 Hz, 0.75 H), 3.77 (app t, J = 8.4 Hz, 0.25 H), 3.07–2.96 (m, 0.25 H),
2.84–2.67 (m, 0.75 H), 2.50–2.22 (m, 3 H), 2.15 (dd, J = 12.8, 9.6 Hz,
0.75 H), 1.73 (dd, J = 12.9, 10.6 Hz, 0.25 H).
13C NMR (CDCl3, 75 MHz): δ = 198.9, 198.6, 135.3, 135.2, 134.9, 132.6,
132.2, 130.4, 130.1, 129.7, 129.6, 128.8, 127.8, 126.5 (q, J = 277.0 Hz),
125.8, 125.7, 85.0, 83.2, 74.5, 74.3, 42.8, 41.7, 35.9 (q, J = 28.9 Hz), 34.3
(q, J = 3.1 Hz).
HRMS: m/z [M + Na]+ calcd for C19H15ClO2Na: 333.0658; found:
333.0659.
HRMS: m/z [M + Na]+ calcd for C15H12ClF3O2Na: 339.0376; found:
339.0374.
(±)-4′-Bromo-4-methyl-4,5-dihydro-1′H,3H-spiro[furan-2,2′-
naphthalen]-1′-one (2j)
(±)-4-Benzyl-4′-chloro-4,5-dihydro-1′H,3H-spiro[furan-2,2′-naph-
thalen]-1′-one (2g)
Eluent: 1:19 EtOAc/hexanes; yield: 24 mg (48%) as a mixture of dia-
stereomers from 50 mg of (±)-1j; light yellow oil; ca. 7:3 mixture of
syn- and anti-2j.
Eluent: 1:19 to 1:9 EtOAc/hexanes; yield: 24 mg (48%) as a mixture of
diastereomers from 50 mg of (±)-1g; light yellow oil; 7:3 mixture of
syn- and anti-2g.
IR (film): 1691 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.02–7.96 (m, 1 H), 7.70–7.63 (m, 2 H),
7.46–7.41 (m, 1 H), 6.67–6.66 (m, 1 H), 4.38 (app t, J = 7.6 Hz, 0.3 H),
4.24 (app t, J = 7.6 Hz, 0.7 H), 3.75 (dd, J = 9.9, 8.4 Hz, 0.7 H), 3.64 (app
t, J = 8.1 Hz, 0.3 H), 2.78–2.66 (m, 0.3 H), 2.61–2.45 (m, 0.7 H), 2.37
(dd, J = 12.9, 7.0 Hz, 0.3 H), 2.20 (dd, J = 12.5, 7.5 Hz, 0.7 H), 1.97 (dd,
J = 12.3, 10.6 Hz, 0.7 H), 1.66–1.62 (m, 0.3 H), 1.13–1.07 (m, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 199.6, 138.4, 138.1, 135.8, 135.7, 135.0
(2 C), 129.5, 129.4, 129.3, 129.0, 128.3, 128.2, 127.6, 119.8, 119.5,
86.7, 85.4, 77.0, 46.0, 43.9, 35.2, 32.7, 16.7, 15.6.
IR (film): 1691 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.05 (d, J = 9.0 Hz, 0.7 H), 7.97 (d, J = 6.0
Hz, 0.3 H), 7.71–7.64 (m, 2 H), 7.49–7.43 (m, 1 H), 7.32–7.16 (m, 5 H),
6.40 (s, 0.3 H), 6.37 (s, 0.7 H), 4.38 (app t, J = 9.0 Hz, 0.3 H), 4.22 (app t,
J = 6.0 Hz, 0.7 H), 3.94 (app t, J = 9.0 Hz, 0.7 H), 3.83 (app t, J = 7.5 Hz,
0.3 H), 3.00–2.66 (m, 3 H), 2.29 (dd, J = 12.0, 6.0 Hz, 0.3 H), 2.12 (app
d, J = 6.0 Hz, 1.4 H), 1.75 (dd, J = 15.0, 10.5 Hz, 0.3 H).
13C NMR (CDCl3, 75 MHz): δ = 199.4, 140.3, 140.0, 135.1, 135.0, 134.9,
133.6, 133.3, 129.5, 129.4, 129.2 (2 C), 129.1, 128.7 (3 C), 128.6, 127.7,
126.5, 125.6 (2 C), 85.6, 84.3, 75.5, 75.3, 44.0, 42.6, 42.0, 40.0, 38.8,
38.0.
HRMS: m/z [M + Na]+ calcd for C14H1379BrO2Na: 314.9997; found:
314.9993.
HRMS: m/z [M + Na]+ calcd for C20H17ClO2Na: 347.0815; found:
347.0818.
(±)-4-Benzyl-4′-bromo-4,5-dihydro-1′H,3H-spiro[furan-2,2′-naph-
thalen]-1′-one (2k)
Eluent: 1:19 EtOAc/hexanes; yield: 16.7 mg (33%) as a mixture of di-
astereomers from 50 mg of (±)-1k; light yellow oil.; 3:1 mixture of
syn- and anti-2k.
(±)-4′-Chloro-4-cyclohexyl-4,5-dihydro-1′H,3H-spiro[furan-2,2′-
naphthalen]-1′-one (2h)
Eluent: 1:19 EtOAc/hexanes; yield: 15 mg (50%) as a mixture of dia-
stereomers from 30 mg of (±)-1h; colorless oil; 3:1 mixture of syn-
and anti-2h.
IR (film): 1691 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.02 (d, J = 7.7 Hz, 0.75 H), 7.95 (d, J =
7.7 Hz, 0.25 H), 7.67–7.66 (m, 2 H), 7.47–7.41 (m, 1 H), 7.31–7.16 (m,
5 H), 6.66–6.64 (m, 1 H), 4.38 (app t, J = 7.7 Hz, 0.25 H), 4.22 (dd, J =
IR (film): 1692 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

H
N. Jain et al.
Feature
Synthesis
8.1, 6.4 Hz, 0.75 H), 3.94 (app t, J = 8.6 Hz, 0.75 H), 3.82 (app t, J = 8.1
Hz, 0.25 H), 2.99–2.63 (m, 3 H), 2.29 (dd, J = 13.0, 7.0 Hz, 0.25 H),
2.13–2.10 (m, 1.75 H), 3.50 (dd, J = 13.1, 9.8 Hz, 0.25 H).
13C NMR (CDCl3, 75 MHz): δ = 201.8, 137.5 (2 C), 137.2, 136.9, 134.8,
134.7, 129.2, 129.1, 128.2, 128.1, 127.4 (2 C), 127.3, 125.6, 125.2, 85.4,
83.9, 77.0, 46.4, 44.1, 35.3, 32.6, 16.9, 15.7.
13C NMR (CDCl3, 75 MHz): δ = 199.4, 140.2, 140.0, 138.1, 137.8, 135.7,
135.1, 135.0, 129.5, 129.4, 129.2, 128.7 (2 C), 128.6, 128.3, 128.2,
127.6, 126.5, 120.0, 86.6, 85.3, 75.6, 75.3, 43.9, 42.6, 41.8, 39.9, 38.8,
38.0.
HRMS: m/z [M + Na]+ calcd for C20H1779BrO2Na: 391.0310; found:
391.0301.
HRMS: m/z [M + H]+ calcd for C14H15O2: 215.1072; found: 215.1067.
(±)-4-Isopropyl-4,5-dihydro-1′H,3H-spiro[furan-2,2′-naphthalen]-
1′-one (2o)
Eluent: 1:19 to 1:9 EtOAc/hexanes; yield: 8 mg (28%) as a mixture of
diastereomers from 30 mg of (±)-1o; colorless oil; 3:1 mixture of syn-
and anti-2o.
IR (film): 1711 cm–1
.
(±)-4′-Bromo-4-isopropyl-4,5-dihydro-1′H,3H-spiro[furan-2,2′-
naphthalen]-1′-one (2l)
1H NMR (CDCl3, 300 MHz): δ = 8.00–7.95 (m, 1 H), 7.57–7.52 (m, 1 H),
7.36–7.31 (m, 1 H), 7.20–7.17 (m, 1 H), 6.50–6.46 (m, 1 H), 6.23 (d, J =
9.9 Hz, 0.75 H), 6.18 (d, J = 9.9 Hz, 0.25 H), 4.48 (app t, J = 7.8 Hz, 0.25
H), 4.27 (app t, J = 7.6 Hz, 0.75 H), 3.90 (dd, J = 9.8, 8.5, 0.75 H), 3.78
(app t, J = 8.5 Hz, 0.25 H), 2.44–1.97 (m, 3 H), 1.68–1.46 (m, 1 H),
0.94–0.88 (m, 6 H).
13C NMR (CDCl3, 75 MHz): δ = 201.8, 137.5 (2 C), 137.1, 137.0, 134.8,
134.7, 129.2, 129.1, 128.2, 128.1, 127.4 (3C), 127.3, 125.6, 125.2, 86.0,
83.9, 75.0, 74.9, 48.5, 45.2, 43.7, 40.8, 32.2, 31.6, 22.1, 22.0 (2 C), 21.7.
Eluent: 1:19 EtOAc/hexanes; yield: 22 mg (44%) as a mixture of dia-
stereomers from 50 mg of (±)-1l; light yellow oil; 4:1 mixture of syn-
and anti-2l.
IR (film): 1692 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.02–7.97 (m, 1 H), 7.70–7.63 (m, 2 H),
7.46–7.41 (m, 1 H), 6.68 (s, 0.8 H), 6.64 (s, 0.2 H), 4.42 (app t, J = 7.8
Hz, 0.2 H), 4.26 (app t, J = 7.6 Hz, 0.8 H), 3.86 (app t, J = 9.5 Hz, 0.8 H),
3.76 (app t, J = 8.5 Hz, 0.2 H), 2.39–1.97 (m, 3 H), 1.70–1.60 (m, 1 H),
0.95–0.88 (m, 6 H).
13C NMR (CDCl3, 75 MHz): δ = 199.6, 138.3, 138.2, 135.8, 135.7, 135.0
(2 C), 129.5, 129.3 (2 C), 128.3, 128.2, 127.6, 119.8, 87.2, 85.5, 75.1,
74.9, 48.4, 45.3, 43.3, 40.6, 32.9, 31.6, 22.0, 21.9 (2 C), 21.7.
HRMS: m/z [M + Na]+ calcd for C16H18O2Na: 265.1204; found:
265.1213.
(±)-4-Cyclohexyl-4,5-dihydro-1′H,3H-spiro[furan-2,2′-naphtha-
len]-1′-one (2p)
HRMS: m/z [M + Na]+ calcd for C16H1779BrO2Na: 343.0310; found:
343.0315.
Eluent: 1:19 to 1:9 EtOAc/hexanes; yield: 10 mg (20%) as a mixture of
diastereomers from 50 mg of (±)-1p; colorless oil; 3:1 mixture of syn-
and anti-2p.
(±)-4′-Bromo-4-cyclohexyl-4,5-dihydro-1′H,3H-spiro[furan-2,2′-
naphthalen]-1′-one (2m)
IR (film): 1711 cm–1
.
Eluent: 1:19 EtOAc/hexanes; yield: 21 mg (43%) as a mixture of dia-
stereomers from 50 mg of (±)-1m; light yellow oil; ca. 4:1 mixture of
syn- and anti-2m.
1H NMR (CDCl3, 300 MHz): δ = 8.00–7.95 (m, 1 H), 7.57–7.52 (m, 1 H),
7.36–7.31 (m, 1 H), 7.18 (app d, J = 7.5 Hz, 1 H), 6.50–6.45 (m, 1 H),
6.22 (d, J = 9.9 Hz, 0.75 H), 6.17 (d, J = 9.9 Hz, 0.25 H), 4.45 (app t, J =
7.8 Hz, 0.25 H), 4.27 (app t, J = 7.6 Hz, 0.75 H), 3.90 (dd, J = 10.2, 8.2
Hz, 0.75 H), 3.78 (app t, J = 8.8 Hz, 0.25 H), 2.47–2.38 (m, 0.25 H),
2.31–1.97 (m, 2.75 H), 1.75–1.59 (m, 5 H), 1.38–1.13 (m, 4 H), 1.08–
0.89 (m, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 201.9, 137.5 (2 C), 137.2, 137.0, 134.8,
134.7, 129.2, 129.1, 128.2, 128.1, 127.4 (3 C), 127.3, 125.5, 125.2, 85.8,
83.7, 74.9, 74.8, 47.1, 43.8, 43.3, 41.9, 41.3, 40.5, 32.7, 32.6, 32.4, 32.1,
26.5, 26.4, 26.2 (2 C).
IR (film): 1692 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.01–7.96 (m, 1 H), 7.70–7.63 (m, 2 H),
7.46–7.40 (m, 1 H), 6.67 (s, 0.8 H), 6.63 (s, 0.2 H), 4.42 (app t, J = 7.7
Hz, 0.2 H), 4.27 (app t, J = 7.7 Hz, 0.8 H), 3.86 (app t, J = 9.5 Hz, 0.8 H),
3.77 (app t, J = 8.7 Hz, 0.2 H), 2.44–1.97 (m, 3 H), 1.74–1.59 (m, 5 H),
1.37–1.13 (m, 4 H), 1.08-0.92 (m, 2 H).
13C NMR (CDCl3, 75 MHz): δ = 199.7, 138.4, 138.2, 135.8, 135.7, 135.0,
134.9, 129.4, 129.3 (2 C), 129.0, 128.3, 128.2, 127.6, 119.7, 119.3, 87.1,
85.3, 74.9, 74.8, 47.0, 43.9, 43.0, 41.8, 41.2, 40.3, 32.7, 32.5, 32.3, 32.1,
26.4, 26.2.
HRMS: m/z [M + Na]+ calcd for C19H22O2Na: 305.1517; found:
305.1520.
HRMS: m/z [M + H]+ calcd for C19H2279BrO2: 361.0803; found:
361.0800.
Kinetic Resolution: (S)-(+)-1d; Typical Procedure
Note: The theoretical yield of enantioenriched alcohols 1 is 50%. A
solution of MCPBA (53 mg of commercial, 70% pure reagent, corre-
sponding to 37 mg of MCPBA, 215 μmol, 0.6 equiv) in CH2Cl2 (4 mL)
was added over 5 min (syringe) to a cold (–20 °C) solution of (±)-1d
(100 mg, 358 μmol, 1.0 equiv) and iodide 4 (50 mg, 72 μmol, 0.2
equiv) in CH2Cl2 (14 mL). The mixture was stirred at –20 °C and moni-
tored for completion by TLC. After 13 h, the reaction was as quenched
with sat. aq NaHCO3 (10 mL) and sat. aq Na2S2O3 (5 mL) solutions and
extracted with CH2Cl2 (3 × 15 mL). The combined extracts were dried
(Na2SO4) and evaporated. A 1H NMR spectrum of the crude residue in-
dicated a conversion of 56%. Flash column chromatography (eluent:
1:19 EtOAc/hexanes for the retrieval of syn- and anti-2d; → 3:17
EtOAc/hexanes for 1d) afforded an 83:17 mixture of spiroethers syn-
2d (major; 94% ee) and anti-2d (minor, 98% ee) (52 mg, 52% com-
(±)-4-Methyl-4,5-dihydro-1′H,3H-spiro[furan-2,2′-naphthalen]-1′-
one (2n)
Eluent: 1:19 to 1:9 EtOAc/hexanes; yield: 6 mg (18%) as a mixture of
diastereomers from 30 mg of (±)-1n; colorless oil; 7:3 mixture of syn-
and anti-2n.
IR (film): 1685 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.00–7.95 (m, 1 H), 7.55 (app td, J = 7.5,
1.2 Hz, 1 H), 7.34 (app t, J = 7.2 Hz, 1 H), 7.19 (app d, J = 7.6 Hz, 1 H),
6.50–6.46 (m, 1 H), 6.24–6.18 (m, 1 H), 4.41 (app t, J = 7.6 Hz, 0.30 H),
4.24 (app t, J = 7.6 Hz, 0.7 H), 3.79 (dd, J = 10.1, 8.2 Hz, 0.7 H), 3.65
(app t, J = 8.1 Hz, 0.3 H), 2.84–2.68 (m, 0.3 H), 2.63–2.45 (m, 0.7 H),
2.35 (dd, J = 12.8, 7.0 Hz, 0.3 H), 2.13 (dd, J = 12.4, 7.6 Hz, 0.7 H), 1.97
(dd, J = 12.3, 10.4 Hz, 0.7 H), 1.60–1.52 (m, 0.3 H), 1.13–1.07 (m, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

I
N. Jain et al.
Feature
Synthesis
bined yield) plus enantioenriched (S)-(+)-1d (35 mg, 35%, 79% ee). The
diastereomeric ratio and enantiomeric excess of the purified products
were then determined by supercritical fluid chromatography (SFC).
(+)-2-(2-Benzyl-3-hydroxypropyl)-4-chloronaphthalen-1-ol [(+)-
1g]
The above procedure afforded 40 mg of (+)-1g (40% recovery) from
100 mg of (±)-1g; eluent: 1:4 EtOAc/hexanes; off-white solid; [α]D
+22.4 (c 0.37, CHCl3). SFC analysis indicates a 72% ee. Column: AD-H,
i-PrOH/liq CO2/Et2NH (7:93:0.1); flow rate = 1.0 mL/min; tR (1) =
59.40 min (major), tR (2) = 64.56 min (minor).
22
For syn- and anti-2d: Column: OJ-H, i-PrOH/liq CO2/Et2NH (2:98:0.1)
flow rate = 1.0 mL/min; tR(minor diast) (1) = 20.21 min (major), tR(major diast)
(2) = 21.71 min (major), tR(major diast) (3) = 29.42 min (minor), tR(minor diast)
(4) = 31.33 min (minor).
IR (film): 3666–3099 (br) cm–1
.
For (S)-(+)-1d: Column (OD-H), i-PrOH/liq CO2/Et2NH (5:95:0.1), flow
rate = 1.0 mL/min; tR (1) = 45.39 min (major), tR (2) = 55.28 min (mi-
nor). Alcohol (S)-(+)-1d (82 mg, 294 μmol) of 76% ee was subjected to
a second round of the above procedure, whereupon 42 mg (51%) of
material of 96% ee was obtained as a low-melting white solid; [α]D
+39.5 (c 1.86, CHCl3).
1H NMR (CDCl3, 300 MHz): δ = 8.32 (d, J = 7.7 Hz, 1 H), 8.16 (d, J = 7.8
Hz, 1 H), 7.60–7.50 (m, 2 H), 7.37–7.20 (m, 6 H), 3.56–3.45 (m, 2 H),
2.99–2.71 (m, 4 H), 2.27–2.14 (m, 1 H).
13C NMR (CDCl3, 75 MHz): δ = 149.9, 139.9, 130.6, 129.1, 128.9, 128.8,
126.8, 126.7, 126.6, 125.9, 124.1, 123.0, 122.5, 119.3, 62.9, 43.0, 38.5,
30.9.
24
IR (film): 3654, 3035 (br) cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.32 (d, J = 9.0 Hz, 1 H), 8.15 (d, J = 9.0
Hz, 1 H,), 7.58–7.49 (m, 2 H), 7.30 (s, 1 H), 3.73 (dd, J = 9.0, 4.5 Hz, 1
H), 3.65 (dd, J = 9.0, 3.0 Hz, 1 H), 2.98 (dd, J = 15.0, 9.0 Hz, 1 H), 2.78
(dd, J = 15.0, 3.0 Hz, 1 H), 1.90–1.78 (m, 1 H), 1.64–1.54 (m, 1 H), 1.11
(d, J = 6.0 Hz, 3 H), 1.02 (d, J = 6.0 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 149.9, 130.5, 128.9, 126.8, 126.7, 125.8,
124.1, 123.0, 122.4, 120.6, 62.9, 48.0, 29.9, 29.1, 21.2, 20.7.
HRMS: m/z [M – H]– calcd for C20H18ClO2: 325.0995; found: 325.0988.
(+)-4-Chloro-2-(2-cyclohexyl-3-hydroxypropyl)naphthalen-1-ol
[(+)-1h]
The above procedure afforded 38 mg of (+)-1h (38% recovery) from
23
100 mg of (±)-1h; eluent: 1:9 EtOAc/hexanes; off-white solid; [α]D
+43.4 (c 0.34, CHCl3). SFC analysis indicates a 76% ee. Column: OD-H,
i-PrOH/liq CO2/Et2NH (5:95:0.1); flow rate = 1.0 mL/min; tR (1) =
73.27 min (major), tR (2) = 90.21 min (minor).
HRMS: m/z [M – H]– calcd for C16H18ClO2: 277.0995; found: 277.0994.
IR (film): 3662–3004 (br) cm–1
.
(+)-4-Chloro-2-(3-hydroxy-2-methylpropyl)naphthalen-1-ol [(+)-
1e]
1H NMR (CDCl3, 300 MHz): δ = 8.46 (br s, 1 H), 8.31 (d, J = 7.8 Hz, 1 H),
8.15 (d, J = 7.9 Hz, 1 H), 7.58–7.49 (m, 2 H), 7.29 (s, 1 H), 3.73–3.68 (m,
1 H), 3.60–3.57 (m, 1 H), 2.95 (dd, J = 14.1, 8.7 Hz, 1 H), 2.76 (dd, J =
14.2, 4.1 Hz, 1 H), 2.22 (br s, 1 H), 1.94–1.69 (m, 5 H), 1.59–1.46 (m, 2
H), 1.34–0.99 (m, 5 H).
13C NMR (CDCl3, 75 MHz): δ = 149.8, 130.4, 128.8, 126.8, 126.7, 125.8,
124.1, 122.9, 122.4, 120.8, 62.5, 47.0, 39.8, 31.5, 30.8, 29.1, 26.7 (2 C),
26.6.
The above procedure afforded 40 mg of (+)-1e (40% recovery) from
100 mg of (±)-1e; eluent: 1:9 to 1:4 EtOAc/hexanes; off-white solid;
23
[α]D +1.7 (c 0.40, CHCl3). SFC analysis indicates a 47% ee. Column:
OD-H, i-PrOH/liq CO2/Et2NH (5:95:0.1), flow rate = 1.0 mL/min; tR (1)
= 48.32 min (major), tR (2) = 54.15 min (minor).
IR (film): 3643–3017 (br) cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.32 (d, J = 7.7 Hz, 1 H), 8.20 (br s, 1 H),
8.15 (d, J = 7.9 Hz, 1 H), 7.59–7.50 (m, 2 H), 7.30 (s, 1 H), 3.63 (dd, J =
10.3, 3.5 Hz, 1 H), 3.39 (dd, J = 9.9, 6.8 Hz, 1 H), 2.92–2.78 (m, 2 H),
2.18–2.00 (m, 2 H), 1.09 (d, J = 6.9 Hz, 3 H).
HRMS: m/z [M – H]– calcd for C19H22ClO2: 317.1308; found: 317.1315.
(+)-4-Chloro-2-(3-hydroxy-2-phenylpropyl)naphthalen-1-ol
[(+)1i]
13C NMR (CDCl3, 75 MHz): δ = 149.8, 130.5, 129.3, 126.8, 126.7, 125.8,
124.1, 122.9, 122.4, 119.1, 65.4, 35.8, 32.5, 17.2.
HRMS: m/z [M – H]– calcd for C14H14ClO2: 249.0682; found: 249.0682.
The above procedure afforded 40 mg of (+)-1i (40% recovery) from
100 mg of (±)-1i; eluent: 3:17 EtOAc/hexanes; colorless oil; [α]D24 +5.2
(c 0.40, CHCl3). SFC analysis indicates a 51% ee. Column: AS-H, i-PrOH/
liq CO2/Et2NH (5:95:0.1); flow rate = 1.0 mL/min; tR (1) = 61.37 min
(minor), tR (2) = 68.02 min (minor).
(+)-4-Chloro-2-[4,4,4-trifluoro-2-(hydroxymethyl)butyl]naphtha-
len-1-ol [(+)-1f]
IR (film): 3650–3098 (br) cm–1
.
The above procedure afforded 40 mg of (+)-1f (37% recovery) from
100 mg of (±)-1f; eluent: 1:9 to 1:4 EtOAc/hexanes; pale yellow solid;
1H NMR (CDCl3, 300 MHz): δ = 8.34 (d, J = 7.7 Hz, 1 H), 8.18 (d, J = 8.0
Hz, 1 H), 8.03 (br s, 1 H), 7.62–7.52 (m, 2 H), 7.41–7.28 (m, 5 H), 7.18
(s, 1 H), 3.80 (app d, J = 4.4 Hz, 2 H), 3.42 (dd, J = 13.8, 9.3 Hz, 1 H),
3.16–3.08 (m, 1 H), 3.00 (dd, J = 13.8, 4.7 Hz, 1 H), 2.35 (br s, 1 H).
24
[α]D +5.8 (c 0.37, CHCl3). SFC analysis indicates a 71% ee. Column:
OD-H, i-PrOH/liq CO2/Et2NH (5:95:0.1); flow rate = 1.0 mL/min; tR (1)
= 31.23 min (major), tR (2) = 35.46 min (minor).
IR (film): 3687–3032 (br) cm–1
.
13C NMR (CDCl3, 75 MHz): δ = 149.7, 142.4, 130.6, 128.9 (2 C), 127.8,
1H NMR (CDCl3, 300 MHz): δ = 8.30 (d, J = 8.3 Hz, 1 H), 8.17 (d, J = 8.3
Hz, 1 H), 7.62–7.52 (m, 2 H), 7.30 (s, 1 H), 3.65–3.64 (m, 2 H), 3.03–
2.87 (m, 2 H), 2.41–2.29 (m, 3 H).
127.3, 126.9, 126.7, 126.0, 124.2, 122.9, 122.8, 119.4, 64.8, 47.6, 31.7.
HRMS: m/z [M + Na]+ calcd for C19H17ClO2Na: 335.0815; found:
335.0818.
13C NMR (CDCl3, 75 MHz): δ = 150.2, 130.8, 128.6, 127.2, 127.0 (q, J =
277.0 Hz), 126.7, 126.2, 124.3, 123.1, 122.9, 117.7, 62.2, 35.7 (q, J =
28.2 Hz), 35.3 (q, J = 2.0 Hz), 30.8.
(+)-4-Bromo-2-(3-hydryoxy-2-methylpropyl)naphthalen-1-ol [(+)-
1j]
HRMS: m/z [M – H]– calcd for C15H13ClF3O2: 317.0556; found:
317.0561.
The above procedure afforded 35 mg of (+)-1j (35% recovery) from
100 mg of (±)-1j; eluent: 3:17 EtOAc/hexanes; light brown solid;
[α]D +2.3 (c 0.35, CHCl3). SFC analysis indicates a 49% ee. Column:
26
OD-H, i-PrOH/liq CO2/Et2NH (5:95:0.1); flow rate = 1.0 mL/min; tR (1)
= 58.93 min (major), tR (2) = 67.57 min (minor).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

J
N. Jain et al.
Feature
Synthesis
IR (film): 3638–3022 (br) cm–1
.
13C NMR (CDCl3, 75 MHz): δ = 150.6, 132.5, 131.7, 127.0 (2 C), 126.7,
125.8, 123.0, 121.4, 112.5, 62.5, 47.0, 39.9, 31.6, 30.8, 29.0, 26.7 (2 C),
26.6.
HRMS: m/z [M – H]– calcd for C19H2279BrO2: 361.0803; found:
361.0805.
1H NMR (CDCl3, 300 MHz): δ = 8.31 (d, J = 7.7 Hz, 1 H), 8.11 (d, J = 7.9
Hz, 1 H), 7.58–7.50 (m, 3 H), 3.48 (dd, J = 10.3, 3.8 Hz, 1 H), 3.39 (dd,
J = 10.3, 6.7 Hz, 1 H), 2.92–2.78 (m, 2 H), 2.15–2.06 (m, 1 H), 1.09 (d,
J = 6.9 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 150.7, 133.0, 131.8, 127.1, 126.9, 126.7,
125.9, 123.0, 119.6, 112.4, 65.5, 35.8, 32.4, 17.2.
(+)-2-(3-Hydroxy-2-methylpropyl)naphthalen-1-ol [(+)-1n]
HRMS: m/z [M – H]– calcd for C14H1479BrO2: 293.0177; found:
293.0182.
The above procedure afforded 40 mg of (+)-1n (40% recovery) from
100 mg of (±)-1n;11 eluent: 1:9 to 3:7 EtOAc/hexanes; white solid;
[α]D +1.3 (c 0.40, CHCl3). SFC analysis indicates a 48% ee. Column:
25
OD-H, i-PrOH/liq CO2/Et2NH (10:90:0.1), flow rate = 1.0 mL/min;
tR (1) = 19.58 min (major), tR (2) = 21.72 min (minor).
(+)-2-(2-Benzyl-3-hydroxypropyl)-4-bromonaphthalen-1-ol [(+)-
1k]
The above procedure afforded 42 mg of (+)-1k (42% recovery) from
100 mg of (±)-1k; eluent: 1:9 to 1:4 EtOAc/hexanes; light brown sol-
id; [α]D +13.5 (c 0.42, CHCl3). SFC analysis indicates a 71% ee. Col-
umn: AD-H, i-PrOH/liq CO2/Et2NH (6:94:0.1), flow rate = 1.0 mL/min;
tR (1) = 95.24 min (major), tR (2) = 102.94 min (minor).
(+)-2-[2-(Hydroxymethyl)-3-methylbutyl]naphthalen-1-ol [(+)-
1o]
25
The above procedure afforded 35 mg of (+)-1o (35% recovery) from
100 mg of (±)-1o; eluent: 1:9 to 1:4 EtOAc/hexanes; off-white solid;
26
[α]D +34.3 (c 0.36, CHCl3). SFC analysis indicates a 62% ee. Column:
IR (film): 3662–3099 (br) cm–1
.
OD-H, i-PrOH/liq CO2/Et2NH (10:90:0.1), flow rate = 1.0 mL/min;
tR (1) = 18.69 min (major), tR (2) = 22.35 min (minor).
1H NMR (CDCl3, 300 MHz): δ = 8.31 (d, J = 8.3 Hz, 1 H), 8.10 (d, J = 7.8
Hz, 1 H), 7.58–7.49 (m, 2 H), 7.39–7.32 (m, 3 H), 7.28–7.22 (m, 3 H),
3.58–3.48 (m, 2 H), 2.99–2.73 (m, 4 H), 2.28–2.15 (m, 1 H).
13C NMR (CDCl3, 75 MHz): δ = 150.7, 139.9, 132.6, 131.8, 129.2, 128.8,
127.1, 126.9, 126.7, 126.6, 125.9, 123.0, 119.9, 112.6, 62.9, 43.0, 38.5,
30.9.
IR (film): 3650–3021 (br) cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.28 (d, J = 7.7 Hz, 1 H), 8.21 (s, 1 H),
7.76 (d, J = 6.9 Hz, 1 H), 7.49–7.41 (m, 2 H), 7.36 (d, J = 8.3 Hz, 1 H),
7.21 (d, J = 8.3 Hz, 1 H), 3.74–3.61 (m, 2 H), 2.99 (dd, J = 14.1, 8.5 Hz, 1
H), 2.82 (dd, J = 14.2, 4.4 Hz, 1 H), 1.99 (br s, 1 H), 1.90–1.79 (m, 1 H),
1.65–1.52 (m, 1 H), 1.12 (d, J = 6.6 Hz, 3 H), 1.02 (d, J = 6.7 Hz, 3 H).
HRMS: m/z [M – H]– calcd for C20H1879BrO2: 369.0490; found:
369.0498.
13C NMR (CDCl3, 75 MHz): δ = 150.4, 133.5, 129.1, 127.2, 125.5 (2 C),
125.0, 122.3, 119.9, 119.6, 62.8, 48.0, 29.7, 29.1, 21.1, 20.6.
HRMS: m/z [M – H]– calcd for C16H19O2: 243.1385; found: 243.1385.
(+)-4-Bromo-2-(2-(hydroxymethyl)-3-methylbutyl)naphthalen-1-
ol [(+)-1l]
The above procedure afforded 35 mg of (+)-1l (35% recovery) from
100 mg of (±)-1l; eluent: 1:9 to 1:4 EtOAc/hexanes; off-white solid;
(+)-2-(2-Cyclohexyl-3-hydroxypropyl)naphthalen-1-ol [(+)-1p]
[α]26 +20.6 (c 0.35, CHCl3). SFC analysis indicates a 67% ee. Column:
The above procedure afforded 33 mg of (+)-1p (33% recovery) from
100 mg of (±)-1p; eluent: 3:17 to 1:4 EtOAc/hexanes; off-white solid;
D
OD-H, i-PrOH/liq CO2/Et2NH (5:95:0.1), flow rate = 1.0 mL/min; tR (1)
= 54.37 min (major), tR (2) = 69.16 min (minor).
26
[α]D +40.8 (c 0.14, CHCl3). SFC analysis indicates a 41% ee. Column:
OD-H, i-PrOH/liq CO2/Et2NH (10:90:0.1), flow rate = 1.0 mL/min;
tR (1) = 24.67 min (major), tR (2) = 30.55 min (minor).
IR (film): 3655–3018 (br) cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.31 (d, J = 7.7 Hz, 1 H), 8.10 (d, J = 7.8
Hz, 1 H), 7.58–7.48 (m, 3 H), 3.73 (dd, J = 10.4, 5.5 Hz, 1 H), 3.64 (dd,
J = 10.3, 3.7 Hz, 1 H), 2.97 (dd, J = 14.3, 8.6 Hz, 1 H), 2.77 (dd, J = 14.3,
4.5 Hz, 1 H), 1.90–1.79 (m, 1 H), 1.64–1.54 (m, 1 H), 1.11 (d, J = 6.7 Hz,
3 H), 1.02 (d, J = 6.8, 3 H).
13C NMR (CDCl3, 75 MHz): δ = 150.6, 132.5, 131.7, 127.0 (2 C), 126.7,
125.8, 123.0, 121.3, 112.5, 62.8, 48.0, 29.9, 29.1, 21.2, 20.7.
IR (film): 3648–3004 (br) cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.41 (s, 1 H), 8.31 (d, J = 8.7 Hz, 1 H),
7.79 (d, J = 8.6 Hz, 1 H), 7.50–7.43 (m, 2 H), 7.39 (d, J = 8.3 Hz, 1 H),
7.21 (d, J = 8.3 Hz, 1 H), 3.68–3.57 (m, 2 H), 2.98 (dd, J = 15.0, 8.4 Hz, 1
H), 2.82 (dd, J = 14.2, 4.5 Hz, 1 H), 2.45 (br s, 1 H), 1.97–1.71 (m, 5 H),
1.61–1.44 (m, 2 H), 1.39–0.99 (m, 5 H).
13C NMR (CDCl3, 75 MHz): δ = 150.4, 133.6, 129.2, 127.4, 125.6 (2 C),
125.1, 122.3, 120.4, 119.8, 62.6, 47.1, 39.7, 31.5, 30.8, 29.2, 26.7 (3 C).
HRMS: m/z [M – H]– calcd for C16H1879BrO2: 321.0490; found:
321.0499.
HRMS: m/z [M + Na]+ calcd for C19H24O2Na: 307.1674; found:
307.1669.
(+)-4-Bromo-2-(2-cyclohexyl-3-hydroxypropyl)naphthalen-1-ol
[(+)-1m]
(+)-2-[4,4,4-Trifluoro-2-(hydroxymethyl)butyl]naphthalen-1-ol
[(+)-1q]
The above procedure afforded 28 mg of (+)-1m (28% recovery) from
100 mg of (±)-1m; eluent: 1:9 EtOAc/hexanes; off-white solid; [α]D
+37.5 (c 0.28, CHCl3). SFC analysis indicates a 65% ee. Column: OD-H,
i-PrOH/liq CO2/Et2NH (10:90:0.1), flow rate = 1.0 mL/min; tR (1) =
27.60 min (major), tR (2) = 32.59 min (minor).
26
The above procedure afforded 44 mg of (+)-1q (44% recovery) from
100 mg of (±)-1q; eluent: 1:9 to 3:17 EtOAc/hexanes; light yellow oil;
20
[α]D +4.6 (c 0.42, CHCl3). SFC analysis indicates a 57% ee. Column:
OD-H, i-PrOH/liq CO2/Et2NH (10:90:0.1), flow rate = 1.0 mL/min;
tR (1) = 14.50 min (major), tR (2) = 16.38 min (minor).
IR (film): 3648–3008 (br) cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.31 (d, J = 7.7 Hz, 1 H), 8.10 (d, J = 7.8
Hz, 1 H), 7.57–7.49 (m, 3 H), 3.75 (dd, J = 10.4, 5.1 Hz, 1 H), 3.61 (dd,
J = 10.4, 3.5 Hz, 1 H), 2.96 (dd, J = 14.2, 8.8 Hz, 1 H), 2.77 (dd, J = 14.1,
4.3 Hz, 1 H), 1.96–1.70 (m, 5 H), 1.61–1.45 (m, 2 H), 1.39–0.99 (m, 5
H).
IR (film): 3710–3104 (br) cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 8.27–8.24 (m, 1 H), 7.80–7.77 (m, 1 H),
7.52–7.45 (m, 2 H), 7.41 (d, J = 8.4 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 1 H),
3.65–3.55 (m, 2 H), 3.05–2.91 (m, 2 H), 2.39–2.25 (m, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

K
N. Jain et al.
Feature
Synthesis
13C NMR (CDCl3, 75 MHz): δ = 150.7, 133.9, 129.1, 127.6, 127.1 (q, J =
277.1 Hz), 126.1, 125.5 (2 C), 122.2, 120.4, 117.4, 62.2, 35.6 (q, J = 28.1
Hz), 35.5 (q, J = 2.0 Hz), 30.9.
References
(1) Jain, N.; Xu, S.; Ciufolini, M. A. Chem. Eur. J. 2017, 23, 4542.
(2) General reviews on hypervalent iodine chemistry:
(a) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328.
(b) Wirth, T. Hypervalent Iodine Chemistry; Springer-Verlag:
Berlin, 2016. (c) Zhdankin, V. V. Hypervalent Iodine Chemistry;
Wiley: Chichester, 2014.
(3) For an excellent bibliography of chiral iodides as promoters of
enantioselective reactions see: Fujita, M. Heterocycles 2018, 96,
563; and literature cited therein.
(4) (a) Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem. Int. Ed. 2010,
49, 2175. (b) Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem. Int.
Ed. 2013, 52, 9215. (c) Uyanik, M.; Yasui, T.; Ishihara, K. J. Org.
Chem. 2017, 82, 11946.
(5) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans.
1915, 107, 1080. (b) Bachrach, S. M. J. Org. Chem. 2008, 73, 2466.
(6) This would be an example of oxidative kinetic resolution; for
review, see: Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth.
Catal. 2001, 343, 5; (see esp. 11 ff).
HRMS: m/z [M – H]– calcd for C15H14F3O2: 283.0946; found: 283.0942.
Compound (+)-syn-2q
Yield: 36 mg (36%) from 100 mg of (±)-1q; white solid; mp 39–41 °C;
[α]D25 +132.7 (c 0.93, CHCl3).
IR (film): 1685 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 7.98 (d, J = 7.7 Hz, 1 H), 7.57 (app t, J =
7.5 Hz, 1 H), 7.36 (app t, J = 7.5, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 6.54 (d,
J = 9.8 Hz, 1 H), 6.17 (d, J = 9.9 Hz, 1 H), 4.32 (app t, J = 7.8 Hz, 1 H),
3.93 (app t, J = 9.0 Hz, 1 H), 2.83–2.41 (m, 1 H), 2.37–2.07 (m, 4 H).
13C NMR (CDCl3, 75 MHz): δ = 200.9, 137.3, 135.5, 135.2, 128.8, 128.5,
127.6, 127.5, 126.4, 126.6 (q, J = 276.8 Hz), 82.6, 74.4, 43.1, 36.0 (q, J =
28.7 Hz), 34.4 (q, J = 2.6 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C15H13F3O2Na: 305.0765; found:
305.0765.
(7) To illustrate: (a) Oxidative kinetic resolution of rac-1-pheny-
lethanol: Zhdankin, V. V.; Koposov, A. Y.; Netzel, B. C.; Yashin, N.
V.; Rempel, B. P.; Ferguson, M. J.; Tykwinski, R. R. Angew. Chem.
Int. Ed. 2003, 42, 2194; (see especially p 2195, paragraph above
Table 1). (b) Oxidative kinetic resolution of rac-1-(2-naph-
thyl)ethanol and meso-1,2-diphenylethane-1,2-diol: Ladziata,
U.; Carlson, J.; Zhdankin, V. V. Tetrahedon Lett. 2006, 47, 6301.
(c) Kinetic resolution of a secondary homoallyl alcohol via oxi-
dative lactonization: Fujita, M.; Mori, K.; Shimogaki, M.;
Sugimura, T. Org. Lett. 2012, 14, 1294. (d) We thank the referees
for bringing the above literature to our attention.
Compound (+)-anti-2q
Yield: 4.0 mg (4%) from 100 mg of (±)-1q; colorless oil; [α]D25 +190.1
(c 0.31, CHCl3).
IR (film): 1688 cm–1
.
1H NMR (CDCl3, 300 MHz): δ = 7.97 (d, J = 7.7 Hz, 1 H), 7.56 (app t, J =
7.5 Hz, 1 H), 7.35 (app t, J = 7.4 Hz, 1 H), 7.19 (d, J = 7.5 Hz, 1 H), 6.54
(d, J = 9.8 Hz, 1 H), 6.14 (d, J = 9.8 Hz, 1 H), 4.53 (app t, J = 8.0 Hz, 1 H),
3.78 (app t, J = 8.4 Hz, 1 H), 3.10–2.97 (m, 1 H), 2.44 (dd, J = 13.0, 7.1
Hz, 1 H), 2.33–2.11 (m, 2 H), 1.68 (dd, J = 12.8, 10.6 Hz, 1 H).
(8) See Supporting Information for relevant synthetic, chemical,
and spectroscopic data, and other characterization details.
(9) Fluoroalcohols such as CF3CH2OH and (CF3)2CHOH are privi-
leged media for the conduct of many reactions mediated by
hypervalent iodine species: Dohi, T.; Yamaoka, N.; Kita, Y. Tetra-
hedron 2010, 66, 5775.
(10) (a) Terakado, D.; Koutaka, H.; Oriyama, T. Tetrahedron: Asymme-
try 2005, 16, 1157. (b) Sakai, T.; Kishimoto, T.; Tanaka, Y.; Ema,
T.; Utaka, M. Tetrahedron Lett. 1998, 39, 7881. (c) Ghanemi, A.;
Aboul-enein, H. Y. Chirality 2005, 17, 1. (d) Strübing, D.;
Krumlinde, P.; Piera, J.; Bäckvall, J.-E. Adv. Synth. Catal. 2007,
349, 1577.
13C NMR (CDCl3, 75 MHz): δ = 201.1, 137.3, 135.8, 135.1, 128.7, 128.4,
127.5, 126.7, 126.5 (q, J = 277.1 Hz), 84.6, 74.6, 41.7, 36.6 (q, J = 29.0
Hz), 32.1 (q, J = 2.3 Hz).
Funding Information
We thank NSERC for support of this research.
)(
Supporting Information
(11) Racemic 1n is a known compound: Kongkathip, N.; Kongkathip,
B.; Siripong, P.; Sangma, C.; Luangkamin, S.; Niyomdecha, M.;
Pattanapa, S.; Piyaviriyagul, S.; Kongsaeree, P. Bioorg. Med.
Chem. 2003, 11, 3179.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610214. Preparation and kinetic
resolution of alcohols 1a–q; characterization data; 1H and 13C NMR
spectra (104 pages).
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K